Lenalidomide (REVLIMID ® ) Celgene Corporation New Drug Application (021880) Oncology Drug Advisory...

Lenalidomide (REVLIMIDLenalidomide (REVLIMID®®))Celgene CorporationCelgene Corporation

New Drug Application (021880)New Drug Application (021880)

Lenalidomide (REVLIMIDLenalidomide (REVLIMID®®))Celgene CorporationCelgene Corporation

New Drug Application (021880)New Drug Application (021880)

Oncology Drug Advisory CommitteeOncology Drug Advisory CommitteeSept 14, 2005Sept 14, 2005

Lenalidomide Review TeamLenalidomide Review TeamDivision of Drug Oncology ProductsDivision of Drug Oncology Products

Oncology Drug Advisory CommitteeOncology Drug Advisory CommitteeSept 14, 2005Sept 14, 2005

Lenalidomide Review TeamLenalidomide Review TeamDivision of Drug Oncology ProductsDivision of Drug Oncology Products

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

NDA 21880 Review TeamNDA 21880 Review TeamNDA 21880 Review TeamNDA 21880 Review Team

MedicalEfficacy: Maitreyee Hazarika, MDSafety: Edvardas Kaminskas, MDAnn Farrell, MD

StatisticsYuan Li Shen, DrPHRajeshwari Sridhara, PhD

Pharmacology/Toxicology Pharm Tox: Anwar Goheer, PhD Reproductive Safety: Kimberly Benson, PhD John Leighton, PhD

MedicalEfficacy: Maitreyee Hazarika, MDSafety: Edvardas Kaminskas, MDAnn Farrell, MD

StatisticsYuan Li Shen, DrPHRajeshwari Sridhara, PhD

Pharmacology/Toxicology Pharm Tox: Anwar Goheer, PhD Reproductive Safety: Kimberly Benson, PhD John Leighton, PhD

Clinical PharmacologyGene Williams, PhDBrian Booth, PhD

Chemistry Hari Sarker, PhD Nallaperumal Chidambaram, PhD

Project Manager Carl Huntley, RPh, MBA

Clinical PharmacologyGene Williams, PhDBrian Booth, PhD

Chemistry Hari Sarker, PhD Nallaperumal Chidambaram, PhD

Project Manager Carl Huntley, RPh, MBA

Proposed IndicationProposed IndicationProposed IndicationProposed Indication

Treatment of patients with transfusion dependent

anemia due to low- or intermediate-1 risk

myelodysplastic syndromes associated with a

deletion 5q cytogenetic abnormality with or

without additional cytogenetic abnormalities

Treatment of patients with transfusion dependent

anemia due to low- or intermediate-1 risk

myelodysplastic syndromes associated with a

deletion 5q cytogenetic abnormality with or

without additional cytogenetic abnormalities

Issues for ODACIssues for ODACIssues for ODACIssues for ODAC

• Single-arm trial design in a heterogenous disease (MDS) (FDA recommended a randomized controlled trial)

• ‘8-week transfusion-free’ endpoint to demonstrate clinical benefit

• Toxicity of 10 mg dose

• Benefit vs. risk of the drug for this population

• Implementation of additional risk management measures

• Single-arm trial design in a heterogenous disease (MDS) (FDA recommended a randomized controlled trial)

• ‘8-week transfusion-free’ endpoint to demonstrate clinical benefit

• Toxicity of 10 mg dose

• Benefit vs. risk of the drug for this population

• Implementation of additional risk management measures

OutlineOutlineOutlineOutline

• Drug Approvals for MDS

• Reproductive Safety Assessment

• Clinical Review Efficacy

• Integrated Safety Summary

• Risk Management

• Summary

• Drug Approvals for MDS

• Reproductive Safety Assessment

• Clinical Review Efficacy

• Integrated Safety Summary

• Risk Management

• Summary

FDA Approval for MDSFDA Approval for MDS Azacitidine (Vidaza Azacitidine (Vidaza®®) injection) injection

