Post on 07-Aug-2020
Study drug: IBI308
Clinical Study Protocol
Study Title: A Single-center, Phase Ib Study of IBI308 Monotherapy as
Neoadjuvant Therapy for Resectable Non-Small Cell Lung
Cancer
Protocol No.: CIBI308Y002
Version Date and
Number:
August 12, 2017/Version 1.0
Product Name: IBI308
Phase of Study: Ib
Sponsor: Cancer Hospital Chinese Academy of Medical Sciences
(CAMS)
Contact person: Li Ning
010-87788713
No.17 Panjiayuan Nanli, Chaoyang District, Beijing, P.R. China
Confidentiality Statement
This document contains confidential information.
The contents of this document may not be disclosed to any persons other than the investigator(s),
study advisor(s) or relevant personnel, institutional review board/independent ethics committee.
Without prior written permission of the sponsor, the information contained herein may not be used
for any purpose other than the evaluation or conduct of this clinical study.
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Signature Page
Protocol Title: An Open-label, Single-center, Phase Ib Study of IBI308 Monotherapy as
Neoadjuvant Therapy for Resectable Non-small Cell Lung Cancer
Project ID: CIBI308Y002
Title Name (Print) Signature Date
Investigator He Jie
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Protocol Synopsis
Protocol No. CIBI308Y002
Sponsor Cancer Hospital Chinese Academy of Medical Sciences (CAMS)
Study Drug IBI308
Active Ingredient Recombinant fully human anti-programmed cell death receptor 1 (PD-1) monoclonal
antibody
Study Titl A Single-center, Phase Ib Study of IBI308 Monotherapy as Neoadjuvant Therapy for
Resectable Non-Small Cell Lung Cancer
Phase Ib
Estimated Duration of
Study
30 months estimated
Objectives of Study Primary:
To evaluate the study-related adverse events (90 days after the first dosing of
IBI308 or 30 days after surgery, whichever occurs later)
To evaluate the incidence of surgical complications (both intraoperative and
perioperative)
To evaluate the rate of non-delayed surgery (surgical delay is defined as no
performance of surgery for more than 43 days from the day of the first dosing)
Secondary:
To evaluate the objective response rate (ORR) and major pathologic response
(MPR) after IBI308 monotherapy as neoadjuvant therapy for resectable NSCLC
To evaluate the 1-year and 2-year DFS, the 1-year and 2-year recurrence rate (RR)
and the 2-year survival rate;
Exploratory:
To evaluate the relationship between pathological response and DFS and RR after
IBI308 monotherapy as neoadjuvant therapy
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To evaluate the distribution of IBI308 across tumor tissues and its correlation with
efficacy.
To evaluate the relationship of biomarkers in tumor tissue with efficacy, including
but not limited to the expression of PD-L1, tumor infiltrating lymphocytes (TIL),
and tumor mutational burden (TMB)
To evaluate the relationship of biomarkers in peripheral blood with efficacy,
including but not limited to the relationship between efficacy and dynamic
changes in the overall mutational burden of ctDNA
Study Design It is a phase Ib single-center study to evaluate IBI308 monotherapy as neoadjuvant
therapy for resectable NSCLC. A safety run-in study of 6 patients will be conducted
first, and if no major safety event occurs, the study will be expanded to a total of 30
patients.
After the signing of the informed consent form (ICF), patients with treatment-naïve
operable NSCLC who are confirmed eligible for the inclusion/exclusion criteria after
screening will be administered IBI308 200 mg IV Q3W for 2 cycles, and will receive
radical operation for NSCLC within 29 to 43 days following the first dose of IBI308, as
well as standard adjuvant treatment.
Imaging assessment will be conducted per RECIST v1.1 in this study, with PET-
enhanced CT performed at baseline and prior to radical operation (after the second dose
of IBI308 but within 1 week prior to operation), as well as CT or enhanced CT on Day
30 post-operation and every 3 months post-operation, until 2 years after the operation,
disease recurrence or death. Enhanced MRI is required at baseline to rule out brain
metastases.
The subjects will be followed for safety (90 days after the first dose of IBI308 or 30
days post-operation, whichever occurs later) and post-operative recurrence-free
survival visit (every 90 ± 7 days until 2 years post-operation).
Inclusion Criteria The subjects are required to meet the following inclusion criteria:
1. Cytologically or histologically confirmed NSCLC;
2. Assent to the collection of tumor histological specimens required for this study for
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relevant studies;
3. Presence of treatment-naïve, surgically resectable NSCLC, with a tumor diameter
of > 2 cm;
4. Consent to receive radical operation;
5. No surgical contraindications in the judgment of a thoracic surgeon;
6. Presence of at least one measurable lesion (RECIST v1.1);
7. Male or female, at an age ≥ 18 years and ≤ 75 years;
8. An ECOG score of 0;
9. Adequate functions of vital organs and bone marrow that meet the following
requirements:
- Hematology: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets (PLT) ≥
100 × 109/L, hemoglobin (HGB) ≥ 9 g/dL;
- Liver function: serum total bilirubin (TBIL) ≤ 1.5 × ULN (upper limit of normal),
alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 ×
ULN, serum albumin (ALB) ≥ 2.8 g/dL;
- Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance ≥ 40
mL/min (calculated using the standard Cockcroft -Gault formula):
Females: CrCl = (140-age) x body weight (kg) x 0.85
72 x serum creatinine (mg/dL)
Males: CrCl = (140-age) x body weight (kg) x 1.00
72 x serum creatinine (mg/dL)
10. Provide written ICF and could follow the visit schedule and relevant procedures
specified in the study protocol.
Exclusion Criteria A subject meeting any of the following exclusion criteria will be excluded from this
study:
1. Presence of EGFR-sensitive gene mutation in tumor tissue as revealed by
aspiration biopsy;
2. A past medical history of any anti-tumor therapy, including radiotherapy,
chemotherapy, immunotherapy and traditional Chinese medicine therapy
(excluding therapy for malignancies that were radically treated, without
recurrence or metastasis for a period of ≥5 years);
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3. Use of immunosuppressive agents within 4 weeks prior to the first dose of the
study treatment, excluding topical glucocorticoids for intranasal, inhalation or
other routes of administration, or physiological doses of systemic glucocorticoids
(i.e., no more than 10 mg/day prednisone or equivalent of other glucocorticoids);
4. Known or suspected active autoimmune diseases (congenital or acquired), such as
interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis,
nephritis, thyroiditis, etc. (patients with vitiligo or complete remission of asthma
in childhood, without requiring any intervention after adulthood can be enrolled;
patients with type I diabetes well controlled by insulin can also be enrolled);
5. Known allotransplant (excluding corneal transplantation) or allogeneic
hematopoietic stem cell transplantation;
6. Allergy to any ingredient of the monoclonal antibody;
7. Current interstitial lung disease;
8. Presence of other uncontrolled serious medical conditions, including but not
limited to:
− Active or clinically uncontrolled severe infection;
− HIV-infection (HIV antibody positive);
− Acute or chronic active hepatitis B (HBsAg positive and HBV DNA >
1*103/mL) or acute or chronic active hepatitis C (HCV antibody positive and
HCV RNA > 15 IU/mL);
− Active pulmonary tuberculosis;
− Class III-IV congestive heart failure (New York Heart Association
classification), poorly controlled and clinically significant arrhythmia;
− Uncontrolled arterial hypertension (systolic blood pressure ≥ 160 mmHg or
diastolic blood pressure ≥ 100 mmHg);
− Any arterial thrombosis, embolism or ischemia within 6 months prior to
inclusion for treatment, such as myocardial infarction, unstable angina,
cerebrovascular accident or transient ischemic attack;
− Disease requiring anticoagulation with warfarin (coumarin);
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− Uncontrolled hypercalcemia (calcium ion > 1.5 mmol/L or calcium greater
than 12 mg/dL or corrected serum calcium > ULN), or symptomatic
hypercalcemia requiring continued bisphosphonate therapy;
− Other malignant tumors (excluding cancer that has been cured, such as
cervical carcinoma in situ, non-melanoma skin cancer, etc.);
9. Other acute or chronic diseases, psychiatric disorders or abnormal laboratory
values, which may result in an increased risk associated with study participation
or use of the study drug, or interfere with the interpretation of study results and
render the patient ineligible for the study in the investigator’s judgment;
10. Pregnant or breastfeeding women.
Study Drug, Strength
and Route of
Administration
IBI308
− Strength: 100 mg/10 ml
− Route of administration: 200 mg intravenous infusion (IV) Q3W for 2 cycles
Evaluation Criteria Efficacy evaluation:
ORR: total of complete response (CR) and partial response (PR)
MPR: defined as < 10% visible tumor cells by microscopy
DFS: Percentage of patients without disease recurrence or death at 1 and 2 years
RR: Percentage of patients with 1-year and 2-year disease recurrence
Overall survival (OS): 2-year overall survival
Safety evaluation:
Incidence rates of all adverse events (AEs), adverse events of special interest
(AESI) and serious adverse events (SAEs), treatment-related adverse events
(TRAEs) and severity, etc.
Changes in vital signs, physical examination findings, and laboratory findings
before, during, and after study treatment
Biomarker evaluation:
To evaluate the distribution of IBI308 across tumor tissues and its correlation with
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efficacy.
To evaluate the relationship of biomarkers in tumor tissues and peripheral blood
with the efficacy
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Table 1. Visit Schedule
Period Screening
Neoadjuvant therapy Radical
operationSafety follow-up17
Recurrence-free survival follow-up18
Cycle 1 Cycle 2
Visits 1 2 3 4 5 6 7~N
Days -28 - -1 1 22 (±3)29 - 43 30 (± 7) days after
radical operation90 (± 7) days after the last dose
Every 90 (± 7) days after operation
General Study ProceduresWritten ICF1 XInclusion & exclusion criteria XDemographics/past medical history/past medications2
X
Vital signs3 X X X X X XBody weight/height4 XPhysical examination X X X X XECOG score X12-lead ECG5 X X X X XHematology/blood biochemistry/urinalysis6
X X X X X
Pregnancy test7 X X
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Period ScreeningNeoadjuvant
therapy Radical operation
Safety follow-up17Recurrence-free survival
follow-up18
Cycle 1 Cycle 2Visits 1 2 3 4 5 6 7~N
Days -28 - -1 1 22 (±3)29 - 43 30 (± 7) days after
radical operation90 (± 7) days after the last dose
Every 90 (± 7) days after operation
Thyroid function8 X X X XHIV, HBV and HCV9 XEGFR mutation status10 XAE evaluation11 X X X X X XConcomitant medications X X X X X X XSurvival status X X X X XSubsequent anti-tumor treatment
X X X
Efficacy EvaluationTumor imaging evaluation12 X X X X
Study Drug InfusionIBI30813 X X
Biomarker Evaluation
Fresh tumor tissue samples14 X X
Blood samples15 X X X XImmunogenicity16 X X X
Notes:1. The signing of the ICF should precede any protocol-specified procedures.
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2. Past medication includes treatment for initial diagnosis, including chemotherapy, radiation therapy and surgical treatment.3. Vital signs include body temperature, pulse rate, respiratory rate, and blood pressure.4. Height and weight measurements are only performed during the screening period.5. 12-lead ECG is scheduled at screening, prior to the second dose, prior to operation, Day 30 post-operation, and Day 90 after the last dose.6. Hematology includes: red blood cell count (RBC), HGB, white blood cell count (WBC), PLT, WBC differential [lymphocyte count (LYM), ANC]. Blood
biochemistry includes: liver function [TBIL, ALT, AST, γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), lactate dehydrogenase (LDH)], renal function [blood urea nitrogen (BUN), Cr], blood electrolytes (Na, K, Cl, Mg, Ca, P), lipase, amylase and fasting blood glucose (FBG). Urinalysis includes pH, urine albumin (UALB), urine protein (UPRO), urine RBC (URBC) and urine glucose (UGLU). Hematology, blood biochemistry and urinalysis are performed within 7 days prior to the first dose, within 3 days prior to the second dose, before surgery, within 3 days prior to and on Day 30 post-operation and Day 90 after the last dose, respectively.
7. For women of child-bearing potential, urine or serum pregnancy test will be performed within 3 days prior to the first dose and on Day 90 after the last dose. If negative cannot be confirmed with the result of urine pregnancy test, serum pregnancy test is required and the result of serum pregnancy test should prevail.
8. T3, T4, FT3, FT4 and TSH tests are performed at screening, prior to the second dose, and on Day 30 post-operation and Day 90 after the last dose.9. HIV antibody, hepatitis B (HBsAg, HBsAb, HBcAb, HBeAg and HBeAb) and HCV antibody tests are performed during the screening period. For hepatitis B
virus carriers, regular monitoring of virus activity is recommended throughout this study.10. Tissue biopsy is preformed at baseline for the detection of EGFR mutations.11. AE and laboratory safety evaluations will be performed according to NCI CTCAE 4.03 (For the definitions, documentation, relevance judgment, severity
judgment, reporting time limit and handling of AEs and SAEs, please refer to the protocol).12. Tumor assessment is performed based on RECIST v1.1, through PET-CT and enhanced CT at baseline and prior to operation (after the second IBI308 dose but
within 1 week prior to operation), and through CT or enhanced CT on Day 30 post-operation and every 3 months after operation, until 2 years after operation, disease recurrence, or death. Enhanced MRI is required at screening to rule out brain metastasis. The results of imaging examination performed before the signing of the ICF can be used at screening.
13. IBI308 200 mg IV, 2 cycle, is administered on Days 1 and 22, respectively. 14. Subjects are required to undergo a tissue biopsy during the screening period to provide tumor tissue samples for detection of EGFR mutations, and those
subjects meeting the inclusion criteria are also required to assent the provision of biopsy tumor samples left after clinical examination for biomarker analysis; subjects are also required to agree to provide surgically removed tumor tissues left after completion of pathological diagnosis for a comparative study of biomarkers before and after the study treatment.
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15. At baseline and each imaging evaluation, 10 ml of whole blood will be provided for relevant studies of peripheral blood biomarkers.16. Immunogenicity testing is performed before administration of each IBI308 dose and on Day 90 after the last dose.17. Safety follow-up takes place on Day 30 post-operation and Day 90 after the last dose. If these two follow-ups are expected to occur at an interval of less than 2
weeks, they can be combined as one follow-up (whichever occurs later).18. Imaging evaluation and recurrence-free survival follow-up are performed every 90 days (± 7 days) after surgery.
