A Randomized, Double-Blind, Phase II, Efficacy and...

Sponsor: APGD ISN/Protocol 9785-CL-0222- CONFIDENTIAL -

10 Aug 2010 Astellas of 81

A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100 (ASP9785) vs. Bicalutamide in Castrate Men

with Metastatic Prostate Cancer

Protocol for Phase II Study of MDV3100

ISN/Protocol 9785-CL-0222

August 10, 2010

EudraCT 2010-021868-15

IND 74,563

Astellas Pharma Global Development, Inc. (APGD)Research & Development

3 Parkway North Deerfield, IL 60015

This confidential document is the property of the sponsor. No unpublished information contained in this document may be disclosed without prior written approval of the sponsor.



Table of Contents

I. SIGNATURES·····················································································································8

II. CONTACT DETAILS OF KEY SPONSOR'S PERSONNEL ·····································10

III. LIST OF ABBREVIATIONS AND KEY TERMS························································11

List of Abbreviations ··················································································································11

List of Key Study Terms·············································································································14

IV. SYNOPSIS·························································································································15

V. FLOW CHART AND SCHEDULE OF ASSESSMENTS ············································22

Flow Chart ··································································································································22

Table 1: Schedule of Assessments······························································································23

1 INTRODUCTION·············································································································25

1.1 Background ·················································································································25

1.2 Non-clinical and Clinical Data····················································································26

1.2.1 Non-clinical Data·································································································261.2.2 Clinical Data········································································································26

1.3 Summary of Key Safety Information for Study Drugs ···············································27

1.3.1 MDV3100············································································································271.3.2 Bicalutamide········································································································27

1.4 Risk-Benefit Assessment·····························································································27

2 STUDY OBJECTIVE(S), DESIGN AND VARIABLES···············································28

2.1 Study Objectives ·········································································································28

2.2 Study Design and Dose Rationale ···············································································29

2.2.1 Study Design ·······································································································292.2.2 Dose Rationale·····································································································30

2.3 Variables······················································································································30

2.3.1 Primary Variable ·································································································302.3.2 Secondary Variables ····························································································302.3.3 Exploratory Variables··························································································302.3.4 T2:ERG················································································································312.3.5 Optional Pharmacogenomics Sub-Study ·····························································31

3 STUDY POPULATION ···································································································31

3.1 Selection of Study Population ·····················································································31



3.2 Inclusion Criteria·········································································································31

3.3 Exclusion Criteria········································································································32

3.4 Discontinuation Criteria for Individual Subjects·························································34

4 STUDY DRUGS ················································································································35

4.1 Description of Study Drugs·························································································35

4.1.1 Test Drug(s)·········································································································354.1.2 Comparative Drug(s) ···························································································35

4.2 Packaging and Labeling ······························································································35

4.3 Study Drug Handling ··································································································35

4.3.1 Test Drug·············································································································364.3.2 Comparative Drug ·······························································································36

4.4 Blinding·······················································································································36

4.4.1 Blinding Method··································································································374.4.2 Confirmation of Indistinguishability of the Study Drugs ····································374.4.3 Breaking the Treatment Code for Emergency ·····················································37

4.5 Assignment and Allocation ·························································································37

5 TREATMENTS AND EVALUATION···········································································38

5.1 Dosing and Administration of Study Drugs and Other Medications···························38

5.1.1 Dose/Dose Regimen and Administration Period·················································385.1.2 Interruption in Dose of the Study Drugs ·····························································385.1.3 Previous and Concomitant Medication (Drugs and Therapies)···························38

5.1.3.1 Previous Medication (Drugs and Therapies) ···············································385.1.3.2 Concomitant Medication (Drugs and Therapies)·········································38

Table 2: Potent CYP Inhibitors and Inducers ·············································································39

5.1.4 Treatment Compliance ························································································405.1.5 Emergency Procedures and Management of Overdose ·······································40

5.2 Demographics and Baseline Characteristics ·······························································40

5.2.1 Demographics······································································································405.2.2 Chest X-Ray and/or Chest CT·············································································405.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease ··················405.2.4 Medical History ···································································································405.2.5 Performance Status······························································································40

Table 3: ECOG Performance Status ··························································································41



5.3 Efficacy Assessment ···································································································41

5.3.1 CT/MRI and Bone Scan ······················································································415.3.2 PSA······················································································································42

5.4 Safety Assessment·······································································································42

5.4.1 Vital Signs ···········································································································425.4.2 Adverse Events····································································································425.4.3 Laboratory Assessments ······················································································42

5.4.3.1 Hematology··································································································435.4.3.2 Chemistry·····································································································43

5.4.4 Physical Examination ··························································································435.4.5 Electrocardiogram (ECG)····················································································43

5.5 Adverse Events and Other Safety Aspects ··································································43

5.5.1 Definition of Adverse Events (AEs)····································································435.5.2 Disease Progression·····························································································445.5.3 Definition of Serious Adverse Events (SAEs)·····················································445.5.4 Criteria for Causal Relationship to the Study Drug·············································45

Table 4: Criteria for Causal Relationship ···················································································45

5.5.5 Criteria for Defining the Severity of an Adverse Event ······································45Table 5: Criteria for Severity of Adverse Event Terms Not Specified Within NCI-CTCAE·····45

5.5.6 Reporting of Serious Adverse Events (SAEs) ·····················································465.5.7 Follow-up to Adverse Events ··············································································475.5.8 Procedure in Case of Pregnancy··········································································475.5.9 Supply of New Information Affecting the Conduct of the Study························47

5.6 Test Drug Concentration ·····························································································48

5.7 Other Measurements, Assessments, or Methods·························································48

5.7.1 CTC Sampling ·····································································································485.7.2 FACT-P ···············································································································485.7.3 BPI·······················································································································485.7.4 EQ-5D··················································································································485.7.5 Tissue, Blood and Urine Sampling for Gene Fusion Analysis ····························495.7.6 Whole Blood Sample for Optional Genotype Analysis·······································49

5.8 Total Amount of Blood ·······························································································49

6 TERMINATION OF THE CLINICAL STUDY····························································49

7 STATISTICAL METHODOLOGY················································································50



7.1 Sample Size ·················································································································50

7.2 Analysis Set·················································································································50

7.2.1 Full Analysis Set (FAS)·······················································································507.2.2 Per Protocol Set (PPS)·························································································517.2.3 Safety Analysis Set (SAF)···················································································51

7.3 Demographics and Other Baseline Characteristics ·····················································51

7.3.1 Demographics······································································································517.3.2 Medical History ···································································································517.3.3 Diagnosis of the Target Disease, Severity and Duration of Disease ···················51

7.4 Analysis of Efficacy ····································································································51

7.4.1 Analysis of Primary Variable ··············································································517.4.2 Analysis of Secondary Variables·········································································52

7.4.2.1 PSA Response······························································································527.4.2.2 Time to PSA Progression·············································································52

7.4.3 Analysis of Other Variables ················································································537.4.3.1 FACT-P········································································································537.4.3.2 EQ-5D··········································································································537.4.3.3 BPI ···············································································································537.4.3.4 CTC Conversion Rate··················································································547.4.3.5 Gene Fusion Analysis ··················································································54

7.5 Analysis of Safety ·······································································································54

7.5.1 Adverse Events····································································································547.5.2 Clinical Laboratory Evaluations··········································································547.5.3 Physical Examination ··························································································557.5.4 Vital Signs ···········································································································557.5.5 Electrocardiogram (ECG)····················································································557.5.6 Concomitant Medications····················································································557.5.7 Extent of Exposure ······························································································55

7.6 Analysis of Pharmacokinetics ·····················································································55

7.7 Other Analyses ············································································································55

7.8 Interim Analysis (and Early Discontinuation of the Clinical Study) ··························56

7.9 Handling of Missing Data, Outliers, Visit Windows, and Other Information·············56

7.9.1 Missing Data········································································································567.9.2 Visit Windows·····································································································56



8 OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS···························56

8.1 Procedure for Clinical Study Quality Control·····························································56

8.1.1 Data Collection····································································································568.1.2 Specification of Source Documents ····································································578.1.3 Clinical Study Monitoring···················································································578.1.4 Direct Access to Source Data/Documents···························································588.1.5 Data Management································································································58

8.2 Ethics and Protection of Subject Confidentiality ························································58

8.2.1 Institutional Review Board/ Independent Ethics Committee ······························588.2.2 Ethical Conduct of the Study···············································································588.2.3 Informed Consent of Subjects ·············································································59

8.2.3.1 Subject Information and Consent·································································598.2.3.2 Supply of New and Important Information Influencing the Subject’s

Consent and Revision of the Written Information·······································598.2.4 Subject Confidentiality························································································60

8.3 Administrative Matters································································································61

8.3.1 Arrangement for Use of Information and Publication of the Clinical Study·······618.3.2 Documents and Records Related to the Clinical Study·······································618.3.3 Protocol Amendment and/or Revision·································································628.3.4 Signatory Investigator for Clinical Study Report ················································62

9 QUALITY ASSURANCE·································································································63

10 STUDY ORGANIZATION······························································································63

10.1 Data Monitoring Committee ·······················································································63

10.2 Other Evaluation Committee(s)···················································································63

10.3 Other Study Organization····························································································63

11 REFERENCES··················································································································64

12 APPENDICES···················································································································65

12.1 Appendix 1: Laboratory Tests····················································································65

12.2 Appendix 2: Events Always Considered To Be Serious ············································66

12.3 Appendix 3: Elements of Informed Consent ·······························································67

12.4 Appendix 4: Elements of HIPPA Authorization (U.S. Sites Only)····························69

12.5 Appendix 5: European Quality of Life 5-Domain Scale ············································70

12.6 Appendix 6: Soft Tissue Assessment (RECIST 1.1)··················································72



12.7 Appendix 7: BPI-SF ···································································································73

12.8 Appendix 8: Functional Assessment of Cancer Therapy – Prostate ···························75

12.9 Appendix 9: Optional Pharmacogenomic Sub-study ·················································78

13 ATTACHMENT 1: SPONSOR’S SIGNATURES························································81



I. SIGNATURES

1. SPONSOR’S SIGNATURE

A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100(ASP9785) vs. Bicalutamide in Castrate Men with Metastatic Prostate CancerISN/Protocol 9785-CL-0222 / August 10, 2010Required signatures (e.g., protocol authors, sponsor’s reviewers and contributors, and Quality Assurance) are located in Attachment 1; e-signatures (when applicable) are located at the end of this document.



2. INVESTIGATOR’S SIGNATURE

A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100(ASP9785) vs. Bicalutamide in Castrate Men with Metastatic Prostate CancerISN/Protocol 9785-CL-0222 / August 10, 2010I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree to conduct the study as outlined in the protocol and to comply with all the terms and conditions set out therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines. I will also ensure that sub-investigator(s) and other relevant members of my staff have access to copies of this protocol and the ICH GCP guidelines to enable them to work in accordance with the provisions of these documents.Principal Investigator:

Signature:

Printed Name:Date

Address:



II. CONTACT DETAILS OF KEY SPONSOR'S PERSONNEL

24h-Contact for Serious Adverse Events (SAEs)

See Section 5.5.5

North AmericaRobert Hall, MDICON Clinical Research Inc.Direct telephone: 215-616-3101 After hours telephone: 1-888-723-9952EuropeWouter Verborg, MD, MRCPICON Clinical Research (UK) LtdDirect telephone: +44 (0) 2380 688 500After hours telephone: +49 6103 904 1953

Please fax the SAE Worksheet to:Astellas Pharma Global Development, Inc. Product Safety & PharmacovigilanceFax Number: +1 847-317-1241Email: [email protected]

Clinical Research Contact: Kenya BarberStudy Manager, Global Clinical ScienceOffice: 1-847-317-5268Email: [email protected]

Medical Monitors: North AmericaRobert Hall, MDICON Clinical Research Inc.212 Church RoadNorth Wales, PA 19454Direct telephone: 215-616-3101 After hours telephone: 1-888-723-9952Email: [email protected]

EuropeWouter Verborg, MD, MRCPICON Clinical Research (UK) LtdConcept House6 Stoneycroft RiseChandlers Ford, EastleighHampshire UKSO53 3LDDirect telephone: +44 (0) 2380 688 500After hours telephone: +49 6103 904 1953Fax: +44 (0) 2380 688 506Email: [email protected]

mailto:[email protected]





III. LIST OF ABBREVIATIONS AND KEY TERMSList of AbbreviationsAbbreviations Description of AbbreviationsADT Androgen Deprivation TherapyAE Adverse EventALT Alanine Aminotransferase APGD Astellas Pharma Global DevelopmentAR Androgen ReceptorAST Aspartate Aminotransferase AUST Astellas United States TechnologiesbALP Bone Alkaline PhosphataseBHA Butylated HydroxyanisoleBHT Butylated HydroxytolueneBPI-SF Brief Pain Inventory-Short FormBUN Blood Urea NitrogenCmax Maximum concentrationCmin Minimum concentrationCBC Complete Blood CountCFR Code of Federal RegulationsCO2 bicarbonateCRF Case Report FormCRO Contract Research OrganizationCRPC Castration Resistant Prostate CancerCT Computed TomographyCTC Circulating Tumor CellsCTD Common Technical DocumentCXR Chest X-RayCYP Cytochrome P450DES DiethylstilbestrolDHEA DihydroepiandrosteroneDMC Data Monitoring CommitteeDNA Deoxyribonucleic AcidECG ElectrocardiogramECOG Eastern Cooperative Oncology GroupeCRF Electronic Case Report FormEDC Electronic Data CaptureEDTA Ethylenediaminetetraacetic AcidEMEA European Medicines AgencyEQ-5D European Quality of Life 5 DomainERG Ets Related GeneEU European UnionFACT-P Functional Assessment of Cancer Therapy - ProstateFAS Full Analysis SetFDA Food and Drug AdministrationF/U Follow upGCP Good Clinical Practiceg/dL grams per deciliterg/L grams per liter



Abbreviations Description of AbbreviationsGGT gamma glutamyl transferaseGMP Good Manufacturing PracticeHCT HematocritHgb HemoglobinHIPAA Health Insurance Portability and Accountability ActICF Informed Consent FormICH International Conference on Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human UseIEC Independent Ethics CommitteeIND Investigational New DrugIRB Institutional Review BoardISN International Study NumberIVRS/IWRS Interactive Voice/Web Response Systemkg kilogramLDH lactic dehydrogenaseLHRHa Luteinizing Hormone Receptor Hormone Agonist/AntagonistMedDRA Medical Dictionary for Regulatory ActivitiesMDV3100 3-(4-cyano-3-trifluoromethylphenyl)-1-[3-fluoro-4-(methylcarbamoyl)phenyl]-5,5-

dimethyl-2-thioxoimidazolin-4-onemg miligrammmHg Millimeters of MercuryMRI Magnetic Resonance ImagingMUGA Multi-Gated Acquisition NCI-CTCAE National Cancer Institute’s Common Terminology Criteria for Adverse EventsNDA New Drug Applicationnmol nanomoles per literNYHA New York Heart AssociationPB Privacy BoardPCWG2 Prostate Cancer Clinical Trials Working Group 2PD PharmacodynamicsPET Positron Emission TomographyPFS Progression Free SurvivalPHI Personal Health InformationPK PharmacokineticsPPS Per Protocol SetPR Pulse ratePSA Prostate Specific AntigenQRSQT QT IntervalRBC Red Blood CellRECIST Response Evaluation Criteria In Solid TumorsRR Respiration rateSAE Serious Adverse EventSAF Safety Analysis SetSD Standard DeviationSFL Screening Failure LogSOP Standard Operating ProcedureSRE Skeletal Related Event



Abbreviations Description of Abbreviationst½ Apparent Terminal Elimination Half-lifeULN Upper Limit of NormalUSP United States PharmacopeiaWBC White Blood CellWHO World Health Organization



List of Key Study Terms

Terms Definition of termsBaseline 1) Observed values/findings which are regarded as calibrated zero status in

the present study, 2) Time when ‘Baseline’ is observed.

Comparative Drug Agent that the test drug is being compared to in a clinical trial. In this study, bicalutamide is the comparative drug.

Discontinuation A discontinuation is a subject who is enrolled in the study and for whom study drug is terminated for any reason.

Investigational Period

Period of time where major interests of protocol objectives are observed, and where the test drug or comparative drug is given to a subject, and continues until the last assessment after completing administration of the test drug or comparative drug.

Randomization Action to allocate a subject to the treatment group or treatment cohort. ‘Randomization’ is executed just before entering the ‘investigational period’.

Screening 1) Process for retrieving candidates for the study. 2) Process for checking the eligibility of subjects done prior to the investigational period.

Screening Failure Subject that was screened, but did not fulfill protocol inclusion and/or exclusion criteria and failed to receive randomized study drug, or decided not to participate anymore (withdrew consent) prior to randomization.

Screening Period Period of time between Day -28 and Day -1.

Study Drug Agents given as part of a clinical trial. In this study, MDV3100 and bicalutamide are both study drugs.

Study Period Period of time beginning with the first subject consented through to the last observation collected for the study.

Subject An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.

Test Drug Agent under investigation in a clinical trial. In this study, MDV3100 is the test drug.

Variable Any quantity that varies; any attribute, phenomenon or event that can have different qualitative or quantitative values.



IV. SYNOPSISTitle of Study A Randomized, Double-Blind, Phase II Efficacy and Safety Study of MDV3100

(ASP9785) vs. Bicalutamide in Castrate Men with Metastatic Prostate Cancer[ISN 9785-CL-0222]

Planned Study Period

From 4Q2010 to 2Q2014

Study Objective(s) The primary study objective is:

• To determine the progression free survival (PFS) of MDV3100 as compared to bicalutamide

The secondary objectives are:

• To determine the safety of treatment with MDV3100 as compared to bicalutamide

• To determine the prostate specific antigen (PSA) response of MDV3100 at week 13 as compared to bicalutamide

• To determine the time to PSA progression of MDV3100 as compared to bicalutamide

The exploratory objectives are:

• To evaluate quality of life using the Functional Assessment of Cancer Therapy – Prostate (FACT-P), European Quality of Life- 5 Domain Scale (EQ-5D) and Brief Pain Inventory Short Form (BPI-SF) instruments

• To determine the benefit of MDV3100 as compared to bicalutamide as assessed by the circulating tumor cell (CTC) conversion rate

Planned Total Number of Study Centers and Location

Approximately 60 centers

North America and Europe

Design and Methodology

This is a multinational phase II, randomized, double-blind, parallel study to determine the efficacy and safety of oral MDV3100 (160 mg/day) compared to bicalutamide (50 mg/day) in castrate men with metastatic prostate cancer who have progressed while on LHRH agonist/antagonist or after receiving a bilateral orchiectomy.

Approximately 300 eligible subjects will be randomized 1:1 to one of two treatment arms: MDV3100, 160 mg orally once daily, or bicalutamide, 50 mg orally once daily. Subjects will be stratified by whether bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases.

For the study duration, all subjects will maintain castration therapy with an LHRH agonist/antagonist or bilateral orchiectomy.

Subjects will be discontinued from study drug at the time of confirmed radio-graphic disease progression, skeletal-related event, or the initiation of a new anti-neoplastic therapy.



Design and Methodologycontinued

All subjects will have a safety follow-up visit 30 days from date of last dose or prior to initiation of a subsequent anti-neoplastic therapy for prostate cancer, whichever occurs first.

Subjects that discontinue study drug treatment for a reason other than radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy will have a PSA test performed 60 days from date of last dose and undergo long-term follow-up every 12 weeks from date of last dose. Long term follow-up will assess for the following until they occur: radiographic progression, skeletal related events, or the start of new anti-neoplastic therapy for prostate cancer.

PSA progression alone is not a criterion for disease progression. PSA progression alone will not be considered as a determinant for discontinuation of study drug in the first 24 weeks of the study period and is discouraged thereafter.

The occurrence of an adverse event or toxicity, where continued administration of study drug is deemed to be not in the subject’s best interest by the investigator and/or the sponsor, will result in the removal of the subject from therapy.

The consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) have been utilized to determine disease progression.

Soft tissue disease progression will be defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.

Bone disease progression is considered when a minimum of two new lesions are observed. Progression on bone scan at time points on/or after Week 13 require a confirmatory scan performed six or more weeks later (or the next scheduled scan). This confirmatory scan should demonstrate additional new lesions.

The following assessments of prostate cancer status will be collected during the course of the trial: soft tissue disease on computed tomography (CT) scan or onmagnetic resonance imaging (MRI), bone disease on radionuclide bone scans, skeletal-related events, FACT-P, EQ-5D and BPI-SF quality of life questionnaires and PSA.

Study films (abdominopelvic [lung when applicable] CT/MRI and bone scan) should be read on site and also be submitted in digital format to the sponsor or designee for an independent central review. Each site should ideally designate the same reader who will evaluate the images for any one subject for the duration of the trial.

Throughout the study, safety and tolerability will be assessed by the recording of adverse events, monitoring of vital signs and physical examinations, safety laboratory evaluations, and 12-lead electrocardiograms. An independent Data Monitoring Committee will monitor safety and efficacy data on an ongoing basis.

A formal interim analysis on PFS will be performed after 129 progression events (50% of the total number of events required for final analysis) have occurred.

Historical tumor tissue samples, urine and blood samples will be collected to allow evaluation of T2:ERG gene fusions. Samples will be obtained and stored until qualified assays become available.



Number of Subjects Planned

Approximately 300 subjects will be randomized 1:1 to MDV3100 or bicalutamide.

Selection Criteria Subjects must meet the following inclusion criteria:

1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] for U.S. sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).

2. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features.

3. Ongoing androgen deprivation therapy with a LHRH agonist or antagonist at a stable dose and schedule within 4 weeks of randomization or bilateral orchiectomy (i.e., surgical or medical castration).

4. Serum testosterone level ≤ 1.7 nmol/L (50 ng/dL) at Screening.

5. Metastatic disease documented by at least two bone lesions on bone scan or by soft tissue disease observed by CT/MRI, on or before screening visit,except subjects with regional pelvic lymph node disease only. Measurable disease is not required for entry.

6. Progressive disease at study entry defined as one or more of the following three criteria occurring in the setting of castrate levels of testosterone:

• PSA progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the Screening visit should be ≥ 2 µg/L (2 ng/mL);

• Soft tissue disease progression defined by RECIST 1.1;• Bone disease progression defined by two or more new lesions on bone

scan.7. Asymptomatic or mildly symptomatic from prostate cancer (i.e. the score on

BPI-SF Question #3 must be < 4); no use of opiate analgesics for prostatecancer-related pain currently or anytime within 4 weeks prior to randomization.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, including subjects with decreased performance status not attributed to progressive and symptomatic prostate cancer.

9. Estimated life expectancy of ≥ 12 months.

10. Able to swallow the study drug and comply with study requirements.

Selection Criteria continued

Subjects will be excluded from participation if any of the following apply:

1. Prior cytotoxic chemotherapy for prostate cancer.

2. Severe concurrent disease, infection, or comorbidity that, in the judgment of the investigator, would make the subject inappropriate for enrollment.

3. Known or suspected brain and/or skull metastasis or active epidural disease.



Selection Criteriacontinued

Exclusion continued:

4. Absolute neutrophil count < 1,500/µL, platelet count < 100,000/µL, and hemoglobin < 5.6 mmol/L (9 g/dL) at Screening; (NOTE: subjects must not have received any growth factors or blood transfusions within seven days of the hematologic laboratory values obtained at Screening).

5. Total bilirubin > 1.5 times the upper limit of normal (ULN) at Screening. This will not apply to subjects with Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly uncongugated in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with the sponsor.

6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times ULN at Screening.

7. Creatinine > 177 µmol/L (2 mg/dL) at Screening.

8. Albumin ≤ 30 g/L (3.0 g/dL) at Screening.

9. History of another malignancy within the previous 5 years other than curatively treated non-melanomatous skin cancer.

10. Current or prior treatment with estrogens and/or drugs with anti-androgenic properties such as spironolactone > 50 mg/kg, or progestational agents for the treatment of prostate cancer within 6 months prior to randomization.

11. Current or prior use of ketoconazole for the treatment of prostate cancer.

12. Current or prior treatment with anti-androgens, except if the medications were during LHRH analogue induction for < 6 weeks. No use within 3 months prior to randomization.

13. Current or prior treatment with 5-α reductase inhibitors or anabolic steroids within 6 months prior to randomization.

14. Prior use of systemic glucocorticoids (the equivalent of 10 mg of prednisone)within 3 months prior to randomization or expectation of their use during the study.

15. Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to randomization.

16. Major surgery within 2 months prior to randomization.

17. History of seizure including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization). Also, current or prior treatment with anti-epileptic medications for the treatment of seizures or history of loss of consciousness or transient ischemic attack within 12 months prior to randomization.

18. Clinically significant cardiovascular disease including:

• Myocardial infarction within six months prior to Screening;• Uncontrolled angina within three months prior to Screening;



• Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%;

• History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes);

• History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;

• Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at Screening.

19. Prior use or participation in a clinical trial of an investigational agent that blocks androgen synthesis and/or androgen receptor activity.

20. Participation in a previous clinical trial of MDV3100.

21. Use of an investigational agent within four weeks prior to randomization.

22. Gastrointestinal disorder affecting absorption.

Discontinuation Criteria

Subjects will be discontinued from study drug if any of the following occur:

• Radiographic disease progression.

• Skeletal related events. Skeletal related events are defined as:o Radiation therapy or surgery to boneo Pathologic bone fractureo Spinal cord compressiono Change in anti-neoplastic therapy to treat bone pain

• Decision of the investigator and subject to initiate a new anti-neoplastic therapy.

• Subject develops an adverse event or toxicity, where continued administration of study drug is deemed not in the subject’s best interest by the investigator and/or the sponsor.

Test Drug Dose:Mode of Administration:Duration of Treatment:

Subjects randomized to the MDV3100 study arm, will receive 160 mg (four capsules) of MDV3100 and one placebo tablet orally once daily at the same time each day.

Subjects will receive their assigned therapy until any of the following occurs:

• Radiographic disease progression or a skeletal-related event.• Initiation of a new anti-neoplastic therapy.• Subject develops an adverse event or toxicity, where continued

administration of study drug is deemed not in the subject’s best interest by the investigator and/or the sponsor.

Reference TherapyDose:Mode of Administration:

Subjects randomized to the bicalutamide study arm will receive 50 mg (one tablet) of bicalutamide and four placebo capsules orally once daily at the same time each day.



Duration of Treatment:


• Radiographic disease progression or a skeletal-related event.• Initiation of a new anti-neoplastic therapy.• Subject develops an adverse event or toxicity, where continued

administration of study drug is deemed not in the subject’s best interest by the investigator and/or the sponsor.

Concomitant Medication

The following medications are prohibited while the subject is on study drug:

• Chemotherapeutic, biologic, or other agents with anti-tumor activity against prostate cancer

• Anti-androgens (steroidal and non-steroidal) other than assigned study medication

• 5-α reductase inhibitors• Estrogens, progestational agents• Systemic glucocorticoids (the equivalent of 10 mg of prednisone) for the

treatment of prostate cancer• Androgens • Ketoconazole

• Anti-epileptic medications for the treatment of seizure

• Prior use of investigational agents that block androgen synthesis

The dosage and regimen of the following medications and any chronic permitted concomitant medications should be stabilized during the screening period (> 4 weeks prior to randomization) and held constant throughout the study:

• bisphosphonates • LHRH agonist/antagonist

It is currently unknown which CYP enzyme pathways are responsible for clearing MDV3100. To limit the risk of unpredictable increases or decreases in circulating concentrations of MDV3100, potent inhibitors or inducers should be taken with caution and alternative products used when available. See Section 5.1for additional information.

Primary Efficacy Variable

The primary efficacy variable is progression free survival.

Secondary Variables

Secondary variables are PSA response and time to PSA progression.

Safety variables are adverse events, laboratory evaluations, vital signs, physical examinations and ECGs.

Exploratory Variables

The exploratory variables will include a quality of life score using the FACT-P, EQ-5D, and BPI-SF instruments and the CTC conversion rate.



Statistical Methods Sample Size Calculations:

The sample size calculation for the PFS endpoint is based on the following considerations:

• A 1:1 randomization ratio between the two treatment arms (MDV3100 versus bicalutamide);

• Target hazard ratio of 0.67. Based on published clinical trials and expert opinion, expected median PFS for the bicalutamide arm is 6 months. A target hazard ratio of 0.67 corresponds to a 50% increase in PFS for the MDV3100 arm relative to the bicalutamide arm (9 versus 6 months);

• Uniform accrual rate of 20 subjects per month;• Two-stage group sequential design with Lan and DeMets alpha-spending

function that resembles O’Brien-Fleming’s boundary will be used;• A minimum of 257 progression events provides 90% power to detect a

target hazard ratio of 0.67 based on a two-sided log-rank test and the overallsignificance level of 0.05;

• A sample size of approximately 288 subjects (144 subjects per treatment arm) will achieve 257 progression events within approximately 33 months (15 months for accrual and 18 months for follow-up) from the date the first subject is randomized. A four percent lost to follow-up rate will be assumed giving a final sample size of 300 subjects (150 subjects per treatment arm).

A formal interim analysis on PFS will be performed after 129 progression events (50% of the total number of events required for final analysis) have occurred.

The primary efficacy analyses will be conducted using a Full Analysis Set defined as all randomized subjects using Cox regression and Kaplan-Meier method.

Primary and secondary efficacy endpoints will be tested at the significance level of 0.05 (two-sided). No adjustment will be made for the multiple comparisons.

Safety Analyses:

The severity of all adverse events will be evaluated by the investigator based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0 and all adverse events will be coded to preferred term, higher level term, and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects with adverse events will be presented by MedDRA system organ class and preferred term, relationship to study treatment, and severity. Descriptive statistics will be used rather than inferential statistics.

Laboratory values will be classified by toxicity grade based on the NCI-CTCAE, version 4.0. Laboratory shift tables of the baseline results to each of the subsequent visits will be produced.



V. FLOW CHART AND SCHEDULE OF ASSESSMENTSFlow Chart

Obtain informed consent prior to performing any study related procedures Bicalutamide and

LHRH agonist/antagonist, or bilateral orchiectomy

MDV3100 and LHRH agonist/antagonist or bilateral orchiectomy

Documented radiographic progression,skeletal related event, or initiation of new

anti-neoplastic therapy

30 days after last dose

Every 12 weeks to assess for subsequent anti-neoplastic therapy, radiographic progression, and skeletal related event

Discontinued for reasons other than radiographic progression, skeletal related event, or initiation of new anti-neoplastic therapy

Discontinued for reasons other than radiographic progression, skeletal related event or initiation of new anti-neoplastic therapy

60 day PSA assessment

ScreeningWeek -4 to -1

Safety Follow-up Double Blind Treatment Period

Patients will be randomized 1:1 to one of two treatment arms

Long Term Follow-up *

*The 60 day PSA assessment and Long Term follow-up will be performed only for subjects who discontinue for reasons other than radiographic progression, a skeletal related event, or a initiation of new anti-neoplastic therapy



Table 1: Schedule of Assessments

Study Day Screening Visit 1 8 36 64 92 120 148 176 Safety F/U 60 Daym Long-Term F/Um

Week -4 to -1 (28 days) 1 2 5 9 13 17 21

25 and every subsequent 12 weeks

30 days from date of last

dosel

60 days from date

of last dose

Every 12weeks from date

of last doseWindow (days) ± 2 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 7 ± 7 ± 7

Informed Consent XDemographics/Medical History XInclusion/Exclusion Criteria X XRandomization XVital Signsa X Xa Xa Xa Xa X X X X XPhysical Examination, Weight, Heightb X Xe X X X X X X X X12-Lead ECG X Xe X X X X X X X XClinical Labsc X Xe X X X X X X X XPSA X Xe X X X X XCT/MRI and Bone Scand X X X XCXR or Chest CTf XECOG Performance Status X X X X X X X X X XBPI -SF X X XBlood Sample for CTC X X XBlood Sample for PK Analysisg X XWhole Blood Sample for Optional Genotype Analysish X

Blood Sample for T2:ERG Analysis XUrine Sample for T2:ERG Analysis i XTumor Tissue Sample for T2:ERG Analysis j X

FACT-P and EQ-5D Assessment X X XAdverse Events X X X X X X X X X XConcomitant Medications X X X X X X X X X XStudy Drug Dispensingk X X X X X X X



Table 1 Footnotes:a. Vital signs (blood pressure, pulse rate, respiration rate, and temperature) will be obtained prior to and 1-2 hours after study drug administration on

study weeks 1, 2, 5, and 9.b. Height obtained at screening visit onlyc. Clinical labs, hematology and chemistry, will be obtained prior to study drug administration.d. Subjects must be assessed with CT/MRI and bone scan within 28 days prior to randomization (Day 1). Scans should be scheduled in such a way that

the scan results are available at the regularly scheduled visit.e. If Day 1 visit occurs within 72 hours after screening, these assessments do not need to be repeated.f. Chest CT is required if screening chest X-Ray demonstrates metastatic chest disease.g. Blood PK sample to be obtained pre-dose. Sample may be assayed for study drug, metabolites, and/or concomitant medications at the discretion of the

sponsor.h. In the event of unusual PK/PD patterns or safety findings, genotype analysis of relevant metabolism, transporter, pharmacodynamic, and/or safety

genes will be conducted. If there is no requirement for analysis, the whole blood sample will be destroyed. Separate subject consent required.i. A 30 mL urine sample post digital rectal prostate examination will be collected at Day 1 for gene fusion analysis. This sample is collected only from

subjects who have not undergone prostatectomy.j. Tissue sample is from historical tumor blocks/slides. The sample will be used for gene fusion analysis.k. Subjects should withhold dosing on all clinic visit days. Dose will be administered in clinic.l. Safety follow-up visit will occur 30 days following the last dose of study drug or prior to the start of a systemic anti-neoplastic therapy, whichever

occurs first. m. Subjects that discontinue study drug for reasons other than radiographic progression, skeletal related event, or initiation of a new anti-neoplastic

therapy will have a PSA test performed 60 days after last dose and undergo long-term follow-up every 12 weeks from date of last dose until radiographic progression is documented, a skeletal related event, or a new anti-neoplastic therapy is initiated.



1 INTRODUCTION1.1 BackgroundWorldwide, prostate cancer ranks third in cancer incidence and sixth in cancer mortality in men. Androgen deprivation therapy with either medical or surgical castration is the preferred initial treatment for advanced prostate cancer [Singer et al 2008]. Despite disease control for a period of time, subjects will inevitably progress while on hormonal therapies. If prostate cancer progression is observed during standard androgen deprivation therapy (gonadotropin-releasinghormone analogues), non-steroidal anti-androgens such as bicalutamide have been added. Although, bicalutamide has been used as a second-line treatment in this subject population, the percent of subjects responding and the length of response time has been low. [Kucuk et al, 2001;Fujii et al, 2006] MDV3100 (ASP9785) is a novel androgen receptor antagonist and in preclinical studies has been shown to provide a more superior suppression of the androgen receptor pathway than bicalutamide.

It is generally believed that increased androgen receptor (AR) expression in the castration-resistant state allows prostate cancer cells to thrive even though circulating androgen levels are low. Preclinical studies have demonstrated that increased androgen receptor expression as seen in the castrate resistant prostate cancer (CRPC) state is associated with reduced effectiveness of the anti-androgen bicalutamide. Overexpression of the androgen receptor has been documented in upwards of 50% of subjects failing androgen deprivation therapy and is thought to contribute to tumor progression. [Chen et al, 2004] In CRPC models, bicalutamide shows agonist activity in the setting of AR overexpression. Bicalutamide shows agonist activity in two critical aspects of the androgen receptor pathway, namely translocation of the androgen receptor from the cytoplasm to the nucleus and association of the androgen receptor with nuclear DNA. This in part may explain some of the disappointing clinical results with bicalutamide in this subjectpopulation. In clinical trials with subjects that have failed treatment with gonadotropin-releasing hormone analogues, the response rates with bicalutamide were poor and short lived. [Joyce et al, 1998; Kojima et al, 2004; Scher et al, 1997] Studies investigating treatment with bicalutamide after failure of androgen deprivation monotherapy have observed a median time to PSA progression of 3 months, [Scher et al, 1997] a median time to objective progression of 4 months, and a median overall survival of 15 months [Kucuk et al, 2001].

MDV3100 (ASP9785) is a novel small molecule designed to have increased affinity for the androgen receptor and more effective suppression of the androgen pathway. In addition to increased binding affinity, MDV3100 also demonstrated AR downstream effects that were superior to bicalutamide. MDV3100 has no known agonist activity when the androgen receptor is overexpressed, and in pre-clinical models of CRPC with AR overexpression, MDV3100 suppresses growth of prostate cancer cells while bicalutamide was less effective. Most importantly, MDV3100 slows growth and induces cell death in bicalutamide-resistant cancers via three complementary actions – MDV3100 blocks testosterone binding to the androgen receptor, impedes movement of the androgen receptor to the nucleus of prostate cancer cells (nuclear translocation), and inhibits binding of DNA. Thus, MDV3100 is a novel androgen



receptor antagonist with qualities that surpass the conventional therapy, bicalutamide.[Investigator’s Brochure 2010]

1.2 Non-clinical and Clinical Data1.2.1 Non-clinical Data

In mice, rats, and dogs, oral MDV3100 had a half-life (t1/2) of approximately 0.25 to 3 days. The t1/2 did not appear to be affected by the dose size; however, the bioavailability appeared to decrease with increasing dose size. Plasma protein binding of MDV3100 in human plasma ranged from 97% to 98% and was similar in mice, rats, rabbits, and dogs. In vitro drug metabolism studies suggest that MDV3100 undergoes very slow rates of metabolism. In vitro drug metabolism studies suggest that MDV3100 may have the potential to induce cytochrome P450 (CYP) 3A4 and to directly inhibit CYP2B6, CYP2C8, CYP2C9, and CYP2C19. In consideration of time-dependent inhibition data, a metabolite of MDV3100 may inhibit CYP1A2. [Investigator’s Brochure 2010]

1.2.2 Clinical Data

The tolerability, pharmacokinetics (PK), and antitumor activity of MDV3100 were studied in a multi-center, open-label, dose-escalation study of MDV3100 in 140 subjects with advanced prostate cancer. Subjects were treated with MDV3100 at doses of 30–600 mg/day until disease progression or intolerable side effects developed.

The antitumor activity of MDV3100 was assessed by post-therapy changes in PSA, soft tissue and osseous disease, and circulating tumor cell count. PSA declines of ≥ 50% from baseline were observed in 62% of chemotherapy-naïve and 51% of post-chemotherapy subjects. At the time of the analyses, the median time to PSA progression was not yet reached for chemotherapy-naïve subjects and was 186 days for post-chemotherapy subjects. Among the chemotherapy-naïve subjects, there was evidence of radiographic control (no progression) in 80% of subjects with evaluable soft tissue disease and 63% of subjects with bone lesions. Among the post-chemotherapy subjects, there was evidence of radiographic control in 65% of subjects with evaluable soft tissue disease and 51% of subjects with bone lesions. The median time to radiographic progression was not yet reached for chemotherapy-naïve subjects and was 201 days for post-chemotherapy subjects. Enumeration of circulating tumor cells demonstrated that 91% of subjects with favorable pretreatment counts (i.e., < 5 circulating tumor cells/7.5 mL of blood) maintained favorable post-treatment counts, while 49% of subjects converted from unfavorable pretreatment counts (i.e., ≥ 5 circulating tumor cells/7.5 mL of blood) to favorable post-treatment counts.

At the highest dose of 600 mg/day, two of three subjects had dose-limiting toxicities (seizure and rash, respectively). One witnessed seizure at 360 mg/day and a possible seizure at 480 mg/day were also reported. No deaths and no other drug-related serious adverse events were reported. Fatigue was the most frequently reported adverse event, with dose-dependent increases of Grade 3 fatigue (0% at 150, 9% at 240, 15% at 360, and 20% at 480 mg/day groups). Only one subject



discontinued treatment due to fatigue. The dose of 240 mg/day was defined as the maximum tolerated dose.

MDV3100 was absorbed rapidly after oral administration, with maximum plasma concentration (Cmax) occurring approximately 30 minutes to four hours after dosing. The t1/2 in subjects was approximately one week (range 3 to 13 days) and did not appear to be affected by the dose size. MDV3100 plasma concentrations exhibited a low degree of inter- and intra-subject variability and increased linearly with dose. The pharmacokinetics (PK) remained linear over time, and there was no evidence of inhibition or autoinduction of metabolism during chronic administration. In accordance with a one week t1/2, it took approximately one month to reach steady state. The daily fluctuation in steady-state plasma concentrations (i.e., the difference between Cmax and minimum plasma concentration [Cmin]) was low, and PK profiles approximated a constant infusion. At 160 mg/day, the mean steady-state Cmin is expected to be approximately 12 ± 4 µg/mL.

1.3 Summary of Key Safety Information for Study Drugs1.3.1 MDV3100

The most common adverse events reported by subjects exposed to MDV3100 were fatigue, nausea, constipation, and anorexia at a frequency of ≥ 20%. Back pain and diarrhea were also observed in 19% of enrolled subjects. Fatigue was the most common grade 3/4 adverse event reported with an increasing frequency at doses of ≥ 240 mg/day necessitating dose reductions. The fatigue generally resolved with reduction in dose.

All reports of serious adverse events with the exception of two reports of witnessed seizure and one report of unwitnessed seizure were considered unrelated to MDV3100 by the investigator.

1.3.2 Bicalutamide

The most common adverse events occurring in more than 10% of patients reported for bicalutamide, 50 mg/day, plus a LHRH analogue reported in the United States package insert include: hot flashes, pain (including general, back, pelvic and abdominal), asthenia, constipation, infection, nausea, peripheral edema, dyspnea, diarrhea, hematuria, nocturia, and anemia.

Hypersensitivity reactions including angioneurotic edema and urticaria have been reported.

Hepatic changes (elevated transaminases, jaundice), rarely severe, may occur and periodic liver function tests should be considered. Additional safety information can be found in the bicalutamide Package Insert.

1.4 Risk-Benefit Assessment MDV3100 is a novel small molecule designed to have an increased affinity for the androgen receptor and more effective suppression of the androgen pathway in the setting of androgen overexpression [Tran et al, 2009]. MDV3100 has a higher binding affinity to the AR (8-10 times



greater), has no agonist activity, and has demonstrated superior AR downstream effects compared to bicalutamide in pre-clinical studies. In a clinical trial (Phase I-II) involving 140 castrate subjects with progressive prostate cancer who have either failed androgen deprivation therapy or chemotherapy, MDV3100 has shown strong anti-tumor effects. These effects include reduction of PSA, prolonged time to radiographic and PSA progression and CTC conversion from unfavorable to favorable status.

The maximum well-tolerated dose on multiple dosing is 240 mg. Two witnessed seizures occurred in subjects receiving doses of 600 mg and 360 mg per day, and one possible seizure at 480 mg per day. The dose in this trial, 160 mg/day, is below the maximum well-tolerated dose. The most common adverse events at this dose were fatigue, nausea, and constipation, all of which were considered manageable and tolerable. To further reduce the risk of seizures, subjects are excluded from enrollment in this trial if they have a history of seizure or have concomitant diseases that would predispose to seizures.

In randomized clinical trials, bicalutamide 50 mg in combination with castration has been shown to be generally well tolerated. Common adverse events include hot flashes, constipation and asthenia. Rarely, liver function test abnormalities have been observed. To reduce the risk of hepatic complications, liver function tests will be followed throughout the study and subjects with elevated transaminases at screening will be excluded from enrollment.

The Phase I-II data provide a convincing rationale to study MDV3100 in a subset population of subjects with metastatic progressive prostate cancer who have failed androgen deprivation therapy; namely castration monotherapy (either LHRH analogues or surgical castration). With the investigation of a defined cohort of subjects, MDV3100 will be compared to bicalutamide for efficacy and safety.

Given the promising non-clinical data and the robust clinical data from the Phase I-II in a subset of subjects that have failed bicalutamide therapy, the benefits of studying MDV3100 outweigh the risks involved. Furthermore it is appropriate to study MDV3100 in comparison to bicalutamide in this Phase II trial, as bicalutamide is the most common agent administered to the population being studied.

2 STUDY OBJECTIVE(S), DESIGN AND VARIABLES

2.1 Study ObjectivesThe primary study objective is:• to determine the PFS of MDV3100 as compared to bicalutamide.

The secondary objectives are:• to determine the safety of treatment with MDV3100 as compared to bicalutamide;• to determine the PSA response of MDV3100 at week 13 as compared to bicalutamide;• to determine the time to PSA progression of MDV3100 as compared to bicalutamide.