FDA Approval for MDSFDA Approval for MDS Azacitidine (Vidaza Azacitidine (Vidaza®®) injection) injection

• MDS subtypes: RA, RARS, RAEB, RAEB-t, CMML

• 1 randomized, controlled trial comparing azacitidine +

supportive care (SC) vs. SC (N=191)

• 2 single-arm studies

• Response rate (16%) ≥ 4 weeks duration (p<0.0001) based

on complete or partial response (CR + PR) of bone marrow peripheral blood (all cell counts)

• MDS subtypes: RA, RARS, RAEB, RAEB-t, CMML

• 1 randomized, controlled trial comparing azacitidine +

supportive care (SC) vs. SC (N=191)

• 2 single-arm studies

• Response rate (16%) ≥ 4 weeks duration (p<0.0001) based

on complete or partial response (CR + PR) of bone marrow peripheral blood (all cell counts)

Structural ComparisonStructural ComparisonStructural ComparisonStructural Comparison

Lenalidomide

Thalidomide

Lenalidomide

Thalidomide

N

O

NH

O

O

NH2

N

O

NH

O

O

O

Clinical PharmacologyClinical PharmacologyClinical PharmacologyClinical Pharmacology

• Metabolism

Not a cytochromes P450 substrate

Presence and identity of circulating

metabolites not studied in humans

• Excretion: Approximately 2/3 eliminated as parent

via urine

• Metabolism

Not a cytochromes P450 substrate

Presence and identity of circulating

metabolites not studied in humans

• Excretion: Approximately 2/3 eliminated as parent

via urine

Reproductive Reproductive Safety AssessmentSafety Assessment

Reproductive Reproductive Safety AssessmentSafety Assessment

Embryo-Fetal Development Embryo-Fetal Development Study RequirementsStudy Requirements

Embryo-Fetal Development Embryo-Fetal Development Study RequirementsStudy Requirements

• Study in first species

• Conduct confirmatory study in second species

• Study in first species

• Conduct confirmatory study in second species

If results are negative - If results are negative - No evidence of drug-No evidence of drug-induced embryo-fetal induced embryo-fetal development adverse development adverse eventsevents

Lenalidomide Embryo-Fetal Lenalidomide Embryo-Fetal Development StudiesDevelopment Studies

Rat StudyRat Study


Rat StudyRat Study

Methods and Results

• Pregnant rats dosed during gestational days 6-17

• No adverse effects seen on the embryo or fetus, including limb bud effects, at the doses studied

Methods and Results

• Pregnant rats dosed during gestational days 6-17

• No adverse effects seen on the embryo or fetus, including limb bud effects, at the doses studied


Rat StudyRat Study


Rat StudyRat Study

Conclusion

Rat not sensitive species for thalidomide limb bud developmental effects

While this study does provide some information regarding developmental effects, it is inadequate for full assessment of lenalidomide developmental effects

Conclusion

Rat not sensitive species for thalidomide limb bud developmental effects

While this study does provide some information regarding developmental effects, it is inadequate for full assessment of lenalidomide developmental effects


Rabbit StudyRabbit Study



Methods and Results

• Pregnant rabbits dosed during gestational days 7-19

• A Thalidomide dose group was also included

• Acceptable study endpoints (maternal or developmental effects) not achieved

• Thalidomide caused expected limb deformities, lenalidomide did not

Methods and Results

• Pregnant rabbits dosed during gestational days 7-19

• A Thalidomide dose group was also included

• Acceptable study endpoints (maternal or developmental effects) not achieved

• Thalidomide caused expected limb deformities, lenalidomide did not




Rabbit StudyRabbit StudyConclusion

• This study was inadequate Drug-related effects on maternal or

developmental endpoints in the high dose group did not meet standard study criteria

There was a confounding variable - some rabbits were not eating prior to study onset

Conclusion

• This study was inadequate Drug-related effects on maternal or

developmental endpoints in the high dose group did not meet standard study criteria