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Table of Contents
Protocol Synopsis..........................................................................................................................................3
Table of Contents........................................................................................................................................13
Abbreviations and Definitions of Terms...................................................................................................18
1 STUDY BACKGROUND........................................................................................................................21
1.1 Disease Background..........................................................................................................................21
1.2 Study Drug (IBI308).........................................................................................................................22
1.3 Risk/BenefitAssessment....................................................................................................................25
2 Objectives of Study..................................................................................................................................26
2.1 Primary..............................................................................................................................................26
2.2 Secondary..........................................................................................................................................26
2.3 Exploratory:......................................................................................................................................26
2.4 Overall Design...................................................................................................................................27
3 STUDY POPULATION..........................................................................................................................29
3.1 Inclusion Criteria..............................................................................................................................29
3.2 Exclusion Criteria.............................................................................................................................30
3.3 Restrictions throughout Study.........................................................................................................31
3.4 Discontinuation of Treatment/Withdrawal of Subjects from Study.............................................31
3.4.1 Discontinuation of any study drug for subjects....................................................................................31
4 STUDY DRUG AND OTHER TREATMENTS....................................................................................33
4.1 Dosing regimen..................................................................................................................................33
4.1.1 Dosing regimen....................................................................................................................................33
4.2 Study Drug (IBI308).........................................................................................................................33
4.2.1 Description...........................................................................................................................................33
4.2.2 Labeling................................................................................................................................................34
4.2.3 Storage conditions...............................................................................................................................34
4.2.4 Preparation and infusion......................................................................................................................34
4.3 Dose Modifications............................................................................................................................35
4.4 Principles for Management of Toxicities Associated with Immune Checkpoint Inhibitors........37
4.5 Concomitant Treatment....................................................................................................................38
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4.5.1 Prohibited medications........................................................................................................................38
4.5.2 Permitted medications.........................................................................................................................38
5 STUDY EVALUATIONS AND PROCEDURES..................................................................................39
5.1 Subject Enrollment Process..............................................................................................................39
5.1.1 Subject inclusion criteria......................................................................................................................39
5.2 Study Plan and Schedule..................................................................................................................40
5.2.1 Screening.............................................................................................................................................40
5.2.2 Baseline (prior to dosing on Day 1/Cycle 1..........................................................................................41
5.2.3 Visits during therapy period.................................................................................................................41
5.2.4 Safety Follow-up...................................................................................................................................41
5.2.5 Recurrence-free survival follow-up......................................................................................................42
5.3 Safety Evaluation..............................................................................................................................42
5.3.1 Routine Laboratory Safety evaluations................................................................................................42
5.3.2 Physical examination............................................................................................................................43
5.3.3 12-lead ECG..........................................................................................................................................43
5.4 Immunogenicity.................................................................................................................................45
5.5 Biomarker Analysis...........................................................................................................................45
5.6 Storage and Destruction of Biological Samples..............................................................................46
6 SAFETY REPORT AND AE MANAGEMENT...................................................................................46
6.1 Definition of Adverse Event.............................................................................................................46
6.2 Definition of Serious Adverse Event................................................................................................46
6.3 Criteria for AE Severity Judgment..................................................................................................47
6.4 Judgment on correlation between AE and study drug...................................................................48
6.5 Recording of AEs...............................................................................................................................49
6.6 Expedited reporting of SAEs and pregnancies...............................................................................53
7 STATISTICAL CONSIDERATIONS....................................................................................................56
7.1 Statistical analysis plan.....................................................................................................................56
7.2 Hypothesis Test..................................................................................................................................56
7.3 Statistical Analysis Population.........................................................................................................56
7.4 Methods of Statistical Analysis........................................................................................................57
7.4.1 General methods forstatistical analysis...............................................................................................57
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7.4.2 Analysis of primary endpoint...............................................................................................................57
7.4.3 Analysis of efficacy outcome measures...............................................................................................57
7.4.4 Biomarker Analysis...............................................................................................................................58
7.4.5 Drug exposure......................................................................................................................................58
7.4.6 Analysis of safety outcome measures..................................................................................................58
7.5 Sample size determination................................................................................................................60
8 QUALITY ASSURANCE AND QUALITY CONTROL.....................................................................61
8.1 Clinical Monitoring...........................................................................................................................61
8.2 Data Management/Coding...............................................................................................................61
8.3 Quality Assurance Audit...................................................................................................................63
9 ETHICS....................................................................................................................................................63
9.1 Ethics Committee..............................................................................................................................63
9.2 Ethics in the Study............................................................................................................................64
9.3 Subject Information and Informed Consent..................................................................................64
9.4 Protection of Subject Data................................................................................................................65
10 STUDY MANAGEMENT.....................................................................................................................65
10.1 Data Processing and Record Retention.........................................................................................65
10.2 Source Data/Document Access.......................................................................................................66
10.3 Protocol Amendments.....................................................................................................................66
10.4 Responsibilities of Investigator......................................................................................................66
10.5 Publication Policy............................................................................................................................67
10.6 Finance and Insurance....................................................................................................................67
11 References...............................................................................................................................................68
12 Appendixes.............................................................................................................................................69
Appendix 1: ECOG PS scoring system.....................................................................................................70
Appendix 2: Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)................................71
Appendix 3: Guidance for IBI308 dose modification and toxicity management...................................87
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Listing of Tables
Table 1. Visit Schedule...........................................................................................................................9
Table 2. Dose and dosing regimen.......................................................................................................33
Table 3. Dose adjustment scheme of IBI308........................................................................................35
Table 4. Routine Laboratory safety evaluations...................................................................................42
Table 5. Judgment on correlation between AE and study drug............................................................48
Table 6. Contact information for SAE reporting..................................................................................54
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Listing of Figures
FIGURE 1. SCHEMATIC DIAGRAM OF STUDY DESIGN AND DOSING REGIMEN OF CIBI308Y002..................28
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Abbreviations and Definitions of Terms
ADA Anti-drug antibodyAE Adverse eventAESI Adverse event of special interestALB AlbuminALK Anaplastic lymphoma kinaseALP Alkaline phosphataseALT Alanine aminotransferaseANC Absolute neutrophil countAST Aspartate aminotransferaseAUC Drug exposureBUN Urea nitrogenCCr Creatinine clearanceCFDA China Food and Drug AdministrationCI Confidence intervalCmax Observed maximum concentration Cr Serum creatinineCR Complete responseCRO Contract Research OrganizationCSR Clinical Study ReportCT Computed tomographyCTC Circulating tumor cellsCTCAE Common Terminology Criteria for Adverse EventsCTLA-4 Cytotoxic T lymphocyte antigen-4DCR Disease control rateDLT Dose-limiting toxicityDoR Duration of responseECG ElectrocardiogramECOG PS Eastern Cooperative Oncology Group Performance StatuseCRF Electronic Case Report FormEGFR Epidermal growth factor receptor
EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30
EORTC QLQ-LC13 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13
FAS Full analysis setFBG Fasting blood glucoseFDA Food and Drug AdministrationFFPE Formalin-fixed paraffin-embeddedFT3 Free triiodothyronineFT4 Free thyroxineGCP Good Clinical PracticeHBV Hepatitis B virusHCT Hematocrit
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HCV Hepatitis CHGB Hemoglobin contentHR Hazard ratioHIV Human immunodeficiency virusICF Informed consent formIHC ImmunohistochemistryiDMC Independent Data Monitoring CommitteeIgG Immunoglobulin GirAE Immune-related adverse eventIRR Infusion-related reactionirRECIST Immune-Related Response Evaluation Criteria in Solid TumorsIV Intravenous IWRS Interactive web response systemLDH Lactic dehydrogenaseLYM Lymphocyte countMedDRA Medical Dictionary for Regulatory ActivitiesmOS Median overall survivalmRNA Messenger ribonucleic acidMRI Magnetic resonance imagingMTD Maximum tolerated doseNAb Neutralizing antibodyNCI National Cancer InstituteNOAEL No-observed-adverse-effect levelNOEL No-observed-effect levelNSCLC Non-small-cell lung cancerORR Objective response rateOS Overall survivalPBMC Peripheral blood mononuclear cellPD Progressive diseasePD-1 Programmed death 1PD-L1 Programmed death-ligand 1DFS Disease-free survivalPH pHPK/PD Pharmacokinetics/PharmacodynamicsPLT Platelet countPR Partial responsePV PharmacovigilanceQ2W every 2 weeksQ3W every 3 weeksRBC Red blood cell countRECIST Response Evaluation Criteria in Solid TumorsSAE Serious adverse eventSAP Statistical analysis planSD Stable diseasesqNSCLC Squamous NSCLCSS Safety Analysis Set
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t½ Half-lifeT3 TriiodothyronineT4 ThyroxineTBIL Total bilirubinTEAE Treatment-emergent adverse eventTP Total proteinTPS Tumor proportion scoreTRAE Treatment-related adverse eventTSH Thyroid-stimulating hormoneUALB Urine albuminUGLU Urine glucoseULN Upper limit of normalUPRO Urine proteinURBC Urine RBCWBC White blood cellγ-GT Gamma-glutamyl transferase
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1 STUDY BACKGROUND
1.1 Disease Background
With the increase in human average life span and changes in lifestyle, malignant
tumor has become a major life-threatening disease that poses a serious threat to the
health of Chinese people. According to the 2015 statistics, the morbidity and mortality
of lung cancer in China are 733,000 and 600,000, respectively, ranking first in the
world[1]. Non-small-cell lung cancer (NSCLC) is a systemic disease and has a potential
for micrometastases even in Stage I. Reactionary hemorrhage during a surgical
procedure can promote local transplantation of cancer cells or their metastases through
blood/lymph circulation, and immunity decrease of the patient after surgery further
promotes the metastasis of cancer. Therefore, how to design and reasonably arrange the
comprehensive therapy before and after surgery to reduce the recurrence and cancer
metastasis has emerged as an important research topic. Immune checkpoint inhibitors
(PD-1/PD-L1 inhibitors) not merely have the potential to kill invisible submicroscopic
lesions to reduce post-operative recurrence by activating the immune system, but
produce less adverse effects than traditional chemotherapy, thereby providing a new
approach for the clinical treatment of NSCLC.
In January 2015, the phase III clinical trial of Opdivo (Nivolumab), a PD-1
inhibitor developed by Bristol-Myers Squibb (BMS), in the treatment of squamous cell
carcinoma of the lung was prematurely terminated[2]. In this head-to-head study
comparing Nivolumab and docetaxel second-line therapy, the Independent Data
Monitoring Committee (IDMC) evaluated the overall survival (OS) in the Nivolumab
treatment group as significantly better compared with the docetaxel control group
(median 9.2 vs 6.0 months; HR 0.59, 95% CI 0.44 - 0.79; P < 0.001), with a longer
PFS (median 3.5 vs 2.8 months; HR 0.62, 95% CI 0.47-0.81; p < 0.001) and a higher
ORR (20% vs 9%; P = 0.008)[2]. In March of the same year, Nivolumab was approved
by the US FDA for advanced squamous cell carcinoma of the lung that failed second-
line therapy.
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Based on the results of Keynote-010 study, the PD-1 inhibitor Keytruda
(Pembrolizumab) developed by Merck Sharp & Dohme Ltd (MSD) was also approved
by US FDA for second-line treatment of PD-L1-positive NSCLC in 2015. In
Keynote010 where a total of 1034 subjects were enrolled and randomized at 1:1: 1
ratio to receive Pembrolizumab 2 mg/kg, Pembrolizumab 10 mg/kg and Docetaxel 75
mg/m2, and the OS was 10.4, 12.7, and 8.5 months respectively in the three groups,
showing that both Pembrolizumab treatment groups had a significantly improved OS
compared with the Docetaxel[3] group. The indications of Pembrolizumab as
monotherapy and in combination with chemotherapy for first-line treatment of NSCLC
were approved by the FDA in September 2016 and May 2017, respectively [4-5].
Based on the results of POPLAR study and OAK study, the PD-L1 antibody
Tecentriq (Atezolizumab) of Roche was approved by US FDA in 2016 under the
indication for second-line treatment of NSCLC. Both studies were randomized
controlled studies comparing Atezolizumab and docetaxel in the second-line and above
treatment of NSCLC, with an OS of 12.6 months vs 9.7 months [6] and 13.8 months vs
9.6 months [7], respectively.
To sum up, immunotherapy blocking the PD-1/PD-L1 axis in the treatment of
advanced NSCLC has shown encouraging results, but clinical studies are yet required
for confirmation as to whether immunotherapy can be used as neoadjuvant therapy in
operable NSCLC to overcome recurrence and metastasis resulting from surgical
trauma-associated low immunity, kill subclinical lesions that are invisible to the naked
eye, and control tumor activity.
1.2 Study Drug (IBI308)
1.2.1 Mechanism of action of IBI308
Immune checkpoints can regulate or balance the intensity and extent of immune
response to avoid damage to the normal cells or tissues through the mechanism of
immune suppression. However, it is found that tumor cells will manipulate immune
checkpoints to escape the body's immune surveillance and refrain themselves from
being eliminated. With respect to multiple immune checkpoints that have been
identified so far, inhibitors of CTLA-4 and PD-1/PD-L1 are already available for
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clinical practice. PD-1/PD-L1 inhibitors have a profile of good safety and broad
indications, with a promising future for clinical application.
PD-1 is mainly expressed on the surface of activated T cells and has two ligands:
PD-L1 and PD-L2, of which PD-L1 is its main ligand and is expressed in activated T
cells, antigen-presenting cells, and tumor cells[4]. PD-1/PD-L1 binding plays an
important role in regulating T cell activation and maintaining peripheral immune
tolerance. When T cells do not express PD-1, T cells interact with antigen-presenting
cells to induce the activation and proliferation of T cells, with the secretion of activated
cytokines that act on tumor cells to kill tumor cells; the activated T cells begin to
express PD-1, and when they bind to ligand PD-L1 on antigen-presenting cells or
tumor cells, the inhibitory signals in the downstream of PD-1 will inhibit the
proliferation of T cells and the secretion of activated cytokines, thereby decrease the
function of T cells. Most tumor cells escape from immune surveillance through this
mechanism. However, if the interaction between PD-1 and PD-L1 is blocked by drugs,
the activity of T cells and their ability to kill cancer cells can be restored [8].
Up to date, three PD-1/PD-L1 products have been approved for marketing by the
US FDA, i.e., anti-PD-1 monoclonal antibody Nivolumab (trade name: OPDIVO) of
BMS, anti-PD-1 monoclonal antibody Pembrolizumab (trade name: KEYTRUDA) of
MSD, and anti-PD-L1 monoclonal antibody Atezolizumab (trade name: TECENTRIQ)
of Roche, under the indications for advanced melanoma, advanced NSCLC, advanced
classical Hodgkin lymphoma, advanced renal cell carcinoma, advanced urothelial
carcinoma, and advanced head and neck tumors. In addition, many indications are
currently under phase III clinical studies or NDA submissions. The marketing of the
above drugs has determined the important role of PD-1/PD-L1 immune checkpoint
inhibitors in cancer immunotherapy. For the moment, there is no PD-1/PD-L1 immune
checkpoint inhibitor marketed in China. Therefore, it is of great significance to actively
develop such inhibitors to provide better treatment options for Chinese patients.
Recombinant fully human anti-PD-1 monoclonal antibody injection (R&D code:
IBI308) is a recombinant fully human IgG4 monoclonal antibody. The effect of
blocking PD-1 pathway with IBI308 has been verified in various preclinical in vitro
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tests, and the anti-tumor activity of the murine analogue of IBI308 has been
demonstrated in several non-immunocompromised mouse tumor models (refer to the
Investigator's Brochure for detailed study results). The results of preclinical studies
suggested a promising future for the development of IBI308 for PD-1 blockade.
1.2.2 Results of IBI308 Clinical Study
In September 2016, a phase Ia dose-escalation trial of IBI308 was initiated. The
phase Ia was planned to enroll approximately 12 to 24 subjects with advanced solid
tumors who had failed standard of care, to evaluate IBI308 at four dose levels (1
mg/kg, 3 mg/kg, 200 mg, and 10 mg/kg), with the dose escalation decision based on
the classic “3+3” design. After completion of the 1 mg/kg dose group, subjects were
randomized to the 3 mg/kg and 200 mg dose groups at a 1:1 ratio for independent
evaluation. There was a 28-day DLT observation period for the two dose groups each
after initial dosing, and only subjects who completed the DLT observation period could
enter the subsequent treatment period to receive IBI308 Q2W (1 mg/kg, 3 mg/kg and
10 mg/kg) or Q3W (200 mg), until disease progression, intolerable toxicity, withdrawal
of consent, or occurrence of other conditions that require discontinuation of study
treatment, whichever occurs first.
Within the dose range studied (1 mg/kg - 10 mg/kg), the elimination half-life of
IBI308 was about 14 days, with a clearance of about 12 mL/h, a steady-state volume of
distribution of approximately 5 L and an apparent volume of distribution of about 84
mL/kg. The exposure (Cmax, AUC0-28, AUC0-inf) of IBI308 in the cancer patients
increased with dose across the dose range of 1 mg/kg - 10 mg/kg. For the doses 1
mg/kg, 3 mg/kg and 10 mg/kg, the geometric mean Cmax (µg/mL) of unit dose was
21.9, 23.2 and 21.6, respectively. The geometric mean AUC0-28 (μg*d/mL) of unit dose
was 199.8, 170.9 and 173.0, respectively. The geometric mean AUC0-inf (μg*d/mL) of
unit dose was 291.1, 215.7 and 213.7, respectively. The dose 1 mg/kg, 3 mg/kg and 10
mg/kg, presented similar profiles of clearance in the body, suggesting that IBI308
presented a linear pharmacokinetic (PK) profile mg/kg in the dose range of 1 - 10
mg/kg.
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At the dose of 1 mg/kg: the geometric mean Cmax values of IBI308, Nivolumab [1]and Pembolizumab [2] were 21.9 µg/mL, 16 µg/mL, and 16.4 µg/mL, respectively, and
their geometric mean t1/2 was 17.0 days, 17 days, and 14.1 days, respectively. The three
drugs had similar profiles of disposition and clearance. The exposure parameters (Cmax,
AUC0-28) of IBI308 were positively correlated with the dose across the dose range of 1
- 10 mg/kg, and this characteristic was also similar to that observed for Nivolumab and
Pembolizumab. IBI308 preliminarily showed similar human PK profiles to Nivolumab
and Pembolizumab.
The results of PD-1 receptor occupancy assay showed that single-dose
administration of IBI308 1 mg/kg achieved saturated PD-1 receptor occupancy (mean
> 95%) in peripheral blood rapidly (24h) and could maintain the PD-1 occupancy level
during the study period (28 days) when the drug concentration decreased continuously.
The results of PD-1 receptor occupancy in the 3 mg/kg, 200 mg/kg and 10 mg/kg dose
groups were similar to that in the 1 mg/kg group. The pharmacodynamic results
suggest that IBI308 has an excellent ability to target PD-1 and good affinity in cancer
patients.
Based on the previous PK/ PD results and acceptable safety events, and taking into
account potential individual differences, the recommended dose of IBI308 for further
clinical study is 200 mg Q3W.
1.3 Risk/BenefitAssessment
Based on the pharmacological mechanism of this product of this product and on
the clinical safety information from products with the same mechanism, the possibly
adverse events of this product are mainly various immune-mediated inflammations
caused by immune activation, such as pneumonia, colitis, hepatitis, renal insufficiency
and inflammation of the endocrine system. According to available clinical data of anti-
PD-1 monoclonal antibody drugs, although the incidence of adverse reactions is high,
the drugs were well tolerated, and only a small portion of subjects discontinued
treatment due to adverse reactions, most of which were resolved after appropriate
treatment. As the early symptoms of immune-related adverse reactions are variable, the
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immune-related reactions in the clinical study, make appropriate judgment in a timely
fashion, and perform dose adjustment and appropriate effective treatment as described
in Section 5.4.1 of the protocol to reduce the risks of drug use for the patients. In
addition, the investigator(s) should exclude patients with autoimmune diseases during
the clinical trial to avoid worsening of pre-existing diseases as a result of immune
system activation.
The phase Ia clinical pharmacology and safety data for IBI308 show that IBI308
has clear pharmacological activity and is well tolerated in patients with advanced
tumors.
The above data have preliminarily demonstrated the good safety and
pharmacological activity of IBI308, supporting the conduct of clinical studies of
IBI308 in patients with NSCLC.
2 Objectives of Study
2.1 Primary
To evaluate the disease-free survival (DFS) after IBI308 monotherapy as
neoadjuvant/adjuvant therapy for resectable non-small cell lung cancer (NSCLC)
To evaluate the study-related adverse events (90 days after the first dosing of IBI308
or 30 days after surgery, whichever occurs later)
To evaluate the incidence of surgical complications (both intraoperative and
perioperative)
To evaluate the rate of non-delayed surgery (surgical delay is defined as no
performance of surgery for more than 43 days from the day of the first dosing)
2.2 Secondary
To evaluate the objective response rate (ORR) and major pathologic response (MPR) after IBI308
monotherapy as neoadjuvant therapy for resectable NSCLC ;
To evaluate the 1-year and 2-year disease-free survival, the 1-year and 2-year
recurrence rate (RR) and the 2-year survival rate;
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2.3 Exploratory:
To evaluate the relationship between pathological response and DFS and RR after
IBI308 monotherapy as neoadjuvant therapy
To evaluate the distribution of IBI308 across tumor tissues and its correlation with
efficacy.