The exploratory objectives are:• to evaluate quality of life using the FACT-P, EQ-5D and BPI-SF instruments;• to determine the benefit of MDV3100 as compared to bicalutamide as assessed by the

CTC conversion rate.

2.2 Study Design and Dose Rationale2.2.1 Study DesignThis is a multinational phase II, randomized, double-blind, parallel study to determine the efficacy and safety of oral MDV3100 (160 mg/day) compared to bicalutamide (50 mg/day) incastrate men with metastatic prostate cancer who have progressed while on LHRH agonist/antagonist or after receiving a bilateral orchiectomy.Approximately 300 eligible subjects will be randomized 1:1 to one of two treatment arms: MDV3100, 160 mg orally once daily, or bicalutamide, 50 mg orally once daily. Subjects will be stratified by whether bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases. For the study duration, all subjects will maintain castration therapy with an LHRH agonist/antagonist or bilateral orchiectomy. Subjects will be discontinued from study drug at the time of confirmed radiographic disease progression, skeletal-related event, or the initiation of a new anti-neoplastic therapy.All subjects will have a safety follow-up visit 30 days from date of last dose or prior to initiation of a subsequent anti-neoplastic therapy for prostate cancer, whichever occurs first. Subjects that discontinue study drug treatment for a reason other than radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy will have a PSA test performed 60 days from date of last dose and undergo long-term follow-up every 12 weeks from date of last dose. Long term follow-up will assess for the following until they occur: radio-graphic progression, skeletal related events, or the start of new anti-neoplastic therapy for prostate cancer.PSA progression alone is not a criterion for disease progression. PSA progression alone will not be considered as a determinant for discontinuation of study drug in the first 24 weeks of the study period and is discouraged thereafter.The occurrence of an adverse event or toxicity, where continued administration of study drug is deemed to be not in the subject’s best interest by the investigator and/or the sponsor, will result in the removal of the subject from therapy. The consensus guidelines of the PCWG2 have been utilized to determine disease progression. Soft tissue disease progression will be defined by RECIST 1.1.Bone disease progression is considered when a minimum of two new lesions are observed. Progression on bone scan at time points on/or after Week 13 require a confirmatory scan performed six or more weeks later (or the next scheduled scan). This confirmatory scan should demonstrate additional new lesions.



The following assessments of prostate cancer status will be collected during the course of the trial: soft tissue disease on CT scan or on MRI , bone disease on radionuclide bone scans, skeletal-related events, FACT-P, EQ-5D and BPI-SF quality of life questionnaires, and PSA.Study films (abdominopelvic [lung when applicable] CT/MRI and bone scan) should be read on site and also be submitted in digital format to the sponsor or designee for an independent central review. Each site should ideally designate the same reader who will evaluate the images for any one subject for the duration of the trial. Throughout the study, safety and tolerability will be assessed by the recording of adverse events, monitoring of vital signs and physical examinations, safety laboratory evaluations, and 12-lead electrocardiograms. An independent Data Monitoring Committee will monitor safety and efficacy data on an ongoing basis.A formal interim analysis on PFS will be performed after 129 progression events (50% of the total number of events required for final analysis) have occurred.Historical tumor tissue samples, urine and blood samples will be collected to allow evaluation of T2:ERG gene fusions. Samples will be obtained and stored until qualified assays become available.

2.2.2 Dose RationaleThe dose of 160 mg/day of MDV3100 was selected for evaluation in this study. The durability of disease suppression is similar between the 150 mg/day and the 240 mg/day dose cohorts in the Phase 1-2 study. In the Phase 1-2 study, subjects were administered five 30 mg capsules. In an effort to decrease the total number of capsules administered to the subject, this study will utilize four 40 mg capsules. The dose of 50 mg/day of bicalutamide will be used in this study. The dose of 50 mg/day is thecommercially approved dosage for use in combination therapy with LHRH analogues.

2.3 Variables2.3.1 Primary Variable


2.3.2 Secondary VariablesThe secondary variables are PSA response and time to PSA progression. Safety variables are adverse events, laboratory evaluations, vital signs, physical examinations and ECGs.

2.3.3 Exploratory Variables




2.3.4 T2:ERG

To evaluate the relevance of T2:ERG gene fusions in tissue, urine and blood samples, archival prostate tumor tissue, urine collected post digital rectal prostate examination (for subjects whohave not undergone prostatectomy), and blood samples will be obtained and stored until qualified assays become available.

2.3.5 Optional Pharmacogenomics Sub-Study

Subjects may consent to participate in an optional pharmacogenomics sub-study. One blood sample will be collected for storage. The pharmacogenomic research that will be conducted in the future with acquired blood samples is exploratory. The objective of this research is to comprehensively analyze suspected disease-related genes and genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues, etc. In the event of unusual PK/PD patterns or safety findings, genotype analysis of relevant metabolism, transporter, pharmaco-dynamic, and/or safety genes will be conducted.

3 STUDY POPULATION

3.1 Selection of Study PopulationThe study population will include approximately 300 men with metastatic prostate cancer who have progressed while on LHRH agonist/antagonist or after receiving a bilateral orchiectomy.

3.2 Inclusion CriteriaSubject is eligible for the study if all of the following apply:

1. IRB/IEC approved written Informed Consent and privacy language as per national regulations (e.g., HIPAA for U.S. sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).




5. Metastatic disease documented by at least two bone lesions on bone scan or by soft tissue disease observed by CT/MRI on or before screening visit, except subjects with regional pelvic lymph node disease only. Measurable disease is not required for entry.




• PSA progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the Screening visit should be ≥ 2 µg/L (2 ng/mL);

• Soft tissue disease progression defined by RECIST 1.1.;• Bone disease progression defined by two or more new lesions on bone scan.

7. Asymptomatic or mildly symptomatic from prostate cancer (i.e. the score on BPI-SF Question #3 must be < 4); no use of opiate analgesics for prostate cancer-related pain currently or anytime within 4 weeks prior to randomization.

8. ECOG performance status of 0-1, including subjects with decreased performance status not attributed to progressive and symptomatic prostate cancer.



3.3 Exclusion CriteriaSubjects will be excluded from participation if any of the following apply:





5. Total bilirubin > 1.5 times the upper limit of normal (ULN) at Screening. This will not apply to subjects with Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly uncongugated in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with the sponsor.







10. Current or prior treatment with estrogens and/or drugs with anti-androgenic properties such as spironolactone > 50 mg/kg, or progestational agents for the treatment of prostate cancer within 6 months prior to randomization.


12. Current or prior treatment with anti-androgens, except if the medications were during LHRHanalogue induction for < 6 weeks. No use within 3 months prior to randomization.


14. Prior use of systemic glucocorticoids (the equivalent of 10 mg of prednisone) within 3 months prior to randomization or expectation of their use during the study.




18. Clinically significant cardiovascular disease including: • Myocardial infarction within six months prior to Screening;• Uncontrolled angina within three months prior to Screening;• Congestive heart failure NYHA class 3 or 4, or subjects with history of congestive

heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or MUGA scan performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%;

• History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes);

• History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;

• Uncontrolled hypertension as indicated by a resting systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at Screening.

19. Prior use or participation in a clinical trial, of an investigational agent that blocks androgen synthesis and/or androgen receptor activity.






3.4 Discontinuation Criteria for Individual SubjectsA discontinuation is a subject who enrolled in the study and for whom study drug is terminated for any reason.

The subject is free to withdraw from the study treatment and/or study for any reason and at any time without giving reason for doing so and without penalty or prejudice. The investigator is also free to terminate a subject's involvement in the study at any time if the subject's clinical condition warrants it.Subjects will be discontinued from study drug if any of the following occur:

• Radiographic disease progression;

• Skeletal-related events. Skeletal related events are defined as:

o Radiation therapy or surgery to boneo Pathologic bone fractureo Spinal cord compressiono Change in anti-neoplastic therapy to treat bone pain;

• Decision of the investigator and subject to initiate a new anti-neoplastic therapy;

• Subject develops an adverse event or toxicity, where continued administration of study drug is deemed not in the subject’s best interest by the investigator and/or the sponsor.


Unless the subject withdraws consent, all subjects discontinuing study drug for any reason willhave a safety follow-up visit 30 days after their last dose of study drug or prior to initiation of subsequent anti-neoplastic therapy for prostate cancer, whichever occurs first.

Subjects that discontinue study drug for a reason other than radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy will have a PSA test performed 60 days from date of last dose and undergo long-term follow-up every 12 weeks from date of last dose. Long term follow-up will assess for subsequent anti-neoplastic therapy for prostate cancer, radiographic progression, and the occurrence of skeletal related events. Long-term follow-up will be performed until radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy is documented. Reasonable effort should be made to contact any subject lost to follow-up during the course of the study in order to complete study related assessments and retrieve any outstanding data and study drug. Following unsuccessful telephone contact, an effort to contact the subject by mail using a method that provides proof of receipt should be attempted. Such efforts should be documented in the source documents.



4 STUDY DRUGS4.1 Description of Study Drugs4.1.1 Test Drug(s)

MDV3100 has the chemical name 3-(4-cyano-3-trifluoromethylphenyl)-1-[3-fluoro-4-(methylcarbamoyl)phenyl]-5,5-dimethyl-2-thioxoimidazolin-4-one. It is a white to off-white solid that is insoluble in water and no salt forms are available at ~pH 2 to 10.

The drug substance is formulated in the surfactant, Labrasol, to create a self-emulsifying (or microemulsifying) dosage form. The product will be supplied as white to off white gelatin capsules containing 40 mg of MDV3100.

The corresponding placebo is manufactured by Catalent Pharma Solutions (St. Petersburg, Florida) and consists of Labrasol filled in identical capsules. Both active and placebo formulation contain the same relative concentrations of the two preservatives, BHA and BHT.

4.1.2 Comparative Drug(s)

Bicalutamide has the chemical name propanamide, N [4 cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+-). It is a fine white to off-white powder which is practically insoluble in water at 37◦C (5 mg per 1000mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran.

Bicalutamide 50 mg tablets, USP, is supplied as white to off-white, film coated tablets.

Bicalutamide and the corresponding placebo to match will be produced by Zydus Pharma (Moraiya, India) as white to off-white, film coated tablets.

4.2 Packaging and LabelingAll medication used in the study will be prepared, packaged, and labeled under the responsibilityof a qualified individual at Astellas U.S. Technologies (AUST) in accordance with AUST Standard Operating Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and applicable local laws/regulations.

MDV3100 soft gelatin capsules, bicalutamide tablets and the respective matching placebo capsules/tablets will be blister packaged according to this study design using the appropriate transparent thermo formable film(s) with foil backing and placed in child resistant wallets for individual subject dispensing.

4.3 Study Drug HandlingCurrent ICH GCP Guidelines require the investigator to ensure that study drug deliveries from the sponsor are received by a responsible person (e.g., pharmacist), and

• that such deliveries are recorded;



• that study drug is handled and stored safely and properly;• that study drug is only dispensed to study subjects in accordance with the protocol;• that any unused study drug is returned to the sponsor or standard procedures for the

alternative disposition of unused study drug are followed.

Drug inventory and accountability records for the study drugs will be kept by the investigator/pharmacist. Study drug accountability throughout the study must be documented. The following guidelines are therefore pertinent:

• The investigator agrees not to supply study drugs to any persons except the subjects in this study.

• The investigator/pharmacist will keep the study drugs in a pharmacy or other locked and secure storage facility under controlled storage conditions, accessible only to those authorized by the investigator to dispense these test drugs.

• A study drug inventory will be maintained by the investigator/pharmacist. The inventory will include details of material received and a clear record of when they were dispensed and to which subject.

• At the conclusion or termination of this study, the investigator/pharmacist agrees to conduct a final drug supply inventory and to record the results of this inventory on the Drug Accountability Record. It must be possible to reconcile delivery records with those of used and returned medication. Any discrepancies must be accounted for. Appropriate forms of deliveries and returns must be signed by the person responsible.

• Used or unused study drug may be destroyed at the study center according to standard institutional procedures after drug accountability has been conducted by the Sponsor or representative, only if agreed upon by the Sponsor. A copy of the standard institutional procedure for destroying investigational drugs will be provided to the Sponsor or designee upon request. Unused study drug not destroyed at the site must be returned to the Sponsor or designee at the end of the study or upon expiration.

4.3.1 Test Drug

MDV3100 and placebo to match should be stored at controlled room temperature of 20o C to 25o C (68o F - 77 o F); excursions are permitted to 15o to 30o C (59o F - 86o F) in a secured area inaccessible to unauthorized individuals.

4.3.2 Comparative Drug

Bicalutamide and placebo to match should be stored at controlled room temperature of 20o C to 25o C (68o F - 77o F); excursions are permitted to 15o to 30o C (59o F - 86o F) in a secured area inaccessible to unauthorized individuals.

4.4 BlindingThe study will be performed in a double-blind fashion, so neither the subject, the investigator northe sponsor will be aware of the treatment group assigned to each subject.



4.4.1 Blinding Method

The study medication blind will be maintained by the IVRS, which will be accessed by the study sites for randomization number and study medication assignments.

4.4.2 Confirmation of Indistinguishability of the Study Drugs

The control for this blinded study will be the placebo capsules and placebo tablets that appear identical to the MDV3100 capsules and bicalutamide tablets, respectively.

Study drug will be dispensed in the same manner regardless of assigned treatment arm. Subjects will ingest the same number of capsules and or tablets throughout the study.

4.4.3 Breaking the Treatment Code for Emergency

Treatment unblinding may only occur if the knowledge of the treatment assignment will materially change the planned management of a medical emergency. If a medical emergency requiring unblinding occurs, the investigator or designee at the site will contact the sponsor or designee to assess the necessity of breaking the blind.

For unblinding a subject, the assigned study medication information is accessible through IVRS. The sponsor must be immediately notified if the blind is broken. The date, time, and reason the blind was broken must be recorded in the source documents and on the appropriate eCRF if applicable.

If the investigator is unblinded, study medication must be stopped immediately and the subject must be discontinued from the study.

4.5 Assignment and AllocationSubjects who meet the inclusion/exclusion criteria will be randomly assigned to receive MDV3100 or bicalutamide using a 1:1 randomization schedule. Subjects will be stratified by whether bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases. Randomization will be further stratified by site. The sponsor or designee will generate the randomization schedule.

The investigator or designee will contact the IVRS to randomize the subject into the study. The investigator or designee will provide the necessary subject identifying information. The medication number of the medication to be dispensed will be provided by the IVRS. At subsequent drug dispensing visits, the investigator or designee will again contact the IVRS to request additional study medication for a subject. The medication number provided by the IVRS should be included in the source documentation.

If the subject is assigned to a treatment arm and given a subject number, but does not receive study drug, the subject number will not be used again.



5 TREATMENTS AND EVALUATION5.1 Dosing and Administration of Study Drugs and Other Medications5.1.1 Dose/Dose Regimen and Administration PeriodIn this study, subjects will be randomized to receive blinded oral doses of study drug.Subjects randomized to the MDV3100 treatment arm will take 160 mg (four capsules) of active MDV3100 and one placebo tablet orally once daily. Subjects randomized to the bicalutamide treatment arm will take 50 mg (one tablet) of active bicalutamide and four placebo capsules orally once daily. Study drug should be taken as close to the same time each day as possible. Study drug can be taken with or without food.Subjects should be instructed to withhold dosing on all clinic visit days. Dose will be administered in clinic.

5.1.2 Interruption in Dose of the Study DrugsSubjects who experience a Grade 3 or greater toxicity that cannot be ameliorated by the use of adequate medical intervention should have their treatment interrupted until the toxicity improves to a Grade 2 or lower severity.

5.1.3 Previous and Concomitant Medication (Drugs and Therapies)

5.1.3.1 Previous Medication (Drugs and Therapies)Medication taken within four weeks prior to randomization and any medications prescribed chronically or intermittently during the study or dose adjustments of these medications must be captured on the case report form.

5.1.3.2 Concomitant Medication (Drugs and Therapies)All concomitant medications must be recorded in the appropriate case report form. Concomitant medications will be assessed at screening, visits 1, 2, 5, 9, 13, 17, 21, 25, subsequent 12 week visits and 30 day follow up.The dosage and regimen of the following medications and any chronic permitted concomitant medications should be stabilized during the screening period (> 4 weeks prior to randomization) and held constant throughout the study:• bisphosphonates • LHRH agonist/antagonist

The following medications are prohibited while the subject is on study drug:• Chemotherapeutic, biologic, or other agents with anti-tumor activity against prostate cancer;• Anti-androgens (steroidal or non-steroidal) such as cyproterone acetate, flutamide, nilutamide,

bicalutamide, etc. other than assigned study drug.• 5-α reductase inhibitors such as finasteride, dustasteride, anabolic steroids, etc.



• Estrogens, progestational agents such as megestrol, medroxyprogesterone, DES, cyproterone, spirinolactone > 50 mg/kg, etc.

• Systemic glucocorticoids (the equivalent of 10 mg of prednisone) for the treatment of prostate cancer

• Androgens such as testosterone, dihydroepiandrosterone [DHEA], etc.• Ketoconazole• Anti-epileptic medications for the treatment of seizure• Prior use of any investigational agents that block androgen synthesis are prohibited including

abiraterone acetate, TAK-700, TAK 683, TAK 448, VN-124-1 or androgen receptor activity including BMS-641988, 17-allylamino-geldanamycin, etc.

It is currently unknown which CYP enzyme pathways are responsible for clearing MDV3100. To limit the risk of unpredictable increases or decreases in circulating concentrations of MDV3100, potent inhibitors or inducers should be taken with caution, and alternative products used when available. In vitro data suggest that MDV3100 may have the potential to induce CYP3A4 and inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5; therefore, concomitant medications that are substrates of any of these enzymes should be used with caution, and relevant monitoring should be considered, especially for substrates known to cause seizure, because the possibility of drug-drug interactions cannot be fully excluded. To determine if a particular drug is a potent CYP inhibitor or inducer, investigators should consult Table 2; for drugs not listed in Table 2, the investigator should consult the product label.

Table 2: Potent CYP Inhibitors and InducersCYP Inhibitors CYP Inducersamiodaroneatazanavirclarithromycindisulfirumfluconazolefluoxetinefluvoxaminegemfibrozilindinaviritraconazolemoclobemidenefazodonenelfinaviromeprazoleparoxetinequinidineritonavirsaquinavirtelithromycin

carbamazepinerifampinphenobarbitalphenytoin



To determine if a particular concomitant drug should be considered for dose-reduction or discontinuation during treatment with MDV3100, investigators should consult the product label.

5.1.4 Treatment Compliance

Study drug accountability will be performed to document compliance with the dosing regimen. Subjects will be asked to bring back all remaining study drug and all study drug packaging at each study visit for drug accountability.

5.1.5 Emergency Procedures and Management of Overdose

If an overdose of study drug occurs, the Medical Monitor must be contacted. An overdose is defined as 2 days of study drug taken over the course of a 24 hour period. Neither the effects of overdose of MDV3100 nor an antidote to overdose are known. In case of overdose of MDV3100, symptomatic treatment with frequent monitoring is recommended. In case of bicalutamide overdose, there is no specific antidote; treatment of an overdose should be symptomatic. Refer to bicalutamide package insert for additional information.

5.2 Demographics and Baseline Characteristics5.2.1 Demographics

Demographic information is to be obtained at screening and will include date of birth, ethnicity, race as described by the subject, height and weight.

5.2.2 Chest X-Ray and/or Chest CT

At screening, a chest x-ray will be performed. A chest CT is required if the screening chest x-ray demonstrates metastatic chest disease.

5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease

A complete medical history of the target disease will be recorded at screening. This includes documenting the subject’s initial diagnosis of prostate cancer, Gleason score at time of diagnosis, dates and type of primary therapy and other disease specific information as designated in the eCRF.

5.2.4 Medical History

Medical history will include any significant conditions or diseases other than prostate cancer that stopped at or prior to screening.

5.2.5 Performance Status

The ECOG scale [Oken et al, 1982] will be used to assess performance status.



Table 3: ECOG Performance StatusGrade Description

0 Fully active, able to carry on all pre-disease performance without restriction1 Restricted in physically strenuous activity but ambulatory and able to carry out

work of a light or sedentary nature, e.g., light house work, office work2 Ambulatory and capable of all self-care but unable to carry out any work

activities. Up and about more than 50% of waking hours3 Capable of only limited self-care, confined to bed or chair more than 50% of

waking hours4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or

chair5 Dead

ECOG score will be collected at Screening, Week 1 (baseline), and at every clinic visit including the safety follow-up visit.

5.3 Efficacy Assessment5.3.1 CT/MRI and Bone Scan

Imaging will be performed at Screening (baseline) and assessed at week 13, week 25, and at subsequent 12 week intervals. For subjects that discontinue for reasons other than radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy, imaging will be performed every 12 weeks from date of last dose as part of long-term follow up. Baseline imaging performed prior to informed consent may be used so long as it is performed within 28 days prior to randomization.

Scans should be scheduled in such a way that the scan results are available at the regularly scheduled visit.

The imaging method utilized for baseline scans must be utilized throughout the entire study.

Imaging may be performed at any time to confirm suspected progression of disease.

Radiographic evaluation of metastatic disease is determined separately for soft -tissue and bone disease. Radiographic disease assessment for soft tissue disease is based on CT or MRI scan and is defined by RECIST 1.1. Radiographic disease assessment for bone lesions is based on bone scan and is considered when a minimum of two new lesions are observed.

Progression on bone scan at time points on/or after Week 13 require a confirmatory scan performed six or more weeks later (for example, the scheduled Week 25 scan). This confirmatory scan should demonstrate additional new lesions.

Assessment will include tumor measurements for target lesions, non-target lesions, and assessment for any new lesions. An overall assessment will be characterized for that time point evaluation. At the end of study for that subject, the overall best response to the study regimen will be characterized.



Study films (abdominopelvic [lung when applicable] CT/MRI and bone scan) should be read on site and also be submitted in digital format to the sponsor or designee for an independent central review. Each site should ideally designate the same reader who will evaluate the images for any one subject for the duration of the study.

The same imaging method used for an individual patient at baseline should be used throughout the entire study for that patient.

PET scans should not be used to determine disease progression.

5.3.2 PSA

Samples for PSA will be collected and analyzed at a central laboratory designated by the Sponsor. PSA testing will be performed at screening, week 1 (baseline), week 13, week 25, at subsequent 12 week intervals, at the safety follow-up visit, at the 60 day visit (if applicable), and during long term follow-up visits.

The PSA test performed at the screening visit does not need to be repeated on Day1 if the Day 1 visit occurs within 72 hours of screening.

5.4 Safety Assessment5.4.1 Vital Signs

Vital signs including blood pressure, pulse rate, respiration rate, and temperature will be assessed at screening, at every clinic visit while on study drug and at the safety follow-up visit.

At Weeks 1, 2, 5 and 9, vital signs will be obtained prior to and 1 to 2 hours after study drug administration. Subjects should withhold dosing of study medication on clinic visit days. Dose will be administered in clinic.

5.4.2 Adverse Events

Adverse event collection will begin at the time of informed consent and continue for 30 days after last dose of study drug. Adverse events will be documented at each clinic visit per the schedule of assessments. See Section 5.5 for details on adverse event collection.

5.4.3 Laboratory Assessments

Routine laboratory assessments for hematology and chemistry will be collected and analyzed at a central laboratory designated by the Sponsor. Laboratory assessments will be assessed at screening, at every clinic visit during the investigational period, and at the safety follow-up visit.

The laboratory assessments performed at the screening visit do not need to be repeated on Day1 if the Day 1 visit occurs within 72 hours of screening.

Laboratory assessments must be obtained prior to study drug administration.



5.4.3.1 Hematology

Analytes to be tested include complete blood count (CBC), red blood cell count (RBC), hemoglobin (Hgb), hematocrit (HCT), white blood cell count (WBC), platelets, and WBC differential.

5.4.3.2 Chemistry

Analytes to be tested include sodium, potassium, calcium, chloride, magnesium, phosphorus, glucose, creatinine, alkaline phosphatase, bone alkaline phosphatase (bALP), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST),gamma-glutamyl transferase (GGT), total bilirubin, total protein, albumin, bicarbonate (CO2), blood urea nitrogen (BUN).

5.4.4 Physical Examination

Standard, full physical examinations will be performed to assess weight, general appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, neurologic status, mental status, lymphatic, genitourinary, and rectal systems. Any abnormalities will be collected as medical history or adverse events. Weight will be recorded at each visit. Height will be recorded at the screening visit only. The physical examination performed at the screening visit does not need to be repeated on Day1 if the Day 1 visit occurs within 72 hours of screening.

5.4.5 Electrocardiogram (ECG)

A standard 12-lead ECG will be performed on all subjects. Parameters that include heart rate, PR interval, RR interval, QRS interval, QT interval will be collected on the (e)CRF. Abnormalities and clinical significance as judged by the Investigator will be reported as well. An anonymized copy of the ECG print-outs will be collected and sent to the sponsor or designee. It is recommended that ECG reports are printed in duplicate and photocopied to prevent fading.

An ECG will be performed at screening, all study visits while on study drug and at the safety follow-up visit. The ECG performed at the screening visit does not need to be repeated on Day1 if the Day 1 visit occurs within 72 hours of screening.

5.5 Adverse Events and Other Safety Aspects5.5.1 Definition of Adverse Events (AEs)

An adverse event (AE) is defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not related to the study drug.



An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, physical exam) should be defined as an AE only if the abnormality meets one of the following criteria:

• Induces clinical signs or symptoms• Requires active intervention• Requires interruption or discontinuation of study medication• The abnormality or investigational value is clinically significant in the opinion of the

investigator.

5.5.2 Disease Progression

It is anticipated that a proportion of subjects will experience disease progression. Disease progression should not be reported as an adverse event. Clinical signs and symptoms due to disease progression will be collected as AEs. Individual signs and symptoms will be listed rather than the term “disease progression” with the following exception: if disease progression is the cause of death, this event may be recorded as an AE with “disease progression” as the reported term.

5.5.3 Definition of Serious Adverse Events (SAEs)

A serious AE is any untoward medical occurrence that at any dose:

• Results in death,• Is life threatening (an event in which the subject is at risk of death at the time of the

event; it does not refer to an event which hypothetically might have caused death if it was more severe),

• Results in persistent or significant disability/incapacity, • Results in congenital anomaly, or birth defect,• Requires inpatient hospitalization or leads to prolongation of hospitalization

(hospitalization for treatment/observation/examination caused by AE is to be considered as serious).

• Other medically important events.

Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above. These events, including those that may result in disability, should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic broncho-spasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse.Additionally, Astellas requests that all medical events listed in Appendix 2 are to be reported by the Investigator, always as serious, even if none of the above criteria would apply.



5.5.4 Criteria for Causal Relationship to the Study Drug

Adverse events that fall under either "Possible" or "Probable" should be defined as "adverse events whose relationship to the study drugs could not be ruled out".

Table 4: Criteria for Causal RelationshipCausal relationshipto the study drug

Criteria for casual relationship

Not Related A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and/or in which other drugs, chemicals or underlying disease provide plausible explanations.

Possible A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.

Probable A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on re- administration (rechallenge) or withdrawal (dechallenge).

5.5.5 Criteria for Defining the Severity of an Adverse Event

Severity of adverse events will be graded according to the Cancer Therapy and Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events v. 4.0 [Dilts et al, 2009]. For terms not specified within NCI-CTCAE, the following guideline should be used to determine grade:

Table 5: Criteria for Severity of Adverse Event Terms Not Specified Within NCI-CTCAE

Grade Description1 Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only;

intervention not indicated.

2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living.

3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; limiting self care activities of daily living.

4 Life-threatening consequences; urgent intervention indicated.

5 Death related to AE.



5.5.6 Reporting of Serious Adverse Events (SAEs)

In the case of a serious adverse event (SAE), the investigator must contact the sponsor by telephone or fax immediately (within 24 hours of awareness or at the earliest possible time point).

The investigator should complete and submit an SAE Worksheet containing all information that is required by the Regulatory Authorities to the sponsor by fax immediately (within 24 hours of awareness or at the earliest possible time point). If the faxing of an SAE Worksheet is not possible or is not possible within 24 hours, the local drug safety contact should be informed by phone.

For contact details, see Section II Contact Details of Key Sponsor's Personnel.

If there are any questions, or if clarification is needed regarding the SAE, please contact the Sponsor's Medical Director/Expert or his/her designee (see Section II Contact Details of Key Sponsor’s Personnel).

Follow-up information for the event should be sent promptly (within 7 days) as necessary.

The sponsor or sponsor's designee will submit expedited safety reports (i.e. IND Safety Reports) to the regulatory agencies (i.e. FDA) as necessary, and will inform the investigators of such regulatory reports. Investigators must submit safety reports as required by their Institutional Review Board/Independent Ethics Committee within timelines set by regional regulations (i.e. EU, (e)CTD, FDA). Documentation of the submission to and receipt by the IRB/IEC of expedited safety reports should be retained by the site.

You may contact the sponsor's Medical Director/Expert for any other problem related to the safety, welfare, or rights of the study participant.

Full details of the SAE should also be recorded on the medical records and on the CRF.

The following minimum information is required:

• ISN/Study number • Subject number, sex and age• The date of report• A description of the SAE (event, seriousness of the event)• Causal relationship to the study drug

SAEs will be collected from the time of informed consent through 30 days after the last dose of study medication.

Investigators must provide written documentation of IRB/IEC notification for each report to the Sponsor.



5.5.7 Follow-up to Adverse Events

All adverse events occurring during the study are to be followed up until resolved or judged to be no longer clinically significant, or until they become chronic to the extent that they can be fully characterized.

If during adverse event follow-up, the adverse event progresses to an "SAE", or if a subject experiences a new SAE whose relationship to the study drug(s) cannot be ruled out, the investigator must immediately report the information to the sponsor.

5.5.8 Procedure in Case of Pregnancy

If during the conduct of the clinical trial, a male subject impregnates his partner, the subject should report the pregnancy to the investigator. The investigator should report the pregnancy to the sponsor as an SAE within 30 days from discontinuation of dosing. The expected date of delivery or expected date of the end of the pregnancy, last menstruation, estimated fertility date, pregnancy result and neonatal data etc., should be included in this information.

The investigator will follow the medical status of the mother, as well as the fetus, as if the pregnancy is an SAE and will report the outcome to the sponsor.

When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a miscarried fetus)], the investigator should respond in accordance with the report procedure for SAEs. Additional information regarding the outcome of a pregnancy (which is categorized as an SAE) is mentioned below.

• "Spontaneous abortion" includes abortion and missed abortion.• Death of an infant within 1 month after birth should be reported as an SAE regardless of

its relationship with the study drug. • If an infant dies more than 1 month after the birth, it should be reported if a relationship

between the death and intrauterine exposure to the study drug is judged as "possible" by the investigator.

• In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at the birth.

• "Normality" of the miscarried fetus is evaluated by visual examination unless test results which indicate a congenital anomaly are obtained prior to miscarriage.

5.5.9 Supply of New Information Affecting the Conduct of the Study

When new information, including "Dear Doctor Letters" but not limited to that, necessary for conducting the clinical study properly will lead to a protocol amendment, the sponsor should inform regulatory authorities, as well as all investigators involved in the clinical study, who will then inform the IRB/IEC of such information, and when needed, should amend the subject information.



5.6 Test Drug Concentration A 4 mL pre-dose blood sample for PK will be collected into an EDTA tube at weeks 13 and 21. Centrifuge the sample to yield plasma and freeze the plasma at approximately -20° C. The sample will be packaged and shipped per vendor instructions.

The PK samples may be assayed for study drug, metabolites, and/or concomitant medications at the discretion of the Sponsor using a validated analytical method.

5.7 Other Measurements, Assessments, or Methods 5.7.1 CTC Sampling

Blood samples for the enumeration of CTCs will be collected at week 1, week 13, week 25, and at subsequent 12 week intervals throughout the treatment period. Samples will be collected, prepared, labeled, and shipped to a central laboratory for testing per vendor instructions.

5.7.2 FACT-P

The FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer patients. It consists of 27 core items which assess patient function in four domains: physical, social/family, emotional, and functional well-being, which is further supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as a global quality of life score with higher scores representing better quality of life.

Subjects will be asked to complete a FACT-P survey at week 1 (baseline), week 13, week 25, and at subsequent 12 week intervals throughout the treatment period.

5.7.3 BPI

The Brief Pain Inventory pain questionnaire is a validated instrument that is a subject self rating scale assessing level of pain, effect of the pain on activities of daily living, and analgesic use. The BPI used in this study is the short form and contains 9 questions. The BPI uses simple numeric rating scales from 0 to 10.

The BPI-SF will be administered during the screening visit, visit 13, visit 25, and at subsequent 12 week visit intervals.

5.7.4 EQ-5D

EQ-5D is a standardized instrument for use as a measure of health outcome. It provides a simple descriptive profile and a single index value for health status. EQ-5D is designed for self-completion by respondents. It consists of two pages comprising the following five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has



3 levels and subjects are asked to indicate his/her health state by ticking the box with the most appropriate statement.

Subjects will be asked to complete a EQ-5D instrument at week 1 (baseline), week 13, week 25, and at subsequent 12 week intervals throughout the treatment period.

5.7.5 Tissue, Blood and Urine Sampling for Gene Fusion Analysis


A tissue sample from historical tumor blocks/slides and a blood sample will be collected at week1. For those subjects who have not undergone prostatectomy, a urine sample (30 mL) post digital rectal prostate examination will be collected at week 1.

5.7.6 Whole Blood Sample for Optional Genotype Analysis

A whole blood sample (5 mL) for biobanking will be collected at week 1. In the event of unusual PK/PD patterns or safety findings, genotype analysis of relevant metabolism, transporter, pharmacodynamic, and/or safety genes will be conducted. If there is no requirement for analysis, the whole blood sample will be destroyed. Separate subject consent required. Samples will be collected, prepared and shipped to a central laboratory per vendor instructions.

5.8 Total Amount of BloodThe total amount of blood for each subject will vary depending on how long they stay on treatment. The maximum amount of blood collected for a subject within 24 hours during the treatment period is approximately 41 mL. The maximum amount of blood during the follow-up period is approximately 20 mL. Furthermore, if any laboratory abnormalities are found for a subject, additional blood may be drawn for monitoring.

6 TERMINATION OF THE CLINICAL STUDYThe sponsor reserves the right to discontinue the study at any time.

When the sponsor is aware of information on matters concerning the quality, efficacy, and safetyof the study drugs, as well as other important information that may affect proper conduct of the clinical study, the sponsor may discontinue the clinical study and send a written notice of the discontinuation along with the reasons to the investigator.

If an investigator intends to discontinue participation in the study, the investigator must immediately inform the sponsor of the discontinuation and the reason for it.



7 STATISTICAL METHODOLOGYUnless otherwise specified, categorical variables will be presented as counts and percentages, and continuous variables will be presented using descriptive statistics (number of subjects, mean, standard deviation, median, min and max). Tables will be summarized by treatment groups and stratum.

7.1 Sample SizeThe sample size calculation for the PFS endpoint is based on the following considerations:

• A 1:1 randomization ratio between the two treatment arms (MDV3100 versus bicalutamide);

• Target hazard ratio of 0.67. Based on published clinical trials and expert opinion, expected median PFS for the bicalutamide arm is 6 months. A target hazard ratio of 0.67 corresponds to a 50% increase in PFS for the MDV3100 arm relative to the bicalutamide arm (9 versus 6 months);

• Uniform accrual rate of 20 subjects per month;

• Two-stage group sequential design with Lan and DeMets alpha-spending function that resembles O’Brien-Fleming’s boundary will be used;

• A minimum of 257 progression events provides 90% power to detect a target hazard ratio of 0.67 based on a two-sided log-rank test and the overall significance level of 0.05;

• A sample size of approximately 288 subjects (144 subjects per treatment arm) will achieve 257 progression events within approximately 33 months (15 months for accrual and 18 months for follow-up) from the date the first subject is randomized. A four percent lost to follow-up rate will be assumed giving a final sample size of 300 subjects (150 subjects per treatment arm);

The sample size calculations are performed using the software package East 5.2 (Cytel Software Corp., Cambridge, MA).

7.2 Analysis SetEfficacy analysis will be conducted on the Full Analysis Set (FAS) and the Per Protocol Set (PPS). The efficacy analysis based on the FAS is considered primary. Safety analysis will be conducted on the Safety Analysis Set (SAF).

7.2.1 Full Analysis Set (FAS)

The FAS is defined as all subjects who are randomized into the study. All subjects will be analyzed as randomized when FAS population is used.



7.2.2 Per Protocol Set (PPS)

The PPS is defined as the subset of the FAS that meet the following:

• Subjects who did not have any major protocol deviations.• Subjects who have initiated at least one dose of assigned study drug.

7.2.3 Safety Analysis Set (SAF)

The SAF is defined as all subjects who have initiated at least 1 dose of study drug. All subjects will be analyzed as treated when SAF population is used.

7.3 Demographics and Other Baseline Characteristics7.3.1 Demographics

Demographic information will be summarized using descriptive statistics by treatment arm and stratum.


A detailed medical history for each subject will be obtained during Screening and will be summarized by treatment arm and stratum.

7.3.3 Diagnosis of the Target Disease, Severity and Duration of Disease

Each subject’s complete cancer history will be collected during the Screening period prior to randomization. The number and percentage of subjects will be used to summarize the type of cancer, disease status, incidence of metastases and previous therapies. Descriptive statistics will be used to summarize the duration of disease.

7.4 Analysis of EfficacyProgression-free survival is the primary efficacy endpoint for the study. The overall significance level for the study is 0.05 (two-sided) and will be allocated to the interim and the final analyses.

7.4.1 Analysis of Primary Variable

The duration of progression-free survival (PFS) will be calculated from the date of randomization to the date of first objective evidence of radiographic disease progression, skeletal-related event, initiation of new anti-neoplastic therapy, or death by any cause, whichever occurs first. Conventions for censoring will be described in the statistical analysis plan.

Radiographic disease progression is defined by RECIST 1.1 for soft tissue disease or by appearance of two or more new lesions on bone scan (PCWG2). The radiological assessment by the Independent Central Review will be used as a primary data source to conduct the analysis.



However, the radiological assessment by the investigator will also be used. The number of concordant and discordant cases will be summarized.

Skeletal-related events include radiotherapy to the bone, surgery to the bone, pathological bone fracture, spinal cord compression, or change of anti-neoplastic therapy to treat bone pain.

The effect of MDV3100 compared to bicalutamide based on PFS will be tested with log-rank test at the overall significance level of 0.05 (two-sided). One interim analysis of PFS will be conducted by an independent statistician and support staff as soon as possible after 129 progression events (50% of the total number of events required for final analysis) have occurred.A final analysis of PFS will be conducted after 257 progression events have occurred.

The benefit of MDV3100 compared to bicalutamide will be evaluated by a single hazard ratio with its 95% confidence interval based on Cox regression model. Kaplan-Meier curves will be used to estimate the distribution of duration of progression-free survival. Median duration of progression-free survival will be estimated using the corresponding 50th percentile of Kaplan-Meier estimates. A two-sided 95% confidence interval will be provided for this estimate. Primary efficacy analysis will be repeated with stratum as a factor in the analyses.

Subgroup analyses of PFS will be performed to determine whether the treatment effect is concordant among subgroups. The following variables will be used to conduct subgroup analyses:

• Age category (< 65, 65-75, and > 75);• Geographic region;• ECOG Performance Status (0 versus 1) at baseline;• Gleason score (Low (2-4), Medium (5-7), and High (8-10)) at baseline;• Disease localization (Bone only versus Soft tissue only versus Both bone and soft tissue)

at baseline;• Baseline PSA value (at or below median versus above median);• Diagnosis of metastases occurring before or after medical (LHRH agonist/antagonist

therapy) or surgical castration (bilateral orchiectomy).

7.4.2 Analysis of Secondary Variables

All secondary efficacy endpoints will be tested at the significance level of 0.05 (two-sided). No adjustment will be made for the multiple comparisons.

7.4.2.1 PSA Response

As defined by PCWG2, the percentage of change of PSA from baseline to week 13, (or earlier for those that discontinue therapy), as well as the maximum decline in PSA that occurs at any point after treatment will be reported using a waterfall plot for each treatment group.

7.4.2.2 Time to PSA Progression

As defined by PCWG2: PSA progression is defined as a ≥ 25% increase and an absolute increase of ≥ 2 ug/L (2 ng/mL) above the nadir (or baseline value for subject who did not have a decline



in PSA value at week 13), this increase must be confirmed by a second consecutive assessment conducted at least 3 weeks later.

Time to PSA progression will be calculated from the date of randomization to the date of first observation of PSA progression. Conventions for censoring will be described in the statistical analysis plan.

The effect of MDV3100 compared to bicalutamide based on time to PSA progression will be tested with log-rank test at the significance level of 0.05 (two-sided).

The benefit of MDV3100 compared to bicalutamide will be evaluated by a single hazard ratio with its 95% confidence interval based on Cox regression model. Kaplan-Meier curves will be used to estimate the distribution of time to PSA progression. Median time to PSA progressionwill be estimated using the corresponding 50th percentile of Kaplan-Meier estimates. A two-sided 95% confidence interval will be provided for this estimate.

7.4.3 Analysis of Other Variables

7.4.3.1 FACT-P

The FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer patients. It consists of 27 core items which assess patient function in four domains: physical, social/family, emotional, and functional well-being, which is further supplemented by a 12-item prostate cancer subscale. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as a global quality of life score with higher scores representing better quality of life.

Appropriate FACT-P subscale scores, global score, and their change from baseline will be summarized by treatment arm and by visit.

7.4.3.2 EQ-5D

The EQ-5D is a standardized instrument for use as a measure of health outcome. Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression are each assessed on 3-point categorical scales ranging from “no problem” to “severe problem.”

EQ-5D domain score and global score will be summarized by treatment arm and by visit.

7.4.3.3 BPI

The BPI questionnaire is a validated instrument that is a patient self-rated scale assessing level of pain, effect of the pain on activities of daily living, and analgesic use. The short form of the BPI is used in this study and contains nine questions. The BPI uses simple numeric rating scales from 0 to10. Pain assessment by the BPI will be summarized bytreatment arm and by visit.



7.4.3.4 CTC Conversion Rate

For subjects with baseline CTC counts ≤ 5 cells per 7.5 ml of blood, a conversion is defined as an increase in the CTC count to > 5 cells per 7.5 ml of blood. The rates between MDV3100-treated and bicalutamide groups will be compared using a two-sided chi-square test.

7.4.3.5 Gene Fusion Analysis

Gene fusions will be summarized by treatment.

If appropriate, further analyses investigating associations between exploratory variables and efficacy endpoints will be performed.

7.5 Analysis of SafetySafety analyses will be conducted using the SAF and summarized by treatment arm as treated.

Baseline laboratory results will be summarized using descriptive statistics by treatment arm. Worst toxicity grades per subject will be tabulated for selected adverse events and laboratory analytes. Clinical safety data (including adverse events, grade 3 and 4 hematologic and non-hematologic events, clinical laboratory evaluations, vital signs, ECGs, and physical examinations) will be summarized by treatment arm using descriptive statistics or frequency distributions, as appropriate.


Treatment-emergent adverse events will be presented within each system organ class by preferred term, by relationship to study drug and by severity (NCI-CTCAE grade). Adverse events leading to permanent discontinuation of study drug, SAEs, and SAEs by NCI-CTCAE grade will be summarized. Adverse events will also be summarized by NCI-CTCAE grade and relationship to study drug jointly.

Adverse events will be tabulated presenting the system organ classes alphabetically and within each system organ class; the preferred term will be presented alphabetically as well.

Adverse events will be coded to system organ class and preferred term using the Medical Dictionary for Regulatory Authorities (MedDRA) and graded using NCI-CTCAE. Listings of deaths, SAEs, and withdrawals due to adverse events will be presented.

7.5.2 Clinical Laboratory Evaluations

Clinical laboratory evaluations (including hematology and serum chemistry) will be presented for each visit using descriptive statistics (n, mean, standard deviation [SD], median, minimum and maximum values). Change from baseline will also be presented. Shift analysis tables will present shift from baseline for these same days using the NCI-CTCAE grade and lab reference range indicator. All clinically significant abnormal laboratory values will be recorded as adverse



events and graded using NCI-CTCAE guidelines. A listing of subject laboratory values will be provided.