There was a confounding variable - some rabbits were not eating prior to study onset

ConclusionConclusionConclusionConclusion

• Structural similarities of lenalidomide and thalidomide suggests risk

• Insufficient information to fully determine the effects on embryo-fetal development for lenalidomideThe rat is not an appropriate model for

full assessment of embryo-fetal effects of this drug

The rabbit study was inadequate

• Structural similarities of lenalidomide and thalidomide suggests risk

• Insufficient information to fully determine the effects on embryo-fetal development for lenalidomideThe rat is not an appropriate model for

full assessment of embryo-fetal effects of this drug

The rabbit study was inadequate

RecommendationsRecommendationsRecommendationsRecommendations

• If approved, Pregnancy Category D is recommended, similar to most other oncologic agents

• Additional studies to fully assess potential developmental effects should be conducted

• If approved, Pregnancy Category D is recommended, similar to most other oncologic agents

• Additional studies to fully assess potential developmental effects should be conducted

Clinical ReviewClinical ReviewClinical ReviewClinical Review

Efficacy StudiesEfficacy StudiesEfficacy StudiesEfficacy Studies

Study Study Design Evaluable patients/N

Doses Primary Endpoint

MDS-003 Single-armOpen-labelMulticenterPhase 2

96/148 10 mg daily10 mg x21d/q28d

RBC transfusion independence

MDS-001 Pilot, phase 1/2, single-arm, 2-stage, dose-finding

10/45 25 mg daily10 mg daily10 mg x21d/q28d

Major and minor erythroid response

MDS-002 Single-armOpen-labelMulticenterPhase 2

118/215 10 mg daily10 mg x21d/q28d

RBC transfusion independence

MDS-003 EfficacyMDS-003 EfficacyMDS-003 EfficacyMDS-003 Efficacy

MDS-003 Study DesignMDS-003 Study DesignMDS-003 Study DesignMDS-003 Study Design

• Single-arm, open-label, multi-center, Phase 2 study

• Local or central laboratory used to determine eligibility

• Adjudication by independent hematologic and cytogenetic

reviewers

• Response criteria based on IWG Standardized Response

Criteria for MDS (Cheson et al, Blood, 2000)

• Single-arm, open-label, multi-center, Phase 2 study

• Local or central laboratory used to determine eligibility

• Adjudication by independent hematologic and cytogenetic

reviewers

• Response criteria based on IWG Standardized Response

Criteria for MDS (Cheson et al, Blood, 2000)

Study EndpointsStudy EndpointsStudy EndpointsStudy Endpoints

• Primary RBC transfusion independence

• Secondary endpoints

• Change of hemoglobin from baseline

• Duration of response

• ≥ 50% decrease in RBC transfusion requirements

• Cytogenetic response

• Platelet response

• Neutrophil response

• Primary RBC transfusion independence

• Secondary endpoints

• Change of hemoglobin from baseline

• Duration of response

• ≥ 50% decrease in RBC transfusion requirements

• Cytogenetic response

• Platelet response

• Neutrophil response

Eligibility CriteriaEligibility CriteriaMDS-003MDS-003


• Low- risk or intermediate- 1- risk MDS

with a del (5q) (q31-33)

(del 5q isolated or associated with other cytogenetic

abnormalities)

• RBC transfusion- dependent anemia defined as requiring

≥ 2 units of RBCs within 8 weeks of study treatment

• Low- risk or intermediate- 1- risk MDS

with a del (5q) (q31-33)

(del 5q isolated or associated with other cytogenetic

abnormalities)

• RBC transfusion- dependent anemia defined as requiring

≥ 2 units of RBCs within 8 weeks of study treatment

MDS-003MDS-003MDS-003MDS-003

• Enrolled 148 patients

• Doses: Oral lenalidomide

• 10 mg x21 d/q28 d (syncopated) (N=45)

• 10 mg daily (continuous) (N=103)