To evaluate the relationship of biomarkers in tumor tissue with efficacy, including but
not limited to the expression of PD-L1, tumor infiltrating lymphocytes (TIL), and
tumor mutational burden (TMB)
To evaluate the relationship of biomarkers in peripheral blood with efficacy, including
but not limited to the relationship between efficacy and dynamic changes in the
overall mutational burden of ctDNA
2.4 Overall Design
It is a phase Ib single-center study to evaluate IBI308 monotherapy as neoadjuvant
therapy for resectable NSCLC. A safety run-in study of 6 patients will be conducted
first, and if no major safety event occurs, the study will be expanded to a total of 30
patients.
After the signing of the informed consent form (ICF), patients with treatment-
naïve operable NSCLC who are confirmed eligible for the inclusion/exclusion criteria
after screening will be administered IBI308 200 mg IV Q3W for 2 cycles, and will
receive radical operation for NSCLC within 29 to 43 days following the first dose of
IBI308, as well as adjuvant treatment according to invergator’s discretion and patients’
status.
Imaging assessment will be conducted per RECIST v1.1 in this study, with PET
and enhanced CT performed at baseline and prior to radical operation (after the second
dose of IBI308 but within 1 week prior to operation), as well as CT or enhanced CT on
Day 30 post-operation and every 3 months post-operation, until 2 years after the
operation, disease recurrence or death. Enhanced CT/MRI is required at baseline to
rule out brain metastases.
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The subjects will be followed for safety (90 days after the first dose of IBI308 or
30 days post-operation, whichever occurs later) and post-operative recurrence-free
survival (every 90 ± 7 days until 2 years post-operation).
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Figure 1. Schematic diagram of study design and dosing regimen of CIBI308Y002
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Postoperative conventional adjuvant therapy
Recurrence-free survival follow-up: every 90 days after operation
Safety follow-up:1. 90 days after the last dose of IBI308
2. 30 days post-operation
Radical resection + lymph node dissection (After 2 cycles of IBI308
200 mg IV Q3W treatment and within 29 to 43 days after the first dose of
IBI308)
IBI308 Group: 200 mg IV Q3W*2 cycles
D1, D22
Patients with pathologically confirmed, untreated, operable NSCLC
of tumor size > 2 cm
Study drug: IBI308
3 STUDY POPULATION
3.1 Inclusion Criteria
The subjects are required to meet the following inclusion criteria:
1 Cytologically or histologically confirmed NSCLC;
2 Assent to the collection of tumor histological specimens required for this study for
relevant studies;
3 Presence of treatment-naïve, surgically resectable NSCLC, with a tumor diameter of > 2
cm;
4 Consent to receive radical operation;
5 No surgical contraindications in the judgment of a thoracic surgeon;
6 Presence of at least one measurable lesion (RECIST v1.1);
7 Male or female, at an age ≥ 18 years and ≤ 75 years;
8 An ECOG score of 0;
9 Adequate functions of vital organs and bone marrow that meet the following
requirements:
- Hematology: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets (PLT) ≥ 100 ×
109/L, hemoglobin (HGB) ≥ 9 g/dL;
- Liver function: serum total bilirubin (TBIL) ≤ 1.5 × ULN (upper limit of normal),
alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN,
serum albumin (ALB) ≥ 2.8 g/dL;
- Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance ≥ 40
mL/min (calculated using the standard Cockcroft -Gault formula):
Females: CrCl = (140-age) x body weight (kg) x 0.85
72 x serum creatinine (mg/dL)
Males: CrCl = (140-age) x body weight (kg) x 1.00
72 x serum creatinine (mg/dL)
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10 Provide signed the written ICF and could follow the visit schedule and relevant
procedures specified in the study protocol.
3.2 Exclusion Criteria
A subject meeting any of the following exclusion criteria will be excluded from
this study:
1. Presence of EGFR-sensitive gene mutation in tumor tissue as revealed by aspiration
biopsy;
2. A past medical history of any anti-tumor therapy, including radiotherapy,
chemotherapy, immunotherapy and traditional Chinese medicine therapy (excluding
therapy for malignancies that were radically treated, without recurrence or metastasis
for a period of ≥5 years);
3. Use of immunosuppressive agents within 4 weeks prior to the first dose of the study
treatment, excluding topical glucocorticoids for intranasal, inhalation or other routes of
administration, or physiological doses of systemic glucocorticoids (i.e., no more than
10 mg/day prednisone or equivalent of other glucocorticoids);
4. Known or suspected active autoimmune diseases (congenital or acquired), such as
interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis,
thyroiditis, etc. (patients with vitiligo or complete remission of asthma in childhood,
without requiring any intervention after adulthood can be enrolled; patients with type I
diabetes well controlled by insulin can also be enrolled);
5. Known allotransplant (excluding corneal transplantation) or allogeneic hematopoietic
stem cell transplantation;
6. Allergy to any ingredient of the monoclonal antibody;
7. Current interstitial lung disease;
8. Presence of other uncontrolled serious medical conditions, including but not limited to:
− Active or clinically uncontrolled severe infection;
− HIV-infection (HIV antibody positive);
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− Acute or chronic active hepatitis B (HBsAg positive and HBV DNA > 1*103/mL)
or acute or chronic active hepatitis C (HCV antibody positive and HCV RNA > 15
IU/mL);
− Active pulmonary tuberculosis;
− Class III-IV congestive heart failure (New York Heart Association classification),
poorly controlled and clinically significant arrhythmia;
− Uncontrolled arterial hypertension (systolic blood pressure ≥ 160 mmHg or
diastolic blood pressure ≥ 100 mmHg);
− Any arterial thrombosis, embolism or ischemia within 6 months prior to inclusion
for treatment, such as myocardial infarction, unstable angina, cerebrovascular
accident or transient ischemic attack;
− Disease requiring anticoagulation with warfarin (coumarin);
− Uncontrolled hypercalcemia (calcium ion > 1.5 mmol/L or calcium greater than 12
mg/dL or corrected serum calcium > ULN), or symptomatic hypercalcemia
requiring continued bisphosphonate therapy;
− Other malignant tumors (excluding cancer that has been cured, such as cervical
carcinoma in situ, non-melanoma skin cancer, etc.);
9. Other acute or chronic diseases, psychiatric disorders or abnormal laboratory values,
which may result in an increased risk associated with study participation or use of the
study drug, or interfere with the interpretation of study results and render the patient
ineligible for the study in the investigator’s judgment;
10. Pregnant or breastfeeding women.
3.3 Restrictions throughout Study
Male and female subjects of childbearing potential are required to use effective
methods of contraception from screening and must agree to maintain these precautions
until 90 days after the last dose of study drug; discontinuation of contraception should
be discussed with a responsible physician after this time point.
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3.4 Discontinuation of Treatment/Withdrawal of Subjects from Study
3.4.1 Discontinuation of any study drug for subjects
Discontinuation of study drug "Must" be performed for a subject if any of the
following circumstances:
The subject requests discontinuation of study treatment
Occurrence of any clinical adverse event (AE), laboratory abnormality, or
intercurrent disease, in which case continued participation in the study is not in the
best interest of the subject based on the investigator’s judgment
Discontinuation criteria specified in the protocol are satisfied
Violation of inclusion/exclusion criteria, which may pose potential risks to the
patient’s safety or jeopardize the accuracy of trial data, rendering it unsuitable for
the subject to continue the study;
The subject has constituted a gross violation of the study protocol, rendering it
unsuitable for the subject to continue the study in the investigator’s judgment;
Participation of the subject in another interventional drug clinical trial at the same
time;
All subjects who discontinued the study drug should be followed up according to
the procedures specified in Table 1, unless a subject has withdrawn informed consent
to all study procedures (including study follow-up after treatment discontinuation).
If a subject discontinued the study drug before completing the study, the reason for
discontinuation must be documented in the subject's medical records and entered into
the appropriate page of the electronic medical records system (EDC).
3.4.2 Study follow-up after treatment discontinuation
For subjects who discontinued the study drug, follow-up must be continued to
collect outcome and/or recurrence-free survival follow-up data as required, until death
of the subject or the end of study as specified in Table 1.
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For subjects who are lost to follow-up, the site should make all possible efforts to
contact the subject to determine the cause(s) of loss to follow-up, and re-schedule a
visit wherever possible. Meanwhile, the site should document the date of the subject to
be contacted and the contact information used in the study file.
3.4.3 Withdrawal of informed consent
A subject that requested discontinuation of study drug is still required to continue
in the study, and must be followed continuously according to the follow-up procedures
specified in the study protocol. However, there is one exceptional situation where the
subject himself or herself or the person previously authorized to provide this
information cannot be contacted again after the subject has clearly withdrawn the
informed consent. Where possible, the subjects should inform the investigator(s) of
their decision to withdraw consent to future follow-up in writing form. The
investigator(s) should provide a delineation of informed consent withdrawal in the
medical records, by clarifying whether it is only a decision not to use the study
treatment or a decision not to perform the study procedures and/or the study follow-up
after treatment discontinuation, and enter such information into the appropriate case
report form (CRF) page. If needed for evaluation of survival status survival (whether
the subject is living or dead), it can be performed only using the publicly available
information in accordance with corresponding provisions and with law.
4 STUDY DRUG AND OTHER TREATMENTS
4.1 Dosing regimen
4.1.1 Dosing regimen
For the purpose of this study, study drug refers to IBI308, and other medications
used during the study are collectively referred to as non-study drugs. The dosing
regimen is presented in the table below.
Table 2. Dose and dosing regimen
Group Dosing regimen Dosage time
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IBI308 group200 mg IV infusion over approximately 1 hour, Q3W, for 2 cycles before surgery
D1 and D22 prior to operation;
4.2 Study Drug (IBI308)
4.2.1 Description
The study drug is recombinant fully human anti-programmed cell death receptor 1
monoclonal antibody injection, referred to as IBI308.
Its main active ingredient is recombinant fully human anti-programmed cell death
receptor 1 monoclonal antibody, with the finished product supplied in strength of 10
mL: 100 mg. IBI308 is at a concentration of 10 mg/mL, free of preservatives, and
contains the following excipients: mannitol 140 mmol/L, histidine 25 mmol/L, sodium
citrate dihydrate 20 mmol/L, sodium chloride 50 mmol/L, edetate disodium (disodium
edetate) 0.02 mmol/L, and polysorbate 80 0.2 mg/mL, with a pH value of 6.0.
This product is a clear, colorless liquid, free of foreign matters, floccules and
precipitates.
Manufacturer: Innovent Biologics (Suzhou) Co., Ltd (hereinafter referred to as
Innovent).
4.2.2 Labeling
IBI308 is supplied in the minimum packaging unit of boxes, with per box
containing 1 piece of IBI308 injection packaged in a vial. Printed on the packaging
boxes of IBI308 are drug name, drug number, dosage form, strength, drug code, lot
number, shelf life, storage conditions, usage and dosage, and precautions. The same
information is also printed on the labels for the vials and packaging boxes, except for
dosage form and precautions information, which is not provided on the vial labels. The
labels of all packaging boxes and vials are clearly indicated with "For clinical trial
only".
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4.2.3 Storage conditions
Store at 2 to 8 , protect from light, shelf life of 24 months. If quality problems ℃such as turbidity and precipitation occur with the injection, seal up the product
immediately and notify Innovent.
4.2.4 Preparation and infusion
IBI308 is prepared and infused according to procedures as follows:
1. Draw the liquids of 2 vials of IBI308 injection completely into an IV infusion bag
containing 100 mL of 0.9% (weight/volume) sodium chloride sterile normal saline,
and record the start time of preparation.
2. Gently invert the infusion bag to mix, to ensure the homogeneity of drug in the
infusion bag and avoid shaking violently to produce bubbles.
3. Administer infusion via an IV pump installed with 0.2 - 1.2 μm in-line filters (it is
recommended that the infusion be completed over 60 minutes), and record the start
time and end time of infusion.
Notes: Prior to preparation, confirm that IBI308 injection is transparent without
turbidity, precipitates or other quality problems; ensure that the time from the puncture
of the first vial of IBI308 injection to the end of infusion does not exceed 24 hours (the
prepared mixture is refrigerated at 2 - 8 ); avoid mixing other drugs; avoid IV bolus.℃
4.3 Dose Modifications
4.3.1 General principle
The subjects must have adequate hematologic, hepatic, and renal functions prior to
dosing of study drug on Day 1, and all toxicities must have been resolved to NCI CTCAE
4.03 grade 0-1 or baseline (excluding alopecia, fatigue).
All dosage modifications should be documented, including the reason and the
method(s) used.
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4.3.2 Dosage modifications for IBI308
No dose adjustment for IBI308 is allowed throughout the study. The dosage
modification scheme for IBI308 (only for AEs judged as IBI308-related by the
investigator) is presented in the table below.
Table 3. Dose adjustment scheme of IBI308
Adverse reactions Severity Dose modifications
Pneumonitis
Grade 2 pneumonitis Interruptiona
Grade 3 or 4 pneumonitis Permanent discontinuation
Diarrhea/enterocolitis
Grade 2 or 3 diarrhea or enterocolitis Interruptiona
Grade 4 diarrhea or enterocolitis Permanent discontinuation
Dermatitis
Grade 3 dermatitis Interruptiona
Grade 4 dermatitis Permanent discontinuation
Hepatitis
Grade 2 increased AST, ALT, or TBIL for subjects with normal ALT, AST, or TBIL at baseline; or AST, ALT, or TBIL elevations ≥ 50% and persisting < 7 days for subjects with AST, ALT, or TBIL > ULN at baseline
Interruptiona
Grade 3 or 4 increased AST, ALT, or TBIL for subjects with normal ALT, AST, or TBIL at baseline; or AST, ALT, or TBIL elevation ≥ 50% and lasting ≥ 7 days for subjects with AST, ALT, or TBIL > ULN at baseline
Permanent discontinuation
Hypophysitis
Grade 2 hypophysitis Interruptionb
Grade 3 or 4 hypophysitis Permanent discontinuation
Adrenal insufficiency Grade 2 adrenal insufficiency Interruptionb
Grade 3 or 4 adrenal insufficiency Permanent
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Adverse reactions Severity Dose modifications
discontinuation
Hyperthyroidism Grade 3 or 4 hyperthyroidism Permanent discontinuation
Type 1 diabetes
Grade 3 hperglycaemia Interruptionb
Grade 4 hperglycaemia Permanent discontinuation
Renal insufficiency
Grade 2 or 3 elevated Cr Interruptiona
Grade 4 elevated Cr Permanent discontinuation
Neurotoxicity
Grade 2 neurotoxicity Interruptiona
Grade 3 or 4 neurotoxicity Permanent discontinuation
Transfusion reaction Grade 3/4 infusion reaction Permanent discontinuation
Other AEs
First occurrence of other grade 3 AE Interruptiona
Second occurrence of the same grade 3 AE Permanent discontinuation
Grade 3 AE that did not return to grade 0 - 2 or the baseline level within 7 days or was not resolved to grade 0/1 or the baseline level within 14 days
Permanent discontinuation
Grade 4 AE Permanent discontinuationc
a: The drug may be resumed after the symptoms are resolved to grade 0 - 1 or the
baseline level.
b: The drug may be resumed after hypophysitis, adrenal insufficiency, and/or type 1
diabetes mellitus is adequately controlled, only requiring physiological hormone
replacement therapy (HRT).
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c: For grade 4 laboratory abnormalities, discontinuation of treatment should be based
on concomitant clinical symptoms/signs and the investigator’s clinical judgment.
The maximum interval between the first and second doses of IBI308 is 5 weeks. If the
abnormalities do not return to a status allowing for resumption of IBI308 within 5 weeks,
the subject will be discontinued from IBI308 permanently and proceed to the radical
surgery stage.
4.4 Principles for Management of Toxicities Associated with Immune Checkpoint
Inhibitors
IBI308 pharmacologically promotes the activation and proliferation of T cells to
cause immune hyperfunction, thereby leading to autoimmune disorders of multiple
systems. Immune-related adverse events were reported with clinical application of
other immune checkpoint inhibitors (Ipilimumab, Nivolumab, Pembrolizumab and
Atezolizumab), including immune-related pneumonia, diarrhea/enterocolitis, renal
insufficiency, rash, hepatitis, endocrine disorders, and peripheral or central neuritis. In
the event any of the above AEs occurs for a subject in this study, appropriate measures
should be taken for the subject, including monitoring of symptoms and signs, and
identification of cause(s). If no alternative causes (e.g., disease progression,
concomitant medication and infection) are identified and treatment with
glucocorticoids and/or other immunosuppressive agents is required (except for
endocrine events such as hyperthyroidism/hypothyroidism, hypophysitis, type 1
diabetes and adrenal insufficiency, which may not be treated with immunosuppressive
therapy but are still considered to be related to immune hyperfunction caused by
IBI308), the above AE should be considered related to hyperfunction of the immune
system caused by IBI308 and diagnosed as irAE.
Guidelines on dose adjustment and toxicity management for potential major irAEs,
potential other irAEs and infusion-related reactions are provided in Appendix 4.
4.5 Concomitant Treatment
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period of study drug:
Other chemotherapy, immunotherapy, targeted therapy and Chinese herbal
medicines with anti-tumor activity for anti - tumors.
Immunosuppressive agents and high-dose glucocorticoids (excluding those for
AEs).
Immunoglobulins.
Live attenuated vaccine.
4.5.2 Permitted medications
Use of the following medications is permitted during the preoperative treatment period
of study drug:
Medications that comply with the protocol requirements in the investigator’s
judgment (e.g., concomitant medications for disease-related symptoms and
treatment-related AEs).