All clinically significant abnormal findings will be recorded as medical history or adverse events.Adverse events will be graded using NCI-CTCAE guidelines.

7.5.4 Vital Signs

Descriptive statistics (n, mean, median, standard deviation [SD], minimum, and maximum) will be presented for each vital signs measurement at each time point. Change from baseline will also be summarized.


Overall ECG interpretation will be summarized for each time point. A shift analysis table showing shifts from baseline in overall ECG (normal, abnormal not clinically significant, and abnormal clinically significant) will be provided.

7.5.6 Concomitant Medications

The frequency of concomitant medications (prescription, over-the-counter, and nutritional supplements) will be summarized by preferred term. Medications will be coded using the World Health Organization (WHO) drug dictionary.

7.5.7 Extent of Exposure

Duration of treatment and total dose administered will be summarized separately for each treatment group. In addition, the number and proportion of subjects with dose reduction will be tabulated for each test article by treatment arm.

7.6 Analysis of PharmacokineticsNot applicable.

7.7 Other AnalysesIf appropriate, further analyses investigating associations between exploratory variables and efficacy endpoints will be explored.



7.8 Interim Analysis (and Early Discontinuation of the Clinical Study)A formal interim analysis on PFS will be performed after 129 progression events (50% of the total number of events required for final analysis) have occurred.

Two-stage group sequential design with Lan and DeMets alpha-spending function that resembles O’Brien-Fleming’s boundary will be used to control overall significance level at 0.05. The nominal alpha levels to reject the null hypothesis at the interim and final analysis of PFS are 0.0031 and 0.049, respectively and were determined using the interim monitoring tool of East 5.2 (Cytel Software Corp., Cambridge, MA). If the p-value at the interim analysis from the log-rank test is less than 0.0031, the Data Monitoring Committee may recommend stopping the study.

In addition to PFS, PSA response and time to PSA progression will be analyzed at the time of the interim analysis. There is no plan to adjust the significance level for any efficacy analysis with the exception of PFS since the decision whether to stop the trial at the interim analysis is based upon the results of PFS only.

7.9 Handling of Missing Data, Outliers, Visit Windows, and Other Information

7.9.1 Missing Data

No imputation of data will be done to determine individual subject response.For continuous variables (e.g., clinical laboratory measurement, vital signs), subjects with missing baseline variable will be excluded from the analysis of change from baseline.

Missing end of treatment information will be imputed by last observation carried forward. Visit-by-visit analyses of data will exclude subjects who did not provide data at the visit in question.

Missing ECOG performance status at end of study will be imputed by last observation carried forward, unless the subject is known to have died. For visit-by-visit summary of ECOG, no imputation will be made.

7.9.2 Visit Windows

Visit windows are allowed for certain visits per the schedule of procedures. Subject data will not be excluded from analyses due to the subject’s failure to comply with the visit schedule.

8 OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS8.1 Procedure for Clinical Study Quality Control8.1.1 Data Collection

The investigator or site designee is responsible to ensure that all data in the eCRFs and queries are accurate and complete and that all entries are verifiable with source documents. These documents should be appropriately maintained by the site.



The investigator or designee will enter data collected using an Electronic Data Capture (EDC) system.

The monitor should verify the data in the eCRFs with source documents and confirm that there are no inconsistencies between them.

For screening failures, the minimum demographic data (sex, age, race and screening date) and reason for screening failure will be collected in screening failure log (SFL), if applicable. This information can be entered into the study database.

Laboratory tests are performed at the institution’s local lab.

8.1.2 Specification of Source Documents

Source data must be available at the site to document the existence of the study subjects and substantiate the integrity of study data collected. Unless specified otherwise, source data must include the original documents relating to the study, as well as the medical treatment and medical history of the subject.

The following information should be included (but is not limited to) in the source medical records:

• Demographic data (age, sex, race, ethnicity, weight and height)• Records to support Inclusion and Exclusion criteria details• Participation in study and sub-study and signed and dated informed consent forms• Visit dates• Disease and prior treatment history. Photocopies or fax documents of original records are

acceptable if obtained from an outside institution.• Medical history• Physical examination details• Key efficacy and safety data as specified in the protocol• Adverse events and concomitant medication• Results of protocol specified evaluations (laboratory, ECG, and MRI or CT scans and

reports with notation of significance).• Dispensing, destruction, and return of study drug details• Reason for discontinuation• Randomization number• Staff notes and phone records • Medical records from other departments or hospitals, including discharge summaries,

correspondence, etc., at which the subject received treatment. Photocopies or fax documents of original records are acceptable if obtained from an outside institution

8.1.3 Clinical Study Monitoring

The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that subject's human rights, safety, and well-being are protected, that the study is properly conducted in adherence to the current protocol and GCP, and study data reported by the investigator/sub-



investigator are accurate and complete and that they are verifiable with study-related records such as source documents. The sponsor is responsible for assigning study monitor(s) to this study for proper monitoring. They will monitor the study in accordance with planned monitoring procedures.

8.1.4 Direct Access to Source Data/Documents

The investigator and the study site must accept monitoring and auditing by the sponsor or delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. In these instances, they must provide all study-related records, such as source documents (refer toSection 8.1.2 "Specification of Source Documents") when they are requested by the sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of the subject's identities shall be well protected consistent with local and national regulations when the source documents are subject to direct access.

8.1.5 Data Management

Data management will be overseen by the responsible department at the sponsor in accordance with the standard operating procedures for data management. All study specific processes and definitions will be documented by Data Management. CRF retrieval and correction process will be referenced in the CRF instructions. Coding of medical terms will be performed using MedDRA.

The study database will be soft-locked when all data that are specified in the study protocol to be collected have been received and cleaned according to applicable SOPs. It will be hard-locked when a data review meeting has been held, and all data related decisions have been made and reflected in the database.

8.2 Ethics and Protection of Subject Confidentiality8.2.1 Institutional Review Board/ Independent Ethics Committee

The clinical study may begin after acquisition of a written approval from the Institutional Review Board/Independent Ethics Committee of record for that site and study.

The investigator shall make accurate and adequate written progress reports to the IRB at appropriate intervals, not exceeding one year. The investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days after the close-out visit.

8.2.2 Ethical Conduct of the Study

The investigator(s) and all parties involved in this study should conduct the study in adherence to GCP, ICH Guidelines and the applicable laws and regulations.



8.2.3 Informed Consent of Subjects

8.2.3.1 Subject Information and Consent

Prior to execution of the clinical study, the investigator should prepare the written informed consent form and other written information in collaboration with the sponsor and revise the information whenever necessary. The written informed consent form and any other written information should be submitted to the sponsor and be subject to prior approval by the Institutional Review Board/Independent Ethics Committee.

• The investigator/sub-investigator is responsible for explaining the nature and purpose of the study as well as other study-related matters to subjects, using the written information, and for obtaining their full understanding and written consent to participate in the study of their own free will.

• The investigator or other responsible personnel who provided explanations (including collaborators who gave supportive information, if applicable) and the subject should sign and date the written information, or write down his/her name, and date the form.

• Informed consent must be obtained by the time that the first observations / examinations of the pre-investigational period are performed.

• The investigator or other responsible personnel must give a copy of the signed consent form to the subject and store the original appropriately in accordance with the rules at the study site concerned.

• The investigator or other responsible personnel should note the following when obtaining consent from subjects:・ No subject may be subjected to undue influence, such as compulsory enrollment into

a study.・ The language and expressions used in the written information should be as plain and

understandable as possible. Subjects should be given the opportunity to ask questions and receive satisfactory answers to the inquiry, and should have adequate time to decide whether or not to participate in the study. Written information should not contain any language or contents that causes the subject to waive or appears to waive any legal rights, or that releases/mitigates or appears to release/mitigate the study site, the investigator/sub-investigator, collaborators, or the sponsor from liability for negligence.

The signed consent forms will be retained by the investigator and made available (for review only) to the study monitor and auditor upon request.

8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent and Revision of the Written Information

1. The investigator/sub-investigator will immediately inform the subject orally whenever new information becomes available that may be relevant to the subject's consent or may influence the subject's willingness to continue participation in the study (e.g., report of serious adverse drug reactions). The communication should be documented in the subject's medical records, and it should be confirmed whether the subject is willing to remain in the study or not.



2. If the investigator recognizes the necessity to revise the written information in the terms and conditions applicable to paragraph 1, the written information should be revised immediately based upon the newly available information, and be re-approved by the IRB/IEC.

3. The investigator/sub-investigator should obtain written informed consent to continue participation with the revised written information defined in paragraph 2, even if subjects are already informed of the relevant information orally. The investigator or other responsible personnel who provided explanations (including collaborators who gave supportive information, if applicable) and the subject should sign and date the informed consent form, or write down his/her name and date the form. The investigator or other responsible personnel should give a copy of the signed informed consent form to the subject who had given consent with the written information and store the original appropriately as done for the previousinformed consent.

8.2.4 Subject ConfidentialityIndividual subject medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited. Such medical information may be given only after approval of the subject to the subject's physician or to other appropriate medical personnel responsible for the subject's well-being.The sponsor shall not disclose any confidential information on subjects obtained during the performance of their duties in the clinical study without justifiable reasons.The sponsor affirms the subject's right to protection against invasion of privacy. Only a subject identification number and/or initials will identify subject data retrieved by the sponsor. However, the sponsor requires the investigator to permit the sponsor, sponsor's representative(s), the IRB/IEC and when necessary, representatives of the regulatory health authorities to review and/or to copy any medical records relevant to the study.The sponsor will ensure that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal and/or regional legislation related to the privacy and protection of personal information (i.e. HIPAA).For US sites, the HIPAA Privacy Rule provides federal protection for the privacy of PHI by implementing standards to protect and guard against the misuse of individually identifiable health information of subjects participating in sponsored clinical trials. "Authorization" is required from each research subject, i.e. specific permission granted by an individual to a covered entity for the use or disclosure of an individual's PHI. A valid authorization must meet the implementation specifications under the HIPAA Privacy Rule. Authorization may be combined into the Informed Consent document (approved by the IRB/IEC) or it may be a separate document (approved by the IRB/IEC or designed PB) or provided by the investigator or sponsor (without IRB/IEC or PB approval). It is the responsibility of the investigator and institution to obtain such waiver/authorization in writing from the appropriate individual.



8.3 Administrative Matters8.3.1 Arrangement for Use of Information and Publication of the Clinical StudyInformation concerning the study drug, patent applications, processes, unpublished scientific data, the Investigator's Brochure and other pertinent information is confidential and remains the property of the sponsor. Details should be disclosed only to the persons involved in the approval or conduct of the study. The investigator may use this information for the purpose of the study only. It is understood by the investigator that the sponsor will use the information obtained during the clinical study in connection with the development of the drug and therefore may disclose it as required to other clinical investigators or to regulatory agencies. In order to allow for the use of the information derived from this clinical study, the investigator understands that he/she has an obligation to provide the sponsor with all data obtained during the study.The study will be considered for publication or presentation at (scientific) symposia and congresses. The investigator will be entitled to publish or disclose the data generated at theirrespective study site only after allowing the sponsor to review all transcripts, texts of presentations, and abstracts related to the study at least 30 days prior for APGD-US-sponsored studies. This is necessary to prevent premature disclosure of trade secrets or patent-protected information and is in no way intended to restrict publication of facts or opinions formulated by the investigator. The sponsor will inform the investigator in writing of any objection or question arising within 30 days of receipt of the proposed publication material.

8.3.2 Documents and Records Related to the Clinical StudyThe sponsor will provide the investigator and/or institution with the following:• Study protocol (and amendments, as applicable)• Investigator’s Brochure (and amendments, as applicable)• CRFs and SAE Report Worksheet• Study drug with all necessary documentation• Study contractIn order to start the study, the investigator and/or study site is required to provide the following documentation to the sponsor: • Financial disclosure in compliance with federal regulation 21CFR Part 54• Signed Investigator's Statement in this protocol• Executed Research Agreement• Signed and dated FDA form 1572• Copy of the approved ICF and separate authorization form, if appropriate.• Independent Ethics Committee/IRB approval of the protocol, protocol amendments

(if applicable) and ICF (and separate authorization form, if appropriate), stating clearly the sponsor's name, study number and study drug, including a membership list with names and qualifications.

• Current Curricula Vitae of all investigators (signed and dated)• Laboratory normal reference ranges (if applicable, signed and dated by the

responsible laboratory employee)



• Medical/Laboratory/Technical procedures/tests certifications or accreditations or established quality control or other validation, where required.

At the end of the study, the sponsor is responsible for the collection of:• Unused CRFs and other study documentation,• Unused study drugThe investigator will archive all study data (e.g., Subject Identification Code List, source data, CRFs, and Investigator's File) and relevant correspondence. These documents are to be kept on file for the appropriate term determined by local regulation (for US sites, two years after approval of the NDA or discontinuation of the IND). It is recommended, however, that records be retained for at least five years in the event follow-up is necessary to help determine any potential hazards to subjects who took part in the study. The sponsor will notify the investigator if the NDA is approved or if the IND is discontinued. The investigator agrees to obtain the sponsor's agreement prior to disposal, moving, or transferring of any study-related records. The sponsor will archive and retain all documents pertaining to the study according to local regulations. Data generated by the methods described in the protocol will be recorded in the subjects' medical records and/or study progress notes. All data will be entered on CRFs supplied for each subject. The investigator and sponsor will mutually agree upon the storage format for the retention of electronic data.

8.3.3 Protocol Amendment and/or RevisionAny changes to the study that arise after approval of the protocol must be documented as protocol amendments/substantial amendments and/or administrative changes/non-substantial amendments. Depending on the nature of the amendment and/or administrative change, either IRB/IEC approval or notification is required. The changes will become effective only after the approval of the sponsor, the investigator, the regulatory authority, and the IRB/IEC (if applicable).Amendments to this protocol must be agreed upon in writing between the Investigator and the Sponsor. Written verification of IRB/IEC approval will be obtained before any amendment is implemented which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the protocol that are administrative in nature do not require IRB/IEC approval, but will be submitted to the IRB/IEC for their information.If there are changes to the Informed Consent, written verification of IRB/IEC approval must be forwarded to the Sponsor. An approved copy of the new Informed Consent must also be forwarded to the Sponsor.

8.3.4 Signatory Investigator for Clinical Study ReportICH E3 guidelines recommend and EMEA Directive 2001/83/EC requires that a final study report which forms part of a marketing authorization application be signed by a Coordinating (principal) Investigator. The Coordinating Investigator will have the responsibility to review the



final study results to confirm to the best of his/her knowledge it accurately describes the conduct and results of the study. A Coordinating Investigator will be selected from the participating investigators by Astellas prior to database lock.

9 QUALITY ASSURANCEThe sponsor is implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (record), and reported in compliance with the protocol, GCP, and applicable regulatory requirement(s).The Sponsor or Sponsor's designee may arrange to inspect/audit the clinical study at any or all investigational sites. The auditor is independent from the clinical monitoring and project management team at the Sponsor. The audit may include on-site review of regulatory documents, case report forms, and source documents. Direct access to these documents will be required by the auditors.

10 STUDY ORGANIZATION

10.1 Data Monitoring Committee A data monitoring committee will be charged with reviewing the safety data as well as the efficacy data from the interim analysis. A separate charter will describe the activities of this committee.

10.2 Other Evaluation Committee(s)Not applicable.

10.3 Other Study OrganizationNot applicable.



11 REFERENCES

Bicalutimide [Package Insert]. Princeton, NJ: Zydus Pharmaceuticals USA, Inc.; 2009.

Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10(1):33-9.

Dilts DM, Sandler AB, Cheng SK, et al. Steps and time to process clinical trials at the Cancer Therapy Evaluation Program. J Clin Oncol 2009; 27(11):1761-6.

Fujii Y, Kawakami S, Masuda H, et al. Deferred combined androgen blockade therapy using bicalutamide in patients with hormone-refractory prostate cancer during androgen deprivation monotherapy. BJU Int 2006; 97(6):1184-9.

Joyce R, Fenton MA, Rode P, et al. High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 1998; 159(1):149-53.

Kojima S, Suzuki H, Akakura K, Shimbo M, Ichikawa T, Ito H. Alternative antiandrogens to treat prostate cancer relapse after initial hormone therapy. J Urol 2004; 171(2 Pt 1):679-83.

Kucuk O, Fisher E, Moinpour CM et al. Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: A Southwest Oncology Group study (SWOG 9235). Urol 2001;58(1):53-8.

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6):649-55.7.

Scher HI, Liebertz C, Kelly WK, et al. Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol 1997; 15(8):2928-38.

Singer EA, Golijanin DJ, Miyamoto H, Messing EM. Androgen deprivation therapy for prostate cancer. Expert Opin Pharmacother 2008; 9(2):211-28.

Tran C, Ouk S, Clegg NJ et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324(5928): 787-790.

Company Reports

Investigator’s Brochure. MDV3100 for the treatment of prostate cancer. 4th edition. Medivation, Inc., 18 Jun 2010.

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Joyce%20R%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Fenton%20MA%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Rode%20P%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed/14713785

http://www.ncbi.nlm.nih.gov/pubmed/14713785



12 APPENDICES12.1 Appendix 1: Laboratory Tests

Visit Collecting Tube Parameters to be Analyzed

Hematology All visits EDTA tube HemoglobinHematocritErythrocytes (RBC)Leukocytes (WBC) Differential WBCPlatelets

Chemistry All visits Serum tube SodiumPotassiumCalciumChlorideMagnesiumPhosphorusGlucoseCreatinineAlkaline phosphataseBone alkaline phosphataseLDHASTALTGGTTotal bilirubinTotal proteinAlbuminCO2BUN

PSA Screening, Week 1,13, 25 and every 12 weeks on treatment, Safety follow-up, 60 day visit,and Long Term follow-up

Serum tube PSA

CTC enumeration Screening, Week 1, 13, 25 and every 12 weekswhile on treatment.

Whole blood CellSave tube

CTC

Blood sample for optional genotype analysis

Week 1 EDTA tube Genotype analysis (separate subject consent required)

Urine sample for gene fusion analysis

Week 1 Specimen cup Gene fusion analysis

Blood sample for gene fusion analysis

Week 1 Serum tube Gene fusion analysis

Blood sample for PK analysis

Week 13 and 21 Serum tube PK analysis



12.2 Appendix 2: Events Always Considered To Be SeriousIf any of the following adverse events occur during the study, they should be considered as serious adverse events and reported as described in Section 5.5.

• acute liver failure• acute renal failure• acute respiratory failure• agranulocytosis• anaphylaxis• any malignancy• aplastic anemia• confirmed or suspected endotoxin shock• confirmed or suspected transmission of infectious agent by marketed product• congenital anomalies• liver necrosis• malignant hypertension• pulmonary fibrosis• pulmonary hypertension• sclerosing syndromes• seizure (only central neurological seizure)• torsades de pointe• toxic epidermal necrolysis• ventricular fibrillation



12.3 Appendix 3: Elements of Informed Consent

A. Basic elements of informed consent. In seeking informed consent, the following information shall be provided to each subject:

1. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental.

2. A description of any reasonable foreseeable risks or discomforts to the subject.

3. A description of any benefits to the subject or to others which may reasonably be expected from the research.

4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.

5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the FDA may inspect the records. Note: If subject data will be transmitted via electronic data capture, it is recommended that the informed consent include a statement noting that data collection may be done using a validated electronic data capture system.

6. For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.

7. An explanation of whom to contact for answers to pertinent questions about the research and research subject's rights, and whom to contact in the event of a research-related injury to the subject.

8. A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subjects is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subjects is otherwise entitled.

B. Additional elements of informed consent. When appropriate, one or more of the following elements of information shall also be provided to each subject:

1. A statement that the particular treatment or procedure may involve risks to the subject (or to an embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable.

2. Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent.

3. Any additional costs to the subject that may result from participation in the research.



4. The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject.

5. A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject.

6. The approximate number of subjects involved in the study.



12.4 Appendix 4: Elements of HIPPA Authorization (U.S. Sites Only)

1. Written in plain language, understandable to the subject or the representative;2. A 'specific and meaningful' description of Protected Health Information (PHI) to be used

and disclosed;

3. The specific identification of the person/class authorized to make the use or disclosure;

4. The specific identification of the person/class to whom the covered entity may make the requested use or disclosure;

5. Description of the purpose of the disclosure;

6. An expiration date or event (e.g., "no expiration date" for data repository use, or "for the duration of a specific research study" permits use until end of study plus time for wrap-up and reporting);

7. A statement of the subject's right to revoke the authorization and any exceptions to the right to revoke;

8. Conditions, if any, on authorization;

9. A statement about possible re-disclosures of PHI by the recipient and that the PHI will no longer be protected by the Privacy Rule in the event of such re-disclosures; and

10. The signature and date of the subject (or the subject's personal representative), along with the personal representative's authority to act.



12.5 Appendix 5: European Quality of Life 5-Domain Scale

By placing a checkmark in one box in each group below, please indicate which statements best describe your own health state today.

Mobility

I have no problems in walking about q

I have some problems in walking about q

I am confined to bed q

Self-Care

I have no problems with self-care q

I have some problems washing or dressing myself q

I am unable to wash or dress myself q

Usual Activities (e.g. work, study, housework, family or leisure activities)

I have no problems with performing my usual activities q

I have some problems with performing my usual activities q

I am unable to perform my usual activities q

Pain/Discomfort

I have no pain or discomfort q

I have moderate pain or discomfort q

I have extreme pain or discomfort q

Anxiety/Depression

I am not anxious or depressed q

I am moderately anxious or depressed q

I am extremely anxious or depressed q



To help people say how good or bad a health state is, we have drawn a scale (rather like a thermometer) on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0.

We would like you to indicate on this scale how good or bad your own health is today, in your opinion. Please do this by drawing a line from the box below to whichever point on the scale indicates how good or bad your health state is today.

© 1990 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group

Your ownhealth state

today

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

100

Worstimaginablehealth state

0

Best imaginablehealth state



12.6 Appendix 6: Soft Tissue Assessment (RECIST 1.1)

Reproduced from: Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247.9



12.7 Appendix 7: BPI-SF



12.8 Appendix 8: Functional Assessment of Cancer Therapy – Prostate



12.9 Appendix 9: Optional Pharmacogenomic Sub-study

INTRODUCTIONPharmacogenomics research aims to provide medical information regarding how variations in a subject’s gene function and/or expression based on their genetic polymorphism may impact what treatment options are best suited for that subject. Through investigation of pharmacogenomics via such technologies as gene sequencing, statistical genetics and gene expression analysis, the relationship between gene profiles and a drug’s efficacy or toxicity may be better understood. Because many diseases may develop as a result of one or more genetic mutations, pharmaco-genomics research may identify the genes that are involved in determining whether a subject may or may not respond to a drug.

STUDY OBJECTIVESThe pharmacogenomic research that will be conducted in the future with acquired blood samples is exploratory. The objective of this research is to comprehensively analyze:

• Suspected disease-related genes;

• Genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues, to be identified in a precautionary/retrospective setting.

By analyzing differing genetic polymorphisms, it may be possible to predict genetic effect on an individual subject’s response to MDV3100.

STUDY POPULATIONSubjects who have consented to participate in the 9785-CL-0222 study may also participate in this optional sub-study. As part of this sub-study, subjects must provide separate written consent prior to providing any blood samples that will be used at a later time for the genetic analysis.

SITE SAMPLE COLLECTION

Subjects who consent to participate in this sub-study will provide one 5 mL sample of whole blood on visit Day 1 per vendor preparation instructions. Each sample will be identified with a unique subject identifier. Sample will be shipped to a Sponsor designated central laboratory. Samples will be anonymized prior to analysis.

CENTRAL LABORATORY AND PHARMACOGENOMIC RESEARCH LABORATORY PROCESSING AND STORAGE / SAMPLE ANONYMIZATIONUpon receipt, the central laboratory will identify each sample by subject number and initials utilizing the shipment documents accompanying each sample. Samples will be stored frozenuntil prompted by Astellas. When prompted, the central laboratory will ship the samples to a separate laboratory for prolonged storage.

When samples are shipped from the central laboratory to the prolonged storage laboratory, they will be identified solely by subject number. Once received at the prolonged storage laboratory, the samples will be assigned a unique sample code and stored frozen. A table linking the subject



number with newly-assigned sample code will be provided to the Astellas’ code administrator. Once the table is provided to Astellas and receipt acknowledged, the link between the subject number and sample code held at the prolonged storage laboratory will be broken.

ASSOCIATING CLINICAL DATA WITH SAMPLE CODESBefore the pharmacogenomics research begins, the Astellas’ code administrator will provide Astellas with the linkage table. Astellas will associate clinical data related to finding with each subject number and corresponding sample code. The clinical data with the corresponding sample codes (without associated subject numbers) will be provided to the Astellas Research Laboratory, who will be responsible for the genetic analysis. After which, the original linkage table and any copies containing the subject number and sample code provided to Astellas will be destroyed by Astellas. No pharmacogenomics data will be traceable back to the original subject number.

PHARMACOGENOMIC ANALYSISThe detailed content of the pharmacogenomic analysis has not been determined. Astellas will initiate the pharmacogenomic research after the targeted genes have been identified.

In the event of unusual PK/PD patterns or safety findings, genotype analysis or relevant metabolism, transporter, pharmacodynamic and/or safety genes will be conducted. If there is not requirement for analysis, the whole blood sample will be destroyed.

DISPOSAL OF PHARMACOGENOMIC SAMPLES/DATAAll collected pharmacogenomic samples will be maintained for a period of up to 15 years following database hardlock. In addition, the Astellas Research Laboratory will retain all raw data and records pertaining to the study for the period of at least 15 years or unless otherwise notified by the Sponsor. At the conclusion of the retention period, Astellas will instruct the central or pharmacogenomics research laboratory to destroy all remaining samples, data and records.

SUBJECT INFORMED CONSENTThis pharmacogenomic sub-study is independent of the clinical study. Each subject participating in the clinical study may choose whether or not to consent to provide pharmaco-genomic blood samples. Refusal to consent to the pharmacogenomic research or withdrawal of pharmaco-genomic consent will not result in any penalty in regards to participation in the clinical study or further treatment received.

Prior to providing any blood samples as part of the pharmacogenomic sub-study, separate written informed consent must be obtained. A subject has the irrevocable right to withdraw consent from solely the pharmacogenomic research at any point during or after completion of the clinical study. Once pharmacogenomic consent is withdrawn, the subject’s samples will be destroyed. However, any genetic analysis data which had been obtained from the subject’s analyzed samples at the time of withdrawal may be used after withdrawal.



INFORMATION DISCLOSURE TO THE SUBJECTSThe exploratory pharmacogenomics research will be conducted following the conclusion of the clinical study. The results of the genetic analysis will not be provided to any Investigators or subjects nor can the results of the genetic analysis be requested at a later date.

Any information that is obtained from the pharmacogenomic research in relation to the contents of the pharmacogenomic research protocol, results of the correlation between genetic data and subject response or toxicity, etc. belong to Astellas.

SITE PARTICIPATION IN THE PHARMACOGENOMICS SUB-STUDYParticipation in the pharmacogenomic sub-study at a given site is contingent on the site’s Institutional Review Board/Ethics Committee/Regulatory Authority approval and on specific local regulations when applicable. If a site’s IRB/EC/Regulatory Authority does not approve the sampling for the pharmacogenomic research, this section will not be applicable to that site.


10 Aug 2010 Astellas of 81[GPF V2.0]

13 ATTACHMENT 1: SPONSOR’S SIGNATURES

Sponsor: APGD ISN/Protocol 9785-CL-0222 EudraCT number 2010-021868-15 - CONFIDENTIAL -

28 Jul 2014 Astellas Page 1 of 115 Version 5.0, Incorporating Substantial Amendment 4

A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100 (ASP9785) vs. Bicalutamide in Castrate Men


Protocol for Phase II Study of MDV3100

ISN/Protocol 9785-CL-0222

Version 5.0

Incorporating Substantial Amendment 4 [See Attachment 1]

28 July 2014

EudraCT 2010-021868-15

IND 74,563

Sponsor:

Astellas Pharma Global Development, Inc. (APGD) Research & Development

1 Astellas Way Northbrook, IL 60062

Protocol History:

Original [10Aug2010] Incorporating Substantial Amendment 1 [07Dec2010] Incorporating Substantial Amendment 2 [16Jan2012] Incorporating Administrative Change 1 [02Aug2011] Incorporating Non-Substantial (Administrative Change) Amendment 2 [16Jan2013] Incorporating Substantial Amendment 3 [19Aug2013]

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Table of Contents

I. SIGNATURES ······················································································· 8

II. CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 10

III. LIST OF ABBREVIATIONS AND KEY TERMS ·········································· 11

IV. SYNOPSIS ··························································································· 15

V. FLOW CHART AND SCHEDULE OF ASSESSMENTS ································· 24

1 INTRODUCTION ·················································································· 27

1.1 Background ···················································································· 27

1.2 Non-clinical and Clinical Data ····························································· 28

1.2.1 Non-clinical Data ········································································· 28

1.2.2 Clinical Data ·············································································· 28

1.3 Summary of Key Safety Information for Study Drugs ······························· 31

1.3.1 MDV3100 ················································································· 31

1.3.2 Bicalutamide ·············································································· 31

1.4 Risk-Benefit Assessment····································································· 32

2 STUDY OBJECTIVE(S), DESIGN AND VARIABLES ··································· 33

2.1 Study Objectives ·············································································· 33

2.2 Study Design and Dose Rationale ························································· 33

2.2.1 Study Design ·············································································· 33

2.2.2 Dose Rationale ············································································ 35

2.3 Variables ························································································ 35

2.3.1 Primary Variable ········································································· 35

2.3.2 Secondary Variables ····································································· 35

2.3.3 Exploratory Variables ···································································· 35

2.3.3.1 T2:ERG ·············································································· 35

2.3.4 Optional Pharmacogenomics Sub-Study ·············································· 35

3 STUDY POPULATION ··········································································· 36

3.1 Selection of Study Population ······························································ 36

3.2 Inclusion Criteria ············································································· 36

3.3 Exclusion Criteria ············································································ 37

3.4 Discontinuation Criteria for Individual Subjects ······································ 38

4 STUDY DRUGS ···················································································· 40



4.1 Description of Study Drugs ································································· 40

4.1.1 Test Drug(s) ··············································································· 40

4.1.2 Comparative Drug ········································································ 40

4.2 Packaging and Labeling ····································································· 40

4.3 Study Drug Handling ········································································ 40

4.3.1 Test Drug ·················································································· 41

4.3.2 Comparative Drug ········································································ 41

4.4 Blinding ························································································· 41

4.4.1 Blinding Method ·········································································· 42

4.4.2 Confirmation of the Indistinguishability of the Study Drugs ······················· 42

4.4.3 Breaking the Treatment Code for Emergency ········································ 42

4.4.4 Breaking the Treatment Code by the Sponsor ········································ 42

4.5 Assignment and Allocation ································································· 42

5 TREATMENTS AND EVALUATION ························································ 43

5.1 Dosing and Administration of Study Drugs and Other Medications ·············· 43

5.1.1 Dose/Dose Regimen and Administration Period ····································· 43

5.1.2 Interruption and Reduction in Dose of the Study Drugs ···························· 43

5.1.3 Previous and Concomitant Medication (Drugs and Therapies) ···················· 43

5.1.3.1 Previous Medication (Drugs and Therapies) ···································· 43

5.1.3.2 Concomitant Medication (Drugs and Therapies) ······························· 43

5.1.3.3 Precautions Regarding Concomitant Medications ····························· 45

5.1.4 Treatment Compliance ··································································· 45

5.1.5 Emergency Procedures and Management of Overdose ····························· 45

5.2 Demographics and Baseline Characteristics ············································ 46

5.2.1 Demographics ············································································· 46

5.2.2 Chest X-Ray and/or Chest CT ·························································· 46

5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 46

5.2.4 Medical History ··········································································· 46

5.2.5 Performance Status ······································································· 46

Table 2: ECOG Performance Status ································································ 46

5.3 Efficacy Assessment ·········································································· 47

5.3.1 CT/MRI and Bone Scan ································································· 47

5.3.2 PSA ························································································· 48

5.4 Safety Assessment ············································································· 48



5.4.1 Vital Signs ················································································· 48

5.4.2 Adverse Events ··········································································· 48

5.4.2.1 Adverse Events of Possible Hepatic Origin ····································· 48

5.4.3 Laboratory Assessments ································································· 48

5.4.3.1 Hematology·········································································· 49

5.4.3.2 Chemistry ············································································ 49

5.4.3.3 Abnormal Liver Function Tests ·················································· 49

5.4.4 Physical Examination ···································································· 49

5.4.5 Electrocardiogram (ECG) ······························································· 49

5.5 Adverse Events and Other Safety Aspects ··············································· 50

5.5.1 Definition of Adverse Events (AEs) ··················································· 50

5.5.2 Disease Progression ······································································ 50

5.5.3 Definition of Serious Adverse Events (SAEs)········································ 50

5.5.4 Criteria for Causal Relationship to the Study Drug ·································· 51

5.5.5 Criteria for Defining the Severity of an Adverse Event ····························· 52

Table 3: Criteria for Severity of Adverse Event Terms Not Specified Within NCI-CTCAE ························································································· 52

5.5.6 Reporting of Serious Adverse Events (SAEs) ········································ 52

5.5.7 Follow-up to Adverse Events ··························································· 53

5.5.8 Procedure in Case of Pregnancy ························································ 54

5.5.9 Supply of New Information Affecting the Conduct of the Study ·················· 54

5.5.10 Monitoring of Common Serious Adverse Events ···································· 54

5.6 Test Drug Concentration ···································································· 54

5.7 Other Measurements, Assessments, or Methods ······································· 55

5.7.1 CTC Sampling ············································································ 55

5.7.2 FACT-P ···················································································· 55

5.7.3 BPI·························································································· 55

5.7.4 EQ-5D······················································································ 55

5.7.5 Tissue, Blood and Urine Sampling for Gene Fusion Analysis ····················· 56

5.7.6 Whole Blood Sample for Optional Genotype Analysis ····························· 56

5.8 Total Amount of Blood ······································································ 56

6 TERMINATION OF THE CLINICAL STUDY ············································· 56

7 STATISTICAL METHODOLOGY ···························································· 56

7.1 Sample Size ····················································································· 57

7.2 Analysis Set ···················································································· 57



7.2.1 Full Analysis Set (FAS) ································································· 57

7.2.2 Per Protocol Set (PPS) ··································································· 57

7.2.3 Safety Analysis Set (SAF) ······························································ 57

7.3 Demographics and Other Baseline Characteristics ···································· 58

7.3.1 Demographics ············································································· 58

7.3.2 Medical History ··········································································· 58

7.3.3 Diagnosis of the Target Disease, Severity and Duration of Disease ·············· 58

7.4 Analysis of Efficacy ··········································································· 58

7.4.1 Analysis of Primary Variable ··························································· 58

7.4.2 Analysis of Secondary Variables ······················································· 59

7.4.2.1 PSA Response ······································································· 59

7.4.2.2 Time to PSA Progression ·························································· 59

7.4.3 Analysis of Other Variables ····························································· 60

7.4.3.1 FACT-P ·············································································· 60

7.4.3.2 EQ-5D ················································································ 60

7.4.3.3 BPI ···················································································· 60

7.4.3.4 CTC Conversion Rate ······························································ 60

7.5 Analysis of Safety ············································································· 61

7.5.1 Adverse Events ··········································································· 61

7.5.2 Clinical Laboratory Evaluations ························································ 61

7.5.3 Physical Examination ···································································· 61

7.5.4 Vital Signs ················································································· 61

7.5.5 Electrocardiogram (ECG) ······························································· 62

7.5.6 Concomitant Medications ······························································· 62

7.5.7 Extent of Exposure ······································································· 62

7.6 Analysis of Pharmacokinetics ······························································ 62

7.7 Protocol Deviations and Other Analyses ················································· 62

7.8 Interim Analysis (and Early Discontinuation of the Clinical Study) ··············· 62

7.9 Handling of Missing Data, Outliers, Visit Windows, and Other Information ··· 63

7.9.1 Missing Data ·············································································· 63

7.9.2 Visit Windows ············································································ 63

8 OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ···················· 63

8.1 Procedure for Clinical Study Quality Control ·········································· 63

8.1.1 Data Collection ··········································································· 63



8.1.2 Specification of Source Documents ···················································· 63

8.1.3 Clinical Study Monitoring ······························································ 64

8.1.4 Direct Access to Source Data/Documents ············································ 64

8.1.5 Data Management ········································································ 64

8.1.6 Protocol Deviations ······································································ 65

8.1.7 End of Trial in All Participating Countries ··········································· 65

8.2 Ethics and Protection of Subject Confidentiality ······································ 65

8.2.1 Institutional Review Board/ Independent Ethics Committee /Competent Authorities ················································································· 65

8.2.2 Ethical Conduct of the Study ··························································· 66

8.2.3 Informed Consent of Subjects ·························································· 66

8.2.3.1 Subject Information and Consent ················································· 66

8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent and Revision of the Written Information ····························· 67

8.2.4 Subject Confidentiality ·································································· 67

8.3 Administrative Matters ······································································ 68

8.3.1 Arrangement for Use of Information and Publication of the Clinical Study ····· 68

8.3.2 Documents and Records Related to the Clinical Study ····························· 68

8.3.3 Protocol Amendment and/or Revision ················································· 69

8.3.4 Signatory Investigator for Clinical Study Report ···································· 70

9 QUALITY ASSURANCE ········································································· 70

10 STUDY ORGANIZATION ······································································· 70

10.1 Data Monitoring Committee ······························································· 70

10.2 Other Evaluation Committee(s) ··························································· 70

10.3 Other Study Organization ·································································· 70

11 REFERENCES ······················································································ 71

12 APPENDICES ······················································································· 72

12.1 Appendix 1: Laboratory Tests ···························································· 72

12.2 Appendix 2: European Quality of Life 5-Domain Scale ······························ 73

12.3 Appendix 3: Soft Tissue Assessment (RECIST 1.1) ··································· 75

12.4 Appendix 4: BPI-SF ········································································· 77

12.5 Appendix 5: Functional Assessment of Cancer Therapy – Prostate ··············· 81

12.6 Appendix 6: Optional Pharmacogenomic Sub-study ································· 87

12.7 Appendix 7: Liver Safety Monitoring and Assessment ······························ 90



12.8 Appendix 8: Common Serious Adverse Events ········································ 92

12.9 Appendix 9: Open-Label Period ·························································· 93

13 ATTACHMENT 1: SUBSTANTIAL AMENDMENT 4 ································· 100

14 SPONSOR’S SIGNATURES ··································································· 115



I. SIGNATURES 1. SPONSOR’S SIGNATURE

Required signatures (e.g. Protocol authors, sponsor’s reviewers and contributors) are located in Section 14, Sponsor’s Signatures; e-signatures (when applicable) are located at the end of this document.



2. INVESTIGATOR’S SIGNATURE

A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100 (ASP9785) vs. Bicalutamide in Castrate Men with Metastatic Prostate Cancer

ISN/Protocol 9785-CL-0222 / Version 5.0

Incorporating Substantial Amendment 4 / 28 July 2014

I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree to conduct the study as outlined in the protocol and to comply with all the terms and conditions set out therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines. I will also ensure that sub-investigator(s) and other relevant members of my staff have access to copies of this protocol and the ICH GCP guidelines to enable them to work in accordance with the provisions of these documents.

Principal Investigator: Signature:

Printed Name:

Date (DD Mmm YYYY)

Address:



II. CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 24h-Contact for Serious Adverse Events (SAEs) See Section 5.5.6

North America

Robert Hall, MD ICON Clinical Research Inc. Direct telephone: 215-616-3101 After hours telephone: 1-888-723-9952

Europe

Vikram Bohra, MD ICON Clinical Research (UK) Ltd Direct telephone: +44 (0) 2380 688 735 After hours telephone: 0049 51116 33167

+44 (0) 2380-688500

Please fax the SAE Worksheet to:

Astellas Pharma Global Development Inc. Product Safety and Pharmacovigilance Email: [email protected] Fax Number: 847-317-1241 International Fax Number: +44 800 471 5263

Clinical Research Contacts: Kenya Barber Clinical Study Manager, Global Clinical Science Office: 224-205-5268 Email: [email protected]

Medical Monitors North America

Robert Hall, MD ICON Clinical Research Inc. 212 Church Road North Wales, PA 19454 Direct telephone: 215-616-3101 After hours telephone: 1-888-723-9952 Email: [email protected]

Europe

Vikram Bohra, MD ICON Clinical Research (UK) Ltd 6 Stoneycroft Rise Chandlers Ford, Eastleigh Hampshire UK SO53 3LD Direct telephone: +44 (0) 2380 688 735 After hours telephone: 0049 51116 33167 +44 (0) 2380 688500 Fax: +44 (0) 2380 688 506 Email: [email protected]



III. LIST OF ABBREVIATIONS AND KEY TERMS

List of Abbreviations

Abbreviations Description of Abbreviations ADT Androgen Deprivation Therapy AE Adverse Event ALT Alanine Aminotransferase APGD Astellas Pharma Global Development AR Androgen Receptor AST Aspartate Aminotransferase AUC Area under the plasma concentration versus time curve AUST Astellas United States Technologies bALP Bone Alkaline Phosphatase BHA Butylated Hydroxyanisole BHT Butylated Hydroxytoluene BPI-SF Brief Pain Inventory-Short Form BUN Blood Urea Nitrogen Cmax Maximum concentration Cmin Minimum concentration CBC Complete Blood Count CFR Code of Federal Regulations CO2 Bicarbonate CRF Case Report Form CRO Contract Research Organization CRPC Castration Resistant Prostate Cancer CT Computed Tomography CTC Circulating Tumor Cells CTD Common Technical Document CTEP Cancer Therapy and Evaluation Program CXR Chest X-Ray CYP Cytochrome P450 DES Diethylstilbestrol DHEA Dehydroepiandrosterone DILI Drug Induced Liver Injury DMC Data Monitoring Committee DNA Deoxyribonucleic Acid ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group eCRF Electronic Case Report Form EDC Electronic Data Capture EDTA Ethylenediaminetetraacetic Acid EMEA European Medicines Agency EQ-5D European Quality of Life 5 Domain ERG ETS-Related Gene EU European Union FACT-P Functional Assessment of Cancer Therapy - Prostate FAS Full Analysis Set FDA Food and Drug Administration



Abbreviations Description of Abbreviations F/U Follow-up GCP Good Clinical Practice g/dL grams per deciliter g/L grams per liter GGT gamma glutamyl transferase GMP Good Manufacturing Practice HCT Hematocrit Hgb Hemoglobin HIPAA Health Insurance Portability and Accountability Act ICF Informed Consent Form ICH International Conference on Harmonisation of Technical Requirements for

Registration of Pharmaceuticals for Human Use IEC Independent Ethics Committee IND Investigational New Drug INN International Nonproprietary Name IRB Institutional Review Board INR International Normalized Ratio ISN International Study Number IVRS/IWRS Interactive Voice/Web Response System kg Kilogram LDH lactic dehydrogenase LHRHa Luteinizing Hormone Receptor Hormone Agonist/Antagonist MedDRA Medical Dictionary for Regulatory Activities MDV3100 3-(4-cyano-3-trifluoromethylphenyl)-1-[3-fluoro-4-(methylcarbamoyl)phenyl]-

5,5-dimethyl-2-thioxoimidazolin-4-one mg Milligram mmHg Millimeters of Mercury MRI Magnetic Resonance Imaging MUGA Multi-Gated Acquisition NCI-CTCAE National Cancer Institute’s Common Terminology Criteria for Adverse Events NDA New Drug Application nmol nanomoles per liter NYHA New York Heart Association P-gp P‑glycoprotein PB Privacy Board PCWG2 Prostate Cancer Clinical Trials Working Group 2 PD Pharmacodynamics PET Positron Emission Tomography PFS Progression Free Survival PHI Personal Health Information PK Pharmacokinetics PPS Per Protocol Set PR Pulse rate PSA Prostate Specific Antigen QRS QRS Interval QT QT Interval RBC Red Blood Cell RECIST Response Evaluation Criteria In Solid Tumors



Abbreviations Description of Abbreviations RR Respiration rate SAE Serious Adverse Event SAF Safety Analysis Set SD Standard Deviation SFL Screening Failure Log SOP Standard Operating Procedure SRE Skeletal Related Event SUSAR Suspected Unexpected Serious Adverse Reaction t½ Apparent Terminal Elimination Half-life ULN Upper Limit of Normal USP United States Pharmacopeia WBC White Blood Cell WHO World Health Organization



List of Key Study Terms

Terms Definition of terms Baseline 1) Observed values/findings which are regarded as calibrated zero status in

the present study, 2) Time when ‘Baseline’ is observed.