• Doses: Oral lenalidomide

• 10 mg x21 d/q28 d (syncopated) (N=45)


Disease CharacteristicsDisease CharacteristicsCytogeneticsCytogenetics

MDS-003MDS-003

Disease CharacteristicsDisease CharacteristicsCytogeneticsCytogenetics

MDS-003MDS-003

Cytogenetics ITTN=148 (%)

5q deletion 148 (100)

Isolated 5q del 110 (74.3)

Del 5q with other abnormality 38 (25.7)

≥ 20 metaphases 119 (80.4)

< 20 metaphases 29 (19.6)

Disease CharacteristicsDisease CharacteristicsIPSS Risk ScoreIPSS Risk Score

MDS-003MDS-003

Disease CharacteristicsDisease CharacteristicsIPSS Risk ScoreIPSS Risk Score

MDS-003MDS-003

Risk Category 10 mg syncN=45 (%)

10 mg contN=103 (%)

ITTN=148 (%)

Low 13 (28.9) 42 (40.8) 55 (37.1)

Intermediate-1 25 (55.6) 40 (38.8) 65 (43.2)

Intermediate-2 2 (4.4) 4 (3.9) 6 (4.0)

High 1 (2.2) 1 (1.0) 2 (1.3)

Missing 4 (8.9) 16 (15.5) 20 (13.5)

Patient CharacteristicsPatient CharacteristicsRBC Transfusion Dependent AnemiaRBC Transfusion Dependent Anemia

MDS-003MDS-003

Patient CharacteristicsPatient CharacteristicsRBC Transfusion Dependent AnemiaRBC Transfusion Dependent Anemia

MDS-003MDS-003

Transfusion DependenceAt Baseline

ITTN=148

%

≥ 2 RBC units within 8 weeks of start of study drug ≥ 3 RBC units

141

106

95

71.6

0-2 units within 8 weeks 42 28.4

MedianMin, Max

60-18

Patient PopulationsPatient Populations MDS-003MDS-003

Patient PopulationsPatient Populations MDS-003MDS-003

Population SponsorN (%)

FDAN (%)

ITT: All enrolled 148 (100) 148 (100)

MITT: Transfusion dependent anemia (≥ 2 U in each of two 8-week periods)

94 (63.5) Not done

FDA Evaluable: Transfusion dependent anemia (≥ 2 U in 8-weeks prior to start of drug)

Not done 96 (64.9)

FDA Evaluable for EfficacyFDA Evaluable for EfficacyMDS-003MDS-003

FDA Evaluable for EfficacyFDA Evaluable for EfficacyMDS-003MDS-003

Reasons for Exclusions Patients N=148 (%)

Adjudicated not MDS 20 (13.5)

Adjudicated no IPSS score 20 (13.5)

Adjudicated IPSS risk category intermediate-2 or high

8 (5.4)

Did not receive ≥ 2 units RBC within 8 weeks 7 (4.7)

< 20 metaphases analyzed at baseline 29 (19.6)

Total FDA Evaluable 96 (64.9)

IWG Response Criteria for MDSIWG Response Criteria for MDSCheson et al,Cheson et al, Blood, 2000Blood, 2000


Hematologic Improvement-Erythroid Response

Major response

for RBC transfusion-dependent patients, transfusion independence

For patients with pretreatment hemoglobin < 11 g/dL, greater than 2

g/dL increase in hemoglobin

Minor Response

for RBC transfusion-dependent patients, 50% decrease in

transfusion requirements

For patients with pretreatment hemoglobin < 11 g/dL, 1-2 g/dL

increase in hemoglobin

Hematologic Improvement-Erythroid Response

Major response

for RBC transfusion-dependent patients, transfusion independence

For patients with pretreatment hemoglobin < 11 g/dL, greater than 2

g/dL increase in hemoglobin

Minor Response

for RBC transfusion-dependent patients, 50% decrease in

transfusion requirements

For patients with pretreatment hemoglobin < 11 g/dL, 1-2 g/dL

increase in hemoglobin



Hematologic Improvement

Improvements must last at least 2 months in

the absence of ongoing cytotoxic therapy

Hematologic Improvement

Improvements must last at least 2 months in

the absence of ongoing cytotoxic therapy

Definition of Response Definition of Response ** (Protocol) (Protocol)