Long-term medications that are required for management of underlying diseases
such as hypertension and diabetes.
Glucocorticoids that are intended for topical use, such as topical skin application,
eye application, nasal spray and inhalation.
4.6 Treatment Compliance
Study treatment is administered at the study site, and treatment compliance is
monitored using drug receipt & dispensing records, medical records and eCRFs.
4.7 Drug Recovery and Destruction
In this study, the used and partially used containers, bottles, infusion bags, and
syringes of the study drug may be destroyed on site according to the applicable
guidelines and operating procedures established by the study site and local authorities
after confirmation by the clinical research associate (CRA).
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4.8 Documentation of Study Drug
The designated site personnel should keep a record of the receipt, dispensing, use,
inventory, loss, recovery and destruction of the study drugs in time according to the
requirements of relevant regulations and guidelines as well as the operating procedures
of this trial.
5 STUDY EVALUATIONS AND PROCEDURES
5.1 Subject Enrollment Process
5.1.1 Subject inclusion criteria
The investigator(s) will enroll subjects according to the following procedures:
1. Obtain signed ICF the subject prior to initiation of any study-related procedures.
2. The principal investigator (PI) or the appropriately trained designee formally
confirm the subject’s eligibility against the inclusion/exclusion criteria.
Re-screening may be performed for patients who do not meet the relevant criteria
for this study (screening failure). At re-screening, the patient must re-sign the ICF and
will be reassigned with an identification number.
5.2 Study Plan and Schedule
5.2.1 Screening
The following study procedures must be completed during the screening period
(Day -28 - -1) to ensure the subject’s eligibility for the study:
Sign ICF
Inclusion/exclusion criteria
Demographics, past medical history and previous medication
Vital signs, height and weight
Physical examination
ECOG PS score
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12-lead ECG
Hematology/blood biochemistry/urinalysis (within 7 days prior to the first dosing)
Pregnancy test (within 3 days prior to the first dosing)
Thyroid function
HIV antibody, hepatitis B two and a half pairs (HBsAg, HBsAb, HBcAb, HBeAg,
HBeAb), HCV antibody
Adverse event assessment
Concomitant medications
Tumor imaging evaluation (the results of imaging examinations obtained before
signing of ICF can be used for the screening period)
Biopsy of fresh tumor tissue
EGFR testing
Biomarker blood sample collection
5.2.2 Baseline (prior to dosing on Day 1/Cycle 1
Vital signs
Adverse event assessment
Concomitant medications
Immunogenicity
5.2.3 Visits during therapy period
Vital signs
Physical examination
12-lead ECG
Hematology/blood biochemistry/urinalysis
Thyroid function
Adverse event assessment
Concomitant medications
Tumor imaging evaluation
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Administration of study drug
Biomarker blood sample collection
The flow chart of study treatment visits is provided in Table 1.
5.2.4 Safety Follow-up
Safety follow-up takes place on Day 30 post-operation and Day 90 after the last
dose. If these two follow-ups are expected to occur at an interval of less than 2 weeks,
they can be combined as one follow-up (whichever occurs later).
Safety follow-up on Day 30 post-operation covers the following:
Vital signs
Physical examination
12-lead ECG
Hematology/blood biochemistry/urinalysis
Thyroid function
Imaging evaluation
Adverse event assessment
Concomitant medications
Subsequent anti-tumor treatment
Safety follow-up on Day 90 after the last dose covers the following:
Vital signs
Physical examination
12-lead ECG
Hematology/blood biochemistry/urinalysis
Thyroid function
Adverse event assessment
Concomitant medications
Subsequent anti-tumor treatment
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Immunogenicity
Pregnancy test
5.2.5 Recurrence-free survival follow-up
At the time of imaging evaluation performed every 90 days (± 7 days) after
surgery, information regarding the subject's survival and information regarding any
subsequent systemic anticancer therapy and disease recurrence will be recorded until 2
years after surgery. After 2 years post-operation, the investigator may continue to
follow the patient for a long period of time until death of the subject.
5.3 Safety Evaluation
5.3.1 Routine Laboratory Safety evaluations
Table 4 Routine Laboratory safety evaluations
Hematology
RBC、HGB、WBC、PLT、LYM、ANC
Blood chemistry
TBIL, ALT, AST, γ-GT ALP, ALB, TP, LDH, BUN, Cr, Na, K, Cl, Mg, Ca, P, Lipase, Amylase and FBG
Urinalysis PH, UALB, UPRO, URBC, UGLU
5.3.2 Physical examination
Complete physical examination includes: general condition, respiratory,
cardiovascular, abdominal, skin, head and neck (including ears, eyes, nose and throat),
lymph nodes, thyroid, musculoskeletal (including spine and limbs), genital/anal and
neurological assessments.
Refer to Table 1 visit schedule for the specific time of physical examination. Refer
to Appendix 2 for ECOG PS scoring system.
5.3.3 12-lead ECG
Resting 12-lead ECG will be analyzed at a local laboratory according to Table 1
visit schedule.
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A 12-lead ECG is performed for each subject after a rest of minimum 5 minutes in
recumbent position. All 12-lead ECGs should be recorded with the subject in a
recumbent position. Further ECG will be performed as clinically indicated, e.g., when
there is an occurrence of cardiac-related AE. The investigator completes ECG
assessment on the day of the examination and write down the results of assessment on
the electrocardiogram. The same assessment method(s) should be used throughout the
study.
The investigator should assess all ECGs according to the category of clinically
significant abnormality/not clinically significant abnormality. If the abnormality is
clinically significant, the investigator should record this result as an AE in the eCRF.
5.3.4 Vital signs
Vital signs examination will be performed as described in Table 1 study visit
schedule. Vital signs include body temperature, pulse rate, respiratory rate, and blood
pressure.
Additional monitoring of vital signs may be performed at the discretion of the
investigator based on standard clinical practice or as clinically indicated.
In the event of an AE/SAE, additional vital sign values may be collected from the
eCRF (if appropriate). The date(s) and time of collection and measurement will be
recorded in the appropriate section of the eCRF.
5.3.4.1 Pulse and blood pressure
Blood pressure (BP) and pulse rate are measured with the subject a supine position
after a rest of at least 5 minutes. Two ore more readings should be obtained with
measurement performed at intervals of two minutes, and the mean of the measurements
is calculated. If the first two systolic blood pressure readings differ by more than 5
mmHg, another measurement should be performed to calculate the mean value. The
date(s) and time of collection and measurement will be recorded in the appropriate
section of the eCRF.
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Measurement of pulse and blood pressure measurements needs to be performed
prior to administration of the study drug.
5.3.4.2 Body temperatureand respiratory rate
Blood temperature and respiratory rate should be collected prior to infusion on the
scheduled dosing day(s).
5.3.5 Body weight and height
Body height is measured only during the screening period.
Body weight measurement needs to be performed prior to each scheduled dosing
throughout this study. If a subject's body weight fluctuations from baseline (the day of
the first dose of study treatment) are less than 10%, the baseline body weight will be
used to calculate the dose for the subject. Otherwise, the subject's body weight on the
scheduled dosing day will be used for calculating the actual dose.
5.3.6 Pregnancy test
For women of childbearing potential (see 4.3 for definition), a pregnancy test
using urine or serum human chorionic gonadotropin (hCG) samples should be
performed within 3 days prior to the first dose of study drug. If urine hCG test reports
positive or negative cannot be confirmed, a pregnancy test should be using serum β-
hCG samples, and the result of serum pregnancy test should prevail. If the pregnancy
test is positive, the subject is not eligible for enrollment/must be discontinued from the
study. In the event of suspected pregnancy during the study, a test should be repeated
for confirmation.
5.3.7 Other safety tests
HIV antibody
Hepatitis B: Two and a half pairs (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb).
Hepatitis C: HCV antibody.
Thyroid function: T3, T4, TSH, FT3 and FT4.
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5.4 Immunogenicity
Immunogenicity testing will be performed before each IBI308 dose and on Day 90
after last dose. If a subject experienced an IBI308 infusion reaction, blood samples
should be collected as close as possible to the start and resolution of the event, and at
approximately 30 days after the end of the event for comparison of immunogenicity
before and after IBI308 infusion.
Testing on anti-drug antibody titer will be performed for each subject, and ADA-
positive serum specimens will be further tested for neutralizing antibodies (NAbs).
Four (4) mL of whole blood will be collected into a coagulation-promoting
vacuum tube, then separated serum, split and frozen for ADA and NAb analysis.
See the "Laboratory Manual" for details on the sample collection method and
sample preservation, transport & analysis.
5.5 Biomarker Analysis
Where permitted by the Ethics Committee, all subjects who meet the inclusion
criteria are required to provide tissue biopsy specimens at baseline for biomarker
analysis, including but not limited to PD-L1 expression, TIL, and TMB. See Specimen
Collection Manual for specific requirements regarding the amounts of specimens to be
collected, specimen preservation and transportation. Subjects are required to provide
10 ml of whole blood specimens at the following time points: during the screening
period and at each efficacy evaluation, until 2 years after surgery. See Specimen
Collection Manual for specific requirements.
5.6 Storage and Destruction of Biological Samples
Samples will be anonymized and pooled. In addition, they will be disposed of or
destroyed appropriately. Additional analyses may be performed for the anonymized,
pooled samples to further assess and validate the analytical methods. Any results
obtained from these analyses may be reported separately from the CSR.
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Sample reproducibility analysis (if performed) will be performed in parallel with
the bioanalysis of the test samples. The assessment results will be separately reported
in a bioanalysis report rather than in the clinical study report.
6 SAFETY REPORT AND AE MANAGEMENT
6.1 Definition of Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a clinical
trial subject from the signing of the ICF through 90 days after administration of the last
study treatment, irrespective of a causal relationship with the drug. Therefore, AEs
include but are not limited to the following:
Worsening of preexisting medical conditions/diseases (including worsening of
symptoms, signs and laboratory abnormalities);
Any new adverse medical conditions (including symptoms, signs and newly
diagnosed diseases);
Clinically significant abnormal laboratory values or findings.
6.2 Definition of Serious Adverse Event
A serious adverse event (SAE) is defined as the AE that meets at least one of the
following criteria:
Results in death, excluding deaths due to disease progression from the studied
indication.
Is life-threatening ("life-threatening"in the definition refers to an AE that
places the subject at immediate risk of death as it occurred, and therefore it does
not include an AE that might have caused death had it occurred in more severe
form).
Requires inpatient hospitalization or prolongation of existing hospitalization,
with the exception of the following:
- Admission to a rehabilitation facility;
- Admission to nursing homes;
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- Routine admission to the emergency room
- Same-day surgery (e.g. outpatient/same-day/ambulatory surgery)
- Inpatient hospitalization that is not related to worsening of AE, or
prolongation of hospitalization which itself is not an SAE. For example,
hospitalization due to preexisting diseases, without occurrence of new adverse
events or worsening of preexisting diseases (for example, in order to examine the
laboratory abnormalities that have already existed before initiation of the trial and
been persisting throughout the study); administrative hospitalization (for example,
routine annual physical examination); hospitalization specified in the trial protocol
during the clinical trial (for example, operations performed according to the
requirements of the trial protocol); elective hospitalization unrelated to worsening
of an adverse event (for example, selective operation); scheduled treatment or
surgery, which should be recorded in the whole trial protocol and/or the subject’s
baseline data; hospitalization only due to the use of blood products.
Results in persistent or significant disability/incapacity.
Is a congenital anomaly/birth defect.
Other important medical events: defined as events that jeopardize the subject
or require medical intervention to prevent any of the above consequences.
6.3 Criteria for AE Severity Judgment
The investigator(s) will assess the severity of AEs according to the five-grade
judgment criteria as established in NCI CTCAE v4.03.
AEs that are not included in CTCAE v4.03 will be graded according to the
following CTCAE principles:
Grade 1- Mild; asymptomatic or minimal signs; clinical or diagnostic
observations only; intervention not indicated.
Grade 2 - Moderate; minimal, local or non-invasive intervention indicated;
limiting age-appropriate instrumental activities of daily living (ADL, e.g.,
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preparing meals, shopping for groceries, using the telephone, managing money,
etc.).
Grade 3 - Severe or clinically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting
self-care ADL (e.g., bathing, dressing and undressing, feeding self, using the
toilet, and taking medications), but not bedridden.
Grade 4 - Life-threatening consequences; urgent intervention indicated.
Grade 5 - Death related to AE
6.4 Judgment on correlation between AE and study drug
The relationship of the study drug with the AE or the role it plays in the occurrence
of AE can be judged using the following classification and criteria:
Table 5. Judgment on correlation between AE and study drug
Correlation Criteria
Definitely
related
- There exists a reasonable temporal consequence in use of the study
drug with occurrence of the AE;
- The AE can be more reasonably explained by the investigational drug
than other causes (e.g., the subject's preexisting disease,
environmental or toxic factors or other treatments the subject
received, etc.);
- The AE disappeared or is mitigated after treatment discontinuation or
dose reduction;
- It falls into the known AE types of the suspected drug or similar
drugs;
- The adverse event appears again after resumption of the drug;
Possibly
related
- There exists a reasonable temporal consequence in use of the study
drug with occurrence of the AE;
- The AE can be reasonably explained by the investigational drug as
well as by other causes (e.g., the subject's preexisting disease,
environmental or toxic factors or other treatments the subject
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Correlation Criteria
received, etc.);
- The AE disappeared or is mitigated after treatment discontinuation or
dose reduction (if applicable).
Possibly
unrelated
- The AE can be more reasonably explained by other reasons (e.g., the
subject's preexisting disease, environmental or toxic factors or other
treatments the subject received, etc.) than the investigational drug;
- It is unknown whether the AE disappeared or is mitigated after
treatment discontinuation or dose reduction (if applicable);
- It is unknown whether the AE appeared again or not after resumption
of the drug.
Definitely
unrelated
- There does not exist a reasonable temporal consequence in use of the
drug with occurrence of the AE, or
- There are other obvious explanations for the AE (e.g., the subject's
preexisting disease, environmental or toxic factors or other treatments
the subject received, etc.).
Unable to
judge
- The above information is unknown; the investigator considers it
impossible to judge based on available information and is unable to
obtain further follow-up information.
6.5 Recording of AEs
The investigator(s) should record AEs or SAEs using medical
terminology/concepts. Use of colloquialisms and abbreviations should be avoided. All
AEs (including SAEs) should be recorded on the adverse event form of the eCRF.
6.5.1 Collection of AEs and time period
The investigator is aware of AEs by asking the subjects non-inductive questions.
All AEs (including SAEs), whether observed by the investigator or spontaneously
reported by the subjects, should be collected from the signing of the ICF through 90
days after the last dose.
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After 90 days after the last dose, the investigator should report SAEs that are
considered related to the study drug or procedures.
6.5.2 Follow-up of AEs
All AEs should be followed up until they are resolved to baseline or grade 0 - 1 or
the investigator consider further follow-up unnecessary for good justification (e.g, the
AE cannot be resolved or has improved). If the AE cannot be resolved, the reasonable
explanation(s) should be recorded on the eCRF. The outcomes of AEs or SAEs in the
subjects and their dates should be documented on the eCRF and medical records,
irrespective of their relationship with the study drug.
6.5.3 AE records
The investigator should keep a complete record of any adverse event, including
diagnosis (if no diagnosis, record the symptoms and signs including abnormal
laboratory findings), start and end dates and time (if applicable), CTCAE severity
grade and change (Grade 3 events and above), whether it is an SAE, whether it is an
AESI, actions taken for the study drug, treatment administered due to AE and the
outcome of the event, and the relationship of AE with the study drug.
For an SAE, the investigator should also provide the following details: the date
on which the AE is judged to meet the criteria for an SAE, the date the investigator
became aware of the SAE, rationale for the determining the AE as an SAE, the date of
hospitalization, the date of discharge, the possible cause(s) of death, the date of death,
whether an autopsy was performed, the assessment of causality with the study
procedures, assessment of causality with other drugs, and other possible explanations
for the SAE. The investigator should also provide the rationale for correlation
judgment and a description of the SAE. The description of SAE needs to address the
following: the subject's number, age, gender, height and weight; the subject’s
indication for the investigational treatment, disease stage and general conditions;
clinical course of the SAE, including occurrence, development, outcome and
consequence; laboratory findings related to the SAE (the time of laboratory test, unit
and normal range must be provided); past medical history/ concomitant diseases
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related to the SAE, and their occurrence time and duration; medication history and
concomitant medications related to the SAE, and their start date, duration and dosage;
details about the investigational treatment, including the start time, duration and
dosage.
The items of AE records are described as follows:
Diagnosis, symptoms and signs
If a diagnosis has been made, the diagnosis should be recorded in the eCRF rather
than the individual signs and symptoms (e.g., record liver failure other than jaundice,
elevated transaminases, and asterixis). If symptoms and signs cannot be determined to
be a result of the diagnosis at the time of reporting, they should be recorded as a
separate AE/SAE. If the symptoms and signs are determined to be a result of the
diagnosis, only the diagnosis is reported separately, with the symptoms and signs
included in the diagnosis. For an AE, the records of signs and symptoms need to be
deleted; for an SAE, the updated follow-up report needs to be sent.
AEs secondary to other events
For adverse events secondary to other events (e.g. caused by other events or
clinical sequelae), their primary events should be documented in general, unless such a
secondary event is of high severity or an SAE. However, a secondary event of great
clinical significance should be recorded as a separate AE in the eCRF provided it
occurred at different time from the primary event. If the correlation between the events
is unclear, the events should be recorded separately in the eCRF.
Persistent or recurred AE
A persistent AE refers to an AE that is not resolved between two evaluations for
the subject and persists. Such AEs should be recorded only once on the eCRF. The
initial severity of the event should be recorded, and should be updated to the greatest
severity when there is a worsening of the event.
A recurred AE refers to an AE that was already resolved between two evaluations
but occurs later again. The occurrence of such events should be recorded separately on
the eCRF.