Comparative Drug Agent that the test drug is being compared to in a clinical trial. In this study, bicalutamide is the comparative drug.

Discontinuation A discontinuation is a subject who is enrolled in the study and for whom study drug is terminated for any reason.

Investigational Period





Screening Period Period of time between Day -28 and Day -1.

Study Drug Agents given as part of a clinical trial. In this study, MDV3100 and bicalutamide are both study drugs.

Study Period Period of time beginning with the first subject consented through to the last observation collected for the study.

Subject An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.

Test Drug Agent under investigation in a clinical trial. In this study, MDV3100 is the test drug.

Variable Any quantity that varies; any attribute, phenomenon or event that can have different qualitative or quantitative values.



IV. SYNOPSIS

Title of Study A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100 (ASP9785) vs. Bicalutamide in Castrate Men with Metastatic Prostate Cancer [ISN 9785-CL-0222]

Planned Study Period

From 4Q2010 to 2Q2015

Double-Blind Period:

The double-blind period is the study period when investigators and subjects are blinded to the study drug they receive. The double-blind period will conclude at the time of database lock and unblinding. At the time of unblinding, the study investigators will be informed of the treatment of their subjects and the open-label period will begin.

Open-Label Period:

The open label period begins when unblinding of the double-blind period occurs. At the time of unblinding, the sponsor will offer open-label study participation to subjects who meet eligibility criteria. At the discretion of study investigators and subjects, subjects will be able to continue treatment on enzalutamide or change their treatment from bicalutamide to open-label enzalutamide. The data collected during the open-label period will be limited to safety assessments. Study visits will occur at week 5 (if applicable) and every 12 weeks until discontinuation criteria have been met. The complete details for the conduct of the open-label period are provided in Appendix 9: Open-Label Period.

Study Objective(s) The primary study objective is:

To determine the progression free survival (PFS) of MDV3100 as compared to bicalutamide


To determine the safety of treatment with MDV3100 as compared to bicalutamide

To determine the prostate specific antigen (PSA) response of MDV3100 at week 13 as compared to bicalutamide

To determine the time to PSA progression of MDV3100 as compared to bicalutamide


To evaluate quality of life using the Functional Assessment of Cancer Therapy – Prostate (FACT-P), European Quality of Life- 5 Domain Scale (EQ-5D) and Brief Pain Inventory Short Form (BPI-SF) instruments

To determine the benefit of MDV3100 as compared to bicalutamide as assessed by the circulating tumor cell (CTC) conversion rate

Planned Total Number of Study Centers and Location

Approximately 90 centers

North America and Europe



Design and Methodology

This is a multinational phase II, randomized, double-blind, parallel study to determine the efficacy and safety of oral MDV3100 (160 mg/day) compared to bicalutamide (50 mg/day) in castrate men with metastatic prostate cancer who have progressed while on LHRH agonist/antagonist or after receiving a bilateral orchiectomy.

Approximately 370 eligible subjects will be randomized 1:1 to one of two treatment arms: MDV3100, 160 mg orally once daily, or bicalutamide, 50 mg orally once daily. Subjects will be stratified by whether bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases.

For the study duration, all subjects will maintain castration therapy with an LHRH agonist/antagonist or bilateral orchiectomy.

Subjects will be discontinued from study drug at the time of confirmed radio-graphic disease progression, skeletal-related event, or the initiation of a new anti-neoplastic therapy.


Subjects who discontinue study drug treatment for a reason other than radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy will have a PSA test performed 60 days from date of last dose and undergo long-term follow-up every 12 weeks from date of last dose. Long term follow-up will assess for the following until they occur: radiographic progression, skeletal related events, or the start of new anti-neoplastic therapy for prostate cancer.



The consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) have been utilized to determine disease progression.

Soft tissue disease progression will be defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.

Bone disease progression is defined by the appearance of a minimum of two new lesions. Disease progression is considered unconfirmed in all cases until a confirmatory scan is done. The confirmatory scan must be performed 6 or more weeks later (or the next scheduled scan). Progression on bone scan at Week 13 will be proven if the confirmatory scan shows at least 2 additional new bone lesions compared to the week 13 scan. For all other visits, progression on bone scan will be proven if the confirmatory scan shows at least one new lesion compared to the previous scan. When progression is documented on the confirmatory scan, the date of progression is the date of the initial scan that shows the disease progression.



Design and Methodology continued

The following assessments of prostate cancer status will be collected during the course of the trial: soft tissue disease on computed tomography (CT) scan or on magnetic resonance imaging (MRI), bone disease on radionuclide bone scans, skeletal-related events, FACT-P, EQ-5D and BPI-SF quality of life questionnaires and PSA.


Throughout the study, safety and tolerability will be assessed by the recording of adverse events, monitoring of vital signs and physical examinations, safety laboratory evaluations, and 12-lead electrocardiograms. An independent Data Monitoring Committee will monitor safety data on an ongoing basis.


Number of Subjects Planned

Approximately 370 subjects will be randomized 1:1 to MDV3100 or bicalutamide.

Selection Criteria Inclusion Criteria Subjects must meet the following inclusion criteria:

1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] for U.S. sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).




5. Metastatic disease documented at screening by one of the following:

At least two bone lesions on bone scan, or Soft tissue disease documented by CT/MRI, or Unequivocal pelvic adenopathy short axis > 2.0 cm in diameter by

CT/MRI. 6. Progressive disease at study entry defined as one or more of the

following three criteria occurring in the setting of castrate levels of testosterone:

PSA progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the Screening visit should be ≥ 2 µg/L (2 ng/mL);



Soft tissue disease progression defined by RECIST 1.1; Bone disease progression defined by two or more new lesions on

bone scan. 7. Asymptomatic or mildly symptomatic from prostate cancer (i.e. the

score on BPI-SF Question #3 must be < 4); no use of opiate analgesics for prostate cancer-related pain currently or anytime within 4 weeks prior to randomization.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, including subjects with decreased performance status not attributed to progressive and symptomatic prostate cancer.



11. A male subject and his female spouse/partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at Screening and continuing throughout the study period, and for 3 months after final study drug administration. Two acceptable forms of birth control include:

1. Condom (barrier method of contraception), AND

2. In addition to a condom, one of the following acceptable forms of contraception is required:

Established use of oral, injected or implanted hormonal methods of contraception.

Placement of an intrauterine device (IUD) or intrauterine system (IUS).

Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.

Tubal ligation for at least 6 months prior to Screening Vasectomy or other surgical castration at least 6 months prior to

Screening

Waivers to inclusion criteria will not be allowed.

Exclusion Criteria Subjects will be excluded from participation if any of the following apply:







5. Total bilirubin > 1.5 times the upper limit of normal (ULN) at Screening. This will not apply to subjects with Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with the sponsor.





10. Current or prior treatment with estrogens and/or drugs with anti-androgenic properties such as spironolactone > 50 mg/day, or progestational agents for the treatment of prostate cancer within 6 months prior to randomization.


12. Use of antiandrogens within 6 weeks prior to randomization.

13. Documented prior disease progression while receiving antiandrogens. Disease progression defined as PSA progression, radiographic progression and/or clinical deterioration.







Myocardial infarction within six months prior to Screening;

Uncontrolled angina within three months prior to Screening;

Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%;

History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes);



History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;

Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at Screening.





Waivers to exclusion criteria will not be allowed.

Discontinuation Criteria


Radiographic disease progression. Skeletal related events. Skeletal related events are defined as:

o Radiation therapy or surgery to bone o Pathologic bone fracture o Spinal cord compression o Change in anti-neoplastic therapy to treat bone pain

Decision of the investigator and subject to initiate a new anti-neoplastic therapy.

Seizure or any condition that significantly predisposes the patient to seizure such as brain metastasis or clinically evident stroke.

Subject develops an adverse event or toxicity, where continued administration of study drug is deemed not in the subject’s best interest by the investigator and/or the sponsor.

Test Drug Dose:

Mode of Administration:


Subjects randomized to the MDV3100 study arm, will receive 160 mg (four capsules) of MDV3100 and one placebo tablet orally once daily at the same time each day.


Radiographic disease progression. Skeletal-related event. Initiation of a new anti-neoplastic therapy.


Reference Therapy Dose:

Mode of Administration:


Subjects randomized to the bicalutamide study arm will receive 50 mg (one tablet) of bicalutamide and four placebo capsules orally once daily at the same time each day.


Radiographic disease progression. Skeletal-related event.



Initiation of a new anti-neoplastic therapy.


Concomitant Medication


bisphosphonates LHRH agonist/antagonist denosumab


Chemotherapeutic, biologic, or other agents with anti-tumor activity against prostate cancer

Anti-androgens (steroidal and non-steroidal) other than assigned study medication

5-α reductase inhibitors Estrogens, progestational agents Systemic glucocorticoids (the equivalent of 10 mg of prednisone) for

the treatment of prostate cancer Androgens Radiopharmaceuticals such as alpharadin Ketoconazole Anti-epileptic medications for the treatment of seizure Prior use of investigational agents that block androgen synthesis

Enzalutamide

Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. Concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4, CYP2C9 and CYP2C19 should be avoided, as enzalutamide may decrease their plasma exposure. If enzalutamide is co-administered with warfarin (CYP2C9 substrate), additional international normalized ratio (INR) monitoring is to be conducted [Investigator’s Brochure 2013].

Concomitant medications can affect exposure to enzalutamide.

Co-administration of gemfibrozil (a strong CYP2C8 inhibitor) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2 fold; therefore, strong CYP2C8 inhibitors are to be avoided.

Coadministration of itraconazole (strong CYP3A4 inhibitor) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold.

In addition, the effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [Astellas Pharma US Inc. Aug 2012].

Also the effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo. Co-administration of



enzalutamide with strong CYP3A4 inducers may decrease the plasma exposure of enzalutamide and should be avoided if possible. Moderate CYP3A4 inducers may reduce the plasma exposure of enzalutamide and should be avoided if possible [Astellas Pharma US Inc., Aug 2012].

Bicalutamide Clinical studies have not shown any evidence that bicalutamide induces hepatic enzymes. Co-administration of bicalutamide with midazolam (a CYP3A4 substrate) can lead to 1.5 fold (for Cmax) and 1.9 fold (for AUC) levels of midazolam. Hence, caution should be exercised when bicalutamide is co-administered with CYP3A4 substrates.

In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. Prothrombin times should be closely monitored in patients already receiving coumarin anticoagulants who are started on bicalutamide and adjustment of the anticoagulant dose may be necessary [Casodex [Package Insert] Wilmington, DE AstraZeneca Pharmaceuticals; 2002].

Primary Efficacy Variable


Secondary Variables

Secondary variables are PSA response and time to PSA progression.


Exploratory Variables


Statistical Methods Sample Size Calculations


A 1:1 randomization ratio between the two treatment arms (MDV3100 versus bicalutamide);

Target hazard ratio of 0.67. Based on published clinical trials and expert opinion, expected median PFS for the bicalutamide arm is 6 months. A target hazard ratio of 0.67 corresponds to a 50% increase in PFS for the MDV3100 arm relative to the bicalutamide arm (9 versus 6 months);

A minimum of 257 progression events provides 90% power to detect a target hazard ratio of 0.67 based on a two-sided log-rank test and the overall significance level of 0.05;

A sample size of approximately 356 subjects (178 subjects per treat-ment arm) will achieve 257 progression events within approximately 24 months (18 months for accrual and 6 months for follow-up) from the date the first subject is randomized. A four percent lost to follow-up rate will be assumed giving a final sample size of 370 subjects (185 subjects per treatment arm).

Efficacy Analysis:

The final analysis will be conducted with a minimum of 220 progression events which provides at least 85% power to detect a target hazard ration of 0.67.



The primary efficacy analyses will be conducted using a Full Analysis Set defined as all randomized subjects using Cox regression and Kaplan-Meier method.

Primary and secondary efficacy endpoints will be tested at the significance level of 0.05 (two-sided). No adjustment will be made for the multiple comparisons.

Safety Analyses:

The severity of all adverse events will be evaluated by the investigator based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0 and all adverse events will be coded to preferred term, higher level term, and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects with adverse events will be presented by MedDRA system organ class and preferred term, relationship to study treatment, and severity. Descriptive statistics will be used rather than inferential statistics.

Laboratory values will be classified by toxicity grade based on the NCI-CTCAE, version 4.0. Laboratory shift tables of the baseline results to each of the subsequent visits will be produced.



V. FLOW CHART AND SCHEDULE OF ASSESSMENTS

Flow Chart

Obtain informed consent prior to performing any study related procedures Bicalutamide and

LHRH agonist/antagonist, or bilateral orchiectomy

MDV3100 and LHRH agonist/ antagonist or bilateral orchiectomy

Documented radiographic progression, skeletal related event, or initiation of new

anti-neoplastic therapy

30 days after last dose

Every 12 weeks to assess for subsequent anti-neoplastic therapy, radiographic progression, and skeletal related event

Discontinued for reasons other than radiographic progression, skeletal related event, or initiation of new anti-neoplastic therapy

Discontinued for reasons other than radiographic progression, skeletal related event or initiation of new anti-neoplastic therapy

Screening Week -4 to -1

Safety Follow-up Double Blind Treatment Period

Patients will be randomized 1:1 to one of two treatment arms

Long Term Follow-up *

60 day PSA assessment



Table 1: Schedule of Assessments

Study Day Screening Visit 1 8 29 57 85 113 141 169 Safety F/U 60 Daym Long-Term F/Um

Week -4 to -1

(28 days) 1 2 5 9 13 17 21

25 and every subsequent 12

weeks


dosel


dose

Every 12 weeks from

date of last dose

Window (days) ± 2 ± 3 ± 3 ± 7 ± 3 ± 3 ± 7 ± 7 ± 7 ± 7

Informed Consent X

Demographics/Medical History X

Inclusion/Exclusion Criteria X X

Randomization X

Vital Signsa X Xa Xa Xa Xa X X X X X

Physical Examination, Weight, Heightb X Xe X X X X X X X X

12-Lead ECG X Xe X X X X X X X X

Clinical Labsc X Xe X X X X X X X X

PSA X Xe X X X X X

CT/MRI and Bone Scand X X X X

CXR or Chest CTf Xf Xf Xf

ECOG Performance Status X X X X X X X X X X

BPI -SF X X X

Dispense Dosing Diaries X X

Subject Return Completed Dosing Diaries Xn Xn

Blood Sample for CTC X X X

Blood Sample for PK Analysisg X X

Whole Blood Sample for Optional Genotype Analysish

X

Blood Sample for T2:ERG Analysis X

Urine Sample for T2:ERG Analysis i X

Tumor Tissue Sample for T2:ERG Analysis j

X

FACT-P and EQ-5D Assessment X X X

Adverse Events X X X X X X X X X X

Concomitant Medications X X X X X X X X X X

Study Drug Dispensingk X X X X X X X



Table 1 Footnotes:

a. Vital signs (blood pressure, pulse rate, respiration rate, and temperature) will be obtained prior to and 1-2 hours after study drug administration on study weeks 1, 2, 5, and 9.

b. Height obtained at screening visit only

c. Clinical labs, hematology and chemistry, will be obtained prior to study drug administration.

d. Subjects must be assessed with CT/MRI and bone scan within 28 days prior to randomization (Day 1). Scans should be scheduled in such a way that the scan results are available at the regularly scheduled visit.

e. If Day 1 visit occurs within 72 hours after screening, these assessments do not need to be repeated.

f. At screening, a chest x-ray or chest CT will be performed. If a Chest X-Ray is performed and demonstrates metastatic chest disease, a Chest CT is required. In case of metastatic chest disease, additional chest CTs are required to be performed at subsequent imaging visits (week 13, week 25, etc).

g. Blood PK sample to be obtained pre-dose. Sample may be assayed for study drug, metabolites, and/or concomitant medications at the discretion of the sponsor.

h. In the event of unusual PK/PD patterns or safety findings, genotype analysis of relevant metabolism, transporter, pharmacodynamic, and/or safety genes will be conducted. If there is no requirement for analysis, the whole blood sample will be destroyed. Separate subject consent required.

i. A 30 mL urine sample post digital rectal prostate examination will be collected at Day 1 for gene fusion analysis. This sample is collected only from subjects who have not undergone prostatectomy.

j. Tissue samples, if available, are from historical tumor blocks/slides. The sample will be used for gene fusion analysis.

k. Subjects should withhold dosing on all clinic visit days. Dose will be administered in clinic.

l. Safety follow-up visit will occur 30 days following the last dose of study drug or prior to the start of a systemic anti-neoplastic therapy, whichever occurs first.

m. Subjects who discontinue study drug for reasons other than radiographic progression, skeletal related event, or initiation of a new anti-neoplastic therapy will have a PSA test performed 60 days after last dose and undergo long-term follow-up every 12 weeks from date of last dose until radiographic progression is documented, a skeletal related event, or a new anti-neoplastic therapy is initiated.

n. A dosing diary will be completed for 7 days prior to week 13 and week 21. In the diary, the subject will be asked to document date and time of medication intake and the time of last meal.

Sponsor: APGD EudraCT number 2010-021868-15 ISN/Protocol 9785-CL-0222 - CONFIDENTIAL -


1 INTRODUCTION

1.1 Background

Worldwide, prostate cancer ranks third in cancer incidence and sixth in cancer mortality in men. Androgen deprivation therapy with either medical or surgical castration is the preferred initial treatment for advanced prostate cancer [Singer et al 2008]. Despite disease control for a period of time, subjects will inevitably progress while on hormonal therapies. If prostate cancer progression is observed during standard androgen deprivation therapy (gonadotropin-releasing hormone analogues), non-steroidal anti-androgens such as bicalutamide have been added. Although, bicalutamide has been used as a second-line treatment in this subject population, the percent of subjects responding and the length of response time has been low. [Kucuk et al, 2001; Fujii et al, 2006] MDV3100 (ASP9785) is a novel androgen receptor antagonist and in preclinical studies has been shown to provide a more superior suppression of the androgen receptor pathway than bicalutamide.

It is generally believed that increased androgen receptor (AR) expression in the castration-resistant state allows prostate cancer cells to thrive even though circulating androgen levels are low. Preclinical studies have demonstrated that increased androgen receptor expression as seen in the castrate resistant prostate cancer (CRPC) state is associated with reduced effectiveness of the anti-androgen bicalutamide. Overexpression of the androgen receptor has been documented in upwards of 50% of subjects failing androgen deprivation therapy and is thought to contribute to tumor progression. [Chen et al, 2004] In CRPC models, bicalutamide shows agonist activity in the setting of AR overexpression. Bicalutamide shows agonist activity in two critical aspects of the androgen receptor pathway, namely translocation of the androgen receptor from the cytoplasm to the nucleus and association of the androgen receptor with nuclear DNA. This in part may explain some of the disappointing clinical results with bicalutamide in this subject population. In clinical trials with subjects who have failed treatment with gonadotropin-releasing hormone analogues, the response rates with bicalutamide were poor and short lived. [Joyce et al, 1998; Kojima et al, 2004; Scher et al, 1997] Studies investigating treatment with bicalutamide after failure of androgen deprivation monotherapy have observed a median time to PSA progression of 3 months, [Scher et al, 1997] a median time to objective progression of 4 months, and a median overall survival of 15 months [Kucuk et al, 2001].

MDV3100 (ASP9785) is a novel small molecule designed to have increased affinity for the androgen receptor and more effective suppression of the androgen pathway. In addition to increased binding affinity, MDV3100 also demonstrated AR downstream effects that were superior to bicalutamide. MDV3100 has no known agonist activity when the androgen receptor is overexpressed, and in pre-clinical models of CRPC with AR overexpression, MDV3100 suppresses growth of prostate cancer cells while bicalutamide was less effective.

Most importantly, MDV3100 slows growth and induces cell death in bicalutamide-resistant cancers via three complementary actions – MDV3100 blocks testosterone binding to the androgen receptor, impedes movement of the androgen receptor to the nucleus of prostate cancer cells (nuclear translocation), and inhibits binding of DNA.



Thus, MDV3100 is a novel androgen receptor antagonist with qualities that surpass the conventional therapy, bicalutamide. For the most current information, refer to the current edition of the Investigator’s Brochure.[]

1.2 Non-clinical and Clinical Data

1.2.1 Non-clinical Data

Following oral administration in animals, MDV3100 is eliminated slowly from plasma with a long half-life (t1/2) across species. The t1/2 does not appear to be affected by the dose size; but, the bioavailability in animals appears to decrease with increasing dose size. The 2 major human metabolites (N-desmethyl MDV3100 and an inactive carboxylic acid metabolite) are also produced in animals. In vitro studies show that MDV3100 is metabolized by human recombinant cytochrome P450 (CYP) isoenzymes CYP2C8 and CYP3A4/5. MDV3100 and/or its major human metabolites caused direct in vitro inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19,CYP2D6 and CYP3A4/5; however, subsequent clinical data showed that MDV3100 is an inducer of CYP2C9, CYP2C19 and CYP3A4/5 and has no clinically meaningful effect on CYP2C8 in vivo. In vitro data show that MDV3100 and N-desmethyl MDV3100 are potential inhibitors, but not substrates, of the efflux transporter P‑glycoprotein (P-gp). The protein binding of MDV3100 in human plasma is 97% to 98% and is similar in mice, rats, rabbits and dogs. The protein binding of the carboxylic acid derivative and N-desmethyl MDV3100 in human plasma are 98% and 95%, respectively, and are comparable across species. The extent of binding for MDV3100, the carboxylic acid derivative and N-desmethyl MDV3100 is constant over a wide range of concentrations.

There were no treatment-related, toxicologically important, adverse clinical pathology findings. The main findings in repeat-dose oral studies in rats and dogs were MDV3100-related macroscopic findings, microscopic findings and organ weight changes in reproductive and hormone-sensitive tissues. All of these tissue changes were consistent with the pharmacological activity of MDV3100. Full or partial reversibility was noted after treatment-free periods ranging from 4 to 21 weeks.

1.2.2 Clinical Data

The pharmacokinetics and metabolism of MDV3100 have been evaluated in 7 clinical studies in 954 patients with CRPC and in 140 healthy male volunteers, including 16 subjects with mild or moderate hepatic impairment. Individual doses have ranged from 30 to 600 mg. Pharmacokinetic studies of MDV3100 in women have not been completed.

After oral administration to patients with CRPC, the median time to reach maximum MDV3100 plasma concentrations was 1 hour, and the mean terminal half‑life was 5.8 days. MDV3100 steady state was achieved by day 28, and the accumulation ratio was 8.3-fold. At steady state, MDV3100 showed approximately dose proportional pharmacokinetics over the range of 30 to 360 mg/day.



In a drug-drug interaction study in male patients with CRPC (9785-CL-0007), a single oral dose of a substrate for CYP2C8, CYP2C9, CYP2C19, or CYP3A4 was administered before and concomitantly with MDV3100 (after at least 55 days of dosing at 160 mg daily). MDV3100 at steady state reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate) by 86%, 56%, and 70%, respectively. Based on the magnitude of the decreases in exposure, MDV3100 is considered a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Substrates of CYP3A4, CYP2C9, and CYP2C19 with a narrow therapeutic index should be avoided if possible, as MDV3100 may decrease plasma exposure of these drugs. If MDV3100 is coadministered with warfarin (CYP2C9 substrate), additional international normalized ratio (INR) monitoring should be conducted. MDV3100 did not cause clinically meaningful changes in exposure to pioglitazone (CYP2C8 substrate).

In a drug-drug interaction study in healthy male volunteers (9785-CL-0006), a single 160 mg oral dose of MDV3100 was administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor). Gemfibrozil increased the composite area under the curve from time zero to infinity (AUC0-∞) of MDV3100 plus N-desmethyl MDV3100 by 2.2-fold with minimal effect on Cmax; therefore, strong CYP2C8 inhibitors should be avoided if possible as they can increase plasma exposure to MDV3100 plus N-desmethyl MDV3100. If coadministration with a strong CYP2C8 inhibitor is necessary, the dose of MDV3100 should be reduced to 80 mg once daily. If coadministration of the strong CYP2C8 inhibitor is discontinued, the MDV3100 dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor. The effects of CYP2C8 inducers on the PK of MDV3100 have not been evaluated in vivo.

In the drug-drug interaction study in healthy male volunteers (9785-CL-0006), a single 160 mg oral dose of MDV3100 was administered alone or after multiple oral doses of itraconazole (strong CYP3A4 inhibitor). Itraconazole increased the composite AUC0-∞ of MDV3100 plus N-desmethyl MDV3100 by 1.3-fold with no effect on Cmax. As this small change is not clinically meaningful, no starting dose adjustment is needed when coadministering MDV3100 with CYP3A4 inhibitors. The effects of CYP3A4 inducers on the PK of MDV3100 have not been evaluated in vivo.

Additional information on the PK and drug metabolism of enzalutamide is provided in the Enzalutamide Investigator Brochure.

Efficacy was evaluated in 3 studies (in a total of 1399 patients with CRPC), including a large placebo-controlled, phase III study of MDV3100 (160 mg/day) in patients with CRPC who had disease progression during or after receiving docetaxel-based chemotherapy (AFFIRM study). At the pre-specified interim analysis of the AFFIRM study, MDV3100 therapy resulted in a clinically meaningful and statistically significant prolongation of overall survival in patients with CRPC. Results showed a 37% decrease in the risk of death for patients receiving MDV3100 compared with those receiving placebo (hazard ratio 0.631) and a 4.8-month increase in survival in the MDV3100 arm. The study met its primary endpoint at the interim analysis and was stopped, with the interim analysis results becoming the



definitive results and the placebo patients being permitted to cross over to MDV3100 treatment.

The overall survival benefit of MDV3100 was seen in all pre-specified patient subgroups. MDV3100 therapy also resulted in significant improvements in the key secondary endpoints of time to prostate-specific antigen (PSA) progression (hazard ratio 0.248), radiographic progression-free survival (hazard ratio 0.404) and time to first skeletal related event (hazard ratio 0.688). The benefit of MDV3100 on radiographic progression-free survival was further supported by a significant benefit of MDV3100 on best overall radiographic response (28.9% vs. 3.8% [complete + partial responses]). MDV3100 therapy also resulted in significant improvements in the other secondary efficacy endpoints of response rate for quality of life (Functional Assessment of Cancer Therapy – Prostate [FACT-P], 43.2% response rate in the MDV3100 arm vs. 18.3% response rate in the placebo arm) and over 50% PSA response rate (54.0% vs. 1.5%). MDV3100 therapy also resulted in significant improvements in the exploratory efficacy endpoints of pain progression rate at week 13 (27.8% vs. 39.0%) and time to pain progression based on FACT-P (hazard ratio 0.548).

Additional data from a phase 1 study and another phase 1/2 study in CRPC patients are relevant to the efficacy of MDV3100 and supportive of the AFFIRM study efficacy data. In the dose-escalation phase 1 study, MDV3100 demonstrated antitumor activity in men with CRPC, both with and without previous exposure to chemotherapy. This antitumor activity was demonstrated consistently across a number of efficacy endpoints. PSA decreases occurred at all doses and in men with and without previous chemotherapy. The median time to PSA progression was not reached in patients without previous chemotherapy as compared with 316 days (10.4 months) in patients with previous chemotherapy; and, in patients with measurable disease at study entry, 22/31 (71%) of those without previous chemotherapy had radiographic partial responses or stable disease. In patients with previous chemotherapy and measurable disease, 23/42 (55%) had partial responses or stable disease.

In the phase 1/2 study, of the 58 CRPC patients treated with 160 mg daily of MDV3100 who were evaluable for PSA response, 74.1% had a reduction from baseline in PSA levels on therapy, 46.6% had a ≥ 50% reduction and 22.4% had a ≥ 90% reduction from baseline in PSA levels. PSA response rates were comparable despite the use of previous docetaxel chemotherapy.

Although minor variability in the data from 3 efficacy studies was observed for patient populations, PSA sampling intervals and PSA progression definitions, the aggregate data demonstrate consistency of efficacy results across all studies, favoring MDV3100 therapy and confirming the significant therapeutic benefits that MDV3100 provides in patients with metastatic CRPC who previously received docetaxel therapy.



1.3 Summary of Key Safety Information for Study Drugs

1.3.1 MDV3100

Enzalutamide 160 mg daily was generally well-tolerated in patients with CRPC. At the daily dose of 160 mg enzalutamide, the following TEAEs were reported at a 5% or greater incidence in the integrated safety population with ≥ 2% absolute increase in incidence over the placebo group of CRPC2: fatigue (37% vs. 30%), arthralgia (21% vs. 17%), diarrhea (20% vs. 18%), hot flush (20% vs. 10%), peripheral edema (16% vs. 13%), musculoskeletal pain (14% vs. 12%), headache (12% vs. 6%), muscular weakness (9% vs. 7%), insomnia (9% vs. 6%), hematuria (7% vs. 5%), hypertension (6% vs. 3%) and pollakiuria (5% vs. 3%). Other TEAEs reported in fewer than 5% of patients, but that may be associated with enzalutamide treatment include: falls (4.5% vs. 1.3%), nonpathologic fracture (4.0% vs. 0.8%), dry skin (3.6% vs. 1.3%) and pruritus (3.3% vs. 1.3%). A possible cognitive effect of enzalutamide was observed with a greater proportion of patients in the enzalutamide-treated group (4.5% vs. 1.8%) reporting the following TEAE terms: memory impairment, cognitive disorder, amnesia, disturbance of attention and dementia. In addition, event terms related to hallucination (visual hallucination, tactile hallucination, hallucination) were reported more frequently in the enzalutamide-treated group (1.6% vs. 0.3%).

In clinical studies, seizure was identified as a risk associated with enzalutamide treatment. In the controlled clinical Study CRPC2, seizures occurred in 0.9% (7/800) of patients receiving enzalutamide 160 mg daily, whereas no seizures occurred in patients treated with placebo. Confounding factors may have contributed to the occurrence of seizures in several of these cases. Dose appears to be an important predictor of seizure, with a greater risk of seizure at daily doses higher than 160 mg. In a dose escalation study involving 140 patients, no patients experienced seizures at or below daily doses of 240 mg, whereas 3 seizures were reported, 1 each at 360, 480 and 600 mg/day. Caution should be used in administering enzalutamide to patients with a history of seizures or other predisposing factors including, but not limited to, underlying brain injury, stroke, primary brain tumors or brain metastases or alcoholism. In addition, the risk of seizure may be increased in patients receiving concomitant medications that may lower the seizure threshold. Enzalutamide should be permanently discontinued in patients who have a seizure while on treatment.

1.3.2 Bicalutamide

The most common adverse events occurring in more than 10% of patients reported for bicalutamide, 50 mg/day, plus a LHRH analogue reported in the United States package insert include: hot flashes, pain (including general, back, pelvic and abdominal), asthenia, constipation, infection, nausea, peripheral edema, dyspnea, diarrhea, hematuria, nocturia, and anemia. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported. Hepatic changes (elevated transaminases, jaundice), rarely severe, may occur and periodic liver function tests should be considered. Additional safety information can be found in the bicalutamide Package Insert.



1.4 Risk-Benefit Assessment

MDV3100 is a novel small molecule designed to have an increased affinity for the androgen receptor and more effective suppression of the androgen pathway in the setting of androgen overexpression [Tran et al, 2009]. MDV3100 has a higher binding affinity to the AR (8-10 times greater), has no agonist activity, and has demonstrated superior AR downstream effects compared to bicalutamide in pre-clinical studies.

In clinical trials (Phase I-II) involving subjects with progressive metastatic castration-resistant prostate cancer who have either failed androgen deprivation therapy or chemotherapy, MDV3100 has shown strong anti-tumor effects. These effects include reduction of PSA, prolonged time to radiographic and PSA progression and CTC conversion from unfavourable to favourable status.

In the Phase 3 study CRPC2 (AFFIRM), the prespecified interim analysis at the time of 520 events demonstrated a statistically significant improvement in overall survival in patients with metastatic CRPC treated with enzalutamide versus placebo (hazard ratio [HR] = 0.631; 95% CI: 0.529, 0.752, p < 0.0001). The median survival was 18.4 months in the enzalutamide arm and 13.6 months in the placebo arm (Δ = 4.8 months). The overall survival benefit was consistent across all subgroups, including age, baseline pain intensity, geographic region, and type of disease progression at entry. Enzalutamide treatment was superior to placebo for all secondary endpoints including the proportion of patients with a reduction in PSA level by 50% or more (54% vs 2%, p < 0.001), soft tissue response rate (29% vs 4%, p < 0.001), quality-of-life response rate (43% vs 18%, p < 0.001), time to PSA progression (8.3 vs 3.0 months; HR 0.25, p < 0.001), rPFS (8.3 vs 2.9 months; HR 0.40, p < 0.001), and time to first skeletal-related event (16.7 vs 13.3 months; HR 0.69, p < 0.001). Based on the AFFIRM data, the US FDA approved enzalutamide in August 2012 for men with metastatic CRPC who previously received docetaxel therapy.

The most common adverse reactions (≥ 5%) in patients treated with enzalutamide (N = 800) in the Phase 3 study CRPC2 (AFFIRM) (N = 1199) were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 1-4 neutropenia occurred in 15% of enzalutamide-treated patients (1% grade 3-4) and in 6% of placebo-treated patients (no grade 3-4). Other treatment-emergent adverse events reported in fewer than 5% of patients, but that may have been associated with enzalutamide treatment, included falls, nonpathologic fracture, dry skin, and pruritus. A possible cognitive effect of enzalutamide was reported in a greater proportion of patients in the enzalutamide group for the following adverse event terms: memory impairment, cognitive disorder, amnesia, and disturbance of attention. In addition, event terms related to hallucination (visual hallucination, tactile hallucination, hallucination) were reported more frequently in the enzalutamide group. Discontinuations due to adverse events were reported for 16% of enzalutamide-treated patients and 18% of placebo-treated patients. The most common adverse



reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the enzalutamide-treated patients and none (0%) of the placebo-treated patients.

The safety and tolerability of enzalutamide were evaluated in an integrated safety analysis including patients from AFFIRM and 3 open-label studies, and continues to be evaluated on an ongoing basis for all enzalutamide program studies. No study has been terminated early for safety reasons.

The totality of the efficacy and safety data suggests a positive benefit-risk assessment for the use of enzalutamide in men with metastatic CRPC who have previously received docetaxel, and for the continued investigation of enzalutamide in men with earlier stage prostate cancer.

2 STUDY OBJECTIVE(S), DESIGN AND VARIABLES

2.1 Study Objectives

The primary study objective is:

to determine the PFS of MDV3100 as compared to bicalutamide.


to determine the safety of treatment with MDV3100 as compared to bicalutamide; to determine the PSA response of MDV3100 at week 13 as compared to bicalutamide; to determine the time to PSA progression of MDV3100 as compared to bicalutamide.


to evaluate quality of life using the FACT-P, EQ-5D and BPI-SF instruments; to determine the benefit of MDV3100 as compared to bicalutamide as assessed by the

CTC conversion rate.

2.2 Study Design and Dose Rationale

2.2.1 Study Design

This is a multinational phase II, randomized, double-blind, parallel study to determine the efficacy and safety of oral MDV3100 (160 mg/day) compared to bicalutamide (50 mg/day) in castrate men with metastatic prostate cancer who have progressed while on LHRH agonist/ antagonist or after receiving a bilateral orchiectomy.

Approximately 370 eligible subjects will be randomized 1:1 to one of two treatment arms: MDV3100, 160 mg orally once daily, or bicalutamide, 50 mg orally once daily. Subjects will be stratified by whether bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases. For the study duration, all subjects will maintain castration therapy with an LHRH agonist/antagonist or bilateral orchiectomy.



Subjects will be discontinued from study drug at the time of confirmed radiographic disease progression, skeletal-related event, or the initiation of a new anti-neoplastic therapy.


Subjects who discontinue study drug treatment for a reason other than radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy will have a PSA test performed 60 days from date of last dose and undergo long-term follow-up every 12 weeks from date of last dose. Long term follow-up will assess for the following until they occur: radio-graphic progression, skeletal related events, or the start of new anti-neoplastic therapy for prostate cancer.



The consensus guidelines of the PCWG2 have been utilized to determine disease progression.

Soft tissue disease progression will be defined by RECIST 1.1.


The following assessments of prostate cancer status will be collected during the course of the trial: soft tissue disease on CT scan or on MRI , bone disease on radionuclide bone scans, skeletal-related events, FACT-P, EQ-5D and BPI-SF quality of life questionnaires, and PSA.


Throughout the study, safety and tolerability will be assessed by the recording of adverse events, monitoring of vital signs and physical examinations, safety laboratory evaluations, and 12-lead electrocardiograms. An independent Data Monitoring Committee will monitor safety data on an ongoing basis.




2.2.2 Dose Rationale

The dose of 160 mg/day of MDV3100 was selected for evaluation in this study. The durability of disease suppression is similar between the 150 mg/day and the 240 mg/day dose cohorts in the Phase 1-2 study. In the Phase 1-2 study, subjects were administered five 30 mg capsules. In an effort to decrease the total number of capsules administered to the subject, this study will utilize four 40 mg capsules.

The dose of 50 mg/day of bicalutamide will be used in this study. The dose of 50 mg/day is the commercially approved dosage for use in combination therapy with LHRH analogues.

2.3 Variables

2.3.1 Primary Variable


2.3.2 Secondary Variables

The secondary variables are PSA response and time to PSA progression.


2.3.3 Exploratory Variables


2.3.3.1 T2:ERG

To evaluate the relevance of T2:ERG gene fusions in tissue, urine and blood samples, archival prostate tumor tissue, urine collected post digital rectal prostate examination (for subjects who have not undergone prostatectomy), and blood samples will be obtained and stored until qualified assays become available.

2.3.4 Optional Pharmacogenomics Sub-Study

Subjects may consent to participate in an optional pharmacogenomics sub-study. One blood sample will be collected for storage. The pharmacogenomic research that will be conducted in the future with acquired blood samples is exploratory. The objective of this research is to comprehensively analyze suspected disease-related genes and genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues, etc. In the event of unusual PK/PD patterns or safety findings, genotype analysis of relevant metabolism, transporter, pharmaco-dynamic, and/or safety genes will be conducted.



3 STUDY POPULATION

3.1 Selection of Study Population

The study population will include approximately 370 men with metastatic prostate cancer who have progressed while on LHRH agonist/antagonist or after receiving a bilateral orchiectomy.

3.2 Inclusion Criteria

Subject is eligible for the study if all of the following apply:





5. Metastatic disease documented at screening by one of the following:

At least two bone lesions on bone scan, or

Soft tissue disease documented by CT/MRI, or

Unequivocal pelvic adenopathy short axis > 2.0 cm in diameter by CT/MRI.


PSA progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination. The PSA value at the Screening visit should be ≥ 2 µg/L (2 ng/mL);

Soft tissue disease progression defined by RECIST 1.1;

Bone disease progression defined by two or more new lesions on bone scan.

7. Asymptomatic or mildly symptomatic from prostate cancer (i.e. the score on BPI-SF Question #3 must be < 4); no use of opiate analgesics for prostate cancer-related pain currently or anytime within 4 weeks prior to randomization.

8. ECOG performance status of 0-1, including subjects with decreased performance status not attributed to progressive and symptomatic prostate cancer.





11. A male subject and his female spouse/partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at Screening and continuing throughout the study period, and for 3 months after final study drug administration. Two acceptable forms of birth control include:



Established use of oral, injected or implanted hormonal methods of contraception. Placement of an intrauterine device (IUD) or intrauterine system (IUS). Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps)

with spermicidal foam/gel/film/cream/suppository. Tubal ligation for at least 6 months prior to Screening Vasectomy or other surgical castration at least 6 months prior to Screening

Waivers to inclusion criteria will not be allowed.

3.3 Exclusion Criteria

Subject will be excluded from participation if any of the following apply:





5. Total bilirubin > 1.5 times the upper limit of normal (ULN) at Screening. This will not apply to subjects with Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with the sponsor.





10. Current or prior treatment with estrogens and/or drugs with anti-androgenic properties such as spironolactone > 50 mg/day, or progestational agents for the treatment of prostate cancer within 6 months prior to randomization.




12. Use of antiandrogens within 6 weeks prior to randomization.

13. Documented prior disease progression while receiving antiandrogens. Disease progression defined as PSA progression, radiographic progression and/or clinical deterioration.



16. Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to randomization




Myocardial infarction within six months prior to Screening;

Uncontrolled angina within three months prior to Screening;

Congestive heart failure NYHA class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or MUGA scan performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%;

History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes);

History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;

Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at Screening.




23. Gastrointestinal disorder affecting absorption

Waivers to exclusion criteria will not be allowed.

3.4 Discontinuation Criteria for Individual Subjects

A discontinuation is a subject who enrolled in the study and for whom study treatment is terminated prematurely for any reason.

The subject is free to withdraw from the study treatment and/or study for any reason and at any time without giving reason for doing so and without penalty or prejudice. The



investigator is also free to terminate a subject's involvement in the study at any time if the subject's clinical condition warrants it.


Radiographic disease progression;

Skeletal-related events. Skeletal related events are defined as:

o Radiation therapy or surgery to bone

o Pathologic bone fracture

o Spinal cord compression

o Change in anti-neoplastic therapy to treat bone pain;

Decision of the investigator and subject to initiate a new anti-neoplastic therapy;

Seizure or any condition that significantly predisposes the patient to seizure such as brain metastasis or clinically evident stroke.

Subject develops an adverse event or toxicity, where continued administration of study drug is deemed not in the subject’s best interest by the investigator and/or the sponsor. Refer to Appendix 7, Liver Safety Monitoring and Assessment.


Unless the subject withdraws consent, all subjects discontinuing study drug for any reason will have a safety follow-up visit 30 days after their last dose of study drug or prior to initiation of subsequent anti-neoplastic therapy for prostate cancer, whichever occurs first.

Subjects who discontinue study drug for a reason other than radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy will have a PSA test performed 60 days from date of last dose and undergo long-term follow-up every 12 weeks from date of last dose. Long term follow-up will assess for subsequent anti-neoplastic therapy for prostate cancer, radiographic progression, and the occurrence of skeletal related events. Long-term follow-up will be performed until radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy is documented. Reasonable effort should be made to contact any subject lost to follow-up during the course of the study in order to complete study related assessments and retrieve any outstanding data and study drug.

Following unsuccessful telephone contact, an effort to contact the subject by mail using a method that provides proof of receipt should be attempted. Such efforts should be documented in the source documents.



4 STUDY DRUGS

4.1 Description of Study Drugs

4.1.1 Test Drug(s)

MDV3100 has the chemical name 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. It is a white to off-white solid that is insoluble in water and no salt forms are available at ~pH 2 to 10.

The drug substance is formulated in the surfactant, caprylocaproyl polyoxylglycerides, or Labrasol®. The product will be supplied as white to off-white gelatin capsules containing 40 mg of MDV3100.

The corresponding placebo is manufactured by Catalent Pharma Solutions (St. Petersburg, Florida) and consists of Labrasol® filled in identical capsules. Both active and placebo formulation contain the same relative concentrations of the two preservatives, BHA and BHT.

Enzalutamide is the international nonproprietary name (INN) for MDV 3100.


Bicalutamide has the chemical name propanamide, N [4 cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+-). It is a fine white to off-white powder which is practically insoluble in water at 37◦C (5 mg per 1000mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran.

Bicalutamide 50 mg tablets, USP, is supplied as white to off-white, film coated tablets.

Bicalutamide and the corresponding placebo to match will be produced by Zydus Pharma (Moraiya, India) as white to off-white, film coated tablets.

4.2 Packaging and Labeling

All medication used in this study will be prepared, packaged, and labeled under the responsibility of a qualified person at APGD-US in accordance with APGD-US Standard Operating Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and applicable local laws/regulations.

MDV3100 soft gelatin capsules, bicalutamide tablets and the respective matching placebo capsules/tablets will be blister packaged according to this study design using the appropriate transparent thermo formable film(s) with foil backing and placed in child resistant wallets for individual subject dispensing.

4.3 Study Drug Handling

Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries from the sponsor are received by a responsible person (e.g. pharmacist), and



that such deliveries are recorded that study drug is handled and stored safely and properly that study drug is only dispensed to study subjects in accordance with the protocol that any unused study drug is returned to the sponsor or standard procedures for the

alternative disposition of unused study drug are followed.

Drug inventory and accountability records for the study drugs will be kept by the investigator/pharmacist. Study drug accountability throughout the study must be documented. The following guidelines are therefore pertinent:

The investigator agrees not to supply study drugs to any persons except the subjects in this study.

The investigator/pharmacist will keep the study drugs in a pharmacy or other locked and secure storage facility under controlled storage conditions, accessible only to those authorized by the investigator to dispense these test drugs.

A study drug inventory will be maintained by the investigator/pharmacist. The inventory will include details of material received and a clear record of when they were dispensed and to which subject.

At the conclusion or termination of this study, the investigator/pharmacist agrees to conduct a final drug supply inventory and to record the results of this inventory on the Drug Accountability Record. It must be possible to reconcile delivery records with those of used and returned medication. Any discrepancies must be accounted for. Appropriate forms of deliveries and returns must be signed by the person responsible.

Used or unused study drug may be destroyed at the study center according to standard institutional procedures after drug accountability has been conducted by the Sponsor or representative, only if agreed upon by the Sponsor. A copy of the standard institutional procedure for destroying investigational drugs will be provided to the Sponsor or designee upon request. Unused study drug not destroyed at the site must be returned to the Sponsor or designee at the end of the study or upon expiration.

4.3.1 Test Drug

MDV3100 and placebo to match should be stored at controlled room temperature of 20o C to 25o C (68o F - 77 o F); excursions are permitted to 15o to 30o C (59o F - 86o F) in a secured area inaccessible to unauthorized individuals.


Bicalutamide and placebo to match should be stored at controlled room temperature of 20o C to 25o C (68o F - 77o F); excursions are permitted to 15o to 30o C (59o F - 86o F) in a secured area inaccessible to unauthorized individuals.

4.4 Blinding

The study will be performed in a double-blind fashion, so neither the subject, the investigator nor the sponsor will be aware of the treatment group assigned to each subject.



4.4.1 Blinding Method

The study medication blind will be maintained by the IVRS, which will be accessed by the study sites for randomization number and study medication assignments.

4.4.2 Confirmation of the Indistinguishability of the Study Drugs

The control for this blinded study will be the placebo capsules and placebo tablets that appear identical to the MDV3100 capsules and bicalutamide tablets, respectively.

Study drug will be dispensed in the same manner regardless of assigned treatment arm. Subjects will ingest the same number of capsules and or tablets throughout the study.

4.4.3 Breaking the Treatment Code for Emergency

Treatment unblinding may only occur if the knowledge of the treatment assignment will materially change the planned management of a medical emergency. If a medical emergency requiring unblinding occurs, the investigator or designee at the site will contact the sponsor or designee to assess the necessity of breaking the blind.

For unblinding a subject, the assigned study medication information is accessible through IVRS. The sponsor must be immediately notified if the blind is broken. The date, time, and reason the blind was broken must be recorded in the source documents and on the appropriate eCRF if applicable.

If the investigator is unblinded, study medication must be stopped immediately and the subject must be discontinued from the study.

4.4.4 Breaking the Treatment Code by the Sponsor

The sponsor may break the treatment code for subjects who experience a Suspected Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual case or a group of cases requires expedited regulatory reporting. Individual Emergency Code will be provided to the limited staff who are empowered to break the codes for all SUSAR cases for reporting purposes.

4.5 Assignment and Allocation

Subjects who meet the inclusion/exclusion criteria will be randomly assigned to receive MDV3100 or bicalutamide using a 1:1 randomization schedule. Subjects will be stratified by whether bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases. Randomization will be further stratified by site. The sponsor or designee will generate the randomization schedule.

The investigator or designee will contact the IVRS to randomize the subject into the study. The investigator or designee will provide the necessary subject identifying information. The medication number of the medication to be dispensed will be provided by the IVRS. At subsequent drug dispensing visits, the investigator or designee will again contact the IVRS to



request additional study medication for a subject. The medication number provided by the IVRS should be included in the source documentation.

If the subject is assigned to a treatment arm and given a subject number, but does not receive study drug, the subject number will not be used again.

5 TREATMENTS AND EVALUATION

5.1 Dosing and Administration of Study Drugs and Other Medications

5.1.1 Dose/Dose Regimen and Administration Period

In this study, subjects will be randomized to receive blinded oral doses of study drug.

Subjects randomized to the MDV3100 treatment arm will take 160 mg (four capsules) of active MDV3100 and one placebo tablet orally once daily.

Subjects randomized to the bicalutamide treatment arm will take 50 mg (one tablet) of active bicalutamide and four placebo capsules orally once daily.

Study drug should be taken as close to the same time each day as possible. Study drug can be taken with or without food.

Subjects should be instructed to withhold dosing on all clinic visit days. Dose will be administered in clinic.

5.1.2 Interruption and Reduction in Dose of the Study Drugs

Subjects who experience a Grade 3 or greater toxicity that cannot be ameliorated by the use of adequate medical intervention may have their treatment interrupted until the toxicity improves to a Grade 2 or lower severity. The bicalutamide (or bicalutamide-placebo) may be subsequently restarted concurrent with restarting of enzalutamide (or enzalutamide-placebo) at the same or a reduced dose (3 or 2 capsules) with the written approval of the medical monitor.

5.1.3 Previous and Concomitant Medication (Drugs and Therapies)

5.1.3.1 Previous Medication (Drugs and Therapies)

Medication taken within four weeks prior to randomization and any medications prescribed chronically or intermittently during the study or dose adjustments of these medications must be captured on the case report form.

5.1.3.2 Concomitant Medication (Drugs and Therapies)

All concomitant medications must be recorded in the appropriate case report form. Concomitant medications will be assessed at screening, visits 1, 2, 5, 9, 13, 17, 21, 25, subsequent 12 week visits and 30 day follow up.




bisphosphonates LHRH agonist/antagonist denosumab


Chemotherapeutic, biologic, or other agents with anti-tumor activity against prostate cancer;

Anti-androgens (steroidal or non-steroidal) such as cyproterone acetate, flutamide, nilutamide, bicalutamide, etc. other than assigned study drug.

5-α reductase inhibitors such as finasteride, dutasteride, anabolic steroids, etc. Estrogens, progestational agents such as megestrol, medroxyprogesterone, DES,

cyproterone, spironolactone > 50 mg/day, etc. Systemic glucocorticoids (the equivalent of 10 mg of prednisone) for the treatment of

prostate cancer Androgens such as testosterone, dehydroepiandrosterone [DHEA], etc. Radiopharmaceuticals, such as alpharadin Ketoconazole Anti-epileptic medications for the treatment of seizure Prior use of any investigational agents that block androgen synthesis are prohibited

including abiraterone acetate, TAK-700, TAK 683, TAK 448, VN-124-1 or androgen receptor activity including BMS-641988, 17-allylamino-geldanamycin,etc.

5.1.3.2.1 Potential Interactions Between MDV3100 and Concomitant Medications

5.1.3.2.1.1 Effects of MDV3100 on Exposure to Other Drugs

Clinical data indicate that MDV3100 is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19 (Section 1.2.2). Concomitant use of MDV3100 with drugs with a narrow therapeutic index that are metabolized by CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (e.g., phenytoin, warfarin), and CYP2C19 (e.g., S-mephenytoin) should be avoided if possible as MDV3100 may decrease their exposure. If coadministration with warfarin cannot be avoided, additional INR monitoring should be conducted.

5.1.3.2.1.2 Drugs That May Affect Exposure to MDV3100

5.1.3.2.1.2.1 Drugs That Inhibit or Induce CYP2C8

Coadministration of a strong CYP2C8 inhibitor (e.g., gemfibrozil) increased the composite AUCinf of MDV3100 plus its active metabolite in healthy volunteers by 2.2-fold (Section 1.2.2); therefore, coadministration of MDV3100 with strong CYP2C8 inhibitors should be avoided if possible.



The effects of CYP2C8 inducers on the PK of MDV3100 have not been evaluated in vivo. Coadministration of MDV3100 with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of MDV3100 and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended.

5.1.3.2.1.2.2 Drugs That Induce CYP3A4

The effects of CYP3A4 inducers on the PK of MDV3100 have not been evaluated in vivo. Coadministration of MDV3100 with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of MDV3100 and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of MDV3100 and should be avoided if possible.

5.1.3.2.2 Potential Interactions Between Bicalutamide and Concomitant Medications

In vitro studies have shown that R-bicalutamide is an inhibitor of CYP3A4 with lesser effects on CYP2C9, CYP2C19, and CYP2D6 activity (CASODEX US Prescribing Information). Clinical studies have shown that with coadministration of bicalutamide, mean midazolam (a CYP3A4 substrate) concentrations may be increased 1.5-fold (for Cmax) and 1.9-fold (for AUC). Hence, caution should be exercised when bicalutamide is coadministered with CYP3A4 substrates.

5.1.3.3 Precautions Regarding Concomitant Medications

Refer to the following websites for updated lists of CYP inhibitors, inducers, and substrates:

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#potency

http://medicine.iupui.edu/clinpharm/ddis/table.aspx

5.1.4 Treatment Compliance

Study drug accountability will be performed to document compliance with the dosing regimen. Subjects will be asked to bring back all remaining study drug and all study drug packaging at each study visit for drug accountability.

5.1.5 Emergency Procedures and Management of Overdose

If an overdose of study drug occurs, the Medical Monitor must be contacted. An overdose is defined as 2 days of study drug taken over the course of a 24 hour period. Neither the effects of overdose of MDV3100 nor an antidote to overdose are known. In case of overdose of MDV3100, symptomatic treatment with frequent monitoring is recommended. In case of bicalutamide overdose, there is no specific antidote; treatment of an overdose should be symptomatic. Refer to bicalutamide package insert for additional information.



5.2 Demographics and Baseline Characteristics

5.2.1 Demographics

Demographic information is to be obtained at screening and will include date of birth, ethnicity, race as described by the subject, height and weight.

5.2.2 Chest X-Ray and/or Chest CT

At screening, a chest x-ray or chest CT will be performed. If a chest x-ray is performed and demonstrates metastatic chest disease, a chest CT is required. In case of metastatic chest disease, additional chest CTs are required to be performed at subsequent imaging visits (week 13, week 25, etc.).

5.2.3 Diagnosis of the Target Disease, Severity, and Duration of Disease

A complete medical history of the target disease will be recorded at screening. This includes documenting the subject’s initial histological and clinical (if applicable) diagnosis of prostate cancer, Gleason score at time of diagnosis, dates and type of primary therapy and other disease specific information as designated in the eCRF.


Medical history will include any significant conditions or diseases other than prostate cancer that stopped at or prior to screening.

5.2.5 Performance Status

The ECOG scale [Oken et al, 1982] will be used to assess performance status.

Table 2: ECOG Performance Status

Grade Description 0 Fully active, able to carry on all pre-disease performance without restriction

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair

5 Dead

ECOG score will be collected at Screening, Week 1 (baseline), and at every clinic visit including the safety follow-up visit.



5.3 Efficacy Assessment

5.3.1 CT/MRI and Bone Scan

Imaging will be performed at Screening (baseline) and assessed at week 13, week 25, and at subsequent 12 week intervals. For subjects who discontinue for reasons other than radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy, imaging will be performed every 12 weeks from date of last dose as part of long-term follow up. Baseline imaging performed prior to informed consent may be used so long as it is performed within 28 days prior to randomization.

Scans should be scheduled in such a way that the scan results are available at the regularly scheduled visit.

The imaging method utilized for baseline scans must be utilized throughout the entire study.

Imaging may be performed at any time to confirm suspected progression of disease.

Radiographic evaluation of metastatic disease is determined separately for soft -tissue and bone disease. Radiographic disease assessment for soft tissue disease is based on CT or MRI scan and is defined by RECIST 1.1. Radiographic disease assessment for bone lesions is based on bone scan and is considered when a minimum of two new lesions are observed.


Assessment will include tumor measurements for target lesions, non-target lesions, and assessment for any new lesions. An overall assessment will be characterized for that time point evaluation. At the end of study for that subject, the overall best response to the study regimen will be characterized.

Study films (abdominopelvic [lung when applicable] CT/MRI and bone scan) should be read on site and also be submitted in digital format to the sponsor or designee for an independent central review. Each site should ideally designate the same reader who will evaluate the images for any one subject for the duration of the study.

The same imaging method used for an individual patient at baseline should be used throughout the entire study for that patient.

PET scans should not be used to determine disease progression.



5.3.2 PSA

Samples for PSA will be collected and analyzed at a central laboratory designated by the Sponsor. PSA testing will be performed at screening, week 1 (baseline), week 13, week 25, at subsequent 12 week intervals, at the safety follow-up visit, at the 60 day visit (if applicable), and during long term follow-up visits.

The PSA test performed at the screening visit does not need to be repeated on Day1 if the Day 1 visit occurs within 72 hours of screening.

5.4 Safety Assessment

Please review the requirements related to the evaluation, reporting, and analysis of Drug-Induced Liver Injury (DILI) information found in Appendix 7 (Liver Safety Monitoring and Assessment). In the event of a confirmed, marked hepatic abnormality as defined in Appendix 7 (Liver Safety Monitoring and Assessment), it is the investigator’s responsibility to ensure contact with the sponsor/delegated CRO by telephone or fax immediately (i.e. within 24 hours of awareness).

5.4.1 Vital Signs

Vital signs including blood pressure, pulse rate, respiration rate, and temperature will be assessed at screening, at every clinic visit while on study drug and at the safety follow-up visit.

At Weeks 1, 2, 5 and 9, vital signs will be obtained prior to and 1 to 2 hours after study drug administration. Subjects should withhold dosing of study medication on clinic visit days. Dose will be administered in clinic.


Adverse event collection will begin at the time of informed consent and continue for 30 days after last dose of study drug. Adverse events will be documented at each clinic visit per the schedule of assessments. See Section 5.5 for details on adverse event collection.

Please refer to Appendix 7 (Liver Safety Monitoring and Assessment) for DILI adverse event assessment.

5.4.2.1 Adverse Events of Possible Hepatic Origin

Subjects with AEs of hepatic origin accompanied by Liver Function Test (LFT) abnormalities should be carefully monitored.

5.4.3 Laboratory Assessments

Please refer to Appendix 7 (Liver Safety Monitoring and Assessment) for additional DILI laboratory testing requirements and timing.

Routine laboratory assessments for hematology and chemistry will be collected and analyzed at a central laboratory designated by the Sponsor. Laboratory assessments will be assessed at



screening, at every clinic visit during the investigational period, and at the safety follow-up visit.

The laboratory assessments performed at the screening visit do not need to be repeated on Day 1 if the Day 1 visit occurs within 72 hours of screening.

Laboratory assessments must be obtained prior to study drug administration.

5.4.3.1 Hematology

Analytes to be tested include complete blood count (CBC), red blood cell count (RBC), hemoglobin (Hgb), hematocrit (HCT), white blood cell count (WBC), platelets, and WBC differential.

5.4.3.2 Chemistry

Analytes to be tested include sodium, potassium, calcium, chloride, magnesium, phosphorus, glucose, creatinine, alkaline phosphatase, bone alkaline phosphatase (bALP), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin, total protein, albumin, bicarbonate (CO2), blood urea nitrogen (BUN).

5.4.3.3 Abnormal Liver Function Tests

If laboratory testing for a subject enrolled in a study and receiving study drug reveals an increase of serum aminotransferases (AT) to > 3× ULN, or bilirubin > 2× ULN, at least all four of the usual serum measures (ALT, AST, ALP, and TBL) should be repeated within 48 - 72 hours of notification of the test results. See Appendix 7 (Liver Safety Monitoring and Assessment) for additional information on monitoring and assessment of abnormal liver function tests.


Standard, full physical examinations will be performed to assess weight, general appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, respiratory, gastrointestinal, musculo-skeletal, neurologic status, mental status, lymphatic and genitourinary systems. A digital rectal exam is required at Week 1 for collection of T2:ERG urine samples for subjects who have not undergone prostatectomy. See section 5.7.5 Tissue, Blood and Urine Sampling for Gene Fusion Analysis.

Any abnormalities will be collected as medical history or adverse events. Weight will be recorded at each visit. Height will be recorded at the screening visit only. The physical examination performed at the screening visit does not need to be repeated on Day 1 if the Day 1 visit occurs within 72 hours of screening.


A standard 12-lead ECG will be performed on all subjects. Parameters that include heart rate, PR interval, RR interval, QRS interval, QT interval will be collected on the (e)CRF.



Abnormalities and clinical significance as judged by the Investigator will be reported as well. It is recommended that ECG reports are printed in duplicate and photocopied to prevent fading.

An ECG will be performed at screening, all study visits while on study drug and at the safety follow-up visit. The ECG performed at the screening visit does not need to be repeated on Day 1 if the Day 1 visit occurs within 72 hours of screening.

5.5 Adverse Events and Other Safety Aspects

5.5.1 Definition of Adverse Events (AEs)

An AE is defined as any untoward medical occurrence in a subject administered a medicinal product or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, physical exam) should be defined as an AE only if the abnormality meets one of the following criteria:

Induces clinical signs or symptoms Requires active intervention Requires interruption or discontinuation of study medication The abnormality or investigational value is clinically significant in the opinion of the

investigator.

5.5.2 Disease Progression

It is anticipated that a proportion of subjects will experience disease progression. Disease progression should not be reported as an adverse event. Clinical signs and symptoms due to disease progression will be collected as AEs. Individual signs and symptoms will be listed rather than the term “disease progression” with the following exception: if disease progression is the cause of death, this event may be recorded as an AE with “disease progression” as the reported term.

5.5.3 Definition of Serious Adverse Events (SAEs)

An adverse event is considered “serious” if, in the view of either the investigator or Sponsor, it results in any of the following outcomes:

Results in death, Is life threatening (an adverse event is considered “life-threatening” if, in the view of

either the investigator or Sponsor, its occurrence places the subject at immediate risk of death. It does not include an adverse event that, had it occurred in a more severe form, might have caused death),



Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions,

Results in congenital anomaly, or birth defect, Requires inpatient hospitalization or leads to prolongation of hospitalization

(hospitalization for treatment/observation/examination caused by AE is to be considered as serious),

Other medically important events.

Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above. These events, including those that may result in disability/incapacity, should also usually be considered serious. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse.

Safety events of interest on a Sponsor medicinal product that may require expedited reporting and/or safety evaluation include, but are not limited to:

Overdose of a Sponsor medicinal product Suspected abuse/misuse of a Sponsor medicinal product Inadvertent or accidental exposure to Sponsor medicinal product Medication error involving a Sponsor product (with or without subject/patient exposure

to the Sponsor medicinal product, e.g., name confusion)

All of the events of interest noted above should be recorded on the (e)CRF. Any situation involving these events of interest that also meets the criteria for an SAE should be recorded on the AE page of the (e)CRF and marked ‘serious’ and the SAE worksheet.

The Sponsor has a list of events that they classify as “always serious” events. If an adverse event is reported that is considered to be an event per this classification as “always serious”, additional information on the event may be requested.

5.5.4 Criteria for Causal Relationship to the Study Drug

Adverse events that fall under either "Possible" or "Probable" should be defined as "adverse events whose relationship to the study drugs could not be ruled out".



Causal relationship to the study drug

Criteria for causal relationship

Not Related A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and/or in which other drugs, chemicals or underlying disease provide plausible explanations.

Possible A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.

Probable A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on re- administration (rechallenge) or withdrawal (dechallenge).

5.5.5 Criteria for Defining the Severity of an Adverse Event

Severity of adverse events will be graded according to the Cancer Therapy and Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events v. 4.0 [Dilts et al, 2009]. For terms not specified within NCI-CTCAE, the following guideline should be used to determine grade:

Table 3: Criteria for Severity of Adverse Event Terms Not Specified Within NCI-CTCAE

Grade Description

1 Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; intervention not indicated.

2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living.

3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; limiting self care activities of daily living.

4 Life-threatening consequences; urgent intervention indicated.

5 Death related to AE.

5.5.6 Reporting of Serious Adverse Events (SAEs)

In the case of a serious adverse event (SAE), the investigator must contact the Sponsor by telephone or fax immediately (within 24 hours of awareness).

The investigator should complete and submit an SAE Worksheet containing all information that is required by the Regulatory Authorities to the Sponsor by fax immediately (within 24



hours of awareness). If the faxing of an SAE Worksheet is not possible or is not possible within 24 hours, the local drug safety contact should be informed by phone.

For contact details, see Section II Contact Details of Key Sponsor's Personnel.

If there are any questions, or if clarification is needed regarding the SAE, please contact the Sponsor's Medical Director/Expert or his/her designee (see Section II Contact Details of Key Sponsor’s Personnel).

Follow-up information for the event should be sent promptly (within 7 days) as necessary.

The sponsor or sponsor's designee will submit expedited safety reports (i.e. IND Safety Reports) to the regulatory agencies (i.e. FDA) as necessary, and will inform the investigators of such regulatory reports. Investigators must submit safety reports as required by their Institutional Review Board/Independent Ethics Committee within timelines set by regional regulations (i.e. EU, (e)CTD, FDA). Documentation of the submission to and receipt by the IRB/IEC of expedited safety reports should be retained by the site.

You may contact the sponsor's Medical Director/Expert for any other problem related to the safety, welfare, or rights of the study participant.

Full details of the SAE should also be recorded on the medical records and on the CRF.

The following minimum information is required:

ISN/Study number Subject number, sex and age The date of report A description of the SAE (event, seriousness of the event) Causal relationship to the study drug

SAEs will be collected from the time of informed consent through 30 days after the last dose of study medication.

Investigators must provide written documentation of IRB/IEC notification for each report to the Sponsor.

5.5.7 Follow-up to Adverse Events

All adverse events occurring during the study are to be followed up until resolved or judged to be no longer clinically significant, or until they become chronic to the extent that they can be fully characterized.

If during adverse event follow-up, the adverse event progresses to an "SAE", or if a subject experiences a new SAE, the investigator must immediately report the information to the Sponsor.

Please refer to Appendix 7 Liver Safety Monitoring and Assessment for detailed instructions on DILI follow- up responsibilities related to history of symptoms, concomitant drug use, alcohol use, and recreational drug use.



5.5.8 Procedure in Case of Pregnancy

If during the conduct of the clinical trial, a male subject impregnates his partner, the subject should report the pregnancy to the investigator. The investigator should report the pregnancy to the sponsor as an SAE within 30 days from discontinuation of dosing. The expected date of delivery or expected date of the end of the pregnancy, last menstruation, estimated fertility date, pregnancy result and neonatal data etc., should be included in this information.

The investigator will follow the medical status of the mother, as well as the fetus, as if the pregnancy is an SAE and will report the outcome to the sponsor.

When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a miscarried fetus)], the investigator should respond in accordance with the report procedure for SAEs. Additional information regarding the outcome of a pregnancy (which is categorized as an SAE) is mentioned below.

"Spontaneous abortion" includes abortion and missed abortion. Death of an infant within 1 month after birth should be reported as an SAE regardless of

its relationship with the study drug. If an infant dies more than 1 month after the birth, it should be reported if a relationship

between the death and intrauterine exposure to the study drug is judged as "possible" by the investigator.

In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at the birth.

"Normality" of the miscarried fetus is evaluated by visual examination unless test results which indicate a congenital anomaly are obtained prior to miscarriage.

5.5.9 Supply of New Information Affecting the Conduct of the Study

When new information becomes available necessary for conducting the clinical study properly, the Sponsor will inform all investigators involved in the clinical study as well as the regulatory authorities. Investigators will inform the IRB/IEC of such information.

5.5.10 Monitoring of Common Serious Adverse Events

Included in Appendix 8 (Common Serious Adverse Events) is a list of SAEs commonly anticipated to occur in the study population independent of drug exposure that will be monitored by the Sponsor throughout the course of the study for any change in frequency. Any changes to this list will be communicated to the participating investigational sites. Investigators must report individual occurrences of these events [Section 5.5].

5.6 Test Drug Concentration

A 4 mL pre-dose blood sample for PK will be collected into an EDTA tube at weeks 13 and 21. Centrifuge the sample to yield plasma and freeze the plasma at approximately -20° C. The sample will be packaged and shipped per vendor instructions.



The PK samples may be assayed for study drug, metabolites, and/or concomitant medications at the discretion of the Sponsor using a validated analytical method.

A dosing diary will be completed for 7 days prior to week 13 and week 21. In the diary, the subject will be asked to document date and time of medication intake and the time of last meal.

5.7 Other Measurements, Assessments, or Methods

5.7.1 CTC Sampling

Blood samples for the enumeration of CTCs will be collected at week 1, week 13, week 25, and at subsequent 12 week intervals throughout the treatment period. Samples will be collected, prepared, labeled, and shipped to a central laboratory for testing per vendor instructions.

5.7.2 FACT-P

The FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer patients. It consists of 27 core items which assess patient function in four domains: physical, social/family, emotional, and functional well-being, which is further supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as a global quality of life score with higher scores representing better quality of life.

Subjects will be asked to complete a FACT-P survey at week 1 (baseline), week 13, week 25, and at subsequent 12 week intervals throughout the treatment period.

5.7.3 BPI

The Brief Pain Inventory pain questionnaire is a validated instrument that is a subject self rating scale assessing level of pain, effect of the pain on activities of daily living, and analgesic use. The BPI used in this study is the short form and contains 9 questions. The BPI uses simple numeric rating scales from 0 to 10.

The BPI-SF will be administered during the screening visit, week 13, week 25, and at subsequent 12 week visit intervals.

5.7.4 EQ-5D

EQ-5D is a standardized instrument for use as a measure of health outcome. It provides a simple descriptive profile and a single index value for health status. EQ-5D is designed for self-completion by respondents. It consists of two pages comprising the following five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels and subjects are asked to indicate his/her health state by ticking the box with the most appropriate statement.

Subjects will be asked to complete a EQ-5D instrument at week 1 (baseline), week 13, week 25, and at subsequent 12 week intervals throughout the treatment period.



5.7.5 Tissue, Blood and Urine Sampling for Gene Fusion Analysis


A tissue sample from historical tumor blocks/slides and a blood sample will be collected at week 1. For those subjects who have not undergone prostatectomy, a urine sample (30 mL) post digital rectal prostate examination will be collected at week 1.

Every effort should be made to obtain the historical tumor tissue sample; however, it is not required for study participation.

5.7.6 Whole Blood Sample for Optional Genotype Analysis

A whole blood sample (5 mL) for biobanking will be collected at week 1. In the event of unusual PK/PD patterns or safety findings, genotype analysis of relevant metabolism, transporter, pharmacodynamic, and/or safety genes will be conducted. If there is no requirement for analysis, the whole blood sample will be destroyed. Separate subject consent required. Samples will be collected, prepared and shipped to a central laboratory per vendor instructions.

5.8 Total Amount of Blood

The total amount of blood for each subject will vary depending on how long they stay on treatment. The maximum amount of blood collected for a subject within 24 hours during the treatment period is approximately 41 mL. The maximum amount of blood during the follow-up period is approximately 20 mL. Furthermore, if any laboratory abnormalities are found for a subject, additional blood may be drawn for monitoring.

6 TERMINATION OF THE CLINICAL STUDY

The sponsor reserves the right to discontinue the study at any time.

When the sponsor is aware of information on matters concerning the quality, efficacy, and safety of the study drugs, as well as other important information that may affect proper conduct of the clinical study, the sponsor may discontinue the clinical study and send a written notice of the discontinuation along with the reasons to the investigator.

If an investigator intends to discontinue participation in the study, the investigator must immediately inform the sponsor of the discontinuation and the reason for it.

7 STATISTICAL METHODOLOGY

Unless otherwise specified, categorical variables will be presented as counts and percentages, and continuous variables will be presented using descriptive statistics (number of subjects, mean, standard deviation, median, min and max). Tables will be summarized by treatment groups and stratum.



7.1 Sample Size





A sample size of approximately 356 subjects (178 subjects per treatment arm) will achieve 257 progression events within approximately 24 months (18 months for accrual and 6 months for follow-up) from the date the first subject is randomized. A four percent lost to follow-up rate will be assumed giving a final sample size of 370 subjects (185 subjects per treatment arm);

The sample size calculations are performed using the software package nQuery Advisor Version 7.0 (Statistical Solutions, Cork, Ireland).

The final analysis will be conducted with a minimum of 220 progression events which provides at least 85% power to detect a target hazard ratio of 0.67.

7.2 Analysis Set

Efficacy analysis will be conducted on the Full Analysis Set (FAS) and the Per Protocol Set (PPS). The efficacy analysis based on the FAS is considered primary. Safety analysis will be conducted on the Safety Analysis Set (SAF).

7.2.1 Full Analysis Set (FAS)

The FAS is defined as all subjects who are randomized into the study. All subjects will be analyzed as randomized when FAS population is used.

7.2.2 Per Protocol Set (PPS)


Subjects who did not have any major protocol deviations.

Subjects who have initiated at least one dose of assigned study drug.

7.2.3 Safety Analysis Set (SAF)

The SAF is defined as all subjects who have initiated at least 1 dose of study drug. All subjects will be analyzed as treated when SAF population is used.



7.3 Demographics and Other Baseline Characteristics

7.3.1 Demographics

Demographic information will be summarized using descriptive statistics by treatment arm and stratum.


A detailed medical history for each subject will be obtained during Screening and will be summarized by treatment arm and stratum.

7.3.3 Diagnosis of the Target Disease, Severity and Duration of Disease

Each subject’s complete cancer history will be collected during the Screening period prior to randomization. The number and percentage of subjects will be used to summarize the type of cancer, disease status, incidence of metastases and previous therapies. Descriptive statistics will be used to summarize the duration of disease.

7.4 Analysis of Efficacy


The duration of progression-free survival (PFS) will be calculated from the date of randomization to the date of first objective evidence of radiographic disease progression, skeletal-related event, initiation of new anti-neoplastic therapy, or death by any cause, whichever occurs first. Conventions for censoring will be described in the statistical analysis plan.

Radiographic disease progression is defined by RECIST 1.1 for soft tissue disease or by appearance of two or more new lesions on bone scan (PCWG2). The radiological assessment by the Independent Central Review will be used as a primary data source to conduct the analysis. However, the radiological assessment by the investigator will also be used. The number of concordant and discordant cases will be summarized.

Skeletal-related events include radiotherapy to the bone, surgery to the bone, pathological bone fracture, spinal cord compression, or change of anti-neoplastic therapy to treat bone pain.

The effect of MDV3100 compared to bicalutamide based on PFS will be tested with log-rank test at the overall significance level of 0.05 (two-sided).

The benefit of MDV3100 compared to bicalutamide will be evaluated by a single hazard ratio with its 95% confidence interval based on Cox regression model. Kaplan-Meier curves will be used to estimate the distribution of duration of progression-free survival. Median duration of progression-free survival will be estimated using the corresponding 50th percentile of Kaplan-Meier estimates. A two-sided 95% confidence interval will be provided for this estimate. Primary efficacy analysis will be repeated with stratum as a factor in the analyses.



Subgroup analyses of PFS will be performed to determine whether the treatment effect is concordant among subgroups. The following variables will be used to conduct subgroup analyses:

Age category (< 65, 65-75, and > 75);

Geographic region (North America versus Europe);

ECOG Performance Status (0 versus 1) at baseline;

Gleason score ( ≤7 and ≥8 ) at initial diagnosis;

Disease localization (Bone only versus Soft tissue only versus both bone and soft tissue) at baseline;

Baseline PSA value (at or below median versus above median);

Diagnosis of metastases occurring before or after medical (LHRH agonist/antagonist therapy) or surgical castration (bilateral orchiectomy);

Previous use of AA (use of anti-androgen therapy prior to randomization versus no use of anti-androgen therapy prior to randomization).


All secondary efficacy endpoints will be tested at the significance level of 0.05 (two-sided). No adjustment will be made for the multiple comparisons.

7.4.2.1 PSA Response

As defined by PCWG2, the percentage of change of PSA from baseline to week 13, (or earlier for those that discontinue therapy), as well as the maximum decline in PSA that occurs at any point after treatment will be reported using a waterfall plot for each treatment group.

7.4.2.2 Time to PSA Progression

As defined by PCWG2: PSA progression is defined as a ≥ 25% increase and an absolute increase of ≥ 2 ug/L (2 ng/mL) above the nadir (or baseline value for subject who did not have a decline in PSA value at week 13), this increase must be confirmed by a second consecutive assessment conducted at least 3 weeks later.

Time to PSA progression will be calculated from the date of randomization to the date of first observation of PSA progression. Conventions for censoring will be described in the statistical analysis plan.

The effect of MDV3100 compared to bicalutamide based on time to PSA progression will be tested with log-rank test at the significance level of 0.05 (two-sided).

The benefit of MDV3100 compared to bicalutamide will be evaluated by a single hazard ratio with its 95% confidence interval based on Cox regression model. Kaplan-Meier curves will be used to estimate the distribution of time to PSA progression. Median time to PSA progression will be estimated using the corresponding 50th percentile of Kaplan-Meier estimates. A two-sided 95% confidence interval will be provided for this estimate.



7.4.3 Analysis of Other Variables

7.4.3.1 FACT-P

The FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer patients. It consists of 27 core items which assess patient function in four domains: physical, social/family, emotional, and functional well-being, which is further supplemented by a 12-item prostate cancer subscale. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as a global quality of life score with higher scores representing better quality of life.

Appropriate FACT-P subscale scores, global score, and their change from baseline will be summarized by treatment arm and by visit.

7.4.3.2 EQ-5D

The EQ-5D is a standardized instrument for use as a measure of health outcome. Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression are each assessed on 3-point categorical scales ranging from “no problem” to “severe problem.”

EQ-5D domain score and global score will be summarized by treatment arm and by visit.

7.4.3.3 BPI

The BPI questionnaire is a validated instrument that is a patient self-rated scale assessing level of pain, effect of the pain on activities of daily living, and analgesic use. The short form of the BPI is used in this study and contains nine questions. The BPI uses simple numeric rating scales from 0 to10. Pain assessment by the BPI will be summarized by treatment arm and by visit.


For subjects with baseline CTC counts of ≥ 5 cells per 7.5 ml of blood (i.e. unfavorable status) a conversion is defined as a decrease in the CTC count to < 5 cells per 7.5 ml of blood (i.e. favorable status).

For subjects with baseline CTC counts of <5 cells per 7.5 ml of blood (i.e. favorable status) a conversion is defined as an increase in the CTC count to ≥5 cells per 7.5 ml of blood (i.e. unfavorable status).

The CTC conversion rates refer to the proportion of subjects with conversion from unfavorable to favorable or favorable to unfavorable status.

The rates between MDV3100-treated and bicalutamide groups will be compared using a two-sided chi-square test.

Gene Fusion Analysis

Gene fusions will be summarized by treatment. If appropriate, further analyses investigating associations between exploratory variables and efficacy endpoints will be performed.



7.5 Analysis of Safety

Safety analyses will be conducted using the SAF and summarized by treatment arm as treated.

Baseline laboratory results will be summarized using descriptive statistics by treatment arm. Worst toxicity grades per subject will be tabulated for selected adverse events and laboratory analytes. Clinical safety data (including adverse events, grade 3 and 4 hematologic and non-hematologic events, clinical laboratory evaluations, vital signs, ECGs, and physical examinations) will be summarized by treatment arm using descriptive statistics or frequency distributions, as appropriate.


Treatment-emergent adverse events will be presented within each system organ class by preferred term, by relationship to study drug and by severity (NCI-CTCAE grade). Adverse events leading to permanent discontinuation of study drug, SAEs, and SAEs by NCI-CTCAE grade will be summarized. Adverse events will also be summarized by NCI-CTCAE grade and relationship to study drug jointly.

Adverse events will be tabulated presenting the system organ classes alphabetically and within each system organ class; the preferred term will be presented alphabetically as well.

Adverse events will be coded to system organ class and preferred term using the Medical Dictionary for Regulatory Authorities (MedDRA) and graded using NCI-CTCAE. Listings of deaths, SAEs, and withdrawals due to adverse events will be presented.

7.5.2 Clinical Laboratory Evaluations

Clinical laboratory evaluations (including hematology and serum chemistry) will be presented for each visit using descriptive statistics (n, mean, standard deviation [SD], median, minimum and maximum values). Change from baseline will also be presented. Shift analysis tables will present shift from baseline for these same days using the NCI-CTCAE grade and lab reference range indicator. All clinically significant abnormal laboratory values will be recorded as adverse events and graded using NCI-CTCAE guidelines. A listing of subject laboratory values will be provided.


All clinically significant abnormal findings will be recorded as medical history or adverse events. Adverse events will be graded using NCI-CTCAE guidelines.

7.5.4 Vital Signs

Descriptive statistics (n, mean, median, standard deviation [SD], minimum, and maximum) will be presented for each vital signs measurement at each time point. Change from baseline will also be summarized.




Overall ECG interpretation will be summarized for each time point. A shift analysis table showing shifts from baseline in overall ECG (normal, abnormal not clinically significant, and abnormal clinically significant) will be provided.

7.5.6 Concomitant Medications

The frequency of concomitant medications (prescription, over-the-counter, and nutritional supplements) will be summarized by preferred term. Medications will be coded using the World Health Organization (WHO) drug dictionary.

7.5.7 Extent of Exposure

Duration of treatment and total dose administered will be summarized separately for each treatment group. In addition, the number and proportion of subjects with dose reduction will be tabulated for each test article by treatment arm.

7.6 Analysis of Pharmacokinetics

Pharmacokinetics analysis will be addressed in the Statistical Analysis Plan.

7.7 Protocol Deviations and Other Analyses

If appropriate, further analyses investigating associations between exploratory variables and efficacy endpoints will be explored.

Protocol deviations as defined in Section 8.1.6 Protocol Deviations will be summarized for all randomized subjects by treatment group and total as well as by site. A data listing will be provided by site and subject.

The protocol deviation criteria will be uniquely identified in the summary table and listing. The unique identifiers will be as follows:

PD1 - Entered into the study even though they did not satisfy entry criteria,

PD2 - Developed withdrawal criteria during the study and was not withdrawn,

PD3 - Received wrong treatment or incorrect dose,

PD4 - Received excluded concomitant treatment.

PD5- Other

7.8 Interim Analysis (and Early Discontinuation of the Clinical Study)

Not applicable.



7.9 Handling of Missing Data, Outliers, Visit Windows, and Other Information

7.9.1 Missing Data

Imputations for missing data, if applicable, will be addressed in the Statistical Analysis Plan.

7.9.2 Visit Windows

Visit windows are allowed for certain visits per the schedule of procedures. Subject data will not be excluded from analyses due to the subject’s failure to comply with the visit schedule.

8 OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS

8.1 Procedure for Clinical Study Quality Control

8.1.1 Data Collection

The investigator or site designee is responsible to ensure that all data in the eCRFs and queries are accurate and complete and that all entries are verifiable with source documents. These documents should be appropriately maintained by the site.

The investigator or designee will enter data collected using an Electronic Data Capture (EDC) system.

The monitor should verify the data in the eCRFs with source documents and confirm that there are no inconsistencies between them.

For screening failures, the minimum demographic data (sex, age, race and screening date) and reason for screening failure will be collected in screening failure log (SFL), if applicable. This information can be entered into the study database.

8.1.2 Specification of Source Documents

Source data must be available at the site to document the existence of the study subjects and substantiate the integrity of study data collected. Unless specified otherwise, source data must include the original documents relating to the study, as well as the medical treatment and medical history of the subject.

The following information should be included (but is not limited to) in the source medical records:

Demographic data (age, sex, race, ethnicity, weight and height) Records to support Inclusion and Exclusion criteria details Participation in study and sub-study and signed and dated informed consent forms Visit dates Disease and prior treatment history. Photocopies or fax documents of original records are

acceptable if obtained from an outside institution. Medical history



Physical examination details Key efficacy and safety data as specified in the protocol Adverse events and concomitant medication Results of protocol specified evaluations (laboratory, ECG, and MRI or CT scans and

reports with notation of significance). Dispensing, destruction, and return of study drug details Reason for discontinuation Randomization number Staff notes and phone records Medical records from other departments or hospitals, including discharge summaries,

correspondence, etc., at which the subject received treatment. Photocopies or fax documents of original records are acceptable if obtained from an outside institution

8.1.3 Clinical Study Monitoring

The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that subject's human rights, safety, and well-being are protected, that the study is properly conducted in adherence to the current protocol and GCP, and study data reported by the investigator/sub-investigator are accurate and complete and that they are verifiable with study-related records such as source documents. The sponsor is responsible for assigning study monitor(s) to this study for proper monitoring. They will monitor the study in accordance with planned monitoring procedures.

8.1.4 Direct Access to Source Data/Documents

The investigator and the study site must accept monitoring and auditing by the sponsor or delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. In these instances, they must provide all study-related records, such as source documents (refer to Section 8.1.2 "Specification of Source Documents") when they are requested by the sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of the subject's identities shall be well protected consistent with local and national regulations when the source documents are subject to direct access.

8.1.5 Data Management

Data management will be overseen by the responsible department at the sponsor in accordance with the standard operating procedures for data management. All study specific processes and definitions will be documented by Data Management. CRF retrieval and correction process will be referenced in the CRF instructions. Coding of medical terms will be performed using MedDRA.

The study database will be soft-locked when all data that are specified in the study protocol to be collected have been received and cleaned according to applicable SOPs. It will be hard-locked when a data review meeting has been held, and all data related decisions have been made and reflected in the database.



8.1.6 Protocol Deviations

A protocol deviation is generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change. The investigator is responsible for ensuring the study is conducted in accordance with the procedures and evaluations described in this protocol and must protect the rights, safety, and welfare of subjects. The investigator should not implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an immediate hazard to trial subjects.

A protocol waiver is a documented prospective approval of a request from an investigator to deviate from the protocol. Protocol waivers are strictly prohibited.

For the purposes of this protocol, deviations requiring notification to Sponsor are defined as any subject who:

Entered into the study even though they did not satisfy entry criteria. Developed withdrawal criteria during the study and not withdrawn Received wrong treatment or incorrect dose. Received excluded concomitant treatment.

When a deviation from the protocol is identified for an individual subject, the investigator or designee must ensure the Sponsor is notified. The Sponsor will follow-up with the investigator, as applicable, to assess the deviation and the possible impact to the safety and / or efficacy of the subject to determine subject continuation in the study.

If a deviation impacts the safety of a subject, the investigator must contact the Sponsor immediately.

The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory authorities’ criteria are documented and communicated appropriately. All documentation and communications to the IRB/IEC and applicable regulatory authorities will be provided to the Sponsor and maintained within the Trial Master File (TMF).

NOTE: Other deviations outside of the categories defined above that are required to be reported by the IRB/IEC in accordance with local requirements will be reported, as applicable.

8.1.7 End of Trial in All Participating Countries

The end of trial in all participating countries is defined as the Last Subject’s Last Visit.

8.2 Ethics and Protection of Subject Confidentiality

8.2.1 Institutional Review Board/ Independent Ethics Committee /Competent Authorities

The clinical study may begin after acquisition of a written approval from the Institutional Review Board/Independent Ethics Committee of record for that site and study.



The investigator shall make accurate and adequate written progress reports to the IRB at appropriate intervals, not exceeding one year. The investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days after the close-out visit.

8.2.2 Ethical Conduct of the Study

The investigator(s) and all parties involved in this study should conduct the study in adherence to GCP, ICH Guidelines and the applicable laws and regulations.

8.2.3 Informed Consent of Subjects

8.2.3.1 Subject Information and Consent

Prior to execution of the clinical study, the investigator should prepare the written informed consent form and other written information in collaboration with the sponsor and revise the information whenever necessary. The written informed consent form and any other written information should be submitted to the sponsor and be subject to prior approval by the Institutional Review Board/Independent Ethics Committee.

The investigator/sub-investigator is responsible for explaining the nature and purpose of the study as well as other study-related matters to subjects, using the written information, and for obtaining their full understanding and written consent to participate in the study of their own free will.

The investigator or other responsible personnel who provided explanations (including collaborators who gave supportive information, if applicable) and the subject should sign and date the written information, or write down his/her name, and date the form.

Informed consent must be obtained by the time that the first observations / examinations of the pre-investigational period are performed.