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Abnormal laboratory findings
Clinically significant abnormal laboratory findings should be reported as AEs. It is
the responsibility of the investigator to review all abnormal laboratory findings and
make medical judgment on each abnormal laboratory finding as to whether they should
be reported as an AE.
Death
All deaths that occurred throughout the trial, including the 90-day follow-up
period that begins following the last dose, should be recorded on the death report form
on the eCRF and reported to the sponsor in a timely manner, irrespective of
relationship with the study drug.
When recording a death event, if the cause of death is identified, the cause of death
should be recorded as an AE, with its outcome recorded as death, and the event should
be reported as SAE (it should not be recorded and reported as an AE/SAE if death is
due to tumor progression, but the investigator should record the death on the death
report form on eCRF and inform the sponsor in a timely fashion); if the cause of death
is unknown at the time of reporting, it should be recorded as "Unexplained death" on
the adverse event form on the eCRF, and then reported as SAE, followed by further
investigation into the exact cause(s) of death.
If the death is clearly due to tumor progression, it will not be recorded and
reported as AE/SAE, but the investigator should keep a record of the death on the death
report form on the eCRF and inform the sponsor timely.
Preexisting medical conditions
The preexisting symptoms/signs a subject has already presented in the screening
period of the trial should be recorded and reported as AE only when there is worsening
in severity, frequency and nature (excluding worsening of the medical condition
studied) after entry into the trial. Changes from the previous state should be reflected in
the record, e.g., “increased frequency of headache”.
Progressive disease
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Progressive disease (PD) is defined as worsening of a subject’s condition due to
the primary tumor the investigational drug is targeted on. Appearance of new lesions
relative to the primary tumor or progression of the original lesions is considered as PD.
PD is not reported as an AE. Death due to signs and symptoms of disease progression,
events that were life-threatening, required inpatient hospitalization or prolongation of
existing hospitalization, resulted in persistent or significant disability/incapacity, or
were a congenital anomaly/birth defect, and other important medical events warrant
expedited reporting as SAE.
Overdosage
Overdose is defined as use beyond the protocol-specified dose. Overdose with AE
should be recorded as AE. Expedited reporting per SAE procedures is required when
overdose is accompanied by an SAE.
6.6 Expedited reporting of SAEs and pregnancies
Reporting of SAEs:
The time limit of SAE reporting is from signing of the ICF to 90 days (including
90 days) after the last dose. In case of an SAE during this period of time, the
investigator must immediately fill out, sign and date "CFDA Serious Adverse Event
Report Form", and submit the completed form to China Food and Drug Administration
(CFDA), Cancer Hospital CAMS and Innovent no later than 24 hours after awareness,
whether it is an initial report or a follow-up report. Detailed contact information on
SAE reporting is provided in the Table below.
If an SAE occurring during the above time limit is considered related to the study
drug, it should also be reported to the Cancer Hospital CAMS and Innovent.
The investigator must submit the completed SAE report form to Cancer Hospital
CAMS and Innovent as soon as possible within 24 hours after awareness of the SAE.
For deaths and life-threatening SAEs, the investigator should conduct an emergency
follow-up to obtain the missing information and provide a complete SAE report.
When reporting SAEs by email, the investigator is advised to encrypt the report
file and send the report file and its cryptogram via different emails.
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Meanwhile, the investigator should report to the drug regulatory authority, the
health administration, Cancer Hospital CAMS and Innovent in accordance with the
regulatory requirements of the country
Table 6 Contact information for SAE reporting
Organizations Contact persons Fax/Phone/Address
Cancer Hospital Chinese
Academy of Medical
Sciences
Ethics Committee Fax/Phone
Division of Drug Research
Supervision, Department of
Drug and Cosmetics
Registration, CFDA
Address: Building 2, No.26
Xuanwumen West Street, Xicheng
District, Beijing. P.R. China
Postcode: 100053
Tel.: 010-88330732
Fax: 010-88363228
The Bureau of Health
Administration, the
National Health
Commission
Address: No. A38 Lishi Road,
Xicheng District, Beijing, P.R.
China
Tel.: 010-68792001
Fax: 010-68792734
Innovent Biologics
(Suzhou) Co., LtdFax number: 021-31652800
Email: drugsafety@innoventbio.com
Pregnancy
Considering embryotoxicity risks are reported for similar drugs, all clinical trial
participants of childbearing potential must take effective contraceptive measures.
If a female subject becomes pregnant during the clinical trial, the subject should be
removed from the study, and the investigator should report to Cancer Hospital CAMS
and Innovent within 24 hours after awareness of the pregnancy, and fill out Innovent
Clinical Trial Pregnancy Report/Follow-up Form.
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If the partner of a male subject becomes pregnant during the clinical trial, the
subject can continue participating in the clinical trial, and the investigator should report
to Cancer Hospital CAMS and Innovent within 24 hours after being informed of the
pregnancy, and complete Innovent Clinical Trial Pregnancy Report/Follow-up Form.
The investigator should follow up the pregnancy outcome until 8 weeks after
delivery of baby by the mother, and report the outcome to Cancer Hospital CAMS and
Innovent.
If the outcome of pregnancy is still birth, spontaneous abortion, fetal malformation
(any congenital anomaly/birth defect), or induced abortion for medical reasons, it
should be considered as SAE and reported according to the procedures and time limit
for SAE reporting.
If a subject experienced a concurrent SAE during pregnancy, CFDA Serious
Adverse Event Report Form should also be completed for reporting according to the
SAE reporting procedures.
6.6.1 Immune-related adverse event
Given that IBI308 pharmacologically acts to cause activation and proliferation of
T cells, immune-related adverse events (irAEs) may be observed during this study. The
definition of irAE is provided in Section 4.4 of the protocol. Subjects should be
monitored for signs and symptoms of irAEs.
The principles for IBI308 dose modifications and AE handling are detailed in
Sections 4.3 and 6 of the protocol. Guidelines for the handling of irAEs are provided in
Appendix 4 (Tables 1 - 2).
6.6.2 Adverse events of special interest
An adverse event of special interest (AESI) refers to an AE that needs to be closely
monitored to better understand the safety profile of the investigational drug, and
therefore AESI can be non-serious events.
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≥ grade 2 diarrhea, colitis, uveitis, interstitial pneumonia
≥ grade 3 other irAEs
7 STATISTICAL CONSIDERATIONS
7.1 Statistical analysis plan
A detailed statistical analysis plan (SAP) will be written after enrollment of the
first subject and finalized before database lock. The SAP will provide a full
presentation of all statistical analyses and their results.
7.2 Hypothesis Test
As this study is a single-arm, exploratory study, rigorous hypothesis testing will
not be performed.
7.3 Statistical Analysis Population
The analysis population includes safety analysis set (SS), full analysis set (FAS),
and per-protocol set (PPS):
1) SS: the population of subjects who received at least one dose of the study
drug.
2) FAS: the population of subjects who received at least one dose of the study
drug and completed the radical surgery.
3) PPS: a subset of the FAS, defined as the population of subjects with good
compliance who constituted no gross protocol violations, without major protocol
violations and used no concomitant medications prohibited by the protocol.
7.4 Methods of Statistical Analysis
7.4.1 General methods forstatistical analysis
Measurement data will be presented by mean, standard deviation (SD), median,
maximum and minimum, and count data will be described by frequency and
percentage.
All statistical analyses will be completed using SAS 9.2 (or a higher version).
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7.4.2 Analysis of primary endpoint
Safety analysis is performed on the SS, and the primary safety outcome measures
include:
Study-related adverse events (90 days after the first dose of IBI308 or 30 days
after surgery, whichever occurs later): ≥ grade 3 adverse events related to the
study drug
Incidence of surgical complications: defined as ≥ grade 3 or severe intraoperative
and perioperative complications
Rate of no-delayed surgery (surgical delay is defined as no performance of
surgery for more than 43 days from the day of the first dosing).
Other safety analysis include adverse event, laboratory examination, vital signs,
electrocardiogram, etc..
7.4.3 Analysis of efficacy outcome measures
Efficacy analysis is mainly based on FAS and PPS, and the primary efficacy
endpoint is Overall response rate (ORR)
ORR=Number of subjects achieving CR+PRTotal number of subjects
∗100%, with its 95% CI calculated
using binomial distribution.
Major pathologic response (MPR), which is defined as < 10% visible tumor cells
under a microscope.
MPR=Number of subjectsachieving MRPTotalnumber of subjects
∗100 %, with its 95% CI calculated
using binomial distribution.
Disease-free survival (DFS): the time from the first dose of study drug to the
occurrence of death or recurrence.
The 1-year and 2-year DFS will be calculated using Kaplan-Meier estimator.
1-year and 2-year recurrence rate (RR): the 1-year and 2-year RR in the patients
will be calculated.
Overall survival (OS): The time from the first dose of study drug to the date of the
subject's death.
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The 2-year survival rate will be calculated using Kaplan-Meier estimator.
7.4.4 Biomarker Analysis
Tumor tissue specimens will be collected to analyze the relationship between
biomarkers and efficacy, including but not limited to the expression of PD-L1,
tumor infiltrating lymphocytes (TIL), tumor mutational burden (TMB)
Peripheral blood samples will be collected to analyze the relationship between
biomarkers and efficacy, including but not limited to the relationship between
efficacy and dynamic changes in overall mutational burden of ctDNA
7.4.5 Drug exposure
The exposure and use duration (cycles) of the study drug in the subjects during the
study period will be summarized.
7.4.6 Analysis of safety outcome measures
Safety analysis is performed on the SS, and the primary safety outcome measures
include:
Study-related adverse events (90 days after the first dose of IBI308 or 30 days
after surgery, whichever occurs later): ≥ grade 3 adverse events related to the
study drug
Incidence of surgical complications: defined as ≥ grade 3 or severe intraoperative
and perioperative complications
Rate of no-delayed surgery (surgical delay is defined as no performance of
surgery for more than 43 days from the day of the first dosing).
7.4.6.1 Adverse events
All AEs will be coded using MedDRA.
The incidence rates (frequency of occurrence) of AEs, TEAEs, ADRs,Immune-
related adverse events (irAEs), adverse events of special interest (AESI), SAE, and
AEs that resulted in study terminationwill be summarized, respectively; the distribution
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of severity will be summarized for TEAEs, ADRs, irAEs and AESI by SOC and PT in
MedDRA coding, respectively.
Subjects who discontinued treatment due to AE, subjects who experienced SAEs
and subjects who died will be tabulated (at least including the start date, end date and
severity of AE, relationship with drug, actions taken, and outcome).
7.4.6.2 Laboratory tests
For hematology and blood biochemistry, the measured values and values of change
before and after treatment will be described using mean ± SD, maximum, minimum
and median, and cross classification table will be employed for describing normal and
abnormal changes before and after treatment.
Urinalysis: cross classification table will be used to describe the normal and
abnormal changes before and after treatment.
The percentage of subjects with abnormal changes evaluated as “abnormal and
clinically significant” will be described. The investigator judges whether the
abnormality is clinically significant or not.
A list of subjects with abnormal changes (clinically significant or not clinically
significant) after treatment will be provided.
7.4.6.3 ECG examination
The changes of ECG indicators from baseline will be descriptively described.
Cross-classification table will be used to describe the normal and abnormal changes
before and after treatment, and a data list will be provided.
7.4.6.4 Vital signs, physical examination and other safety-related examinations
The results of vital signs examination and changes from baseline will be summarized
descriptively.
Subjects with abnormal changes from baseline in physical examination will be
summarized by tabulation.
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7.4.7 Compliance analysis
The following will be summarized: the percentage and number of subjects with a
violation of the intended dosing regimen;
Percentage of subjects who used the study drug at 80% - 120% of the dose specified in
the protocol;
Percentage of subjects having completed the study, and percentage of subjects having
completed different treatment cycles.
7.4.8 Baseline characteristics of subjects
The following baseline characteristics of the subjects will be descriptively
summarized: demographic characteristics (gender, age); tumor diagnosis and treatment
information (pathological diagnosis, clinical stage, previous treatment); baseline tumor
detection (number of target lesions and non-target lesions, their location and total long
diameter, etc.); other baseline information: height and weight (body mass index, body
surface area), vital signs, laboratory findings, previous/concomitant/new combination
medications, etc.
7.4.9 Interim analysis
No interim analysis is planned for this study.
7.4.10 Subgroup analysis
Subgroup analyses are based on the baseline characteristics of the subjects and
other potential clinically significant factors.
Subgroup analyses will be defined in detail in the SAP.
7.5 Sample size determination
As this study is a single-arm study, no rigorous statistical assumptions were made.
Six patients will be enrolled first for safety run-in of this study, and then up to 30
subjects can be enrolled after comprehensive risk assessment by the study team.
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8 QUALITY ASSURANCE AND QUALITY CONTROL
Pursuant to GCP guidelines, the sponsor has the responsibility to implement and
maintain the quality and quality control systems for this study according to
corresponding standard operating procedures (SOPs) to ensure proper conduct of the
clinical trial and the authenticity of data generated, and that the data are collected,
documented and reported in compliance with the requirements of the protocol, GCP
and corresponding regulations.
8.1 Clinical Monitoring
The sponsor or the sponsor-authorized CRO conducts clinical monitoring of the
study. The clinical research associate (CRA) should conduct monitoring according to
the standard operating procedures of the sponsor or CRO, and have the same rights and
responsibilities as the sponsor's monitor. The monitor (CRA) should hold regular
communications with the investigator, the authorized study personnel and the sponsor.
Prior to the initiation of the study, the monitor will assess the competence of each
study site and report problems regarding facilities, technical equipment, and/or medical
personnel to the sponsor. During the study, the monitor will be responsible for
monitoring whether the investigator has obtained the signed written ICFs from all
subjects and whether the data records are correct and complete. Meanwhile, the
monitor will also check the data entries in the eCRF against the original data and
inform the investigator of any errors or omissions. The monitor will also control the
site compliance with the protocol and trial procedures, arrange for supplies of the
investigational drug and the clinical trial supplies, and ensure that the drugs are stored
under the specified conditions.
Monitoring visits will be conducted in accordance with applicable laws and
regulations. Each site will receive regular monitoring visits from the start of subject
enrollment. After each site visit, the monitor will submit a written report to the sponsor.
8.2 Data Management/Coding
An electronic data capture (EDC) system will be used for this study and study data
will be entered into the eCRF by the investigator or the authorized study personnel.
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Prior to site initiation or data entry, appropriate training will be provided to the
investigators and the authorized study personnel, and appropriate security measures
will be taken for equipment used in the study, e.g., computers.
Data entry into the eCRF should be completed during or as soon as possible after a
visit and updated promptly to ensure that it reflects the latest status of the subjects
participating in the study. To avoid differences in the assessment of the results by
different evaluators, it is recommended that the baseline and all subsequent efficacy
and safety evaluations be completed by the same evaluator. The investigator must
review the data to ensure the accuracy and correctness of all data entered into the
eCRF. In the event some evaluations were not performed or some information is
unavailable, not applicable, or unknown on study, the investigator should record it in
the eCRF. The investigator should electronically sign the verified data.
The monitor (CRA) will review the eCRFs and assess their completeness and
consistency. In addition, the CRA will check the eCRFs against the source documents
to ensure consistency of key data. The entry, correction and modification of all data
will be completed by the investigator or the designee. The data in the eCRF are
submitted to the data server, and any changes to the data will be recorded in the audit
trail, i.e. the reason for the change, the name of the operator, the time and date of the
change will all be recorded. The roles and authorities of the site staff responsible for
data entry will be determined in advance. If any data query, the CRA or the data
manager will send a query in the EDC system and the site staff is responsible for
answering the query. The EDC system will document the audit trails of the queries,
including investigator’s name, time and date.
Unless otherwise specified, the eCRF will be used only as a form for collecting
data rather than as source data. Source documents, which are used by the investigators
and related to the subjects, refer to all records that can prove the subjects’ existence and
their eligibility per the inclusion and exclusion criteria as well as participation in this
study, including laboratory records, ECG results, pharmacy dispensing records, subject
folder, etc.
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The investigator is responsible for maintaining all source documents and providing
them to the CRA for monitoring at each visit. In addition, the investigator must submit
a complete eCRF for each enrolled subject, regardless of the duration of study
participation. The protocol number and subject number on all supporting documents
(e.g., laboratory records or hospital records) submitted together with the eCRF should
be carefully verified, and all personal privacy information (including the subject's
name) in these documents should be removed or made illegible to protect the subject's
privacy. The investigator uses electronic signature to testify that he or she has reviewed
the record, and assures the accuracy of the data recorded. The electronic signature will
be completed through the investigator’s user ID and password, with the data and time
of signature generated by the system automatically. The Investigator shall not share the
user ID and password with other personnel. Any changes to the data in the eCRF, if
necessarily required, should be made according to the work procedures as defined in
the EDC system. All changes and the reasons for change will be documented on the
audit trails.
AEs and concomitant diseases/medical history will be coded. The dictionary used
for coding will be described in the final Clinical Study Report (CSR).
8.3 Quality Assurance Audit
During the process of the study, the sponsor or its authorized representative may
perform quality assurance audits of the study site, the study database and related study
documents. Moreover, the appropriate regulatory authorities may conduct inspections
of the study site, the study database and related study documents at their discretion.
The investigator should notify the sponsor immediately upon receipt of an inspection
notification from the regulatory authority.
9 ETHICS
9.1 Ethics Committee
The sponsor or its authorized representative will prepare the relevant documents
that need to be submitted to the corresponding site Ethics Committee (EC) for review,
including the trial protocol, ICF, Investigator's Brochure (IB), subject recruitment
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materials or advertisements and other documents required by laws and regulations.
Written approval of the site EC must be obtained and provided to the sponsor prior to
initiation of the study. The EC approval letter must specify the name, number and
version number of the study protocol, as well as the version number and approval date
of other documents (e.g., ICF). The investigator should inform the sponsor of the EC’s
written comments of delay, suspension and re-approval.