The investigator or other responsible personnel must give a copy of the signed consent form to the subject and store the original appropriately in accordance with the rules at the study site concerned.

The investigator or other responsible personnel should note the following when obtaining consent from subjects: ・ No subject may be subjected to undue influence, such as compulsory enrollment into

a study. ・ The language and expressions used in the written information should be as plain and

understandable as possible. Subjects should be given the opportunity to ask questions and receive satisfactory answers to the inquiry, and should have adequate time to decide whether or not to participate in the study. Written information should not contain any language or contents that causes the subject to waive or appears to waive any legal rights, or that releases/mitigates or appears to release/mitigate the study site, the investigator/sub-investigator, collaborators, or the sponsor from liability for negligence.

The signed consent forms will be retained by the investigator and made available (for review only) to the study monitor and auditor upon request.



8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent and Revision of the Written Information

1. The investigator/sub-investigator will immediately inform the subject orally whenever new information becomes available that may be relevant to the subject's consent or may influence the subject's willingness to continue participation in the study (e.g., report of serious adverse drug reactions). The communication should be documented in the subject's medical records, and it should be confirmed whether the subject is willing to remain in the study or not.

2. If the investigator recognizes the necessity to revise the written information in the terms and conditions applicable to paragraph 1, the written information should be revised immediately based upon the newly available information, and be re-approved by the IRB/IEC.

3. The investigator/sub-investigator should obtain written informed consent to continue participation with the revised written information defined in paragraph 2, even if subjects are already informed of the relevant information orally. The investigator or other responsible personnel who provided explanations (including collaborators who gave supportive information, if applicable) and the subject should sign and date the informed consent form, or write down his/her name and date the form. The investigator or other responsible personnel should give a copy of the signed informed consent form to the subject who had given consent with the written information and store the original appropriately as done for the previous informed consent.

8.2.4 Subject Confidentiality

Individual subject medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited. Such medical information may be given only after approval of the subject to the subject's physician or to other appropriate medical personnel responsible for the subject's well-being.

The sponsor shall not disclose any confidential information on subjects obtained during the performance of their duties in the clinical study without justifiable reasons.

The sponsor affirms the subject's right to protection against invasion of privacy. Only a subject identification number and/or initials will identify subject data retrieved by the sponsor. However, the sponsor requires the investigator to permit the sponsor, sponsor's representative(s), the IRB/IEC and when necessary, representatives of the regulatory health authorities to review and/or to copy any medical records relevant to the study.

The sponsor will ensure that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal and/or regional legislation related to the privacy and protection of personal information (i.e. HIPAA).

For US sites, the HIPAA Privacy Rule provides federal protection for the privacy of PHI by implementing standards to protect and guard against the misuse of individually identifiable health information of subjects participating in sponsored clinical trials. "Authorization" is required from each research subject, i.e. specific permission granted by an individual to a covered entity for the use or disclosure of an individual's PHI. A valid authorization must meet the implementation specifications under the HIPAA Privacy Rule. Authorization may be



combined into the Informed Consent document (approved by the IRB/IEC) or it may be a separate document (approved by the IRB/IEC or designed PB) or provided by the investigator or sponsor (without IRB/IEC or PB approval). It is the responsibility of the investigator and institution to obtain such waiver/authorization in writing from the appropriate individual.

8.3 Administrative Matters

8.3.1 Arrangement for Use of Information and Publication of the Clinical Study

Information concerning the study drug, patent applications, processes, unpublished scientific data, the Investigator's Brochure and other pertinent information is confidential and remains the property of the sponsor. Details should be disclosed only to the persons involved in the approval or conduct of the study. The investigator may use this information for the purpose of the study only. It is understood by the investigator that the sponsor will use the information obtained during the clinical study in connection with the development of the drug and therefore may disclose it as required to other clinical investigators or to regulatory agencies. In order to allow for the use of the information derived from this clinical study, the investigator understands that he/she has an obligation to provide the sponsor with all data obtained during the study.

The study will be considered for publication or presentation at (scientific) symposia and congresses. The investigator will be entitled to publish or disclose the data generated at their respective study site only after submission to the sponsor all transcripts, texts of presentations, and abstracts related to the study at least 30 days prior for APGD-sponsored studies. This is necessary to confirm whether any inventive knowledge should be protected by a patent or not and to prepare and file a patent application accordingly. In addition, this is in no way intended to restrict publication of facts or opinions formulated by the investigator. The sponsor will inform the investigator in writing of any objection or question arising within 30 days of receipt of the proposed publication material.

8.3.2 Documents and Records Related to the Clinical Study

The sponsor will provide the investigator and/or institution with the following:

Study protocol (and amendments, as applicable) Investigator’s Brochure (and amendments, as applicable) CRFs and SAE Report Worksheet Study drug with all necessary documentation Study contract

In order to start the study, the investigator and/or study site is required to provide the following documentation to the sponsor:

Financial disclosure in compliance with federal regulation 21CFR Part 54 Signed Investigator's Statement in this protocol Executed Research Agreement Signed and dated FDA form 1572



Copy of the approved ICF and separate authorization form, if appropriate. Independent Ethics Committee/IRB approval of the protocol, protocol amendments

(if applicable) and ICF (and separate authorization form, if appropriate), stating clearly the sponsor's name, study number and study drug, including a membership list with names and qualifications.

Current Curricula Vitae of all investigators (signed and dated) Laboratory normal reference ranges (if applicable, signed and dated by the

responsible laboratory employee) Medical/Laboratory/Technical procedures/tests certifications or accreditations or

established quality control or other validation, where required.

At the end of the study, the sponsor is responsible for the collection of:

Unused CRFs and other study documentation, Unused study drug

The investigator will archive all study data (e.g., Subject Identification Code List, source data, CRFs, and Investigator's File) and relevant correspondence. These documents are to be kept on file for the appropriate term determined by local regulation (for US sites, two years after approval of the NDA or discontinuation of the IND). It is recommended, however, that records be retained for at least five years in the event follow-up is necessary to help determine any potential hazards to subjects who took part in the study. The sponsor will notify the investigator if the NDA is approved or if the IND is discontinued. The investigator agrees to obtain the sponsor's agreement prior to disposal, moving, or transferring of any study-related records.

The sponsor will archive and retain all documents pertaining to the study according to local regulations.

Data generated by the methods described in the protocol will be recorded in the subjects' medical records and/or study progress notes. All data will be entered on CRFs supplied for each subject.

The investigator and sponsor will mutually agree upon the storage format for the retention of electronic data.

8.3.3 Protocol Amendment and/or Revision

Any changes to the study that arise after approval of the protocol must be documented as protocol amendments: substantial amendments and/or administrative changes/non-substantial amendments. Depending on the nature of the amendment and/or administrative change, either IRB/IEC approval or notification is required. The changes will become effective only after the approval of the sponsor, the investigator, the regulatory authority, and the IRB/IEC (if applicable).

Amendments to this protocol must be agreed upon in writing between the Investigator and the Sponsor. Written verification of IRB/IEC approval will be obtained before any amendment is implemented which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the protocol that are administrative in nature do not require IRB/IEC approval, but will be submitted to the IRB/IEC for their information.



If there are changes to the Informed Consent, written verification of IRB/IEC approval must be forwarded to the Sponsor. An approved copy of the new Informed Consent must also be forwarded to the Sponsor.

8.3.4 Signatory Investigator for Clinical Study Report

ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study report which forms part of a marketing authorization application be signed by the representative for the Coordinating Investigator(s) or the Principal Investigator(s). The representative for the Coordinating Investigator(s) or the Principal Investigator(s) will have the responsibility to review the final study results to confirm to the best of his/her knowledge it accurately describes the conduct and results of the study. A representative for the Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the participating investigators the Sponsor prior to database lock.

9 QUALITY ASSURANCE

The sponsor is implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (record), and reported in compliance with the protocol, GCP, and applicable regulatory requirement(s).

The Sponsor or Sponsor's designee may arrange to inspect/audit the clinical study at any or all investigational sites. The auditor is independent from the clinical monitoring and project management team at the Sponsor. The audit may include on-site review of regulatory documents, case report forms, and source documents. Direct access to these documents will be required by the auditors.

10 STUDY ORGANIZATION

10.1 Data Monitoring Committee

A data monitoring committee will be charged with reviewing the safety data. A separate charter will describe the activities of this committee.

10.2 Other Evaluation Committee(s)

Not applicable.

10.3 Other Study Organization

Not applicable.



11 REFERENCES

Bicalutimide [Package Insert]. Princeton, NJ: Zydus Pharmaceuticals USA, Inc.; 2009.

Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10(1):33-9.

Dilts DM, Sandler AB, Cheng SK, et al. Steps and time to process clinical trials at the Cancer Therapy Evaluation Program. J Clin Oncol 2009; 27(11):1761-6.

Fujii Y, Kawakami S, Masuda H, et al. Deferred combined androgen blockade therapy using bicalutamide in patients with hormone-refractory prostate cancer during androgen deprivation monotherapy. BJU Int 2006; 97(6):1184-9.

Joyce R, Fenton MA, Rode P, et al. High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 1998; 159(1):149-53.

Kojima S, Suzuki H, Akakura K, Shimbo M, Ichikawa T, Ito H. Alternative antiandrogens to treat prostate cancer relapse after initial hormone therapy. J Urol 2004; 171(2 Pt 1):679-83.

Kucuk O, Fisher E, Moinpour CM et al. Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: A Southwest Oncology Group study (SWOG 9235). Urol 2001;58(1):53-8.

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6):649-55.7.

Scher HI, Liebertz C, Kelly WK, et al. Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol 1997; 15(8):2928-38.

Singer EA, Golijanin DJ, Miyamoto H, Messing EM. Androgen deprivation therapy for prostate cancer. Expert Opin Pharmacother 2008; 9(2):211-28.

Tran C, Ouk S, Clegg NJ et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324(5928): 787-790.

Company Reports

Investigator’s Brochure. Enzalutamide (MDV3100) for the treatment of cancer, Current edition.

Enzalutamide, XTANDI, Package Insert, Current edition.



12 APPENDICES

12.1 Appendix 1: Laboratory Tests

Visit Collecting Tube Parameters to be Analyzed Hematology All visits EDTA tube Hemoglobin

Hematocrit Erythrocytes (RBC) Leukocytes (WBC) Differential WBC Platelets

Chemistry All visits Serum tube Sodium Potassium Calcium Chloride Magnesium Phosphorus Glucose Creatinine Alkaline phosphatase Bone alkaline phosphatase LDH AST ALT GGT Total bilirubin Total protein Albumin CO2 BUN

PSA Screening, Week 1,13, 25 and every 12 weeks on treatment, Safety follow-up, 60 day visit, and Long Term follow-up

Serum tube PSA

CTC enumeration Week 1, 13, 25 and every 12 weeks while on treatment.

Whole blood CellSave tube

CTC

Testosterone Screening Serum tube Testosterone Blood sample for optional genotype analysis

Week 1 EDTA tube Genotype analysis (separate subject consent required)

Urine sample for gene fusion analysis

Week 1 Specimen cup Gene fusion analysis

Blood sample for gene fusion analysis

Week 1 Serum tube Gene fusion analysis

Blood sample for PK analysis

Week 13 and 21 Serum tube PK analysis



12.2 Appendix 2: European Quality of Life 5-Domain Scale

By placing a checkmark in one box in each group below, please indicate which statements best describe your own health state today.

Mobility

I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care

I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (e.g. work, study, housework, family or leisure activities)

I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort

I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression

I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed



To help people say how good or bad a health state is, we have drawn a scale (rather like a thermometer) on which the best state you can imagine is marked 100 and the worst state you can imagine is marked 0. We would like you to indicate on this scale how good or bad your own health is today, in your opinion. Please do this by drawing a line from the box below to whichever point on the scale indicates how good or bad your health state is today.

© 1990 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

100

Worst imaginable health state

0

Best imaginable health state

Your own health state

today

9 0

8 0

7 0

6 0

5 0

4 0

3 0

2 0

1 0

100

Worst imaginable health state

0

Best imaginable health state

Your own health state

today



12.3 Appendix 3: Soft Tissue Assessment (RECIST 1.1)



Reproduced from: Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247.9



12.4 Appendix 4: BPI-SF



12.5 Appendix 5: Functional Assessment of Cancer Therapy – Prostate



12.6 Appendix 6: Optional Pharmacogenomic Sub-study

INTRODUCTION

Pharmacogenomics research aims to provide medical information regarding how variations in a subject’s gene function and/or expression based on their genetic polymorphism may impact what treatment options are best suited for that subject. Through investigation of pharmacogenomics via such technologies as gene sequencing, statistical genetics and gene expression analysis, the relationship between gene profiles and a drug’s efficacy or toxicity may be better understood. Because many diseases may develop as a result of one or more genetic mutations, pharmaco-genomics research may identify the genes that are involved in determining whether a subject may or may not respond to a drug.

STUDY OBJECTIVES

The pharmacogenomic research that will be conducted in the future with acquired blood samples is exploratory. The objective of this research is to comprehensively analyze:

Suspected disease-related genes;

Genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues, to be identified in a precautionary/retrospective setting.

By analyzing differing genetic polymorphisms, it may be possible to predict genetic effect on an individual subject’s response to MDV3100.

STUDY POPULATION

Subjects who have consented to participate in the 9785-CL-0222 study may also participate in this optional sub-study. As part of this sub-study, subjects must provide separate written consent prior to providing any blood samples that will be used at a later time for the genetic analysis.

SITE SAMPLE COLLECTION

Subjects who consent to participate in this sub-study will provide one 5 mL sample of whole blood on visit Day 1 per vendor preparation instructions. Each sample will be identified with a unique subject identifier. Sample will be shipped to a Sponsor designated central laboratory. Samples will be anonymized prior to analysis.

CENTRAL LABORATORY AND PHARMACOGENOMIC RESEARCH LABORATORY PROCESSING AND STORAGE / SAMPLE ANONYMIZATION

Upon receipt, the central laboratory will identify each sample by subject number and initials utilizing the shipment documents accompanying each sample. Samples will be stored frozen until prompted by Astellas. When prompted, the central laboratory will ship the samples to a separate laboratory for prolonged storage.

When samples are shipped from the central laboratory to the prolonged storage laboratory, they will be identified solely by subject number. Once received at the prolonged storage laboratory, the samples will be assigned a unique sample code and stored frozen. A table linking the subject



number with newly-assigned sample code will be provided to the Astellas’ code administrator. Once the table is provided to Astellas and receipt acknowledged, the link between the subject number and sample code held at the prolonged storage laboratory will be broken.

ASSOCIATING CLINICAL DATA WITH SAMPLE CODES

Before the pharmacogenomics research begins, the Astellas’ code administrator will provide Astellas with the linkage table. Astellas will associate clinical data related to finding with each subject number and corresponding sample code. The clinical data with the corresponding sample codes (without associated subject numbers) will be provided to the Astellas Research Laboratory, who will be responsible for the genetic analysis. After which, the original linkage table and any copies containing the subject number and sample code provided to Astellas will be destroyed by Astellas. No pharmacogenomics data will be traceable back to the original subject number.

PHARMACOGENOMIC ANALYSIS

The detailed content of the pharmacogenomic analysis has not been determined. Astellas will initiate the pharmacogenomic research after the targeted genes have been identified.

In the event of unusual PK/PD patterns or safety findings, genotype analysis or relevant metabolism, transporter, pharmacodynamic and/or safety genes will be conducted. If there is not requirement for analysis, the whole blood sample will be destroyed.

DISPOSAL OF PHARMACOGENOMIC SAMPLES/DATA

All collected pharmacogenomic samples will be maintained for a period of up to 15 years following database hardlock. In addition, the Astellas Research Laboratory will retain all raw data and records pertaining to the study for the period of at least 15 years or unless otherwise notified by the Sponsor. At the conclusion of the retention period, Astellas will instruct the central or pharmacogenomics research laboratory to destroy all remaining samples, data and records.

SUBJECT INFORMED CONSENT

This pharmacogenomic sub-study is independent of the clinical study. Each subject participating in the clinical study may choose whether or not to consent to provide pharmaco-genomic blood samples. Refusal to consent to the pharmacogenomic research or withdrawal of pharmaco-genomic consent will not result in any penalty in regards to participation in the clinical study or further treatment received.

Prior to providing any blood samples as part of the pharmacogenomic sub-study, separate written informed consent must be obtained. A subject has the irrevocable right to withdraw consent from solely the pharmacogenomic research at any point during or after completion of the clinical study. Once pharmacogenomic consent is withdrawn, the subject’s samples will be destroyed. However, any genetic analysis data which had been obtained from the subject’s analyzed samples at the time of withdrawal may be used after withdrawal.



INFORMATION DISCLOSURE TO THE SUBJECTS

The exploratory pharmacogenomics research will be conducted following the conclusion of the clinical study. The results of the genetic analysis will not be provided to any Investigators or subjects nor can the results of the genetic analysis be requested at a later date.

Any information that is obtained from the pharmacogenomic research in relation to the contents of the pharmacogenomic research protocol, results of the correlation between genetic data and subject response or toxicity, etc. belong to Astellas.

SITE PARTICIPATION IN THE PHARMACOGENOMICS SUB-STUDY

Participation in the pharmacogenomic sub-study at a given site is contingent on the site’s Institutional Review Board/Ethics Committee/Regulatory Authority approval and on specific local regulations when applicable. If a site’s IRB/EC/Regulatory Authority does not approve the sampling for the pharmacogenomic research, this section will not be applicable to that site.



12.7 Appendix 7: Liver Safety Monitoring and Assessment

If laboratory testing for a subject enrolled in study and receiving study drug reveals an increase of serum aminotransferases (AT) to > 3X ULN, or bilirubin > 2X ULN, at least all four of the usual serum hepatic measures (ALT, AST, ALP, and TBL) should be repeated. Testing should be repeated within 48-72 hours of notification of the test results. For studies for which a central laboratory is used, alerts will be generated by the central lab regarding moderate and marked liver abnormality to inform the investigator, study monitor and study team. Subjects should be asked if they have any symptoms suggestive of hepatobiliary dysfunction.

Definition of Liver Abnormalities

Confirmed abnormalities will be characterized as moderate and marked where ULN:

ALT or AST Total Bilirubin Moderate > 3 x ULN or > 2 x ULN Marked > 3 x ULN and > 2 x ULN

In addition, the subject should be considered to have marked hepatic abnormalities for any of the following:

ALT or AST > 8X ULN

ALT or AST > 5X ULN for more than 2 weeks

ALT or AST > 3X ULN and INR > 1.5

ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).

The investigator may determine that abnormal liver function results, other than as described above, may qualify as moderate or marked abnormalities and require additional monitoring and follow-up.

Follow-up Procedures

Confirmed moderate and marked abnormalities in hepatic functions should be thoroughly characterized by obtaining appropriate expert consultations, detailed pertinent history, physical examination and laboratory tests. The site should complete the Liver Abnormality Case Report Form (LA-CRF) or an appropriate document. Subjects with confirmed abnormal liver function testing should be followed as described below.

Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or less if abnormalities stabilize or the study drug has been discontinued and the subject is asymptomatic.

Marked hepatic liver function abnormalities, in the absence of another etiology, may be considered an important medical event and reported as a Serious Adverse Event (SAE). The sponsor should be contacted and informed of all subjects for whom marked hepatic liver function abnormalities possibly attributable to study drug are observed.



To further assess abnormal hepatic laboratory findings, the investigator is expected to:

Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms and new onset-diseases should be recorded as ’adverse events’ on the AE page of CRF. Illnesses and conditions such as hypotensive events, and decompensated cardiac disease that may lead to secondary liver abnormalities should be noted. Non-alcoholic steatohepatitis (NASH) is seen in obese hyperlipoproteinemic, and/or diabetic patients and may be associated with fluctuating aminotransferase levels. The investigator should ensure that the medical history form captures any illness that pre-dates study enrollment that may be relevant in assessing hepatic function.

Obtain a history of concomitant drug use (including non-prescription medication, complementary and alternative medications), alcohol use, recreational drug use, and special diets. Medications, including dose, should be entered on the concomitant medication page of CRF. Information on alcohol, other substance use, and diet should be entered on the LA-CRF or an appropriate document.

Obtain a history of exposure to environmental chemical agents Based on the subject’s history, other testing may be appropriate including:

o acute viral hepatitis (A,B, C, D, E or other infectious agents). o ultrasound or other imaging to assess biliary tract disease o other laboratory tests including INR, direct bilirubin

Consider gastroenterology or hepatology consultations Submit results for any additional testing and possible etiology on the LA-CRF or an

appropriate document.

Study Discontinuation

In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or acute liver disease or exposure to other agents associated with liver injury, the subject may be discontinued from the study. The investigator may determine that it is not in the subject’s best interest to continue study enrollment. Discontinuation of treatment should be considered if:

ALT or AST > 8X ULN

ALT or AST > 5X ULN for more than 2 weeks

ALT or AST > 3X ULN and (TBL > 2X ULN or INR > 1.5)

ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).

In addition, if close monitoring for a subject with moderate or marked hepatic laboratory tests is not possible, drug should be discontinued.

Reference

Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by FDA on July 2009.



12.8 Appendix 8: Common Serious Adverse Events

The following is a list of serious adverse evetns that the Sponsor considers to be associated with the disease state being studied. The list does NOT change your reporting obligations nor prevent the need to report an adverse event meeting the definition of an SAE as detailed in Section 5.5.2 Definition of Serious Adverse Event (SAE). The purpose of this list is to alert you that some events reported as SAEs may not require expedited reporting to the regulatory authorities based on the classification of “common serious adverse events”. You are required to follow the requirements detailed in Section 5.5.5 Reporting of Serious Adverse Events (SAE).

For IND safety reporting, single occurrences of the following events may be excluded from expedited reporting to the FDA. If aggregate analysis of these events indicate they occur more frequently with study drug, an expedited IND safety report may be submitted to the FDA.

Anemia Anorexia Asthenia / Fatigue Back pain Bone pain Catheter related infection Dyspnea Haematuria Hydronephrosis Metastases to bone Metastases to central nervous system Nausea Obstructive uropathy Pain Prostate cancer metastatic Renal failure Renal failure acute Spinal compression fracture Spinal cord compression Urinary retention Urinary tract infection Urinary tract obstruction Vomiting



12.9 Appendix 9: Open-Label Period

NOTE: This supplement contains cross-references to the main protocol text where study procedures are to be performed in the same manner.

Following unblinding at the end of the double-blind period and demonstration of a statistically significant advantage of enzalutamide over bicalutamide as assessed by the primary endpoint, all ongoing enzalutamide treated subjects and ongoing or previous bicalutamide treated subjects who meet eligibility criteria will be offered open-label enzalutamide at the discretion of the subject and study investigators. Subjects will return to the study site at week 5 (if applicable) and every 12 weeks for assessments until any discontinuation criterion is met. Subjects who do not participate in the Open-Label Period or withdraw consent for further treatment will have a 30 day safety follow-up visit as per protocol.

The sponsor has the right to terminate the study at any time. However, the sponsor will ensure that enzalutamide will be available to subjects who participate in the Open-Label Period and have not met discontinuation criteria for as long as they are deriving clinical benefit.

Schedule and Assessments for the Open-Label Period:

Subjects who meet eligibility criteria will sign informed consent on Open-Label day 1(or their next regularly scheduled visit following the halt of the double-blind period and approval of protocol at the study site). Subjects previously treated with bicalutamide during the double-blind period are required to return to the clinical site at Open-Label weeks 5, 13, and every subsequent 12 weeks. Subjects previously treated with enzalutamide during the double-blind period will have clinic visits every 12 weeks

Study assessments will include adverse events, concomitant medications collection/review, laboratory tests, physical examination, weight, and vital signs.

Standard, complete physical examinations will be performed to assess weight, general appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, respiratory, gastrointestinal, musculo-skeletal, neurologic status, mental status, lymphatic and genitourinary systems. Any clinically significant abnormalities will be collected as adverse events. Weight will be recorded at each visit.

Vital signs include blood pressure, pulse rate, respiration rate, and temperature.

The following medications should be maintained during the Open-Label Period at the same dosage and schedule:

LHRH agonist/antagonist unless already had bilateral orchiectomy

Routine laboratory assessment for hematology and chemistry will be collected and analyzed at the local laboratory. Laboratory assessments will be assessed at every clinic visit including Open-Label day 1, week 5 (for subjects previously receiving bicalutamide during the double-blind period), week 13, and every 12 weeks thereafter and the safety follow-up visit.



Hematology assessments required for the Open-Label Period include complete blood count (CBC), red blood cell count (RBC), hemoglobin (Hgb), hematocrit (HCT), white blood cell count (WBC), platelets, and WBC differential.

Chemistry analytes required for the Open-Label Period include sodium, potassium, calcium, chloride, magnesium, phosphorus, glucose, creatinine, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin, total protein, albumin, bicarbonate (CO2), blood urea nitrogen (BUN).

Subjects will have a safety follow-up visit 30 days after the date of last dose of Open-Label enzalutamide. If a new cytotoxic or investigational anticancer treatment is initiated before 30 days after the last dose, then safety follow-up should occur immediately before starting the new treatment.

Refer to Section 5.5, Adverse Events and Other Safety Aspects during the Open-Label Period of the study. Additional assessments and monitoring is required if laboratory testing reveals abnormal liver function results. See Appendix 7 (Liver Safety Monitoring Assessment) for additional information.

Schematic:

Yes

Eligible for open-label

participation?

No

Obtain informed

consent for open label

participation

Double-blind period Open- label period

Bicalutamide

Week 5*

Open-label Enzalutamide

30 day safety follow up visit

Enzalutamide

*Week 5 clinic visit is only required for subjects previously treated with bicalutamide during the double-blind period

Every 12 weeks until

discontinuation criteria are met

30 day safety follow up visit



Inclusion Criteria:

Subjects must meet the following inclusion criteria:


2. Received double-blind study treatment during the study. If treated with enzalutamide during double blind period, treatment must be ongoing at time of Open-Label enrollment.

3. Ongoing androgen deprivation therapy with a LHRH agonist or antagonist at a stable dose and schedule unless already had a bilateral orchiectomy.


5. A male subject and his female spouse/partner who is of childbearing potential must continue to use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) throughout the Open-Label Period, and for 3 months after final study drug administration. Two acceptable forms of birth control include:



Established use of oral, injected or implanted hormonal methods of contraception. Placement of an intrauterine device (IUD) or intrauterine system (IUS). Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps)

with spermicidal foam/gel/film/cream/suppository. Tubal ligation for at least 6 months prior to initial double blind screening Vasectomy or other surgical castration at least 6 months prior to initial double blind

screening

6. Agrees to avoid sperm donation while taking enzalutamide.

Exclusion Criteria:

NOTE: The exclusion criteria apply only to subjects starting treatment with enzalutamide after receiving bicalutamide in the double-blind period.

Subjects must not meet any of the following exclusion criteria:

1. Has taken commercially available enzalutamide (Xtandi);

2. Severe concurrent disease, infection, or comorbidity that, in the judgment of the investigator, would make the subject inappropriate for enrollment;

3. Has current or previously treated brain metastasis or active leptomeningeal disease;

4. Has a history of seizure or a condition that may increase the risk of seizure;

5. Has any of the following: total bilirubin ≥ 1.5 times the ULN (except patients with a diagnosis of Gilbert’s disease), ALT or AST ≥ 2.5 times ULN at enrollment into open-



label period. For patients with documented liver metastases, ALT and AST exclusion is > 5 times ULN;

6. Has creatinine > 2 mg/dL (177 µmol/L) at enrollment into Open-Label Period.

7. Met one or more discontinuation criteria in the double-blind period >30 days prior to enrollment in Open-Label Period.

8. Use of another anti androgen, cytotoxic chemotherapy or other investigational drug within 4 weeks prior to Open-Label enrollment.

Enzalutamide Administration. Storage, Packaging and Accountability:

After signing Open-Label Period informed consent, subjects will be assigned Open-Label enzalutamide through the IVRS.

Enzalutamide will be supplied in bottles and labeled in compliance with local regulations. Enzalutamide should be stored in a secure location with limited access at controlled room temperature of 20o C to 25o C (68o F - 77o F); excursions are permitted to 15o to 30o C (59o F - 86o F). Subjects should be instructed to store bottles at room temperature out of reach of children.

All subjects will self-administer four 40 mg soft gelatin enzalutamide capsules (160 mg/day) by mouth once daily with our without food, unless they were receiving a reduced dose during double-blind treatment (treatment will continue at the reduced dose). Subjects should return all study drug bottles to the site at each visit. Study site personnel must make reasonable efforts to obtain all bottles and unused study drug from subjects.

Concomitant and Prohibited Medications:

All concomitant medications must be recorded in the appropriate case report form at each study visit.

The following medications are prohibited during the Open-Label Period of the study:

Therapies to treat prostate cancer including but not limited to:

Cytotoxic chemotherapy Hormonal therapies (e.g., anti-androgens, abiraterone, estrogens; testosterone, DHEA, etc.); Biologics and vaccines (e.g., sipuleucel-T) Any other investigational agent.

Note: GnRH analogues (agonists or antagonists), bone-targeting agents, such as bisphosphonates and denosumab are allowed.

Duration of Treatment and Criteria for Discontinuation:

Subjects will discontinue treatment if any of the following occur:

Adverse event: If intolerable and cannot be ameliorated by adequate medical intervention; or that in the opinion of the investigator or medical monitor will lead to undue risk if enzalutamide is continued;



Seizure or any condition that significantly predisposes the patient to seizure such as brain metastasis or clinically evident stroke;

Initiation of anti-neoplastic therapy (i.e. cytotoxic chemotherapy) or investigational therapy;

Persistent laboratory abnormality as follows: o Creatinine > 354 µmol/L (4.0 mg/dL) o Bilirubin, AST, or ALT > 5 times the ULN o Absolute neutrophil count ≤ 750/µL

Subjects may also be permanently discontinued enzalutamide treatment for the following reasons:

Withdrawal of consent (subject decision anytime for any reason). Study site personnel should clearly document subject withdrawal in source records;

Gross non-compliance with protocol procedures and study drug management; Sponsor discontinuation of study: The sponsor has the right to terminate the study anytime.

However, the sponsor will ensure that enzalutamide will be available to all subjects who participate in the Open-Label Period for as long as they are deriving clinical benefit;

No longer receiving clinical benefit as assessed by the study investigator; Death.

Statistical Methods:

All variables will be presented using descriptive statistics on all patients who entered in the Open-Label Period. Summary will be presented for subjects who switched treatment from bicalutamide to enzalutamide (i.e. subjects who received bicalutamide during the blinded period), subjects who continued on enzalutamide (i.e. patients who received enzalutamide during the blinded period) and overall (i.e. all subjects who entered in the Open-Label Period).

Descriptive statistics will include number of subjects, mean, standard deviation, minimum, median and maximum for continuous endpoints, and frequency and percentage for categorical endpoints. Baseline will be defined as the latest value recorded prior to the first enzalutamide administration. Enzalutamide exposure and the primary reason for ending treatment in the Open-Label Period will be summarized and listed.

Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of AEs, SAEs, AEs leading to discontinuation, and AEs related to study drug will be summarized by system organ class and preferred term. The number and percentage of AEs by severity (reported according to NCI- CTCAE version 4.03) will also be summarized. All AEs will be listed.

For quantitative laboratory measurements descriptive statistics will be used to summarize results and change from baseline by visit. Using the NCI- CTCAE version 4.03, laboratory values will be classified as Grade 1 through 4, where possible. Laboratory data will be displayed in listings.



Descriptive statistics will be used to summarize vital sign results and changes from baseline by visit. Vital signs data will be displayed in listings.



Table 3 Open-Label Period Schedule of Assessments

Week 1 5c 13 Week 25 and every subsequent 12 weeks

30 days from date of last dose

Window (days) ±7 ± 7 ± 7 ± 7

Informed Consent X

Inclusion/Exclusion Criteria X

Open Label Enrollment (IVRS)a X

Concomitant medications X X X X X

Vital Signs X X X X X

Physical Examination, Weight X X X X X

Clinical Labsb X X X X X

Adverse Events X X X X X

Enzalutamide Dispensing X X X

Enter visit into IVRS X X X X

a. The final visit of the double-blind period will serve as the initial visit (day 1) for the open-label period. b. Clinical labs will be performed and evaluated locally. c. Week 5 clinic visit is only required for subjects previously treated with bicalutamide during the double-blind study period.



13 ATTACHMENT 1: SUBSTANTIAL AMENDMENT 4

I. The purpose of this amendment is:

Substantial Changes

1. Add description of double-blind and open-label period into synopsis

DESCRIPTION OF CHANGE: Detailed description of the double blind and open label periods of the study are added to the synopsis. RATIONALE: An open label extension period is added to ensure continuing treatment of subjects receiving clinical benefit from study participation after unblinding. Descriptions of the double blind and open label period are described in the synopsis to clearly identify and delineate the study periods.

2. Add seizure to discontinuation criteria

DESCRIPTION OF CHANGE: Seizure is added to possible reasons for study discontinuation. RATIONALE: Discontinuation criteria is revised to be consistent with Phase 3 trials and to reflect the most current safety information available about the compound.

3. Add efficacy analysis language

DESCRIPTION OF CHANGE: Efficacy analysis text is added to support current study design. RATIONALE: A statement is added to clarify when the final efficacy analysis would be performed in relation to the number of progression events to achieve 85% power.

4. Add text regarding collection of T2ERG tissue sample in footnote of schedule of assessments and section 5.7.5

DESCRIPTION OF CHANGE: Add text to describe tissue sample collection requirement. RATIONALE: Protocol did not explicitly state that historical tissue samples are not required for study participation. The text is added to ensure clarity regarding the requirement to collect historical tissue samples. This requirement has not changed.



5. Revise variables for subgroup analyses

DESCRIPTION OF CHANGE: The variables used for subgroup analyses are revised. RATIONALE: Subgroup analyses are revised to align with Phase 3 trials AFFIRM and PREVAIL in order to allow for indirect comparisons with these trials, if necessary.

6. Revise Circulating Tumor Cell (CTC) conversion text

DESCRIPTION OF CHANGE: CTC conversion rate text is revised. RATIONALE: The text is revised to further clarify the definition of favorable vs. unfavorable CTC conversions for the purposes of this study and to better demonstrate that both favorable and unfavorable conversion rates (dependent on baseline status) will be examined in both treatment arms in order to appropriately assess the benefit of Enzalutamide.

7. Add protocol deviation category

DESCRIPTION OF CHANGE: Protocol deviation category PD5 Other is added to Protocol Deviation section 7.7 RATIONALE: Additional deviation category is added to capture protocol deviations that fall outside the standard categories. The change reflects the revised statistical analysis plan.

8. Revise list of common serious adverse events

DESCRIPTION OF CHANGE: Appendix 8, common serious adverse events, is corrected with the appropriate list of common adverse events specific to enzalutamide. RATIONALE: The previous version of the protocol contained an incorrect list of common adverse events for enzalutamide. This change corrects the previous version. The safety reporting for this protocol is not affected by this revision.

9. Add Appendix 9

DESCRIPTION OF CHANGE: Appendix 9, “Open Label Period”, is added to the protocol.



RATIONALE: The open label extension period is added to the protocol to ensure continuing treatment of subjects receiving clinical benefit from study participation after unblinding. Appendix 9, describes the procedures associated with the open label period in detail.

Non-Substantial Changes

1. Update Sponsor contact information

DESCRIPTION OF CHANGE: Updated 24hour EU contact phone information is added. RATIONALE: New phone number is being used for 24 hour EU medical support for the study sites. Protocol has been updated to reflect most current information.

2. Revise study period

DESCRIPTION OF CHANGE: The study period is revised from 2014 to 2015. RATIONALE: With addition of open-label extension, the trial will continue to 2015. The study period has been revised to reflect the current study design.

3. Minor administrative changes throughout document.

DESCRIPTION OF CHANGE: Minor administrative-type revisions including spelling, format, grammatical and bibliography updates are made to the protocol. RATIONALE: These changes do not affect the content of the document. Protocol is updated to reflect the most current information available for study references.



II Amendment Summary of Changes: Substantial

1. Add description of double-blind and open-label period into synopsis

IV Synopsis

Page 15

ADDED: Double Blind Period

The double blind period is the study period when subjects are blinded to the study drug they receive. The double-blind period will conclude at the time of database lock and unblinding. At the time of unblinding, the study investigators will be informed of the treatment of their subjects and the open-label period will begin.

Open Label Period

The open label period begins when unblinding of the double-blind period occurs. At the time of unblinding, the sponsor will offer open-label study participation to subjects who meet eligibility criteria. At the discretion of study investigators and subjects, subjects will be able to continue treatment on enzalutamide or change their treatment from bicalutamide to open-label enzalutamide. The data collected during the open-label period will be limited to safety assessments. Study visits will occur at week 5 (if applicable) and every 12 weeks until discontinuation criteria have been met. The complete details for the conduct of the open-label period are provided in Appendix 9: Open-Label Period.

2. Add seizure to discontinuation criteria

IV Synopsis, 3.4 Discontinuation Criteria for Individual Subjects

Pages 20 & 39

ADDED: Seizure or any condition that significantly predisposes the patient to seizure such

as brain metastasis or clinically evident stroke.

3. Add efficacy analysis language

IV Synopsis, Statistical Methods, 7.1 Sample Size

Pages 22 & 57

ADDED: Efficacy Analysis:




4. Add text regarding collection of T2ERG tissue sample in footnote of schedule of assessments and section 5.7.5

Table 1: Schedule of Assessments; Footnote j; Section 5.7.5 Tissue, Blood and Urine Sampling for Gene Fusion Analysis

Pages 26 & 56

WAS:

Footnote j:

Tissue sample is from historical tumor blocks/slides. The sample will be used for gene fusion analysis.

IS AMENDED TO:

Footnote j:

Tissue sample is samples, if available, are from historical tumor blocks/slides. The sample will be used for gene fusion analysis. ADDED:

Section 5.7.5

Every effort should be made to obtain the historical tumor tissue sample; however, it is not required for study participation.

5. Revise variables for subgroup analyses


Page 59, Paragraph 6

WAS: Subgroup analyses of PFS will be performed to determine whether the treatment effect is concordant among subgroups. The following variables will be used to conduct subgroup analyses:

Age category (< 65, 65-75, and > 75); Geographic region; ECOG Performance Status (0 versus 1) at baseline; Gleason score (Low (2-4), Medium (5-7), and High (8-10)) at baseline; Disease localization (Bone only versus Soft tissue only versus Both bone and soft tissue)

at baseline; Baseline PSA value (at or below median versus above median); Diagnosis of metastases occurring before or after medical (LHRH agonist/antagonist

therapy) or surgical castration (bilateral orchiectomy). IS AMENDED TO: Subgroup analyses of PFS will be performed to determine whether the treatment effect is



concordant among subgroups. The following variables will be used to conduct subgroup analyses:

Age category (< 65, 65-75, and > 75); Geographic region (North America versus Europe); ECOG Performance Status (0 versus 1) at baseline; Gleason score (Low (2-4) Medium (5- ≤7) and High (≥8-10) )) at baseline initial

diagnosis; Disease localization (Bone only versus Soft tissue only versus both bone and soft tissue)

at baseline; Baseline PSA value (at or below median versus above median); Diagnosis of metastases occurring before or after medical (LHRH agonist/antagonist

therapy) or surgical castration (bilateral orchiectomy ).); Previous use of AA (use of anti-androgen therapy prior to randomization versus no

use of anti-androgen therapy prior to randomization).

6. Revise Circulating Tumor Cell (CTC) conversion text


Page 60

WAS: For subjects with baseline CTC counts ≤ 5 cells per 7.5 ml of blood, a conversion is defined as an increase in the CTC count to > 5 cells per 7.5 ml of blood. The rates between MDV3100-treated and bicalutamide groups will be compared using a two-sided chi-square test. IS AMENDED TO: For subjects with baseline CTC counts ≤ 5 cells per 7.5 ml of blood ≥ 5 cells per 7.5 ml of blood (i.e. unfavorable status) a conversion is defined as an increase a decrease in the CTC count to > < 5 cells per 7.5 ml of blood (i.e. favorable status).

For subjects with baseline CTC counts of < 5 cells per 7.5 ml of blood (i.e. favorable status) a conversion is defined as an increase in the CTC count to ≥ 5 cells per 7.5 ml of blood (i.e. unfavorable status).

The CTC conversion rates refer to the proportion of subjects with conversion from unfavorable to favorable or favorable to unfavorable status.

The rates between MDV3100-treated and bicalutamide groups will be compared using a two-sided chi-square test.

7. Add protocol deviation category

7.7 Protocol Deviations and Other Analysis




ADDED:

PD5-Other

8. Revise list of common serious adverse events

12.8 Appendix 8: Common Serious Adverse Events

Page 87

WAS: For IND safety reporting, single occurrences of the following events may be excluded from expedited reporting to the FDA. If aggregate analysis of these events indicate they occur more frequently with study drug, an expedited IND safety report may be submitted to the FDA.

acute liver failure acute renal failure acute respiratory failure agranulocytosis anaphylaxis any malignancy aplastic anemia confirmed or suspected endotoxin shock confirmed or suspected transmission of infectious agent by marketed product congenital anomalies liver necrosis malignant hypertension pulmonary fibrosis pulmonary hypertension sclerosing syndromes seizure (only central neurological seizure) torsade de pointes toxic epidermal necrolysis ventricular fibrillation

Note - A Hy’s Law case is considered an SAE.

Please refer to Appendix 7 (Liver Safety Monitoring and Assessment). IS AMENDED TO: For IND safety reporting, single occurrences of the following events may be excluded from expedited reporting to the FDA. If aggregate analysis of these events indicate they occur more frequently with study drug, an expedited IND safety report may be submitted to the FDA.

acute liver Anemia Anorexia Asthenia / Fatigue



Back pain Bone pain Catheter related infection Dyspnea Haematuria Hydronephrosis Metastases to bone Metastases to central nervous system Nausea Obstructive uropathy Pain Prostate cancer metastatic Renal failure acute Renal failure acute Spinal compression fracture Spinal cord compression Urinary retention Urinary tract infection Urinary tract obstruction Vomiting acute liver failure acute renal failure acute respiratory failure agranulocytosis anaphylaxis any malignancy aplastic anemia confirmed or suspected endotoxin shock confirmed or suspected transmission of infectious agent by marketed product congenital anomalies liver necrosis malignant hypertension pulmonary fibrosis pulmonary hypertension sclerosing syndromes seizure (only central neurological seizure) torsade de pointes toxic epidermal necrolysis ventricular fibrillation

Note - A Hy’s Law case is considered an SAE. Please refer to Appendix 7 (Liver Safety Monitoring and Assessment).



9. Add Appendix 9

12. Appendices

Page 97

ADDED: 12.9 Appendix Open-Label Period

NOTE: This supplement contains cross-references to the main protocol text where study procedures are to be performed in the same manner.

Following unblinding at the end of the double-blind period and demonstration of a statistically significant advantage of enzalutamide over bicalutamide as assessed by the primary endpoint, all ongoing enzalutamide treated subjects and ongoing or previous bicalutamide treated subjects who meet eligibility criteria will be offered open-label enzalutamide at the discretion of the subject and study investigators. Subjects will return to the study site at week 5 (if applicable) and every 12 weeks for assessments until any discontinuation criterion is met. Subjects who do not participate in the Open-Label Period or withdraw consent for further treatment will have a 30 day safety follow-up visit as per protocol.

The sponsor has the right to terminate the study at any time. However, the sponsor will ensure that enzalutamide will be available to subjects who participate in the Open-Label Period and have not met discontinuation criteria for as long as they are deriving clinical benefit.

Schedule and Assessments for the Open-Label Period:

Subjects who meet eligibility criteria will sign informed consent on Open-Label day 1 (or their next regularly scheduled visit following the halt of the double-blind period and approval of protocol at the study site). Subjects previously treated with bicalutamide during the double-blind period are required to return to the clinical site at Open-Label weeks 5, 13, and every subsequent 12 weeks. Subjects previously treated with enzalutamide during the double-blind period will have clinic visits every 12 weeks.

Study assessments will include adverse events, concomitant medications collection/ review, laboratory tests, physical examination, weight, and vital signs.

Standard, complete physical examinations will be performed to assess weight, general appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, respiratory, gastro-intestinal, musculo-skeletal, neurologic status, mental status, lymphatic and genitourinary systems. Any clinically significant abnormalities will be collected as adverse events. Weight will be recorded at each visit.

Vital signs include blood pressure, pulse rate, respiration rate, and temperature.

The following medications should be maintained during the Open-Label Period at the same dosage and schedule:

LHRH agonist/antagonist unless already had bilateral orchiectomy

Routine laboratory assessment for hematology and chemistry will be collected and analyzed at the local laboratory. Laboratory assessments will be assessed at every



clinic visit including Open-Label day 1, week 5 (for subjects previously receiving bicalutamide during the double-blind period), week 13, and every 12 weeks thereafter and the safety follow-up visit.

Hematology assessments required for the Open-Label Period include complete blood count (CBC), red blood cell count (RBC), hemoglobin (Hgb), hematocrit (HCT), white blood cell count (WBC), platelets, and WBC differential.

Chemistry analytes required for the Open-Label Period include sodium, potassium, calcium, chloride, magnesium, phosphorus, glucose, creatinine, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin, total protein, albumin, bicarbonate (CO2), blood urea nitrogen (BUN).

Subjects will have a safety follow-up visit 30 days after the date of last dose of Open-Label enzalutamide. If a new cytotoxic or investigational anticancer treatment is initiated before 30 days after the last dose, then safety follow-up should occur immediately before starting the new treatment.

Refer to Section 5.5, Adverse Events and Other Safety Aspects during the Open-Label Period of the study. Additional assessments and monitoring is required if laboratory testing reveals abnormal liver function results. See Appendix 7 (Liver Safety Monitoring Assessment) for additional information.

Schematic:

Inclusion Criteria:

Subjects must meet the following inclusion criteria:


2. Received double-blind study treatment during the study. If treated with enzalutamide during double-blind period, treatment must be ongoing at time of



Open-Label enrollment.

3. Ongoing androgen deprivation therapy with a LHRH agonist or antagonist at a stable dose and schedule unless already had a bilateral orchiectomy.


5. A male subject and his female spouse/partner who is of childbearing potential must continue to use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) throughout the Open-Label Period, and for 3 months after final study drug administration. Two acceptable forms of birth control include:

1. Condom (barrier method of contraception), AND 2. In addition to a condom, one of the following acceptable forms of contraception

is required: Established use of oral, injected or implanted hormonal methods of

contraception. Placement of an intrauterine device (IUD) or intrauterine system (IUS). Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault

caps) with spermicidal foam/gel/film/cream/suppository. Tubal ligation for at least 6 months prior to initial double-blind screening Vasectomy or other surgical castration at least 6 months prior to initial

double-blind screening

6. Agrees to avoid sperm donation while taking enzalutamide.

Exclusion Criteria:

NOTE: The exclusion criteria apply only to subjects starting treatment with enzalutamide after receiving bicalutamide in the double-blind period.

Subjects must not meet any of the following exclusion criteria:

1. Has taken commercially available enzalutamide (Xtandi);

2. Severe concurrent disease, infection, or comorbidity that, in the judgment of the investigator, would make the subject inappropriate for enrollment;

3. Has current or previously treated brain metastasis or active leptomeningeal disease;

4. Has a history of seizure or a condition that may increase the risk of seizure;

5. Has any of the following: total bilirubin ≥ 1.5 times the ULN (except patients with a diagnosis of Gilbert’s disease), ALT or AST ≥ 2.5 times ULN at enrollment into open-label period. For patients with documented liver metastases, ALT and AST exclusion is > 5 times ULN;

6. Has creatinine > 2 mg/dL (177 µmol/L) at enrollment into Open-label period.

7. Met one or more discontinuation criteria in the double-blind period >30 days prior to enrollment in Open-Label Period.

8. Use of another anti androgen, cytotoxic chemotherapy or other investigational drug within 4 weeks prior to Open-Label enrollment.



Enzalutamide Administration, Storage, Packaging and Accountability:

After signing Open-Label Period informed consent, subjects will be assigned Open-Label enzalutamide through the IVRS.

Enzalutamide will be supplied in bottles and labeled in compliance with local regulations. Enzalutamide should be stored in a secure location with limited access at controlled room temperature of 20o C to 25o C (68o F - 77o F); excursions are permitted to 15o to 30o C (59o F - 86o F). Subjects should be instructed to store bottles at room temperature out of reach of children.

All subjects will self-administer four 40 mg soft gelatin enzalutamide capsules (160 mg/day) by mouth once daily with our without food, unless they were receiving a reduced dose during double-blind treatment (treatment will continue at the reduced dose). Subjects should return all study drug bottles to the site at each visit. Study site personnel must make reasonable efforts to obtain all bottles and unused study drug from patients.

Concomitant and Prohibited Medications:

All concomitant medications must be recorded in the appropriate case report form at each study visit.

The following medications are prohibited during the Open-Label Period of the study:

Therapies to treat prostate cancer including but not limited to:

Cytotoxic chemotherapy

Hormonal therapies (e.g., anti-androgens, abiraterone, estrogens; testosterone, DHEA, etc.);

Biologics and vaccines (e.g., sipuleucel-T)

Any other investigational agent.

Note: GnRH analogues (agonists or antagonists), bone-targeting agents, such as bisphosphonates and denosumab are allowed.

Duration of Treatment and Criteria for Discontinuation:

Subjects will discontinue treatment if any of the following occur:

Adverse event: If intolerable and cannot be ameliorated by adequate medical intervention; or that in the opinion of the investigator or medical monitor will lead to undue risk if enzalutamide is continued;

Seizure or any condition that significantly predisposes the patient to seizure such as brain metastasis or clinically evident stroke;

Initiation of anti-neoplastic therapy (i.e. cytotoxic chemotherapy) or investigational therapy;

Persistent laboratory abnormality as follows:

o Creatinine > 354 µmol/L (4.0 mg/dL) o Bilirubin, AST, or ALT > 5 times the ULN o Absolute neutrophil count ≤ 750/µL



Subjects may also be permanently discontinued enzalutamide treatment for the following reasons:

Withdrawal of consent (subject decision anytime for any reason). Study site personnel should clearly document subject withdrawal in source records;

Gross non-compliance with protocol procedures and study drug management;

Sponsor discontinuation of study: The sponsor has the right to terminate the study anytime. However, the sponsor will ensure that enzalutamide will be available to all subjects who participate in the Open-label Period for as long as they are deriving clinical benefit;

No longer receiving clinical benefit as assessed by the study investigator;

Death.

Statistical Methods:

All variables will be presented using descriptive statistics on all patients who entered in the Open-Label Period. Summary will be presented for subjects who switched treatment from bicalutamide to enzalutamide (i.e. subjects who received bicalutamide during the blinded period), subjects who continued on enzalutamide (i.e. subjects who received enzalutamide during the blinded period) and overall (i.e. all subjects who entered in the Open-Label Period).

Descriptive statistics will include number of subjects, mean, standard deviation, minimum, median and maximum for continuous endpoints, and frequency and percentage for categorical endpoints. Baseline will be defined as the latest value recorded prior to the first enzalutamide administration. Enzalutamide exposure and the primary reason for ending treatment in the Open-Label treatment Period will be summarized and listed.

Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of AEs, SAEs, AEs leading to discontinuation, and AEs related to study drug will be summarized by system organ class and preferred term. The number and percentage of AEs by severity (reported according to NCI- CTCAE version 4.03) will also be summarized. All AEs will be listed.

For quantitative laboratory measurements descriptive statistics will be used to summarize results and change from baseline by visit. Using the NCI- CTCAE version 4.03, laboratory values will be classified as Grade 1 through 4, where possible. Laboratory data will be displayed in listings.

Descriptive statistics will be used to summarize vital sign results and changes from baseline by visit. Vital signs data will be displayed in listings.



IIa Amendment Summary of Changes: Non-Substantial

1. Update Sponsor contact information

II Contact Details of Key Sponsor’s Personnel

24h-Contact for Serious Adverse Events (SAEs), Europe and Medical Monitors, Europe Page 10

ADDED: After hours telephone: 0049 51116 33167

2. Revise study period

IV Synopsis, Planned Study Period

Page 16

WAS: From 4Q2010 to 2Q2014 IS AMENDED TO: From 4Q2010 to 2Q2014 2015

3. Minor administrative changes throughout document

Throughout protocol including tables.



1.1 Background


WAS:

Thus, MDV3100 is a novel androgen receptor antagonist with qualities that surpass the conventional therapy, bicalutamide. [Investigator’s Brochure 2013] IS AMENDED TO:

Thus, MDV3100 is a novel androgen receptor antagonist with qualities that surpass the conventional therapy, bicalutamide. [For the most current information, refer to the current edition of the Investigator’s Brochure 2013].

1.2.1 Non-clinical Data, 1.2.2 Clinical Data



DELETED:

[Investigator’s Brochure 2013]

11 References

Page 72, Company Reports

WAS:

Investigator’s Brochure. Enzalutamide (MDV3100) for the treatment of cancer. 6th edition. Medivation, Inc., 31 Jan 2013.

Enzalutamide, XTANDI, Package Insert, August 2012 IS AMENDED TO:

Investigator’s Brochure. Enzalutamide (MDV3100) for the treatment of cancer, 6th Current edition. Medivation, Inc., 31 Jan 2013.

Enzalutamide, XTANDI, Package Insert, August 2012 Current edition.



14 SPONSOR’S SIGNATURES

Sponsor: Astellas Pharma Global Development, Inc. Final version 3.0, 09 January 2015ISN/Protocol 9785-CL-0222

Statistical Analysis Plan Astellas Page 1 of 45

STATISTICAL ANALYSIS PLAN

Final version 3.0, 09 January 2015

A Randomized, Double-Blind, Phase II, Efficacy and SafetyStudy of MDV3100 (ASP9785) vs. Bicalutamide in Castrate Men


ISN: 9785-CL-0222IND number: 74,563

Astellas Pharma Global Development, Inc. (APGD)Research & Development1 Astellas WayNorthbrook, IL 60062USA

----------------------------------------------------------------------------------------------------------------




Table of Contents

1 INTRODUCTION·················································································· 6

2 FLOW CHART AND VISIT SCHEDULE ···················································· 6

3 STUDY OBJECTIVE(S) AND DESIGN······················································· 9

3.1 Study Objective(s) ············································································· 9

3.1.1 Primary Objective ········································································ 9

3.1.2 Secondary Objectives ···································································· 9

3.1.3 Exploratory Objectives ·································································· 9

3.2 Study Design···················································································· 9

3.3 Treatment Assignment and Allocation ·····················································10

4 SAMPLE SIZE·····················································································10

5 ANALYSIS SETS ·················································································10

5.1 Full Analysis Set (FAS) ······································································10

5.2 Per Protocol Set (PPS)········································································11

5.3 Safety Analysis Set (SAF) ···································································11

5.4 Pharmacokinetic Analysis Set (PKAS)·····················································11

5.5 Protocol Deviations ···········································································11

6 ANALYSIS VARIABLES ·······································································12

6.1 Efficacy Variables·············································································12

6.1.1 Primary Efficacy Variable······························································12

6.1.2 Secondary Efficacy Variables··························································12

6.1.3 Other Efficacy Variables ·······························································13

6.2 Exploratory Variables ········································································17

6.2.1 FACT-P···················································································17

6.2.2 EQ-5D ····················································································19

6.2.3 BPI-SF ····················································································19

6.2.4 CTC Conversion Rate···································································20

6.3 Safety Variables ···············································································20

6.4 Pharmacokinetic Variables···································································20

7 STATISTICAL METHODOLOGY ···························································20

7.1 General Considerations·······································································20

7.2 Study Population ··············································································21



7.2.1 Disposition of Subjects ·································································21

7.2.2 Demographics and Other Baseline Characteristics ··································21

7.2.3 Previous and Concomitant Medications ··············································21

7.3 Study Drugs····················································································22

7.4 Analysis of Efficacy ··········································································23

7.4.1 Analysis of Primary Variable ··························································23

7.4.2 Analysis of Secondary Variables ······················································24

7.4.3 Analysis of Other Efficacy Variables ·················································25

7.5 Analysis of Exploratory Variables ··························································26

7.5.1 FACT-P···················································································26

7.5.2 EQ-5D ····················································································26

7.5.3 BPI-SF ····················································································27

7.5.4 CTC Conversion Rate···································································27

7.6 Analysis of Safety·············································································27

7.6.1 Adverse Events ··········································································28

7.6.2 Clinical Laboratory Evaluation ························································28

7.6.3 Vital Signs················································································29

7.6.4 Physical Examination Findings ························································29

7.6.5 Electrocardiograms (ECGs) ····························································29

7.6.6 Other Safety-Related Observations ···················································30

7.7 Analysis of Pharmacokinetics ·······························································30

7.8 Other Analyses ················································································30

7.8.1 Pharmacogenomics······································································30

7.9 Interim Analysis (and Early Discontinuation of the Clinical Study)····················30

7.10 Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········31

7.10.1 Missing Data ·············································································31

7.10.2 Visit Windows ···········································································31

7.10.3 Data Cut-off date ········································································32

7.10.4 Other Information ·······································································33

8 DOCUMENT REVISION HISTORY ·························································34

9 REFERENCES ····················································································34

10 APPENDICES ·····················································································35

10.1 Appendix 1: Primary Variable Derivation Using Investigator and/or ICR Data ······35

10.2 Appendix 2: Key Contributors and Approvers ············································44



I. LIST OF ABBREVIATIONS AND KEY TERMS

List of Abbreviations

Abbreviations Description of abbreviationsAE(s) Adverse Event(s)APGD Astellas Pharma Global DevelopmentATC Anatomical-Therapeutic-ChemicalBPI-SF Brief Pain Inventory-Short FormCR Complete ResponseCRF Case Report FormCT Computed TomographyCTC Circulating Tumor CellsCV Coefficient of VariationCXR Chest X-RayECG(s) Electrocardiogram(s)ECOG Eastern Cooperative Oncology GroupEQ-5D European Quality of Life 5 DomainEQ VAS European Quality Visual Analogue ScaleFACT-G Functional Assessment of Cancer Therapy - GeneralFACT-P Functional Assessment of Cancer Therapy - ProstateFACT- P TOI Functional Assessment of Cancer Therapy - Prostate Trial Outcome IndexFAS Full Analysis SetF/U Follow upLLOQ Lower Limit of QuantitationIND Investigational New DrugLHRHa Luteinizing Hormone Receptor Hormone agonist/antagonistMDV3100 3-(4-cyano-3-trifluoromethylphenyl)-1-[3-fluoro-4-

(methylcarbamoyl)phenyl]-5,5-dimethyl-2-thioxoimidazolin-4-oneMedDRA Medical Dictionary for Regulatory Activitiesmg milligramml milliliterMRI Magnetic Resonance ImagingNCI-CTCAE National Cancer Institute’s Common Terminology Criteria for Adverse Eventsng/mL nanograms per millilitrePCWG2 Prostate Cancer Clinical Trials Working Group 2PFS Progression Free SurvivalPK PharmacokineticPKAS Pharmacokinetic Analysis SetPPS Per Protocol SetPR Partial ResponsePSA Prostate Specific AntigenRECIST Response Evaluation Criteria In Solid TumorsrPFS Radiographic Progression Free SurvivalSAE Serious Adverse EventSAF Safety Analysis SetSAP Statistical Analysis PlanSD Stable DiseaseSTD Standard DeviationTEAE(s) Treatment-Emergent Adverse Event(s)



Abbreviations Description of abbreviationsug/L micrograms per literWHO-DRL World Health Organization Drug Reference List

List of Key Terms

Terms Definition of termsBaseline 1) Observed values/findings which are regarded as calibrated zero status in

the present study, 2) Time when ‘Baseline’ is observed.Comparative Drug Agent that the test drug is being compared to in a clinical trial. In this study,

bicalutamide is the comparative drug.Discontinuation A discontinuation is a subject who is enrolled in the study and for whom

study drug is terminated for any reason.InvestigationalPeriod





Screening Period Period of time between Day -28 and Day -1.Study Drug Agents given as part of a clinical trial. In this study, MDV3100 and

bicalutamide are both study drugs.Study Period Period of time beginning with the first subject consented through to the last

observation collected for the study.Subject An individual who participates in a clinical trial, either as a recipient of the

investigational product(s) or as a control.Test Drug Agent under investigation in a clinical trial. In this study, MDV3100 is the

test drug.Variable Any quantity that varies; any attribute, phenomenon or event that can have

different qualitative or quantitative values.



1 INTRODUCTION

This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol for the blind investigational period, and includes detailed procedures for executing the statistical analysis of the primary and secondary variables and other data. The SAP is finalized and signed prior to soft lock of the database.

All statistical analyses and summary information are to be generated according to this analysis plan. Any deviation from this plan will be documented in the clinical study report(CSR).

Prior to Database Lock, a Final Review of Data and TLFs Meeting will be held to allow a review of the clinical trial data and to verify the data that will be used for analysis set classification. If required, consequences for the statistical analysis will be discussed.

2 FLOW CHART AND VISIT SCHEDULE

Flow Chart

* The 60 day PSA assessment and Long-Term follow-up will be performed only for subjects who discontinue study drug for reasons other than radiographic progression, a skeletal related event, or the initiation of a new anti-neoplastic therapy



Table 1 Schedule of Assessments

Study Day Screening Vst 1 8 29 57 85 113 141 169 Safety F/U 60 Daym Long-Term F/Um

Week-4 to -1

(28 days)1 2 5 9 13 17 21

25 and every subsequent 12

weeks


dosel


dose

Every 12weeks from date

of last dose

Window (days) ± 2 ± 3 ± 3 ± 7 ± 3 ± 3 ± 7 ± 7 ± 7 ± 7

Informed Consent X

Demographics/Medical History X

Inclusion/Exclusion Criteria X X

Randomization X

Vital Signsa X Xa Xa Xa Xa X X X X X

Physical Examination, Weight, Heightb X Xe X X X X X X X X

12-Lead ECG X Xe X X X X X X X X

Clinical Labsc X Xe X X X X X X X X

PSA X Xe X X X X X

CT/MRI and Bone Scand X X X X

CXR or Chest CTf Xf Xf Xf

ECOG Performance Status X X X X X X X X X X

BPI -SF X X X

Dispense Dosing Diaries X X

Subject Return Completed Dosing Diaries Xn Xn

Blood Sample for CTC X X X

Blood Sample for PK Analysisg X X

Whole Blood Sample for Optional Genotype Analysish X

Blood Sample for T2:ERG Analysis X

Urine Sample for T2:ERG Analysis i X

Tumor Tissue Sample for T2:ERG Analysis j X

FACT-P and EQ-5D Assessment X X X

Adverse Events X X X X X X X X X X

Concomitant Medications X X X X X X X X X X

Study Drug Dispensingk X X X X X X X

Table footnotes appear on next page



Footnotes:

a. Vital signs (blood pressure, pulse rate, respiration rate, and temperature) will be obtained prior to and 1-2 hours after study drug administration on study weeks 1, 2, 5, and 9.

b. Height obtained at screening visit only

c. Clinical labs, hematology and chemistry, will be obtained prior to study drug administration.

d. Subjects must be assessed with CT/MRI and bone scan within 28 days prior to randomization (Day 1). Scans should be scheduled in such a way that the scan results are available at the regularly scheduled visit.

e. If Day 1 visit occurs within 72 hours after screening, these assessments do not need to be repeated.

f. At screening, a chest x-ray or chest CT will be performed. If a Chest X-Ray is performed and demonstrates metastatic chest disease, a Chest CT is required. In case of metastatic chest disease, additional chest CTs are required to be performed at subsequent imaging visits (week 13, week 25, etc).

g. Blood PK sample to be obtained pre-dose. Sample may be assayed for study drug, metabolites, and/or concomitant medications at the discretion of the sponsor.

h. In the event of unusual PK/PD patterns or safety findings, genotype analysis of relevant metabolism, transporter, pharmacodynamic, and/or safety genes will be conducted. If there is no requirement for analysis, the whole blood sample will be destroyed. Separate subject consent required.

i. A 30 mL urine sample post digital rectal prostate examination will be collected at Day 1 for gene fusion analysis. This sample is collected only from subjects who have not undergone prostatectomy.

j. Tissue sample is from historical tumor blocks/slides. The sample will be used for gene fusion analysis.

k. Subjects should withhold dosing on all clinic visit days. Dose will be administered in clinic.

l. Safety follow-up visit will occur 30 days following the last dose of study drug or prior to the start of a systemic anti-neoplastic therapy, whichever occurs first.

m. Subjects that discontinue study drug for reasons other than radiographic progression, skeletal related event, or initiation of a new anti-neoplastic therapy will have a PSA test performed 60 days after last dose and undergo long-term follow-up every 12 weeks from date of last dose until radiographic progression is documented, a skeletal related event, or a new anti-neoplastic therapy is initiated.

n. A dosing diary will be completed for 7 days prior to week 13 and week 21. In the diary, the subject will be asked to document date and time of medication intake and the time of last meal.



3 STUDY OBJECTIVE(S) AND DESIGN

3.1 Study Objective(s)

3.1.1 Primary Objective

To determine the progression free survival (PFS) of MDV3100 as compared to bicalutamide.

3.1.2 Secondary Objectives

To determine the safety of treatment with MDV3100 as compared to bicalutamide. To determine the prostate specific antigen (PSA) response of MDV3100 at week 13

as compared to bicalutamide. To determine the time to PSA progression of MDV3100 as compared to bicalutamide.

3.1.3 Exploratory Objectives

To evaluate quality of life using the Functional Assessment of Cancer Therapy -Prostate (FACT-P), European Quality of Life 5 Domain Scale (EQ-5D) and Brief Pain Inventory Short Form (BPI-SF) instruments.

To determine the benefit of MDV3100 as compared to bicalutamide as assessed by the circulating tumor cell (CTC) conversion rate.

3.2 Study Design

This is a multinational phase II, randomized, double-blind, parallel study to determine the efficacy and safety of oral MDV3100 (160 mg/day) compared to bicalutamide (50 mg/day) in castrate men with metastatic prostate cancer who have progressed while on Luteinizing Hormone Receptor Hormone agonist/antagonist (LHRHa) or after receiving a bilateralorchiectomy.

Approximately 370 eligible subjects will be randomized 1:1 to one of two treatment arms: MDV3100, 160 mg orally once daily, or bicalutamide, 50 mg orally once daily. Subjects will be stratified by site and by whether bilateral orchiectomy or receipt of LHRHa therapy startedbefore or after the diagnosis of metastases.

For the study duration, all subjects will maintain castration therapy with an LHRHa or bilateral orchiectomy. Subjects will be discontinued from study drug at the time of confirmed radiographic disease progression, skeletal-related event, or the initiation of a new anti-neoplastic therapy.


Subjects that discontinue study drug treatment for a reason other than radiographic progression, a skeletal related event, or initiation of a new anti-neoplastic therapy will have a PSA test performed 60 days from date of last dose and undergo long-term follow-up every 12 weeks from date of last dose. Long term follow-up will assess for the following until at least one of these occurs: radiographic progression, skeletal related events, the start of new anti-neoplastic therapy for prostate cancer, or death.



3.3 Treatment Assignment and Allocation

Each screened subject receives a unique screening number and this number is used throughout the study. Subjects who meet the inclusion/exclusion criteria are allocated to receive study drug by use of stratified randomization. Each randomized subject received a unique randomization number. Subjects are stratified by site and by whether bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases.

4 SAMPLE SIZE





A sample size of approximately 356 subjects (178 subjects per treatment arm) will achieve 257 progression events within approximately 24 months (18 months for accrual and 6 months for follow-up) from the date the first subject is randomized. A four percent lost to follow-up rate will be assumed giving a final sample size of 370 subjects (185 subjects per treatment arm);

The sample size calculations are performed using the software package nQuery Advisor Version 7.0 (Statistical Solutions, Cork, Ireland).


5 ANALYSIS SETS

5.1 Full Analysis Set (FAS)

The FAS is defined as all subjects who are randomized into the study. All subjects will be analyzed as randomized (not by actual treatment received) when FAS population is used.

The FAS will be the primary set for all efficacy analyses.



5.2 Per Protocol Set (PPS)


Subjects who do not have any major protocol deviations (i.e., deviations in categories 1 to 4 in Section 5.5 which are reviewed during the analysis set classification meeting)

Subjects who have initiated at least one dose of assigned study drug

Primary and secondary efficacy analyses will be repeated on this set.

5.3 Safety Analysis Set (SAF)

The SAF is defined as all subjects who have initiated at least one dose of study drug. All subjects will be analyzed as treated (not by treatment assigned at randomization) when SAF population is used. In case subjects receive more than one protocol therapy, subjects will be analyzed according to the actual treatment received during the majority of the time they were on protocol treatment.

All safety analyses will be performed on this set.

5.4 Pharmacokinetic Analysis Set (PKAS)

The PKAS will consist of a subset of subjects in SAF who have at least one pharmacokinetic(PK) concentration value.

The PKAS will be used for all PK analyses.

5.5 Protocol Deviations

All protocol deviations and whether they lead to the exclusion of the subject from the SAF,PPS and/or PKAS will be listed. Additional protocol deviations that are identified during the analysis set classification meeting (ASCM), which will be held prior to Database Lock, will also be presented.

The following protocol deviations will be defined:

1 Subjects who entered the study even though they did not satisfy the entry criteria2 Subjects who developed withdrawal criteria during the study but were not withdrawn3 Subject who received the wrong treatment or incorrect dose4 Subjects who received an excluded concomitant medication5 Other:

Subjects with change in cancer assessment modality Subjects randomized in the wrong stratum (bilateral orchiectomy or receipt of

LHRH agonist/antagonist therapy started before vs. after the diagnosis of metastases)

Subjects with protocol deviations will not be excluded from the analyses of the safety data (except in the case of subjects with all post baseline safety data missing). The PK specialist will be consulted whether there are any protocol deviations which lead to exclusion of subjects from the PKAS or plasma concentrations at single time points (i.e., schedule day)from the PK analysis.



6 ANALYSIS VARIABLES

6.1 Efficacy Variables

6.1.1 Primary Efficacy Variable

The primary efficacy variable is PFS where a progression event is defined as an objective evidence of radiographic disease progression (by Independent Central Review), skeletal-related event, initiation of new anti-neoplastic therapy or death by any cause, whichever occurs first.

Radiographic disease progression is defined as either a progression in soft tissue on CT/MRI scan according to RECIST 1.1 (not requiring a confirmatory scan), and/or a progression in bone lesions on bone scan (i.e., a minimum of two new bone lesions as compared to previous scan) confirmed by the next bone scan. Bone disease progression on bone scan at week 13 requires a confirmatory bone scan showing at least 2 additional new lesions on the next bone scan. Bone disease progression on bone scan after week 13 (i.e., after day 99) requires a confirmatory bone scan showing at least one additional new lesion on the next bone scan. The radiological assessments by the Independent Central Review will be used. The date of progression is the date the first evidence of radiographic disease progression is documented.Unconfirmed progression on bone scan will not be considered as event.

A skeletal-related event is defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, change in anti-neoplastic therapy to treat bone pain.

The initiation of new anti-neoplastic therapy is defined as the start of any new anti-neoplastic therapy for the treatment of disease progression after the study drug administration started.

In subjects with any documented progression event as defined above, PFS, defined as the time to progression event, will be calculated as the time interval from the date of randomization to the date of the first progression event detected. Should there be more than one event observed on the date of the first progression event, the first event will be selected among those events according to the following order: 1- radiographic disease progression,2- skeletal-related event, 3 – the initiation of a new anti-neoplastic therapy, and 4- death.

In subjects with no documented progression event as defined above, including those who received study drug treatment after the data cut-off date and those who discontinued study drug treatment for a reason other than progression events, PFS will be censored on the date of the last disease assessment performed. Subjects with no post baseline assessments will be censored on the date of randomisation.

6.1.2 Secondary Efficacy Variables

PFS where a progression event is defined as an objective evidence of radiographic disease progression based on the assessments made by investigators (and not the Independent Central



Review), skeletal-related event, initiation of new anti-neoplastic therapy or death by any cause, whichever occurs first.

Other secondary efficacy variables are PSA response and time to PSA progression. For these variables derived from PSA measurements, only results from PSA samples taken before the start of any new anti-neoplastic therapy will be considered and are referred to in this section.

Based on the schedule of assessments, subjects have PSA samples taken at baseline, week 13 and every 12 weeks thereafter, as well as 30 days post treatment (and/or 60 days post treatment if discontinued for any other reason than a protocol defined progression event). The PSA response by week 13 is defined as the percentage change from baseline to the smallest PSA value after baseline and on or before day 99 (i.e., upper boundary of the week 13 visit window). For subjects with no decrease in PSA post baseline by week 13, the PSA response by week 13 is the smallest increase in PSA up to day 99. For subjects with no post baseline PSA values up to day 99, the PSA response by week 13 will be set to missing.

The best PSA response is defined as the percentage change from baseline to the smallest PSA value after baseline including PSA results from samples taken after the study drug was stopped. For subjects with no decrease in PSA post baseline, the best PSA response is the smallest increase in PSA. For subjects with no post baseline PSA values, the PSA response will be set to missing.

For the time to PSA progression analysis, PSA progression is defined as a ≥25% increase and an absolute increase of ≥2 ug/L (i.e., 2 ng/mL or more) above the nadir (or above the baseline value for subject who did not have a decline in PSA post baseline values), and confirmed by a second consecutive PSA assessment at least 3 weeks later. The date of PSA progression is the date the first evidence of PSA progression is documented. In subjects with PSA progression, time to PSA progression will be calculated as the time interval from the date ofrandomization to the date of first observation of PSA progression. In subjects with no PSA progression, time to PSA progression will be censored on the date of the last PSA sample taken. Subjects without PSA progression prior to 2 or more consecutive missed PSA assessments (i.e., time interval >6 months=182 days between 2 consecutive PSA samples)

will be censored on the date of last PSA assessment prior to the assessments missed. Subjects who have no PSA baseline and subjects who only have the PSA baseline will be censored on the date of randomisation.

6.1.3 Other Efficacy Variables

Time to PSA ≤4ng/ml, time to ≥30% PSA decline from baseline, time to ≥50% PSA decline from baseline and time to ≥90% PSA decline from baseline

For these variables derived from PSA measurements, only results from PSA samples taken before the start of any new anti-neoplastic therapy will be considered and are referred to in this section.

In subjects with PSA results ≤4ng/ml, time to PSA ≤4ng/ml is defined as the time interval from the date of randomization to the first date a decline in PSA to a result of 4 ng/ml or below is recorded. In subjects without PSA results ≤4ng/ml, the time to PSA ≤4ng/ml will be



censored on the date of the last PSA sample taken. Subjects with a PSA result ≤4ng/ml at baseline, subjects with no baseline PSA, and subjects with no post-baseline PSA results will be censored on the date of randomization.

In subjects with ≥30% PSA decline from baseline (50% and 90%, respectively), the time to ≥30% PSA decline from baseline (time to ≥50% PSA decline from baseline and time to ≥90% PSA decline from baseline, respectively) is defined as the time interval from the date of randomization to the first date a PSA decline from baseline of at least 30% (50% and 90%, respectively) is recorded. In subjects without ≥30% PSA decline from baseline (50% and 90%, respectively), the time to ≥30% PSA decline from baseline (time to ≥50% PSA decline from baseline and time to ≥90% PSA decline from baseline, respectively) will be censored onthe date of the last PSA sample taken. Subjects who have no baseline PSA and subjects with no post-baseline PSA results will be censored on the date of randomisation.

Radiographic progression free survival

Using the radiological assessments done by the Independent Central Review, the radiographic progression free survival by Independent Central Review in subjects with documented radiographic disease progression or death will be calculated as the time interval from the date of randomization to the first date of radiographic disease progression (asdefined in Section 6.1.1 for the primary variable) or death, whichever occurs first. The radiographic progression free survival by investigators will similarly be defined using the radiological assessments done by the investigators.

In subjects with no documented radiographic progression or death, radiographic progressionfree survival will be censored on the date of the last radiographic assessment prior to the data cut-off date. Subjects with no baseline radiographic assessment, subjects with no post baseline radiographic assessments and subjects with all post-baseline radiographic assessments documented as “Not Evaluable”, the radiographic progression free survival will be censored on the date of randomisation.

Overall response assessment

Objective response assessments are reported by the investigator and the Independent Central Review at each time point for target lesions in soft tissues and non-target lesions in soft tissues based on CT and/or MRI. Response assessment on bone scans for bone lesions, and the overall response were also reported at each time point.

The following categories were used:

CR = complete response PR = partial response (option only for target lesions and overall) SD = stable disease (option only for target lesions and overall) PD = progressive disease Non CR/non PD= not complete response and not progressive disease

(option only for non-target lesions, bone lesions, and overall) Unconfirmed PD (option only for bone lesions)



NE = not evaluated = not all evaluated or evaluable, or scans were not done = inevaluable for overall

NA = not applicable = no lesion of the kind at baseline and scans were done (not an option for overall)

At each time point, the RECIST overall time point response in soft tissue lesions in patients with measurable soft tissue lesions at study entry can be derived according to RECIST for all possible combinations (Table 2) of tumor response assessments in target and non-target lesions in soft tissues with or without the appearance of new soft tissue lesions. Due to the process the Independent Central Review data are collected (with adjudication focusing on the date of progression, best overall response and date of response) the RECIST overall response in soft tissue lesions at each time point cannot adequately present the ICR assessment over time and will therefore not be derived. It will be derived based on the investigator assessments. In absence of new soft tissue lesion in patients with no target and no non-target soft tissue lesion at study entry, the derived RECIST overall time point response in soft tissue lesions is set to ‘Not Applicable’. To derive the RECIST overall time point response in soft tissue lesions, missing assessments in target and non-target lesions and the appearance of new soft tissue will be considered as assessments Not Evaluated.

Table 2 Derived RECIST Overall Time Point Response in Soft Tissue Lesions for All Possible Combinations of Tumor Responses in Target and Non-Target Lesions With or Without Appearance of New Soft Tissue Lesions According to The Investigator Assessments

Target Lesions* Non-Target Lesions*New Soft Tissue

Lesions

RECIST Overall ResponseAssessment in soft

tissue lesionsCR CR No CRCR Not Applicable No CR

Not applicable CR No CRCR Non-CR/Non-PD No PRCR Not evaluated or Missing No PRPR Not PD No PRSD Not PD No SDPD Any Yes or No or Missing PDAny PD Yes or No or Missing PDAny Any Yes PD

Not applicable Non-CR/Non-PD No Non-CR/Non-PDNot applicable Not applicable No Not applicable $

Not applicable Not evaluated or Missing No or Missing NENot evaluated Not PD No or Missing NE

Missing Not PD No or Missing NEAny, except PD Not PD Missing NE

* the category “Any” includes all possible categories (incl. NE, NA, or Missing). The category “Not PD” includes: CR, Non-CR/Non-PD,Unconfirmed PD, Not Evaluated, Not Applicable and Missing.

$ In absence of new soft tissue lesion, the derived RECIST overall time point response in soft tissue lesions is only set to “Not applicable” for patients with no target and no non-target soft tissue lesions at study entry.



At each time point, the overall time point response assessment corresponds to a combination of the RECIST overall time point response in soft tissue lesions by CT/MRI and the overall response assessment on bone lesions by bone scans. All possible combinations are presented in Table 3.

Table 3 Overall Time Point Response Assessment Based on Combinations of The Derived RECIST Overall Response in Soft Tissue Lesions and BoneResponse Assessment

RECIST Overall Response Assessment in

soft tissue lesions*Bone Lesion

Response Assessment*^Overall

Response Assessment^CR CR CRCR Not Applicable CR

Not applicable CR CRCR Non-CR/Non-PD PRCR Unconfirmed PD PRPR CR Eval

= & notPD

PRPR Non-CR/Non-PD PRPR Unconfirmed PD PRPR Not applicable PRSD CR Eval

= & notPD

SDSD Non-CR/Non-PD SDSD Unconfirmed PD SDSD Not Applicable SDPD Any PDAny PD PD

Non-CR/Non-PD CR Eval= & not

PD

Non-CR/Non-PDNon-CR/Non-PD Non-CR/Non-PD Non-CR/Non-PDNon-CR/Non-PD Unconfirmed PD Non-CR/Non-PDNon-CR/Non-PD Not applicable Non-CR/Non-PD

Not applicable Non-CR/Non-PD Non-CR/Non-PDNot applicable Unconfirmed PD Non-CR/Non-PD

Any, except PD Not evaluated / Missing NENot evaluated Any, except PD NE

* The category “Any” includes all possible categories (incl. NE or NA). The category “Not PD” includes: CR, Non-CR/Non-PD, Not Applicable and Unconfirmed PD.

^ Missing assessments for “Bone Lesion Response Assessment” and/or “Overall Response Assessment” at study visits will not be imputed and will be reported as “Missing” at the time of analysis.

The response rate will be estimated as the number of subjects achieving either a complete response (CR) or a partial response (PR), i.e., complete + partial responses based on subject’s best overall response assessed at the end of the treatment by the investigator or by the Independent Central Review, divided by the number of subjects in the analysis population. The best overall response is the best of the overall time point response assessments reported at any time during the study. For subjects still on treatment after the analysis cut-off date, the best overall response will be derived as the best of the overall time point response assessments recorded for the time on study up to the analysis cut-off date. The best of the overall time point response assessments is according to the following order: CR(best), PR,



SD, Non-CR/Non-PD, PD, NA, NE. Subjects with unknown or missing response, or who are still on treatment after the analysis cut-off date but provided no information on tumor response during and at the end of treatment will be treated as non-responders and will be included in the denominator when calculating percentages.

6.2 Exploratory Variables

The exploratory variables are:

Quality of life questionnaires: FACT-P, EQ-5D and BPI-SF; CTC conversion rate.

6.2.1 FACT-P

FACT-P is composed of 27 core items which assess patient function in four domains and 12 prostate-related items, grouped into 5 subscales as follows:

Physical well-being (PWB): 7 items; Social/family well-being (SWB): 7 items; Emotional well-being (EWB): 6 items; Functional well-being (FWB): 7 items; Prostate cancer subscale (PCS): 12 items.

All FACT-P items are rated as: 0=not at all; 1= a little bit; 2= somewhat; 3= quite a bit; 4= very much. For some items a response of “4= very much” is better than a response of “3= quite a bit” (e.g., “I get support from my friends”), while for other items a response of “4= very much” is worse than a response of “3= quite a bit” (e.g. “I have pain”). Before calculating the subscale and global scores, the items for which “4” is worse than “3” must be reversed, by subtracting the response from 4. The reversals are performed in the following:

PWB: reverse all items (GP1 – GP7); SWB: do not reverse any items; EWB: reverse items GE1 and GE3 – GE6;

FWB: do not reverse any items; PCS: reverse items C2, P1 – P3, P6 – P8 and BL2.

After reversing proper items, for all FACT-P scales, the higher the score the better the quality of life.

Each subscale score is the sum of the scores for the items in the subscale. If there are missing items, subscale scores can be prorated, as long as more than 50% of the items are answered in any given subscale (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc). The score is prorated as follows:

Prorated subscale score = (sum of item scores) * (number items in the subscale)/(number of items answered).

The following Table 4 lists each FACT-P item and its appropriate scoring.



Table 4 Scoring of FACT-P items

ScoringItem number Not at all A little bit Somewhat Quite a bite Very much

PWB GP1 4 3 2 1 0GP2 4 3 2 1 0GP3 4 3 2 1 0GP4 4 3 2 1 0GP5 4 3 2 1 0GP6 4 3 2 1 0GP7 4 3 2 1 0

SWB GS1 0 1 2 3 4GS2 0 1 2 3 4GS3 0 1 2 3 4GS4 0 1 2 3 4GS5 0 1 2 3 4GS6 0 1 2 3 4GS7 0 1 2 3 4

EWB GE1 4 3 2 1 0GE2 0 1 2 3 4GE3 4 3 2 1 0GE4 4 3 2 1 0GE5 4 3 2 1 0GE6 4 3 2 1 0

FWB GF1 0 1 2 3 4GF2 0 1 2 3 4GF3 0 1 2 3 4GF4 0 1 2 3 4GF5 0 1 2 3 4GF6 0 1 2 3 4GF7 0 1 2 3 4

PCS C2 4 3 2 1 0C6 0 1 2 3 4P1 4 3 2 1 0P2 4 3 2 1 0P3 4 3 2 1 0P4 0 1 2 3 4P5 0 1 2 3 4P6 4 3 2 1 0P7 4 3 2 1 0

BL2 4 3 2 1 0P8 4 3 2 1 0

BL5 0 1 2 3 4

The FACT-P TOI is the sum of the 3 subscale scores: PWB, FWB and PCS; the FACT-G total score is the sum of 4 subscale scores: PWB, SWB, EWB and FWB; the FACT-P total



score is the sum of all 5 subscale scores. The total score will be calculated only if the overall item response rate is greater than 80% (i.e., a minimum of 21 of 26 items in TOI, 22 of 27 items in FACT-G or 32 of 39 items currently scored in the FACT-P have been answered), and no subscale scores are missing.

Time to FACT-P progression, where FACT-P progression is defined as a decrease from baseline in the FACT-P total score by 10 points or more. In subjects with FACT-P progression, time to FACT-P progression is defined as the time interval from the date of randomization to the first date a decline of 10 points or more in the total FACT-P score is recorded. In subjects without FACT-P progression, the time to FACT-P progression will be censored on the date of the last FACT-P total score is calculable. Subjects who have no baseline score and subjects who only have the baseline score will be censored on the date of randomization.

6.2.2 EQ-5D

EQ-5D consists of two pages: EQ-5D descriptive system and EQ visual analogue scale (EQ VAS).

The EQ-5D descriptive system comprises five questions covering health domains of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. For each domain subjects could fall in three levels of severity (1=no problems, 2=some problems, and 3=severe problems). Ambiguous values should be treated as missing values.

The EQ VAS records the subject’s self-rated health on a vertical, visual analogue scale with values from 100 to 0. The higher the score the better the health state.

6.2.3 BPI-SF

The BPI-SF is a self-report instrument composed of nine questions for assessing pain and its impact.

The BPI-SF scoring will be provided by two parts:

Pain severity: worst, least, average and current pain (Question 3 to 6); Pain interference: general activity, mood, work, walking ability, relations, sleep and

enjoyment of life (item A to G of Question 9).

Composite scores of pain severity and the pain interference will be produced by averaging their subscales. Each score ranges from 0 to 10 with higher scores representing a higher level of pain or interference. To calculate the composite score of severity, all four items should be completed, or otherwise, the score will be treated as a missing value. For the interference score, if there are missing items, the score can be prorated as follows:

Prorated score = (sum of item scores)/(number of items answered), as long as more than 50% of the items are answered in Question 9 (i.e., a minimum of 4 of 7 items).



6.2.4 CTC Conversion Rate

For subjects with baseline CTC counts of ≥5 cells per 7.5 ml of blood (i.e., unfavourable status) a conversion is defined as a decrease in the CTC count to <5 cells per 7.5 ml of blood (i.e., favourable status).

For subjects with baseline CTC counts of <5 cells per 7.5 ml of blood, a conversion is defined as an increase in the CTC count to ≥5 cells per 7.5 ml of blood.

The CTC conversion rates refer to the proportion of subjects with a conversion from unfavourable to favourable status and the proportion of subjects with a conversion from favorable to unfavourable status.

6.3 Safety Variables

Safety will be assessed by evaluation of the following variables:

Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, and relationship to study drug) are defined as adverse events (AEs) that started or worsened after starting administration of study drug through end of the study;

AEs will be coded to system organ class and preferred term using MedDRA v12.0and graded using National Cancer Institute’s Common Terminology Criteria for AEs (NCI-CTCAE v 4.03).

Clinical laboratory variables (hematology and serum chemistry); Physical examination; Vital signs (blood pressure, pulse rate, respiration rate and temperature); Electrocardiogram (ECG).

6.4 Pharmacokinetic Variables

To evaluate the PK of MDV3100 and its main metabolites, blood samples were collected at pre-dose at week 13 and 21 for determining Ctrough.

7 STATISTICAL METHODOLOGY

7.1 General Considerations

For continuous variables, descriptive statistics will include the number of subjects, mean, standard deviation (STD), median, minimum and maximum. In addition, for continuous PK parameters, the coefficient of variation (CV) and geometric mean will be calculated. Frequencies and percentages will be displayed for categorical data. Percentages by categories will be based on the number of subjects with no missing data and will add up to 100%.

All data processing, summarization, and analyses will be performed using SAS Version 9.2or a later version. Specifications for table, graph, and data listing formats can be found in the TLF specifications for this study.

All listings will be produced by site and subject id numbers in ascending order.