The site must observe the requirements of the site EC. Such documents may
include possible protocol amendments, ICF amendments and amendments to subject
recruitment materials, all of which should be submitted to the EC for review and
approval. Safety reports should be submitted and updated periodically per local
requirements and the provisions of the EC, and the final report should be submitted. All
of the above documents and EC approval letters must be provided to the sponsor or its
designee.
9.2 Ethics in the Study
The conduct of this study and the process of obtaining informed consent should be
in compliance with Declaration of Helsinki, relevant GCP requirements and applicable
laws and regulations of China on drug and data protection.
GCP provides scientifically and ethically sound global quality standards for the
design, conduct, recording and reporting of clinical research involving human subjects.
This study will be conducted according to GCP and relevant national regulations and in
compliance with the relevant ethical principles that have their origins in the
Declaration of Helsinki to protect the rights, safety and health of the subjects.
The investigator should follow the procedures specified in this trial protocol and
should not change the procedures without permission of the sponsor. Any protocol
violations will be reported to the EC, the sponsor, and/or the regulatory authorities.
9.3 Subject Information and Informed Consent
Prior to initiation of any study procedures, the possible risks and benefits of this
study will be explained to potential study participants using the informed consent form
(ICF), which should be written in plain language. The ICF statement should clarify that
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signing the ICF is voluntary, the possible risks and benefits associated with
participation in this study, and that the subjects are free to withdraw from the study at
any time. The investigator should not enroll a subject until written consent has been
obtained from the subject or their legal representative, who should be provided with
adequate explanations about details of this study and with adequate time to think over,
and have their questions answered satisfactorily. All signed ICFs must be kept in the
investigator study file or subject folder.
The investigator is responsible for explaining the contents of the ICF to the
subjects and obtaining the signed and dated ICFs from the subjects or their legal
representatives prior to the initiation of the study. After signing the ICF, the
investigator should provide each subject with a copy of the signed ICF. The
investigator should record the informed consent process in the study source documents.
9.4 Protection of Subject Data
The ICF will contain (or in some cases, together with the use of separate files)
information on data protection and privacy protection.
Precautions are taken to ensure the confidentiality of the documents and prevent
the identification of the subjects. However, under special circumstances, the genetic
data and personal identification code of a certain subject may be accessed by some
persons. For example, in the event of a medical emergency, the sponsor, its
representative physician or the investigator will be aware of a subject’s identification
code and have access to the genetic data of this subject. In addition, relevant regulatory
authorities require access to relevant documents.
10 STUDY MANAGEMENT
10.1 Data Processing and Record Retention
Documents (protocol and protocol amendments, completed eCRF, signed ICF,
etc.) in the clinical trial should be retained and managed according to the GCP
requirements. These documents should be retained at the study site until 5 years after
the end of study.
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Study files should be properly kept for access or data traceability in the future. File
retention should security and environmental risk issues into account.
No study files may be destroyed without the written permission of the sponsor and
the investigator. The investigator/study site may transfer the study files to another party
that observes the file retention requirements or to another location that meets the
specified requirements for storage only after having notified the sponsor and obtained
its written permission.
10.2 Source Data/Document Access
The investigator agrees that the sponsor, the CRO and relevant authorized
regulatory authorities will have direct access to all study-related documents, including
the medical records of the subjects.
10.3 Protocol Amendments
Any possible appropriate amendments to the protocol during the conduct of the
study will be communicated and agreed by the sponsor to the investigator. The sponsor
should ensure that protocol amendments are submitted to regulatory authorities in a
timely manner.
All amendments to the protocol should be maintained as addenda to the protocol.
Any amendments to the protocol should be submitted to the Ethics Committee for
approval or filing according to the provisions of the EC. If necessary, they should also
be submitted to the regulatory authority for review and approval, and can be
implemented only after approval by EC and the regulatory authority (if necessary)
(except for changes that were made to protocol to eliminate immediate hazards to trial
subjects).
10.4 Responsibilities of Investigator
The investigator should conduct this study in accordance with the protocol, ethical
principles that have their origins in Declaration of Helsinki, and GCP and
corresponding regulatory requirements of Chia.
The detailed responsibilities of relevant investigators are listed in Chapter 5
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10.5 Publication Policy
All data generated from this study are confidential information of the sponsor. The
sponsor has the right to publish the study results. Information regarding the publication
policies between the sponsor and the investigator will be described in the clinical trial
agreement.
All information about this trial (not limited to the following documents: protocol,
IB) must be kept strictly confidential. The investigator must recognize that the
scientific or medical information derived from this trial may be of commercial value to
the sponsor. The investigator shall keep confidential the information and data related to
this trial. In order to publish the information related to this trial or the conclusions
drawn from this trial, the investigator should negotiate with the sponsor in advance and
obtain the written consent of the sponsor. In order to protect its own rights and
interests, the sponsor may require the investigator not to publish any information about
the trial until the investigational product is approved for marketing.
The sponsor has the right to reveal or publish the information or data related to this
trial or submit it to the drug regulatory authority. If the sponsor needs to include the
investigator's name in a published paper, publication or advertisement, the consent of
the investigator should be obtained.
10.6 Finance and Insurance
The sponsor will buy insurance for subjects participating in this study in
accordance with local regulations and minimum requirements. Relevant insurance
clauses will be kept in the study folder.
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11 References
1. Park S, Ko YH. Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders. J Dermatol 2014,41:29-39.2. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015,373:123-135.3. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016,387:1540-1550.4. Langer CJ1, Gadgeel SM2, Borghaei H3, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. 5. Carbone DP, Reck M, Paz-Ares L, Creelan B, et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Jun 22;376(25):2415-2426.6. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000,18:2095-2103.7. Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000,18:2354-2362.8. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004,22:1589-1597.
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12 Appendixes
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Appendix 1: ECOG PS scoring system
Score Activity level
0 Fully active, able to perform all normal activity 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 Death
References
Oken MM,Creech RH,Tormey DC,Horton J,Davis TE,McFadden ET,and Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.
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Appendix 2: Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
The following is an excerpt from the RECIST v1.1.
1. Measurability of tumor at baseline
1.1 Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows
1.1.1 Measurable lesions
Tumor lesions: must be accurately measured in at least one dimension (longest
diameter in the plane of measurement is to be recorded), with a minimum size of:
10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
10 mm caliper measurement by clinical exam (lesions which cannot be accurately
measured with calipers should be recorded as non-measurable)
20 mm by Chest X-ray
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a
lymph node must be ≥ 15 mm in short axis when measured by CT scan (CT scan slice
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the
short axis will be measured and followed.
1.1.2 Non-measurable lesions
All other lesions, including small lesions (longest diameter < 10 mm or pathological
lymph nodes with ≥ 10 mm to < 15 mm short axis) as well as truly non-measurable lesions.
Lesions considered truly non-measurable include: leptomeningeal disease, ascites, pleural
or pericardial effusion, inflammatory breast cancer, lymphangitic involvement of skin or
lung, abdominal masses that cannot be diagnosed and followed by imaging techniques, as
well as cystic lesions.
1.1.3 Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require
particular comment:
Bone lesions:
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Bone scan, PET scan or plain films are not considered adequate imaging techniques to
measure bone lesions; however, these techniques can be used to confirm the presence or
disappearance of bone lesions;
Lytic bone lesions or mixed lytic/osteogenic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques such as CT or
MRI can be considered as measurable lesions if the soft tissue component meets the
definition of measurability described above.
Blastic bone lesions are non-measurable.
Cystic lesions:
Lesions that meet the criteria for radiographically defined simple cysts should not be
considered as malignant lesions (neither measurable nor non-measurable) since they are, by
definition, simple cysts.
Cystic lesions thought to represent cystic metastases can be considered as measurable
lesions, if they meet the definition of measurability described above. However, if noncystic
lesions are present in the same patient, these are preferred for selection as target lesions
Lesions with prior local treatment:
Tumor lesions situated in a previously irradiated area, or in an area subjected to other
loco-regional therapy, are usually not considered measurable unless there has been
demonstrated progression in the lesion. Study protocols should detail the conditions under
which such lesions would be considered measurable.
1.2 Specifications by methods of measurements
1.2.1 Measurement of lesions
All measurements should be recorded in metric notation, using calipers if clinically
assessed. All baseline evaluations should be performed as close as possible to the treatment
start and never more than 21 days (3 weeks) before the beginning of the treatment.
1.2.2 Method of assessment
The same method of assessment and the same technique should be used to characterize
each identified and reported lesion at baseline and during follow-up. Imaging-based
evaluation should always be done rather than clinical examination unless the lesion(s) being
followed cannot be imaged but are assessable by clinical exam.
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Clinical lesions: Clinical lesions will only be considered measurable when they are
superficial and ≥ 10mm diameter as assessed using calipers (e.g. skin nodules). For the case
of skin lesions, documentation by colour photography including a ruler to estimate the size
of the lesion is suggested. As noted above, when lesions can be evaluated by both clinical
exam and imaging, imaging evaluation should be undertaken since it is more objective and
may also be reviewed at the end of the study.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying
new lesions. However, lesions on chest X-ray may be considered measurable if they are
clearly defined and surrounded by aerated lung.
CT, MRI: CT is the best currently available and reproducible method to measure
lesions selected for response assessment. This guideline has defined measurability of
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. when
CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion
should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for
whole body scan).
Ultrasound: Ultrasound should not be used as a method of measurement. Ultrasound
examinations cannot be reproduced in their entirety for independent review at a later date
and, because they are operator dependent, it cannot be guaranteed that the same technique
and measurements will be taken from one assessment to the next. If new lesions are
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised.
If there is concern about radiation exposure at CT, MRI may be used instead of CT in
selected instances.
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor
evaluation is not advised. However, they can be useful to confirm CR when biopsies are
obtained or to determine relapse in trials where recurrence following CR or surgical
resection is an endpoint.
Tumor markers: tumor markers alone cannot be used to assess objective tumor
response. If markers are initially above the upper normal limit, however, they must
normalize for a patient to be considered in complete response. Because tumor markers are
disease specific, instructions for their measurement should be incorporated into protocols
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on a disease specific basis. Specific guidelines for both CA-125 response (in recurrent
ovarian cancer) and PSA response (in recurrent prostate cancer), have been published. In
addition, the Gynecologic Cancer Intergroup has developed CA125 progression criteria
which are to be integrated with objective tumor assessment for use in first-line trials in
ovarian cancer.
Cytology, histology: These techniques can be used to differentiate between PR and CR
in rare cases if required by protocol (for example, residual lesions in tumor types such as
germ cell tumors, where known residual benign tumors can remain). When effusions are
known to be a potential adverse effect of treatment (e.g. with certain taxane compounds or
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any
effusion that appears or worsens during treatment can be considered if the measurable
tumor has met criteria for response or stable disease (SD) in order to differentiate between
response (or SD) and progressive disease.
2 Tumor Response Evaluation
2.1 Assessment of overall tumor burden and measurable disease
To assess objective response or future progression, it is necessary to estimate the
overall tumor burden at baseline and use this as a comparator for subsequent measurements.
Only patients with measurable disease at baseline should be included in protocols where
objective tumor response is the primary endpoint. Measurable disease is defined by the
presence of at least one measurable lesion. In studies where the primary endpoint is tumor
progression (either time to progression or proportion with progression at a fixed date), the
protocol must specify if entry is restricted to those with measurable disease or whether
patients having non-measurable disease only are also eligible.
2.2 Baseline documentation of target lesions and non-target lesions
When more than one measurable lesion is present at the baseline, all lesions up to a
maximum of 5 lesions total (and a maximum of two lesions per organ) representative all
involved organs should be identified as target lesions (this means in instances where
patients have only one or two organ sites involved a maximum of two and four lesions
respectively will be recorded).
Target lesions must be selected on the basis of their size (lesions with the longest
diameter), be representative of all involved organs, but in addition should be those that lend
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themselves to reproducible repeated measurements. It may be the case that, on occasion, the
largest lesion does not lend itself to reproducible measurement, in which circumstance the
next largest lesion which can be measured reproducibly should be selected.
Lymph nodes merit special mention since they are normal anatomical structures which
may be visible by imaging even if not involved by tumor. Pathological nodes which are
defined as measurable and may be identified as target lesions must meet the criterion of a
short axis of P15 mm by CT scan. Only the short axis of these nodes will contribute to the
baseline sum. The short axis of the node is the diameter normally used by radiologists to
judge if a node is involved by solid tumor. Nodal size is normally reported as two
dimensions in the plane in which the image is obtained (for CT scan this is almost always
the axial plane; for MRI the plane of acquisition may be axial, saggital or coronal). The
smallest of these measures is the short axis. For example, an abdominal node which is
reported as being 20 mm × 30 mm has a short axis of 20 mm and qualifies as a malignant,
measurable node. In this example, 20 mm should be recorded as the node measurement. All
other pathological nodes with short axis ≥ 10 mm but <15 mm should be considered non-
target lesions. Nodes that have a short axis <10 mm are considered non-pathological and
should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for
all target lesions will be calculated and reported as the baseline sum diameters. If lymph
nodes are to be included in the sum, then as noted above, only the short axis is added into
the sum. The baseline sum diameters will be used as reference for baseline disease level.
All other lesions including pathological lymph nodes should be identified as non-
target lesions and require no measurements but should also be recorded at baseline. These
lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’
In addition, it is possible to record multiple non-target lesions involving the same organ as a
single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or
‘multiple liver metastases’).
2.3 Response Criteria
2.3.1 Evaluation of target lesions
Complete response (CR): Disappearance of all target lesions, all pathological lymph
nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
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Partial response (PR): At least a 30% decrease in the sum of the diameters of target
lesions compared with baseline.
Progressive disease (PD): At least a 20% increase in the sum of the diameters of target
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that
is the smallest on study); in addition to the relative increase of 20%, the sum must also
demonstrate an absolute increase of at least 5 mm. (the appearance of one or more new
lesions is also considered progression).
Stable disease (SD): Neither sufficient shrinkage of target lesions to qualify for PR,
nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters
while on study.
2.3.2 Special notes on the assessment of target lesions
Lymph nodes: lymph nodes identified as target lesions should always have the actual
short axis measurement recorded (measured in the same anatomical plane as the baseline
examination), even if the nodes regress to below 10 mm on study. This means that when
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if
complete response criteria are met, since a normal lymph node is defined as having a short
axis of <10 mm. eCRF or other data collection methods may therefore be designed to have
target nodal lesions recorded in a separate section where, in order to qualify for CR, each
node must achieve a short axis <10 mm. For PR, SD and PD, the actual short axis
measurement of the nodes is to be included in the sum of target lesions.
Target lesions that become ‘too small to measure’: while on study, all lesions (nodal
and non-nodal) recorded at baseline should have their actual measurements recorded at
each subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes
lesions or lymph nodes which are recorded as target lesions at baseline become so faint on
CT scan that the radiologist may not feel comfortable assigning an exact measure and may
report them as being ‘too small to measure’. When this occurs it is important that a value be
recorded on the eCRF. If it is the opinion of the radiologist that the lesion has likely
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be
present and is faintly seen but too small to measure, a default value of 5 mm should be
assigned (Note: It is less likely that this rule will be used for lymph nodes since they
usually have a definable size when normal and are frequently surrounded by fat such as in
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the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen
but too small to measure, a default value of 5 mm should be assigned in this circumstance
as well). This default value is derived from the 5 mm CT slice thickness (but should not be
changed with varying slice thickness on CT scans). The measurement of these lesions is
potentially non-reproducible, and therefore providing this default value will prevent false
responses or progressions based upon measurement error. To reiterate, however, if the
radiologist is able to provide an actual measure, that should be recorded, even if it is below
5 mm.
Lesions that split or coalesce on treatment: when non-nodal lesions ‘fragment’, the
longest diameters of the fragmented portions should be added together to calculate the
target lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained
that would aid in obtaining maximal diameter measurements of each individual lesion. If
the lesions have truly coalesced such that they are no longer separable, the vector of the
longest diameter in this instance should be the maximal longest diameter for the coalesced
lesion.
2.3.3 Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor
response for the group of non-target lesions. While some non-target lesions may actually be
measurable, they need not be measured and instead should be assessed only qualitatively at
the time points specified in the protocol.
Complete response (CR): disappearance of all non-target lesions and normalization of
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short
axis).
Non-CR/non-progressive disease: presence of one or more non-target lesions and/or
maintenance of tumor marker level above normal limits.
Progressive disease (PD): unequivocal progression of existing non-target lesions.
(Note: appearance of one or more new lesions is also considered progression).
2.3.4 Special notes on assessment of progression of non-target disease
The concept of progression of non-target disease requires additional explanation as
follows: When the patient also has measurable disease, to achieve ‘unequivocal
progression’ on the basis of the non-target disease, there must be an overall level of
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substantial worsening in non-target disease such that, even in presence of SD or PR in
target disease, the overall tumor burden has increased sufficiently to merit discontinuation
of therapy. A modest increase in the size of one or more non-target lesions is usually not
sufficient to quality for unequivocal progression status. The designation of overall
progression solely on the basis of change in non-target disease in the face of SD or PR of
target disease will therefore be extremely rare.
When the patient has only non-measurable disease: This circumstance arises in some
phase III trials when it is not a criterion of study entry to have measurable disease. The
same general concepts apply here as noted above, however, in this instance there is no
measurable disease assessment. Because worsening in non-target disease cannot be easily
quantified (by definition: if all lesions are truly non-measurable), a useful test that can be
applied when assessing patients for unequivocal progression is to consider if the increase in
overall disease burden based on the change in non-measurable disease is comparable in
magnitude to the increase that would be required to declare PD for measurable disease : i.e.,
an increase in tumor burden representing an additional 73% increase in ‘volume’ (which is
equivalent to a 20% increase diameter in a measurable lesion). Examples include an
increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease
from ‘localized’ to ‘widespread’, or may be described in protocols as ‘sufficient to require a
change in therapy’. Some illustrative examples include pleural effusions from trace to large,
lymphatic involvement spreading from the primary site to distant sites, or may be described
in the protocol as "a change necessarily required in terms of treatment". If ‘unequivocal
progression’ is seen, the patient should be considered to have had overall PD at that point.