7.2 Study Population

7.2.1 Disposition of Subjects

The following subject data will be summarized and presented on the FAS, by treatment armand stratum and also overall:

Number and percentage of subjects in each analysis set Number and percentage of subjects still on treatment Number and percentage of subjects who discontinued from the treatment, overall and

by reason for discontinuation Number and percentage of subjects who completed the study and who prematurely

discontinued from the study by reason for discontinuation Number of subjects with protocol deviations

Unblinding of study subjects, if any, captured in the case report form (CRF) as well as the reason for exclusion of subjects from one or more populations will be listed.

7.2.2 Demographics and Other Baseline Characteristics

Demographic information will be summarized by treatment arm and stratum on both FAS and PPS. Descriptive statistics for age, weight, height and BMI, and frequency tabulations for sex, ethnicity and race will be provided.

Non-prostate cancer related medical history including data up to the start of study drug will be coded using the Medical Dictionary for Regulatory Activities (MedDRA v12.0 or later version) and summarized by presenting the number and percentage of subjects on the FAS by treatment arm. The summary table will be presented alphabetically by system organ class anddecreasing order of frequency of preferred terms within each system organ class.

Prostate cancer history will be summarized by presenting the number and percentage of subjects for tumor and lymph node stages, Gleason scores, incidence of metastases and previous therapies on the FAS. Descriptive statistics will be used to summarize the duration

of disease which is the duration between the date the informed consent is signed and the date of initial diagnosis (expressed in years).

All demographic and baseline characteristics used in efficacy subgroup analysis will be summarized by descriptive statistics.

7.2.3 Previous and Concomitant Medications

Previous and concomitant medications will be coded with World Health Organization Drug Reference List (WHO-DRL) and will be listed.

Previous medications are those medications or therapies taken within four weeks prior to randomization. Concomitant medications are those medications or therapies taken after initial study drug administration through the study.

Previous and concomitant medications (prescription, over-the-counter, and nutritional supplements) will be summarized by presenting the number and percentage on the SAF. A subject taking the same medication multiple times will only be counted once for that



medication. The summary table will be presented alphabetically by Anatomical-Therapeutic-Chemical (ATC) classification and decreasing order of frequency of preferred terms within each ATC class.

7.3 Study Drugs

In this study, subjects are randomized 1:1 to one of two treatment arms: MDV3100 or bicalutamide. Subjects randomized to the MDV3100 study arm will receive 160 mg (fourcapsules) of MDV3100 and one placebo capsule orally once daily at the same time each day.Subjects randomized to the bicalutamide study arm will receive 50 mg (one capsule) ofbicalutamide and four placebo capsules orally once daily at the same time each day. Study drug can be taken with or without food.

The duration of exposure (number of days) to study medication will be summarized using descriptive statistics on the SAF for each treatment group, where the duration of exposure to study drug is defined from the date of first dose to the last known date that subject took study drug. The number and proportion of subjects with dose reduction will be tabulated by treatment arm. A listing of study drug dosing and meal information will be provided.

The total number of capsules taken, total cumulative dose, and percent overall compliance will be calculated and summarized using descriptive statistics on the SAF by treatment arm. A data listing will be provided to present those derived variables for all subjects in the SAF.

The number of capsules taken will be calculated based on the number of capsules dispensed at all study visits (except the last visit before the cut-off date for patients still on treatment by the cut-off date, and for which the number of capsules returned is unknown or the capsules were returned after the cut-off date) minus the number of capsules indicated as returned.

In the MDV3100 study arm, the total cumulative dose in milligrams (mg) will be calculated as (40 mg * number of capsules taken * 4 / 5). In the bicalutamide arm, the total cumulative

dose in milligrams (mg) will be calculated as (50 mg * number of capsules taken / 5).

The percent overall compliance will be defined as the number of capsules taken during the study divided by the expected number of capsules for the theoretical full dose, multiplied by 100. For patients on treatment by the cut-off date, the last kit(s) not returned will not be considered, nor the time since the last kit was dispensed. For patient who discontinued from treatment, the subject’s expected number of capsules will be calculated as [5 * (the last date that subject took study drug – date of first dose of study drug + 1)]. For patients who are still on treatment by the time of the cut-off date, a subject’s expected number of capsules will be calculated as [5 * (the last date drug was dispensed to the subject – date of first dose of study drug)]. Percent overall compliance will be summarized both as a continuous measure and a categorical measure in increments of 20% (<70%, 70-90%, >90-110%, >110%).



7.4 Analysis of Efficacy

Primary and secondary efficacy analysis will be conducted on both FAS and PPS. The efficacy analysis based on the FAS is considered primary. The analysis of other efficacy variables will be conducted on the FAS only.


The primary efficacy variable is PFS where the radiographic component of the endpoint is based on the radiographic assessments made by the Independent Central Review.

The (unstratified) log-rank test with overall significance level of 0.05 (two-sided) will be used to compare the PFS of MDV3100 to bicalutamide. SAS PROC LIFETEST will be used for the analysis.

The (unstratified) Cox proportional hazards model with treatment group as the covariate will

be used to test the hypothesis that the hazard ratio is equal to one. The null and alternative hypotheses regarding PFS can be phrased in terms of the hazard ratio, /ArmA ArmB , where

ArmA represents the hazard of PFS for arm A (MDV3100) and ArmB represents the hazard of

PFS for arm B (bicalutamide). A hazard ratio of 1 indicates that the PFS is prolonged for subjects randomized to arm A (MDV3100) compared with subjects randomized to arm B (bicalutamide). The null and alternative hypotheses, respectively, can be written as follows:

H0: 1ArmA

ArmB

HA: 1ArmA

ArmB

The estimated hazard ratio of MDV3100 to bicalutamide, /ArmA ArmB , and its 95%

confidence interval will be provided. SAS PROC PHREG will be used for the analysis with the “DISCRETE” option for tie breaker. The assumption of proportional hazards will be investigated graphically by plotting log (-log[estimated survival distribution function]) against log(survival time).

If the estimate of the hazard ratio / 1ArmA ArmB and the results from the (unstratified)

log-rank test lead to the rejection of H0 in favor of HA, then it will be concluded that MDV3100 prolongs PFS compared to bicalutamide.

Kaplan-Meier methods will be used to estimate the distribution of PFS by treatment group. The median PFS will be estimated using the corresponding 50th percentile of Kaplan-Meier estimates. A two-sided 95% confidence interval will be provided for this estimate by use of the Brookmeyer and Crowley method. A Kaplan-Meier plot by treatment group will be presented. The estimates of the event free rate on a monthly basis up to 6 months and every 3 months thereafter will be summarized by treatment group on the FAS, as long as at least 10 patients are at risk.

No adjustment will be made for the multiple comparisons of the primary variable in the following sensitivity analyses.



The primary efficacy analysis will be repeated with stratum (bilateral orchiectomy or receipt of LHRH agonist/antagonist therapy started before or after the diagnosis of metastases) as additional factor in the analyses.

Subgroup analyses of PFS will be performed to determine whether the treatment effect isconcordant among subgroups. The following variables will be used to conduct subgroup analyses:

Age category (< 65, 65-75 and > 75); Geographic region (North America versus Europe); Eastern Cooperative Oncology Group (ECOG) Performance Status (0 versus

1) at baseline; Gleason score (7 or less versus 8 or more) at initial diagnosis; Disease localization (Bone only versus Soft tissue only versus Both bone and

soft tissue) at baseline; Baseline PSA value (at or below median versus above median); Diagnosis of metastases occurring before or after medical (LHRHa therapy) or

surgical castration (bilateral orchiectomy). Previous use of anti-androgen therapy (Use of anti-androgen therapy prior to

randomization versus No use of anti-androgen therapy prior to randomization)

A forest plot displaying the hazard ratio and 95% confidence interval by use of (unstratified) Cox proportional hazards models with treatment group as the covariate, by subgroup will be presented.


No adjustment will be made for the multiple comparisons.

The primary efficacy analysis will be repeated on PFS where the radiographic component of the endpoint is based on the radiological assessments made by the investigators.

Descriptive statistics for the PSA response by week 13 and the best PSA response will be

presented by treatment group. For each treatment group, waterfall plots will be reported for both variables.

For time to PSA progression, the (unstratified) log-rank test with overall significance level of 0.05 (two-sided) will be used to compare the estimated survival functions of the two treatment groups. SAS PROC LIFETEST will be used for the analysis.

The (unstratified) Cox proportional hazards model with treatment group as a factor will be used to test the hypothesis that hazard ratio is equal to one. The null and alternative hypotheses regarding time to PSA progression can be phrased in terms of the hazard ratio,

/ArmA ArmB , where ArmA represents the hazard of time to PSA progression for arm A

(MDV3100) and ArmB represents the hazard of time to PSA progression for arm B

(bicalutamide). A hazard ratio of 1 indicates that the time to PSA progression is prolonged



for subjects randomized to arm A (MDV3100) compared with subjects randomized to arm B (bicalutamide).

The null and alternative hypotheses, respectively, can be written as follows:

H0: 1ArmA

ArmB

HA: 1ArmA

ArmB

The estimated hazard ratio of MDV3100 to bicalutamide, /ArmA ArmB , and its 95%

confidence interval will be provided. SAS PROC PHREG will be used for the analysis with the “DISCRETE” option for tie breaker. The assumption of proportional hazards will be investigated graphically by plotting log (-log[estimated survival distribution function]) against log(survival time). If the estimate of the hazard ratio / 1ArmA ArmB and the results

from the (unstratified) log-rank test lead to the rejection of H0 in favor of HA, then it will be concluded that MDV3100 prolongs the time to PSA progression compared to bicalutamide.

Kaplan-Meier method will be used to estimate the distribution of time to PSA progression by treatment group. The median time to PSA progression will be estimated using the corresponding 50th percentile of Kaplan-Meier estimates. A two-sided 95% confidence interval will be provided for this estimate by use of the Brookmeyer and Crowley method. A Kaplan-Meier plot by treatment group will be presented. The estimates of the event free rate on a monthly basis up to 6 months and every 3 months thereafter will be summarized by treatment group on the FAS, as long as at least 10 patients are at risk.

The analyses of time to PSA progression will be repeated with stratum as an additional factor.PSA results will be presented in the listing by subject.

7.4.3 Analysis of Other Efficacy Variables

Descriptive statistics for the percentage of change of PSA by visit will be presented by treatment arm.

Kaplan-Meier method will be used to estimate the distribution of time to PSA ≤ 4ng/ml, time to ≥30% PSA decline from baseline, time to ≥50% PSA decline from baseline, time to ≥90%

PSA decline from baseline, radiographic progression free survival by Independent CentralReview and radiographic progression free survival by the investigators, by treatment group. For these endpoints, the median will be estimated using the corresponding 50th percentile of Kaplan-Meier respective estimates. A two-sided 95% confidence interval will be provided for these estimates by use of the Brookmeyer and Crowley method. The estimated hazard ratio of MDV3100 to bicalutamide and its 95% confidence interval will be provided. SAS PROC PHREG will be used for the analysis with the “DISCRETE” option for tie breaker. The estimates of the event free rate on a monthly basis up to 6 months and every 3 months thereafter will be summarized by treatment group, as long as at least 10 patients are at risk. A Kaplan-Meier plot by treatment group will be presented for all time to event endpoint.

The best overall response rate, as well as the number and percentage of subjects falling in each category of the best overall response (CR, PR, progressive disease (PD),



non-CR/non-PD, SD and not evaluated), and similarly the derived RECIST overall time point response in soft tissue lesions, bone lesion response and overall time point response by visit will be summarized descriptively by treatment arm. It will be presented for both the Independent Central Review and the investigator radiological tumor response assessments. In addition these analyses will also be conducted on the restricted set of subjects with documented soft tissue disease at study entry. The target lesion response, non-target lesion response, unequivocal new lesions, derived overall RECIST time point response in soft tissue lesions, bone lesion response, the overall time point response will be listed by visit for both the Independent Central Review and the investigator radiological tumor response assessmentsalong with their best overall response.

The number and percentage of concordant and discordant cases of radiographic disease progression between the Independent Central Review and the investigator radiological assessments, as well as the best overall tumor response assessments for subjects with response will be summarized descriptively.

7.5 Analysis of Exploratory Variables

The exploratory variables include FACT-P, EQ-5D, BPI-SF and CTC conversion rate. The exploratory analysis will be conducted on FAS. Data listings will be provided for all exploratory variables by subject and visit.

7.5.1 FACT-P

Descriptive statistics will be presented for the FACT-P subscale scores, three total scores (FACT-P Trial Outcome Index (TOI), Functional Assessment of Cancer Therapy-General (FACT-G) total score and FACT-P total score) and their changes from baseline by treatment arm and visit.

Plots of mean (+STD) will be presented for the three total scores by treatment arm and visit.

Kaplan-Meier method will be used to estimate the distribution of time to FACT-P progression by treatment group. The median will be estimated using the corresponding 50th

percentile of Kaplan-Meier respective estimates. A two-sided 95% confidence interval will be provided for this estimate by use of the Brookmeyer and Crowley method. The estimates of the event free rate on a monthly basis up to 6 months and every 3 months thereafter will be summarized by treatment group, as long as at least 10 patients are at risk. A Kaplan-Meier plot by treatment group will be presented.

7.5.2 EQ-5D

EQ-5D consists of two pages:

EQ-5D descriptive system

For each health domain (morbidity, self-care, usual activities, pain/discomfort and anxiety/depression), number and percentage of subjects falling in three levels of severity



(1=no problems, 2=some problems, and 3=severe problems) will be summarized by treatment arm and visit. Ambiguous values should be treated as missing values.

EQ visual analogue scale (EQ VAS).

The EQ VAS records the subject’s self-rated health on a vertical, visual analogue scale with values from 100 to 0. The higher the score the better the health state. Descriptive statistics for the scale values and their changes from baseline will be summarized by treatment arm andvisit.

7.5.3 BPI-SF

The BPI-SF is a self-report instrument composed of nine questions for assessing pain and its impact. Except Question 7 (treatment received), the responses for all questions will be summarized by treatment arm and visit.

The BPI-SF scoring will be provided by two parts:

Pain severity: worst, least, average and current pain (Question 3 to 6); Pain interference: general activity, mood, work, walking ability, relations, sleep and

enjoyment of life (item A to G of Question 9).

Composite scores of pain severity and the pain interference score will be produced by averaging their subscales. Each score ranges from 0 to 10 with higher scores representing a higher level of pain or interference. To calculate the composite score of severity, all four items should be completed, or otherwise, the score will be treated as a missing value. For the interference score, if there are missing items, the score can be prorated as follows:

Prorated score = (sum of item scores)/(number of items answered),

as long as more than 50% of the items are answered in Question 9 (i.e., a minimum of 4 of 7 items). Pain severity score, pain interference score and their changes from baseline will be summarized by treatment arm and visit.

7.5.4 CTC Conversion Rate

The number and percentage of subjects with favourable and unfavourable CTC conversionwill be summarized by treatment arm and visit. Two-sided chi-square tests will be used to compare the two treatment groups for the CTC conversion rate from unfavorable to favorable status and the CTC conversion rate from favorable to unfavorable status, occurring at any time up to and including week 49. Shift table for the CTC conversion will be produced by treatment group.

7.6 Analysis of Safety

Safety analysis will be conducted on the SAF and summarized by treatment arm as treated.




TEAEs will be presented within each system organ class by preferred term, by relationship to study drug and by severity using the NCI-CTCAE grade (grade 1 to grade 5). If an AE for the same preferred term is observed with different severity then the AE will be counted under its maximum severity rating only. In case the AE severity is not reported, it will not be imputed and be handled as a separate category (i.e., ‘missing’). If an AE is observed with different relationships to study drug then the AE will be counted under its maximum relationship only. In case the AE relationship is not reported, it will be handled as the maximum relationship.

TEAEs will be summarized by the number and percentage of subjects with AEs and presented alphabetically by system organ class and by decreasing order of frequency ofpreferred terms within each system organ class. A subject with multiple AEs of maximum severity is only counted once towards the total of subjects (and for percentage of subjects) forthis preferred term. TEAEs will also be summarized by NCI-CTCAE grade and relationship to study drug.

TEAEs leading to death, TEAEs (including or excluding SAEs) with frequency in any treatment group >=5%, TEAEs leading to permanent discontinuation of study drug and SAEs will be summarized by system organ class and preferred term. TEAEs leading to permanent discontinuation of study drug and SAEs by relationship to study drug and by NCI-CTCAE grade will be presented as well. TEAEs of special interest will be summarized by the number and percentage of subjects with the following AEs: fatigue, fall, hypertension, non-pathological fractures, cognitive/memory impairment, loss of consciousness, neutropenia, and convulsion.

All AEs and AEs leading to death will be displayed in data listings. In addition, a separate listing of all deaths with the cause of death will be produced.

7.6.2 Clinical Laboratory Evaluation

Clinical laboratory evaluations (including hematology and serum chemistry) will be summarized for each visit using descriptive statistics, as well as change from baseline.

Baseline is defined as the last available measurement prior to the first study drug dose.

Based on the NCI-CTCAE grade of laboratory data, clinical laboratory evaluations will be summarized by the numbers and percentage of subjects for each visit as well.

Shift analysis tables for selected analytes will be provided to present shift from baseline to each visit using the NCI-CTCAE grade and laboratory reference range indicator.

Laboratory data will be listed for each test. Each laboratory result will be flagged as low (L), normal, or high (H) at each visit according to the laboratory reference ranges.

Liver function tests

The following potentially clinically significant criteria in liver function tests for, Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase (AST) and their combination are defined. The subject’s highest value during the investigational period will be used.



Parameter Criteria

ALT, AST, Total Bilirubin ≥ 2xULN

≥ 3xULN

≥ 5xULN

ALT or AST ≥ 2xULN

≥ 3xULN

≥ 5xULN

ALT and/or AST (ALT and/or AST ≥ 3xULN) and total bilirubin ≥ 2xULNAND Total Bilirubin(*)

(*) Combination of values measured within same sample

The number and percentage of subjects with potentially clinically significant values in liver function tests during the investigational period will be presented.

7.6.3 Vital Signs

Vital signs and change from baseline will be summarized for each visit. Baseline is defined as the last available measurement prior to the first dose. All vital signs will be listed by subject.

Based on the subject’s highest value during the investigational period, a summary will present the number and percentage of subjects with blood pressure elevation (systolic: ≥ 140 mmHg, ≥ 180 mmHg; diastolic: ≥ 90 mmHg, ≥ 105 mmHg), with increase from baseline (systolic: ≥ 10 mmHg, ≥ 20 mmHg; diastolic: ≥ 5 mmHg, ≥ 15 mmHg) or combination criteria (systolic: ≥ 140 mmHg & ≥ 20 mmHg increase from baseline, ≥ 180 mmHg & ≥ 20 mmHg increase from baseline; diastolic: ≥ 90 mmHg & ≥ 15 mmHg increase from baseline, ≥ 105 mmHg & ≥ 15 mmHg increase from baseline) or any of these criteria.

7.6.4 Physical Examination Findings

Any abnormal findings/conditions identified during the physical examination are reported in the medical history form or AE form. As such no separate physical examination listing will be produced.

7.6.5 Electrocardiograms (ECGs)

Should the RR interval or Heart Rate be missing, they will be calculated from one another as RR=(60/HR)*1000 where HR is in beats per min and RR interval is in msec.

12 Lead ECG results and change from baseline will be summarized for each visit. Baseline is defined as the last available measurement prior to the first dose. Number and percent of subjects with normal, not clinically significant abnormal and clinically significant abnormal results for the 12 lead ECG will be tabulated by treatment arm and visit. A shift analysis tableshowing shifts from baseline to each visit in overall ECG interpretation (normal, abnormal



not clinically significant, and abnormal clinically significant) will be provided. All ECG results will be provided in a listing.

QTc will be calculated using Fridericia Formula, QTcF= QT interval / RR0.33.

7.6.6 Other Safety-Related Observations

ECOG scales will be listed and summarized by number and percentage by visit. The BMI and change from baseline will be summarized for each visit.

7.7 Analysis of Pharmacokinetics

Ctrough of MDV3100and his main metabolites will be listed and summarized on PKAS by visit. Values below the lower limit of quantitation (LLOQ) will be set to 0 for calculation of

descriptive statistics. Descriptive statistics will not be calculated if all values are less than the LLOQ. In cases where more than half of the individual data in a group are LLOQ, STD and CV will not be calculated. If one or more values are LLOQ, the geometric mean will not be calculated.

Standard graphics, including mean plasma drug concentration at pre-dose (both linear and semi-log), overlay (“spaghetti”) plots of plasma concentration at pre-dose, individual subject drug plasma concentration at pre-dose (both linear and semi-log) will be produced by visit.

7.8 Other Analyses

7.8.1 Pharmacogenomics

Historical tumor tissue samples, urine and blood samples would be collected to allow evaluation of T2:ERG gene fusions on patient prognosis.

In the event of unusual PK or pharmacodynamic patterns or safety findings, additional genotype analysis of relevant metabolism, transporter, pharmacodynamic, and/or safety genes may be conducted. If appropriate, further analyses investigating associations between exploratory variables and efficacy endpoints will be explored.

However, the analyses mentioned in this section will not be covered in this SAP.

7.9 Interim Analysis (and Early Discontinuation of the Clinical Study)

Not applicable.



7.10 Handling of Missing Data, Outliers, Visit Windows, and OtherInformation

7.10.1 Missing Data

Imputation for FACT-P, EQ-5D and BPI-SF questionnaire responses is described in Section 6.2.1, 6.2.2 and 6.2.3, respectively.

Imputation on missing concomitant medication date (to categorize them as previous medication or concomitant medication) and adverse event dates (to categorize them as TEAE or not) will be done as follows:

Incomplete Start Day: use the later of (first day of the month, first dosing day if first dosing month);

Incomplete End Day: use the earliest of (last day of the month, day of the 30-day follow-up visit);

Incomplete Month or Year: no imputation.

Cases where the onset date of an AE is (partially) missing, will be addressed prior to or during the DRM in order to determine whether the AE must be considered treatment emergent or not.

Imputation on missing date of initial diagnosis (cancer duration) and cancer treatment history (start date, stop date, or date of procedure) will be done as follows:

Incomplete Day: use the 15th day of the month Incomplete Month: use 1st of July if the Year is before Year of dosing, otherwise

missing. Incomplete Year: no imputation, the derived variable is considered to be missing.

Imputation methods will not be used to determine other endpoints.

Listings will always show the original date information without imputation, but derived parameters (TEAE indicator, start day, end day, study day) will be flagged.

7.10.2 Visit Windows

Visit windows are allowed for certain visits per the schedule of assessments. Subject data will not be excluded from analyses due to the subject’s failure to comply with the visit schedule.

Analyses of efficacy and safety variables will be performed according to the analysis visit windows described in the following Table 5.



Table 5 Analysis Visit Windows

Visit day interval Scheduled visit Analysis visitUp to Day 1 Week 1 (Day 1) BaselineDay 2 – Day 15 Week 2 (Day 8) Week 2 Day 16 – Day 43 Week 5 (Day 29) Week 5Day 44 – Day 71 Week 9 (Day 57) Week 9 Day 72 – Day 99 Week 13 (Day 85) Week 13Day 100 – Day 127 Week 17 (Day 113) Week 17 Day 128 – Day 155 Week 21 (Day 141) Week 21Day 156 – Day 183 Week 25 (Day 169) Week 25 Day 184 – Day 295 Week 37 (Day 253) Week 37

Similarly for next visits during the treatment period:Target day = i*12*7 + 169 (i=2,3,4…)

Week X (Wk X target day – 41 days ; Wk X target day + 42 days)

Last schedule visit when last dose givenTarget day as defined above

Week X (Lower limit as defined above ; Wk X target day + 7 days)

(last dose day of study drug +8 ; last dose day of study drug+45)

last dose day + 30 days 30 Day Safety Follow Up (after last dose or prior to new therapy)

(last dose day of study drug +46 ; last dose day of study drug+72)

last dose day + 60 days 60 Day Follow Up(after last dose if subject has no

progression event)

Long Term Follow Up 112 week visit after last dose day:Target day = 12*7+last dose day

(last dose day of study drug+73 ; last dose day of study drug+ 12*7+42 )

Long Term Follow Up inext i*12 week visits after last dose day (i= 2,3,4…):

Target day = i*12*7+last dose day (last dose day of study drug+i*12*7-41 ; last dose day of study drug+i*12*7+42 )

In the case of multiple observations at a specific visit, the observation which is closest to the target date will be used. If the observations have the same distance to the target visit day, the latest one will be used (using date, and time if available). Should there be two assessments made at the same time due to the repetition of analysis of the same sample, the one reported as scheduled will be used.

7.10.3 Data Cut-off date

At the time the final analysis will take place, it is possible that some subjects are still receiving the study drug. A cut-off date will be set so that a minimum of 220 events as defined for the primary variable occurred by that date. All data available for all visits occurring prior to or on the cut-off date will be reported.



7.10.4 Other Information

Age will be calculated in years relative to the informed consent date, rounded up to 1 significant digit. Categorization will be done prior to rounding; for example, a 75.04 years old patient will be considered in the >75 years old patient category.

Baseline is defined as the last available measurement prior to the first dose. If baseline assessments are not performed, the screening visit assessment can be used as baseline.

Post baseline value is defined as a measurement taken after randomization for subjects who did not receive study drug.

Change from baseline is defined as (post baseline value – baseline value). Both date and time of drug administration and measurement should be considered when calculating baseline value. If time is not available, then date only should be used.

To calculate time interval duration, a month is 30.4375 days and a year 365.25 days. Duration expressed in years or months are rounded up to 1 significant digit. The duration between 2 dates d1 and d2 is (d2-d1+1) in days (with d1 before d2).

Study day will be calculated in reference to the date of randomization (Study Day 1). For assessments conducted on or after the randomization date, study day is calculated as (assessment date – randomization date + 1). For assessments conducted prior to the randomization date, study day is calculated as (assessment date – randomization date). There will be no Study Day 0.

Treatment day will be calculated in reference to the date of the first dose of study drug. Treatment Day 1 corresponds to the date the subject received the first dose of study drug. For assessments conducted on or after the date of the first dose of study drug, treatment day will be calculated as (assessment date – date of first dose of study drug) + 1. There will be no Treatment Day 0.

Time to event endpoints will be based on the actual date of event rather than visit date. The date of randomization will always be considered as the start date for the time interval.

For laboratory results collected as < or > a numeric value, 0.0000000001 will be subtracted or added, respectively, to the value unless otherwise specified.

Percentages will be calculated based on the number of subjects with non-missing data as the denominator unless otherwise specified.



8 DOCUMENT REVISION HISTORY

Version Date ChangesComment/rationale for change

1.00 20-JUL-2011 NA Document finalized2.00 19-NOV-2014 Where applicable, adapt procedure description to

newer SOPs and STLs, incl. SAP templateSOP application

Update schedule of assessment, sample size and add protocol deviation sections

Updated due to protocol amendments 1.0, 2.0 and 3.0

Analysis sets section: further detail all populationset definitions.

Needed for programming

Analysis variables section and appendix 10.1. - Add variables: total cumulative dose, percent overall compliance, time to PSA ≤4ng/ml, time to ≥30% PSA decline from baseline (also for ≥50% or ≥90% PSA decline), radiographic progression free survival, overall and best overall response assessment, and time to FACT-P progression. - PK of bicalutamide is not done, so removed.- Provide or further detail all endpoint definitions and derivations.

Further characterize the study outcome and also needed for programming.

Further detail the statistical methodology section for all existing variables and describe the analysis for the added variables. Add subgroup analysis on prior use of anti-androgen therapy.

Further characterize the analysis methods, derivation or calculation of variables. Also needed for programming

3.0 9-JAN-2015 - HR and 95%CI is calculated and presented as “analysis of other TTE efficacy variables”.-Appendix 1 on derivation of the primary endpoint:* use of scan dates reported in the investigator database rather than ICR database * further detail the last visit date derivation

- Missing statement added- Presence of placeholder data in scan date variable for expected timepoints where no scan was acquired, artificially delaying PFS censoring date.

9 REFERENCES

ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)

ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. (www.ich.org; Guidelines; "Efficacy" Topics)

Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, May 2007, US Department of Health and Human Services, FDA

European Journal of Cancer. New Response Evaluation Criteria in Solid Tumours: Revised RECIST guideline, 2009 (www.ejconline.com; version 1.1; 228-247)

Journal of Clinical Oncology. Design and End Points of Clinical Trials for Patients with Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Trials Working Group, March 2008. (www.jco.org; vol 26: 1148-1159)

Applied Survival Analysis, Regression Modeling of Time to Event Data, David W. Hosmer, Jr. and Stanley Lemeshow, 1999, John Wiley & Sons, Inc.



10 APPENDICES

10.1 Appendix 1: Primary Variable Derivation Using Investigator and/or ICR Data

The objective of this appendix is to provide a detailed description of the derivation of Progression free Survival, as defined in Section 6.1.1 and Section 6.1.2, from the available study database (i.e., raw data).

The analysis requires the derivation of the progression events and their corresponding dates. The primary analysis of the primary variable will be based on the independent central review for what concerns the objective radiographic disease progression assessments. This analysis will then be repeated using the investigator’s assessments instead. Only assessment prior to the cut-off date are to be considered.

In this appendix, part A includes a list with all raw datasets and variables to use in the derivation as per the eCRF data specifications, as well as a flow diagram for obtaining the radiographic assessments variable to use from the Independent Central Review. Part B describes in detail the derivation logic for all events and the dates of these events for PFS as well as the derivation to follow in absence of event. Part C provides an overview of this derivation logic in the form of a flow diagram. The name of the variables refers to the raw data in the RAVE database and the name of derived variables are chosen arbitrarily.

A. Primary Variable

1. List of datasets and variables used in the derivation of the primary variable

1.1. Investigators source data

NOTE: The raw study data collected from the study investigators are included in this table.

Table Name Variable Name Variable Description Purpose

Informed Consent Form (one record per subject)

ic_1 SUBJECT Subject identifier To define analysis

cohortDSDTDT Informed consent date

Randomization Form (one record per subjects)

rd_1 SUBJECT Subject identifier To define analysis

cohortDSRDT Randomization date

DSRAND Subject randomized, yes/no

Adverse Events Form (multiple records per subject)

ae_1 SUBJECT Subject identifier Derive skeletal-related

eventsAEANY Any adverse event, yes/no

AETERM Reported term of the adverse

event

AESTDT Start date of adverse event

AEENDT End date of adverse event

AESKLREL Skeletal related adverse event



Long-Term Follow up Skeletal Related Events Form (multiple records per subject)

ce_1 SUBJECT Subject identifier Derive skeletal-related

eventsCEANY Any skeletal related event, yes/no

CESTDT Start date of clinical event

Prior and Current Prostate Cancer Drug Therapy Form (multiple records per subject)

cm_2b SUBJECT Subject identifier Derive new anti-

neoplastic therapy

event

CMTRT Reported name of drug,

medication, or therapy

CMINDC Reason for new therapy – for anti-

neoplastic meds started after first

dose of study drug

CMSTDT Start date of regimen

Non-Medication Therapy (multiple records per subject)

cm_5a SUBJECT Subject identifier Derive new anti-

neoplastic therapy

event

CMTRT Reported name of drug,

medication, or therapy

CMINDCNT Indication of new therapy – for

anti-neoplastic meds started after

first dose of study drug

CMSTDT Start date of regimen

End of Study Form (one record per subject)

ds_3 SUBJECT Subject identifier Derive death events

INSTANCENAME Follow up time point

DATAPAGENAME eCRF page name

DSDT Date of last contact /evaluation

DSDECOD Standardized disposition term

Disposition Dates (multiple records per subject)

ds_1

ds_2

SUBJECT Subject identifier Obtain last visit date


DSDT Date of end of treatment or

30 day follow-up visit

Vital Signs at visits on site (multiple records per subject)

vs_1

vs_2

vs_2b

vs_6

SUBJECT Subject identifier Obtain last visit date


VSDT Visit date

Scan Dates (multiple records per subject)

tu_1 a & b tu_2 a & b tu_3tu_4 a & b

SUBJECT Subject identifier Obtain final radiographic scan date


DATAPAGENAME eCRF page name

TUDT CT/MRI or Bone Scan Date



1.2. Independent Central Review data (IMI data) for the primary variable

NOTE: The raw IMI data on objective radiographic disease progression are included in this table.

Table Name

Variable Name Variable Description Purpose

Overall Assessment (multiple records per subject: -selecting the last PASSMUM per visit -> one record per visit assessment per reader)Overall USUBJID Subject identifier Obtain final

radiographic disease progression date from central review data

READER Reader’s name

PASSNUM Numeric identifier used to distinguishthe read session

DATEPROG Date of progression

Adjudication Assessment (one record per subject: one record where Reviewer’s 1 and 2 disagree on any of the following, best overall response, date of response and/or date of progression) - provides the name of the selected reader to use -selecting the last PASSMUM if neededAdjudic USUBJID Subject identifier Obtain final

radiographic disease progression from central review data

READER Adjudicator’s name

PASSNUM Numeric identifier used to distinguishthe read session

SLCTDDR The name of the selected reader that the adjudicator agrees

1.3. Flow-diagram for obtaining the radiographic assessment from IMI data

The central review of radiographic data includes a dual reading and adjudication process. The main goal is to obtain a systematic and consistent assessment of radiographic disease progression date. The radiographic data for each visit completed by a subject is assessed by 2 independent readers (possibly several times - PASSNUM). A third reader, the adjudicator, completes another independent assessment of the same radiographic data if there is a disagreement between the 2 readers on any of the best overall response and/or the date of response and/or the date of progression. The adjudicator provides the name of the reader whose assessments should be used.

The following flow-chart depicts the steps of this process based on current information of this data.



1.4. Source data for repeating the primary analysis when using the investigators data instead of IMI data for the objective radiographic disease progressions.

NOTE: The raw study data collected from the study investigators on objective radiographic disease progression are included in this table.


Overall Time Point Response Form (multiple records per subject)rs_8 SUBJECT Subject identifier Derive final

radiographic disease progression from investigator assessment

rs_8 INSTANCENAME Follow up time point

rs_8 DATAPAGENAME eCRF page name

rs_8 RSDT Date of assessment

rs_8 RSTIMRES Time point of overall response

rs_8 BONERESP Bone lesion response




Best Overall Responsers_9 SUBJECT Subject identifier Derive final

radiographic disease progression from investigator assessment

rs_9 INSTANCENAME Follow up time point

rs_9 DATAPAGENAME eCRF page name

rs_9 RSDT Date of assessment

rs_9 BESTRESP Best overall response

B. Derivation of Events

The following steps outline the logic used to select the appropriate analysis cohort, define the progression events for PFS and their corresponding dates. The outline also includes all of the variables used from the table list described above.

1 Define analysis cohort

The full analysis set and per protocol set include randomized subjects who consented to participate in the study. In order to select this cohort, the datasets ic_1 and rd_1 are merged by subject (SUBJECT) and limited to the subjects with non-missing informed consent (DSSTDT) and randomization dates (DSRDT) and are classified in the full analysis set/per protocol set during the ASCM meeting (i.e., FASflag=1 / PPSflag=1 as defined in the ASCM spreadsheet).

2 Define events

2.1. Radiographic disease progression

The independent central review of all radiographic images will provide the source data for the primary analysis of the primary variable (Section B.2.1.1 below applies). The primary analysis is then repeated on PFS based on the investigators assessments on objective radiographic disease progression (Section B.2.1.2 below then applies).

2.1.1. Radiographic disease progression according to ICR data

The final assessment from the dual reading and adjudication process will be used for the derivation of the event of objective radiographic progression and its corresponding date (see Section A.1.2 for details of final assessment). If multiple PASSNUM records are present (i.e., several reading review cycle took place) in any of the datasets noted below, the last PASSNUM should be used. Obtain subjects with radiographic PD and the corresponding date:o Use the dataset overall and select all records where reader 1 and 2 assessments

are the same and a date of progression is not missing. Output one record per subject in a dataset with that assessment and date.

o Use the dataset adjudic and select all records where SLCTDDR is not missing and merge this selection with overall by subject and reader (rename variable SLCTDDR as READER for the merge). Keep only the records where the date of progression is not missing.



o Set the two selections from previous steps. This would be the list of subjects with radiographic progression (and corresponding date) identified by the ICRreading process. Save all subjects with an assessment of PD in a datasetradEventICR. Rename variable DATEPROG as rPDDT.

o Merge the datasets radEventICR with the dataset rd_1 by SUBJECT and verify that rPDDT>DSRDT

2.1.2. Radiographic disease progression according to investigator data

o Find events of radiographic disease progression from post baseline visits by use of the datasets rs_8 and rs_9 (set the 2 datasets) and sort by SUBJECT and RSDT. Select the records with the first non-missing date (RSDT) where the overall time response (RSTIMRES) or the best overall response (BESTRESP) is marked as progressive disease and RSDT> DSRDT,

o Rename RSDT as rPDDT and save the dataset as radEvent.

2.2. Skeletal related events

o Use the ae_1 dataset and select all subjects who have skeletal related adverse events (AESKLREL) indicated. Limit this dataset to records with non-missing treatment emergent adverse event start date (AESTDT) after randomization date (i.e., AESTDT > DSRDT). Sort this selection of records by subject (SUBJECT) and increasing adverse event start date and select the first record to obtain a dataset with one record per subject with skeletal related events and their corresponding dates. Name this temporary dataset as sklOutcome.

o Use the ce_1 dataset and select all subjects who have indicated skeletal related events observed between last visit and the current visit/follow up (CEANY=YES) and have a non-missing start date of the event (CESTDT) after randomization date (i.e., CESTDT>DSRDT). Sort this selection of records by subject (SUBJECT) and increasing skeletal related event start date and select the first record to obtain a dataset with one record per subject with skeletal related events during long-term follow up and their corresponding dates. Name this

temporary dataset as sklOutcomeFU.o Merge the datasets sklOutcome and sklOutcomeFU by subject and create one

unified date variable, sklDT, for a skeletal related event from AESTDT and CESTDT (i.e., sklDT=min(AESTDT, CESTDT)). Save this dataset as sklEvent.

2.3. New anti-neoplastic therapyo Use the dataset cm_2b and select all records with non-missing reason for new

therapy (CMINDC) and non-missing start date of treatment regimen (CMSTDT) starting after randomization (i.e., CMSTDT>DSRDT). Sort this selection of records by subject (SUBJECT) and increasing start date of treatment regimen and select the first record to obtain a dataset with one record per subject with new anti-neopleastic therapy and its corresponding date. Name this temporary datasetas newTherapy.



o Use the dataset cm_5a and select all records with non-missing indication of new non-medication therapy (CMINDCNT) and non-missing start date of treatment regimen (CMSTDT) starting after randomization (i.e., CMSTDT> DSRDT). Sort this selection of records by subject (SUBJECT) and increasing start date of treatment regimen and select the first record to obtain a dataset with one record per subject with new anti-neopleastic therapy and its corresponding date. Name this temporary dataset as newNMTherapy.

o Merge the datasets newTherapy and newNMTherapy by subject and create a new variable newTherDT=min(CMSTDT, CMSTDTNMT).

2.4. Deaths by any cause

Use the end of study dataset ds_3 and select all records where DSDECOD=’DEATH’ along with the corresponding non-missing DSDT>DSRDT date. Name this temporary dataset as death and rename DSDT to deathDT.

3 Last Visits and Disposition

3.1. Last visit obtained from investigator’s data

3.1.1. Visits on site

Set all the VS datasets together to obtain the dates of visits at the site where vital signs are measured and disease management options may be decided. Sort the dataset by SUBJECT and visit date (VSDT). Select the last record and save into a temporary dataset, LastVS. Rename the variable VSDT as lastVSDT.

3.1.2. Last scan

Set all the TU datasets together to obtain the dates of all scans used by both ICR and investigators to perform the disease assessments. Sort the dataset by SUBJECT and scan date (TUDT). Select the last record and save into a temporary dataset, LastTU. Rename the variable TUDT as lastTUDT.

3.1.3. Last overall time point assessment

Sort the dataset rs_8 by SUBJECT and assessment date (RSDT). Select the last record and save into a temporary dataset, LastRS8. Rename the variable RSDT as lastRSDT.

3.1.4. Last subject/study disposition

Set all ds datasets together to obtain the last disposition status and date of the subjects. Sort the dataset by SUBJECT and disposition date (DSDT). Select the last record and save into a temporary dataset, LastDS. Rename the variable DSDT as lastDSDT.

3.2. Last scan used in Independent Central Review data

The scans used by ICR are theoretically the same ones than used by investigators unless some are lost or damaged during transportation. However the ICR database contains



place holder data where scans were expected but actually not done (“black box” per ICR vendor terminology). As it was not possible to select and remove those black boxes programmatically, it was not possible to use the scan dates recorded in the ICR database. Based on manual reconciliation scan dates in the ICR and clinical study database match. For each subject, the date of last scan by ICR prior to cut-off date will be the date of last scan used by the investigator prior to cut-off date.

4 Combine the datasets, define the primary variable and time to event variables

Sort all of the temporary datasets created in steps B.1 to B.3 by SUBJECT and merge them together by SUBJECT into one dataset. For the primary analysis of the primary variable, the Section B.2.1.1 applies. When the primary analysis is repeated based on the investigator assessments only, the Section B.2.1.2 applies. Note that the number of records of each event dataset (see step B.2 above) indicates the number of subjects with corresponding type of event. Use temporary indicators in this data step to derive flags for each type of event. Create a categorical variable to define different event types by prioritizing the earliest event for each subject. In the same data step generate a censoring indicator (censorPFS) and a variable for PFS (i.e., time to progression events) expressed in months (timePFSmo). The censoring indicator is 0, if one or more of the events that constitute the primary variable are indicated and 1, if there is no evidence of an event. The time to progression events is calculated in days from randomization to end of follow up as follows:

4.1. For subjects who experienced a progression event.

Select the date of the earliest event for each subject eventDT = min (rPDDT, sklDT, newTherDT, deathDT). For all subjects who experienced an event after randomization, the time to event is calculated as the difference between the event date and the date of randomization plus 1 (i.e., eventDt – DSRDT +1).

4.2. For subjects who did not experience a progression event

Select the latest date from the date of randomization, the last date of visit (lastVSDT),

the last scan date (lastTUDT), the last overall time point response assessment date (lastRSDT) and the last disposition date (lastDSDT) and calculate the time to censoring as the difference between that date and the date of randomization plus 1.

Subjects randomized into the study with no post baseline assessment, the time to censoring is given a value of 1.



C. Flow diagram of derivation logic for primary analysis



10.2 Appendix 2: Key Contributors and Approvers

List of Key Contributors and Approvers

Key Contributors

The following contributed to or reviewed this Statistical Analysis Plan as relevant to their indicated discipline or role.

Primary author

Benoit Baron, MScStudy Statistician

Chiltern FSP for Astellas Global Data Science

Contributors and Reviewers

Mariya Dontchev, MPHSupport Statistician

Biostatistics & Statistical ProgrammingQuintiles

De Phung, BScGlobal Statistician Lead

Astellas Global Data Science

Nahla Hasabou, MDStudy Physician

FSP for Astellas Global Medical Science

Kenya Barber, BS Study Manager

Astellas Global Clinical Science



Author and Approver Signatories

(E-signatures are attached at end of document)

Benoit Baron, MSc, Senior Biostatistics Manager, Chiltern FSP for Astellas Global Data Science was the study statistician for this study.

De Phung, BSc, Biostatistics Director, Astellas Global Data Science was the biostatistics peer reviewer of this Statistical Analysis Plan

This Statistical Analysis Plan was approved by:

Stephen Eck, MDVP Global Medical Head OncologyAstellas Global Medical Science

S-1

ELECTRONIC SIGNATURE PAGE Document Type :

Document Control Number :

Amendment Number :

International Study Number :

Departmental Study Number :

Actual Version Number :

Document Version :

Nonclinical Initial SD Approved Date (UTC) :

Date (UTC) Signed by Sign Off Meaning

Full Name / Legal Name










*UTC: Coordinated Universal Time

01/10/2015 01:09:32

Statistical Analysis Plan

Responsible Medical Officer

Principal Reviewer Approval

01/09/2015 20:07:58

Version 3.0

De Phung

Benoit Baron

Signature as Document Originator

N/A

Stephen Eck

De Phung

01/09/2015 20:04:46

N/A

MGC1401577

Benoit Baron

9785-CL-0222

Stephen Eck

4.0

N/A

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