While it would be ideal to have objective criteria to apply to non-measurable disease, the
very nature of that disease makes it impossible to do so, therefore the increase must be
substantial.
2.3.5 New lesions
The appearance of new malignant lesions denotes disease progression; therefore some
comments on detection of new lesions are important. There are no specific criteria for the
identification of new radiographic lesions; however, the finding of a new lesion should be
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging
modality or findings thought to represent something other than tumor (for example, some
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‘new’ bone lesions may be simply healing or flare of preexisting lesions). This is
particularly important when the patient’s baseline lesions show partial or complete
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a
‘new’ cystic lesion, which it is not.
A lesion identified on a follow-up study in an anatomical location that was not scanned
at baseline is considered a new lesion and will indicate disease progression. An example of
this is the patient who has visceral disease at baseline and while on study has a CT or MRI
brain ordered which reveals metastases. The patient’s brain metastases are considered to be
evidence of PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its small size, continued therapy
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans
confirm there is definitely a new lesion, then progression should be declared using the date
of the initial scan.
While FDG-PET response assessments need additional study, it is sometimes
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in
assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of
FDG-PET imaging can be identified according to the following algorithm:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.
No FDG-PET at baseline and a positive FDG-PET at follow-up:
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed
by CT, this is PD.
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT,
additional follow-up CT scans are needed to determine if there is truly progression
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET
scan).
If the positive FDG-PET at follow-up corresponds to a preexisting site of disease on
CT that is not progressing on the basis of the anatomic images, this is not PD.
2.4 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study
treatment until the end of treatment taking into account any requirement for confirmation.
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On occasion a response may not be documented until after the end of therapy so protocols
should be clear if post-treatment assessments are to be considered in determination of best
overall response. Protocols must specify how any new therapy introduced before
progression will affect best response designation. The patient’s best overall response
assignment will depend on the findings of both target and non-target disease and will also
take into consideration the appearance of new lesions. Furthermore, depending on the
nature of the study and the protocol requirements, it may also require confirmatory
measurement. Specifically, in non-randomized trials where response is the primary
endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall
response’.
2.4.1 Time point response
It is assumed that at each protocol-specified time point, a response assessment occurs.
Table 1 provides a summary of the overall response status calculation at each time point for
patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table 2 is to
be used.
2.4.2 Missing assessments and unevaluable designation
When no imaging/measurement is done at all at a particular time point, the patient is
not evaluable (NE) at that time point. If only a subset of lesion measurements is made at an
assessment, usually the case is also considered NE at that time point, unless a convincing
argument can be made that the contribution of the individual missing lesion(s) would not
change the assigned time point response. This would be most likely to happen in the case of
PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and
at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient
will have achieved PD status, regardless of the contribution of the missing lesion.
2.4.3 Best overall response: all time points
The best overall response can be determined once all the data for the subject are
known.
Best response determination in trials where confirmation of complete or partial
response is NOT required: Best response in these trials is defined as the best response
across all time points (for example, a patient who has SD at first assessment, PR at second
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assessment, and PD on last assessment has a best overall response of PR). When SD is
believed to be best response, it must also meet the protocol-specified minimum time from
baseline. If the minimum time is not met when SD is otherwise the best time point
response, the patient’s best response depends on the subsequent assessments. For example,
a patient who has SD at first assessment, PD at second and does not meet minimum
duration for SD, will have a best response of PD. The same patient lost to follow-up after
the first SD assessment would be considered unevaluable.
Best response determination in trials where confirmation of complete or partial
response is required: Complete or partial responses may be claimed only if the criteria for
each are met at a subsequent time point as specified in the protocol (generally 4 weeks
later). In this circumstance, the best overall response can be interpreted as in Table 3.
2.4.4 Special notes on response assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to
‘normal’ size (< 10 mm), they may still have a measurement reported on scans. This
measurement should be recorded even though the nodes are normal in order not to overstate
progression should it be based on increase in size of the nodes. As noted earlier, this means
that patients with CR may not have a total sum of ‘zero’ on the eCRF.
In trials where confirmation of response is required, repeated ‘NE’ time point
assessments may complicate best response determination. The analysis plan for the trial
must address how missing data/assessments will be addressed in determination of response
and progression. For example, in most trials it is reasonable to consider a patient with time
point responses of PR-NE-PR as a confirmed response.
Patients with a global deterioration of health status requiring discontinuation of
treatment without objective evidence of disease progression at that time should be reported
as ‘symptomatic deterioration’. Every effort should be made to assess objective progression
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an
objective response: it is the reason for stopping study therapy. The objective response status
of such patients is to be determined by evaluation of target and non-target disease as shown
in Tables 1–3.
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Conditions that define early progression, early death and unevaluability are study
specific and should be clearly described in each protocol (depending on treatment duration,
treatment periodicity).
In some circumstances it may be difficult to distinguish local disease from normal
tissue. When the evaluation of complete response depends upon this determination, it is
recommended that biopsy be performed to investigate the local disease before assigning a
status of complete response. FDG-PET may be used to confirm a response to a CR in a
manner similar to a biopsy in cases where a local radiographic abnormality is thought to
represent fibrosis or scarring. The use of FDG-PET in this circumstance should be
prospectively described in the protocol and supported by disease-specific medical literature
for the indication. However, it must be acknowledged that both approaches may lead to
false positive CR due to limitations of FDG-PET and biopsy (resolution/sensitivity).
Table 1 Time point response: patients with target (+/- non-target) disease
Target lesionsNon-target
lesionsNew lesions Overall response
CR CR No CR
CRNon-CR/non-
PDNo PR
CR Not evaluated No PR
PRNon-PD or not
all evaluatedNo PR
SDNon-PD or not
all evaluatedNo SD
Not all
evaluatedNon-PD No NE
PD Any Yes or No PD
Any PD Yes or No PD
Any Any Yes PD
CR = complete
response
PR = partial
response
SD = stable
disease
PD = progressive disease
NE = in evaluable
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Table 2 Time point response: patients with non-target lesions only
Non-target lesions New lesions Overall response
CR No CR
Non-CR/non-PD No Non-CR/non-PD
Not all evaluated No NE
Unequivocal PD Yes or No PD
Any Yes PD
Note: ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since
SD is increasingly used as endpoint for assessment of efficacy in some trials so to assign
this category when no lesions can be measured.
For equivocal findings of progression (e.g. very small and uncertain new lesions;
cystic changes or necrosis in existing lesions), treatment may continue until the next
scheduled assessment. If progression is confirmed at the next scheduled assessment, the
date of progression should be the earlier date when progression was suspected.
Table 3 Best overall response when confirmation of CR and PR required
Overall
response -
First time
point
Overall response -
Subsequent time
pointBest overall response
CR CR CR
CR PR SD, PD or PRa
CR SD SD provided minimum criteria for SD
duration met, otherwise, PD
CR PD SD provided minimum criteria for SD
duration met, otherwise, PD
CR NE SD provided minimum criteria for SD
duration met, otherwise NE
PR CR PR
PR PR PR
PR SD SD
PR PD SD provided minimum criteria for SD
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duration met, otherwise, PD
PR NE SD provided minimum criteria for SD
duration met, otherwise NE
NE NE NE
Notes: CR = complete response; PR = partial response; SD = stable disease; PD =
progressive disease; and NE = unevaluable. Superscript "a": If a CR is truly met at first
time point, then any disease seen at a subsequent time point, even disease meeting PR
criteria relative to baseline, makes the disease PD at that point (since disease must have
reappeared after CR). Best response would depend on whether minimum duration for SD
was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small
lesions were likely still present and in fact the patient had PR, not CR at the first time point.
Under these circumstances, the original CR should be changed to PR and the best response
is PR.
2.5. Frequency of tumor re-evaluation
Frequency of tumor re-evaluation while on treatment should be protocol-specific and
adapted to the type and schedule of treatment. However, in the context of phase II studies,
follow-up every 6 - 9 weeks (timed to coincide with the end of a cycle) is reasonable, and
smaller or greater time intervals than these could be justified in specific regimens or
circumstances. The protocol should specify which organ sites are to be evaluated at
baseline (usually those most likely to be involved with metastatic disease for the tumor type
under study) and how often evaluations are repeated. Normally, target and non-target
lesions are evaluated at each assessment. In selected circumstances, certain non-target
organs may be evaluated less frequently. For example, bone scans may need to repeated
only when CR is identified in target disease is or when progression in bone is suspected.
After the end of the treatment, the need for repetitive tumor evaluations depends on
whether the trial has as a goal the response rate or the time to an event (progression/death).
If ‘time to an event’ (e.g. TTP/DFS1/PFS) is the main endpoint of the study, then routine
scheduled re-evaluation of protocol specified sites of disease is warranted. In randomized
comparative trials in particular, the scheduled assessments should be performed as
identified on a calendar schedule (for example: every 6 - 8 weeks on treatment or every 3 -
4 months after treatment) and should not be affected by delays in therapy, drug holidays or
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any other events that might lead to imbalance in a treatment arm in the timing of disease
assessment.
2.6. Confirmatory measurement/duration of response
2.6.1. Confirmation
In non-randomized clinical studies where response is the primary endpoint,
confirmation of PR and CR is required to ensure responses identified are not the result of
measurement error. This will also permit appropriate interpretation of results in the context
of historical data where response has traditionally required confirmation in such trials.
However, in all other circumstances, i.e. in randomized trials (phase II or III) or studies
where stable disease or progression is the primary endpoint, confirmation of response is not
required since it will not add value to the interpretation of trial results. However,
elimination of the requirement for response confirmation may increase the importance of
central review to protect against bias, in particular in studies which are not blinded.
In the case of SD, measurements must have met the SD criteria at least once after
study entry at a minimum interval (in general not less than 6 - 8 weeks) that is defined in
the study protocol.
2.6.2 Duration of overall response
The duration of overall response is measured from the time measurement criteria are
first met for CR/PR (whichever is first recorded) until the first date that recurrent or
progressive disease is objectively documented (taking as reference for progressive disease
the smallest measurements recorded on study). The duration of overall complete response is
measured from the time measurement criteria are first met for CR until the first date that
recurrent disease is objectively documented.
2.6.3. Duration of stable disease
Stable disease is measured from the start of the treatment (in randomized trials, from
date of randomization) until the criteria for progression are met, taking as reference the
smallest sum on study (if the baseline sum is the smallest, this is the reference for
calculation of PD). The clinical relevance of the duration of stable disease varies in
different studies and diseases. If the proportion of patients achieving stable disease for a
minimum period of time is an endpoint of importance in a particular trial, the protocol
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should specify the minimal time interval required between two measurements for
determination of stable disease.
Note: The duration of response and stable disease as well as PFS are influenced by the
frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to
define a standard follow-up frequency. The frequency should take into account many
parameters including disease types and stages, treatment periodicity and standard practice.
However, these limitations of the precision of the measured endpoint should be taken into
account if comparisons between trials are to be made.
2.7. PFS/TTP
2.7.1. Phase II clinical trials
This guideline is focused primarily on the use of objective response endpoints for
phase II trials. In some circumstances, ‘response rate’ may not be the optimal method to
assess the potential anticancer activity of new agents/regimens. In such cases, PFS or the
proportion progression-free (PPF) at landmark time points, might be considered appropriate
alternatives to provide an initial signal of biologic effect of new agents. It is clear, however,
that in an uncontrolled trial, these measures are subject to criticism since an apparently
promising observation may be related to biological factors such as patient selection and not
the impact of the intervention. Thus, phase II screening trials utilizing these endpoints are
best designed with a randomized control. Exceptions may exist where the behavior patterns
of certain cancers are so consistent (and usually consistently poor), that non-randomized
trial is justifiable. However, in these cases it will be essential to document with care the
basis for estimating the expected PFS or PPF in the absence of an active control.
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Appendix 3: Guidance for IBI308 dose modification and toxicity management
Table 1. Guidelines on dose modification and toxicity management for potentially major irAEs
AE grading/dose adjustment Toxicity management
General AEs are graded according to NCI CTCAE v4.03, and should be handled in reference to the guidelines if identified as irAE
It is recommended that irAEs be handled according to the guidelines presented in this table
- Thorough assessment should be performed for the subject to rule out any alternative causes (e.g., progression, concomitant medications and infection)
- In the absence of a clear alternative cause and if treatment with corticosteroids is required, it should be considered an irAE
- For low-grade events (Grade 1 or 2, unless otherwise specified), symptomatic and local treatments should be considered
- For persisting low-grade events (Grade 1 - 2) or severe (≥ grade 3) events, systemic corticosteroid therapy should be considered
- If relapse or worsening occurs during corticosteroid tapering, dose increase should be performed for the corticosteroid until stabilization or improvement of symptoms, followed with corticosteroid dose reduction at a low rate
Grade 1
Dose modification not indicated
Grade 2
Interruption
• Handle according to grade 3 or 4 if worsening
• If improvement to grade 0 - 1 or baseline, continue on the next scheduled treatment day
Grade 3
Interruption or permanent discontinuation
Grade 4
Permanent discontinuation
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AE grading/dose adjustment Toxicity management
- Once sustained clinical improvement is observed, subjects receiving intravenous corticosteroids may be switched to equivalent of oral corticosteroids at the start of dose tapering or sooner (the issue of lower oral corticosteroid bioavailability should be taken into account)
- For events that did not respond to systemic corticosteroids, more potent immunosuppressive
Pneumonitis Any grade
- Perform monitoring on the patient for signs and symptoms of pneumonia or interstitial lung disease (e.g., new shortness of breath, cough, chest pain, or worsening of existing symptoms and signs), and perform assessment on the patient using imaging, lung function test and other tests
- Initial examination may include clinical assessment, arterial oxygen saturation, laboratory tests, and high-resolution CT scan
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AE grading/dose adjustment Toxicity management
Grade 1
Dose modification not indicated However, interruption of treatment should be considered based on clinical need and during diagnostic workup for other etiologies
For grade 1:
- Perform monitoring of symptoms & signs and arterial oxygen saturation for 2-4 days
- Perform other laboratory tests as clinically indicated
- Consider consultation with the pneumology department and the infection department
Grade 2
Interruption
• Handle according to grade 3 or 4 if worsening
• If improvement to grade 0 - 1 or baseline, continue on the next scheduled treatment day
For grade 2
- Perform monitoring of symptoms and signs every day, consider inpatient hospitalization
- Consider systemic corticosteroids
- Repeat a radiologic examination as clinically indicated
- If no improvement is noted within 3 - 5 days, consider additional tests and increase corticosteroid dose
- If no improvement is noted within 3 - 5 days, a more potent immunosuppressive agent (e.g. infliximab) should be considered
- Once improved, have the glucocorticoid dose reduced gradually over ≥ 4 weeks and consider administering prophylactic antibiotics
- Consider consultation with the pneumology department and the infection department
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AE grading/dose adjustment Toxicity management
Grade 3
or 4
Permanent discontinuation
For grade 3 - 4
- Consider consultation with the pneumology department and the infection department
- Inpatient hospitalization
- Supportive care (oxygen inhalation, etc.)
- Initiate systemic corticosteroids empirically
- If no improvement is noted within 3 - 5 days, consider additional tests and additional immunosuppressants (e.g. infliximab)
- Once improved, have the glucocorticoid dose reduced gradually over ≥ 4 weeks and consider administering prophylactic antibiotics
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AE grading/dose adjustment Toxicity management
Diarrhea or enterocolitis
Any grade
- Monitor for signs and symptoms that may be associated with diarrhea/enterocolitis, e.g., abdominal pain, cramps, change in bowel habits, melena, mucous stool, bloody stool, and muscle guarding
- Thorough assessment should be performed for the subject to rule out any alternative causes (e.g., progression and infection)
- In the event no alternative cause is identified, corticosteroid therapy should also be considered for low-grade events to prevent progression to a higher grade
- Use painkillers with care (for they may mask the symptoms of perforation and peritonitis)
Grade 1
Dose modification not indicated
For grade 1
- Initiate close monitoring on worsening of symptoms
- Consider symptomatic treatment, including hydration, electrolyte replacement, dietary modification, and loperamide
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AE grading/dose adjustment Toxicity management
Grade 2
or 3
Interruption
• Handle according to grade 3 or 4 if worsening
• If improvement to grade 0 - 1 or baseline, continue on the next scheduled treatment day
For grade 2-3
- Consider symptomatic treatment, including hydration, electrolyte replacement, modification of diet, and loperamide and/or budesonide
- Consider systemic corticosteroids if the event is persisting (for > 3 - 5 days) or has worsened
- If not resolved within 3 - 5 days or worsening, consider additional test and increasing the dose of corticosteroids
- If the event is NOT resolved within 3 - 5 days or has worsened, consider additional testing and administration of other immunosuppressive agents (e.g. infliximab)
- Once improved, have the glucocorticoid dose reduced gradually over ≥ 4 weeks and consider administering prophylactic antibiotics
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AE grading/dose adjustment Toxicity management
Grade 4
Permanent discontinuation
For grade 4
- Monitor the frequency and volume of bowel movement and maintain hydration
- If applicable, perform emergency gastrointestinal consultation as well as lower gastrointestinal endoscopy and imaging to confirm whether there is a presence of intestinal perforation
- Initiate systemic corticosteroids empirically
- If improvement is NOT noted within 3 - 5 days, consider increasing the systemic corticosteroid dose
- If improvement is not noted within 3 - 5 days, consider other immunosuppressive agents (such as infliximab, but not in the of perforation or sepsis)
- Once improved, have the glucocorticoid dose reduced gradually over ≥ 4 weeks and consider administering prophylactic antibiotics
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AE grading/dose adjustment Toxicity management
Hepatitis (ALT, AST, or TBIL elevations)
Any grade
Pay close attention to hepatitis-related symptoms and signs (e.g., jaundice, tea-colored urine, nausea, vomiting, decreased appetite, hepatalgia, bleeding and tendency)
Perform monitoring and assessment of liver function
Perform evaluation for identification of alternative cause(s), e.g., viral hepatitis, disease progression, concomitant medications
The guidelines for dose modification and dose adjustment and toxicity management suggested in this table apply to subjects with normal baseline ALT, AST, and TB; for subjects with baseline ALT, AST, or TB > ULN, dose interruption is required when ALT, AST, or TB elevations ≥ 50% and lasting < 7 days; for subjects with baseline ALT, AST, or TB > ULN, permanent discontinuation is required when ALT, AST, or TB elevations ≥ 50% and lasting ≥ 7 days ; toxicity management is at the discretion of the investigator
Grade 1
Dose modification not indicated
For grade 1
- Continue liver function monitoring per protocol
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AE grading/dose adjustment Toxicity management
Grade 2
Interruption
• Handle according to grade 3 or 4 if worsening
• If improvement to grade 0 - 1 or baseline, continue on the next scheduled treatment day
For grade 2
- If ALT, AST, or TBIL is elevated, repeat a liver function test in the next 3 - 4 days and increase the frequency of monitoring
- Consider systemic corticosteroids if the event is persisting (for > 3 - 5 days) or has worsened
- If no improvement is noted within 3 - 5 days, consider additional tests and increase corticosteroid dose
- If no improvement is noted within 3 - 5 days, a more potent immunosuppressant (e.g., mycophenolate mofetil) should be considered
- Once improved, have the glucocorticoid dose reduced gradually over ≥ 4 weeks and consider administering prophylactic antibiotics
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AE grading/dose adjustment Toxicity management
Grade 3
or 4
Permanent discontinuation
For grade 3 - 4
- Initiate systemic corticosteroids empirically
- If no improvement is noted within 3 - 5 days, a more potent immunosuppressant (e.g., mycophenolate mofetil) should be considered
- If further improvement is Note noted within 3 - 5 days, consider treatment with other immunosuppressive agents according to local guidelines
- Perform gastroenterology consultation, abdominal examination and imaging if appropriate
- Once improved, have the glucocorticoid dose reduced gradually over ≥ 4 weeks and consider administering prophylactic antibiotics
Dermatitis Any grade
- Perform monitoring on signs and symptoms of dermatitis, such as rash, exudation, hypopigmentation, photosensitivity, and pruritus
- Consider dermatology consultation
- Perform skin biopsy if necessary
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AE grading/dose adjustment Toxicity management
Grade 1
Dose modification note indicated
For grade 1
- Consider symptomatic treatment including oral antipruritics (e.g., diphenhydramine or hydroxyzine) and topical treatment (e.g., urea ointment or topical corticosteroid ointment)
Grade 2
Dose modification not indicated
• For refractory grade 2 events (which are persisting for > 1 - 2 weeks), interrupt the treatment until resolution to grade 0-1 or baseline and continue the treatment on next scheduled treatment day
For grade 2:
- Consider symptomatic treatment including oral antipruritics and topical therapy
- Consider moderate-intensity topical corticosteroids
- If the event is not improved within 3 - 5 days or has worsened, consider systemic corticosteroids
- Consider dermatology consultation
- Consider skin biopsy if a duration > 1 - 2 weeks duration or recurrence
- Once improved, have the glucocorticoid dose reduced gradually over ≥ 4 weeks and consider administering prophylactic antibiotics
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AE grading/dose adjustment Toxicity management
Grade 3
Interruption
• Handle according to grade 4 if worsening
• Discontinue the treatment permanently if grade 3 rash has not resolved to grade 0-1 or baseline within 30 days
For grade 3-4:
- Consider inpatient hospitalization
- Monitor the extent of rash (nine-point scale)
- Dermatology consultation
- Consider skin biopsy (preferably more than one) if clinically feasible
- Initiate systemic corticosteroids empirically
- If no improvement is noted within 3 - 5 days, consider additional tests and increase corticosteroid dose
- Once improved, have the glucocorticoid dose reduced gradually over ≥ 4 weeks and consider administering prophylactic antibiotics
Grade 4
Permanent discontinuation
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AE grading/dose adjustment Toxicity management
Hypopituitarism All grades
- Performing monitoring on the patient for symptoms and signs of endocrine disorders, including weakness, fatigue, lethargy, nausea, vomiting, cold intolerance, abnormal bowel habits, behavioral changes, altered mental status, hypotension, hypoglycemia, vertigo, headache, visual field impairment, low libido in men, and irregular menstruation in women
- Thorough assessment should be performed for the subject to rule out any alternative causes (e.g., progression, brain metastasis and infection)
- Perform monitoring and evaluation of pituitary function: TSH, FT3, FT4, adrenocorticotropic hormone, cortisol, luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, Na+, blood glucose, estradiol, testosterone and other endocrine laboratory parameters suspected to be related to endocrine disorders, and if necessary, perform function tests (including adrenocorticotropic hormone stimulation test and hypoglycemia stimulation test)
- Consider pituitary MRI scan
- Consider endocrinology consultation
- Consider submitting a blood sample for appropriate autoimmune antibody testing
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AE grading/dose adjustment Toxicity management
Grade 1
Dose modification not indicated
For grade 1:
- Perform appropriate monitoring on the patient’s pituitary function
- Thorough assessment for the patient to rule out any alternative causes
- Consider endocrinology consultation as clinically indicated
Grade 2
Interruption
• Discontinue permanently if worsening to grade 3-4
• If resolution to grade 0-1 or baseline, continue on next scheduled treatment day
For grade 2-4:
Endocrinology consultation
Hospitalization if necessarily required
Perform endocrine function assessment, and consider a pituitary MRI scan as clinically indicated
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AE grading/dose adjustment Toxicity management
Initiate hormone replacement therapy as needed (replacement therapy with cortisone should begin one week prior to levothyroxine therapy)
Initiate immunosuppression empirically and consider systemic corticosteroids
Once improved, have the dose of glucocorticoids reduced gradually over ≥ 4 weeks (cortisone used for replacement therapy is adjusted on the basis of recovery of endocrine function, and should be maintained chronically in a patient who failed to recover); consider prophylactic antibiotics to prevent opportunistic infections during dose reduction
Grade 3
or 4
Permanent discontinuation
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AE grading/dose adjustment Toxicity management
Adrenal insufficiency
Any grade
- Perform monitoring on the patient for signs and symptoms of endocrine disorder, including fatigue, hyperpigmentation, annorexia, hypotension, and weakness
- Thorough assessment should be performed for the subject to rule out any alternative causes
- Perform monitoring and assessment of adrenocortical function: cortisol, adrenocorticotropic hormone, serum sodium, serum potassium, blood glucose, and other endocrine laboratory parameters suspected to be related to adrenocortical function, and if necessary, perform adrenocorticotropic hormone stimulation test
- Immunosuppressive therapy if necessary
- Hormone replacement therapy (cortisone) if necessary
- Consider endocrinology consultation
- Consider submitting a blood sample for appropriate autoimmune antibody testing
Grade 1
Dose modification not indicated
For grade 1
Perform appropriate monitoring on the patient’s adrenal function
Consider endocrinology consultation as clinically indicated
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AE grading/dose adjustment Toxicity management
Grade 2
Interruption
• Discontinue permanently if worsening to grade 3 or 4
• If resolution to grade 0 - 1 or baseline, continue on next scheduled treatment day
For grade 2
Perform assessment of adrenal cortical function, and initiate hormone replacement therapy as needed
Grade 3
Permanent discontinuation
For grade 3 - 4:
Endocrinology consultation
Consider systemic corticosteroids
Intravenous corticosteroids with mineralocorticoid activity should be initiated immediately for adrenal crisis, severe dehydration, hypotension, or shock
Once improved, have the dose of glucocorticoids reduced gradually over ≥ 4 weeks (cortisone used for replacement therapy is adjusted on the basis of recovery of endocrine function, and should be maintained chronically in a patient who failed to recover); consider prophylactic antibiotics to prevent opportunistic infections during dose reduction
Grade 4
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AE grading/dose adjustment Toxicity management
Hyperthyroidism or hypothyroidism
Any grade
- Performing monitoring on the patient for symptoms and signs related to thyroid dysfunction, including hyperthyroidism-related (palpitations, sweating, increased food uptake and bowel movements, and weight loss) and hypothyroidism-related (generalized weakness, fatigue, cold intolerance, memory loss, andconstipation.)
- Thorough assessment should be performed for the subject to rule out any alternative causes
- Monitoring and assessment of thyroid function
- Consider endocrinology consultation
- Consider submitting a blood sample for testing of thyroid autoantibodies (anti-thyroglobulin antibody, anti-thyroid peroxidase antibody, thyroid stimulating hormone receptor antibody)
Grade 1
or 2
Dose modification note indicated
For grade 1 - 2:
- Perform regular monitoring of thyroid function and thyroid autoantibodies
- Initiate levothyroxine replacement therapy or hyperthyroidism medications if necessarily required
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AE grading/dose adjustment Toxicity management
Grade 3
or 4
Hyperthyroidism
• Permanent discontinuation
Hypothyroidism
• Dose modification not indicated
For grade 3 - 4:
- Monitoring of thyroid function and thyroid autoantibodies
- Consultation with endocrinologist
Hyperthyroidism
- Hyperthyroidism medications
- Consider beta-blockers if tachycardia
Hypothyroidism
- Levothyroxine replacement therapy
Type 1 diabetes Any grade
- Pay close attention to relevant symptoms and signs, such as polyuria, polydipsia, polyphagia, fatigue, weakness and weight loss
- Thorough assessment should be performed for the subject to rule out any alternative causes
- Monitoring and evaluation of islet function: blood glucose, insulin, C-peptide, pancreatic β-cell autoantibodies, blood ketone, and other endocrine laboratory parameters suspected to be associated with type 1 diabetes
Grade 1
or 2
Dose modification note indicated
For grade 1 - 2
Monitoring and assessment of islet function
Insulin treatment if necessarily required
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AE grading/dose adjustment Toxicity management
Grade 3
Interruption
• Continue after blood glucose is brought under control
For grade 3 - 4
Monitoring and assessment of islet function
Consider endocrinology consultation
Insulin for controlling blood glucose, and adjust insulin dosage on the basis of blood glucose control
Inpatient hospitalization for insulin therapy, hydration and alakaline supplements if ketoacidosis occurs
Grade 4
Permanent discontinuation
Renal insufficiency (increased serum creatinine)
Any grade
Pay close attention to relevant symptoms and signs (e.g., decreased urine volume, dark urine color, anemia, fatigue and weakness, and weight loss)
Thorough assessment should be performed for the subject to rule out any alternative causes
Monitoring and assessment of renal function
Consider nephrology consultation
Consider renal biopsy to distinguish between inflammatory and non-inflammatory causes if necessary
Grade 1
Dose modification note indicated
For grade 1
- Monitor creatinine levels weekly
- Resume routine creatinine monitoring per protocol if return to baseline
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AE grading/dose adjustment Toxicity management
Grade 2
or 3
Interruption
• If improvement to grade 0 - 1, continue on the next scheduled treatment day
• Handle according to grade 4 if persisting > 7 days or worsening
For grade 2 - 3
- Monitor creatinine levels every 2 - 3 days
- Initiate systemic corticosteroids empirically
- If improved to grade 1, have the corticosteroid dose reduced over at least 1 month, and consider prophylactic antibiotics to prevent opportunistic infections
- Consider renal biopsy
- Consult a nephrologist
Grade 4
Permanent discontinuation
For grade 4
- Monitor creatinine levels daily
- Initiate systemic corticosteroids empirically
- If improved to grade 1, have the corticosteroid dose reduced over at least 1 month, and consider prophylactic antibiotics to prevent opportunistic infections
- Consult a nephrologist
- Consider renal biopsy
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AE grading/dose adjustment Toxicity management
Immune-related neurotoxicity (excluding myasthenia gravis and Guillain-Barre syndrome)
Any grade
- Monitor the patient’s systemic symptoms (headache, nausea, dizziness, behavioral changes, or weakness)
- Thorough assessment should be performed for the subject to rule out any alternative causes (e.g., progression, infection, metabolic syndrome and medications)
- Consider appropriate diagnostic tests (e.g., electromyography and nerve conduction study)
- Perform symptomatic treatment and neurology consultation if applicable
Grade 1
Dose modification not indicated
- Follow the patient closely for symptoms and signs
Grade 2
Interruption
• If improvement to grade 0 - 1, continue on the next scheduled treatment day
• Handle according to grade 3 if worsened
For grade 2 - 4
- Consider neurology consultation
- Hospitalization if necessarily required
- Appropriate agents (e.g., gabapentin, duloxetine) may be used to treat sensory neuropathy and neuropathic pain
- Consider systemic corticosteroids
- If improvement is Not noted within 3 - 5 days, consider additional tests and other immunosuppressive agents (e.g., intravenous immunoglobulin G (IVIgG))
- Once stabilized, have the corticosteroid dose reduced gradually over ≥ 4 weeks
Grade 3
Permanent discontinuation
Grade 4
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Immune-related peripheral nerve syndromes, such as Guillain-Barré syndrome and myasthenia gravis
Any grade
- Pay close attention to the relevant symptoms and signs (myasthenia gravis: sore and swollen eyelids or limbs, blurred vision, and fatigue easily, and characterized by being mild in the morning and severe in the evening; Guillain-Barre syndrome: sudden severe nerve root pain, flaccid paralysis of extremities, paresthesia in limbs (such as numbness, tingling or burning sensation)
- Because the patient is likely to experience unpredictable acute decompensation, which results in a severe disease or death, it is very important that a diagnosis of immune-related peripheral neuropathy be made in a timely manner. Attention should be particularly paid to certain symptoms or signs that may denote serious consequences, such as marked dysphagia, rapidly progressive weakness, respiratory insufficiency, or autonomic instability.
- Electrophysiology and other appropriate examinations should be performed to rule out any alternative causes (e.g., disease progression, infection, metabolic syndrome, and impact of medications). It is worth noting that the diagnosis of immune-related peripheral neuropathy is difficult due to impact of both the patient’s disease itself and treatment that neurology consultation should be sought.
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AE grading/dose adjustment Toxicity management
Grade 1
Dose modification not indicated
For grade 1
- Discuss with study physician
- Monitoringof symptoms and signs
- Consider neurology consultation
Grade 2
Interruption
• If improvement to grade 0 - 1, continue on the next scheduled treatment day
• Handle according to grade 3 - 4 if worsening
For grade 2 - 4
- Monitoring of symptoms and signs
- Neurology consultation
- Hospitalization if necessarily required
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- Appropriate agents may be used to manage sensory neuropathy/neuropathic pain, such as gabapentin, duloxetine, etc.
Myasthenia Gravis
- Corticosteroids may be used to treat myasthenia gravis (since glucocorticoid therapy, especially at high doses, may lead to transient worsening of muscle weakness and therefore should be used under the supervision of a neurologist)
- Plasma exchange or IVIgG may be used for subjects who do not tolerate glucocorticoids
- In the presence of myasthenia gravis-like neurotoxicity, acetylcholinesterase inhibitors should be considered in addition to glucocorticoids
Guillain-Barre syndrome
- Plasma exchange or IVIgG therapy should be considered in Guillain-Barre syndrome (glucocorticoid therapy is usually ineffective)
Grade 3
or 4
Permanent discontinuation
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Table 2. Guidelines on dose modification and toxicity management for other potential irAEs
CTD classification/dose modification
Toxicity management
Any grade
No dose modification is required for adverse events considered unrelated to study treatment or for abnormal laboratory findings considered not clinically significant (i.e., events due to underlying disease)
Handle according to local clinical practice
Grade 1 Dose modification not indicated
Grade 2 Consider drug interruption until recovery to grade 0 - 1 or baseline
Grade 3 • First occurrence, discontinue study drug until recovery to grade 0 - 1 or baseline
• If a second occurrence of the same grade 3 AE, withdraw the drug permanently
• For an AE that decreased to grade 0 - 2 within 7 days or recovered to grade 0 - 1 or baseline within 14 days, interrupt the treatment and resume at the next scheduled treatment day Otherwise, withdraw the drug permanently
Grade 4 Permanent discontinuation (Note: For grade 4 laboratory abnormalities, discontinuation should be based on concomitant clinical symptoms/signs and the investigator’s clinical judgment)
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Table 3. Guidelines on dose modification and toxicity management for infusion reactions
CTD
classification
Dose Modifications Toxicity management
Any grade - Handle according to local clinical
practice
- Monitor the patient for any infusion-
related reactions (e.g., fever or
chills, flushing and/or pruritus,
variations of heart rate and blood
pressure, dyspnea, chest discomfort,
and rashes) and allergic reactions
(e.g., generalized urticaria,
angioedema, asthma, hypotension,
and tachycardia)
Grade 1 Reduce the infusion rate by
50% or interrupt the infusion,
until the infusion reaction is
resolved
For grade 1 or 2:
- Acetaminophen and/or
antihistamines may be administered
at the discretion of the investigator
according to local clinical practice
- Consider prophylaxis prior to
subsequent courses according to
local clinical practice
Grade 2 Reduce the infusion rate by
50% or interrupt the infusion,
until the infusion reaction is
resolved, after which the
subsequent infusion can be
resumed at 50% of the initial
rate
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Grade 3/4 Permanent discontinuation For grade 3 or 4:
- Manage severe infusion-related
reactions according to local clinical
practice (e.g., administration of
epinephrine, diphenhydramine,
ranitidine, and glucocorticoids)
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