RBC Transfusion IndependenceRBC Transfusion Independence

Definition of Response Definition of Response ** (Protocol) (Protocol)

RBC Transfusion IndependenceRBC Transfusion Independence

The absence of the intravenous infusion of any RBC

transfusion during any consecutive “rolling” 56 days (8

weeks) during the treatment period

must last ≥ 2 months

≥ 1.0 g/dL increase in Hgb

* Modified IWG MDS Hematologic Improvement Criteria

The absence of the intravenous infusion of any RBC

transfusion during any consecutive “rolling” 56 days (8

weeks) during the treatment period

must last ≥ 2 months

≥ 1.0 g/dL increase in Hgb

* Modified IWG MDS Hematologic Improvement Criteria

RBC Transfusion Independence RBC Transfusion Independence ResponseResponse

RBC Transfusion Independence RBC Transfusion Independence ResponseResponse

Population Transfusion Independent N (%)

95% CI

ITT N=148

99 (66.9) 0.59, 0.74

FDA EvaluableN=96

64 (66.7) 0.56, 0.76

Change in Hemoglobin from Baseline Change in Hemoglobin from Baseline MDS-003MDS-003

Change in Hemoglobin from Baseline Change in Hemoglobin from Baseline MDS-003MDS-003

• Hemoglobin change

minimum hemoglobin value in the 8 week period preceding

first dose of study drug for baseline and the maximum hgb

value during the response period, excluding the 30 days after

the last transfusion prior to the response period

ITT, Median change 3.3 g/dL

Responders, Median change 5.2 g/dL

• Hemoglobin change

minimum hemoglobin value in the 8 week period preceding

first dose of study drug for baseline and the maximum hgb

value during the response period, excluding the 30 days after

the last transfusion prior to the response period

ITT, Median change 3.3 g/dL

Responders, Median change 5.2 g/dL

≥≥50% Decrease in Transfusion 50% Decrease in Transfusion RequirementsRequirements

≥≥50% Decrease in Transfusion 50% Decrease in Transfusion RequirementsRequirements

Population ≥ 50% decreaseN (%)

95% CI

ITT N=148

112 (75.7) 0.68, 0.82

FDA Evaluable N=96

73 (76.0) 0.66, 0.84

Duration of Transfusion Independence Duration of Transfusion Independence in Respondersin Responders (weeks) (N=99)(weeks) (N=99)

MDS-003MDS-003

Duration of Transfusion Independence Duration of Transfusion Independence in Respondersin Responders (weeks) (N=99)(weeks) (N=99)

MDS-003MDS-003

• Response duration• Measured from end of the consecutive 56 days

during which patient was free of RBC transfusions to the date of first RBC transfusion

• Median 52.3 weeks (Min, Max 8.1- 74.6)

• Response duration• Measured from end of the consecutive 56 days

during which patient was free of RBC transfusions to the date of first RBC transfusion

• Median 52.3 weeks (Min, Max 8.1- 74.6)

Relapsed PatientsRelapsed PatientsRelapsed PatientsRelapsed Patients

• Relapses from transfusion independent to

transfusion dependent : 32/99 patients

• Relapses occurred within treatment period: 13/32

patients

• Relapses from transfusion independent to

transfusion dependent : 32/99 patients

• Relapses occurred within treatment period: 13/32

patients



Major Cytogenetic Response

Major: No detectable cytogenetic abnormality if

preexisting abnormality was present

(Requires 20 analyzable metaphases using conventional

cytogenetic techniques)

Major Cytogenetic Response

Major: No detectable cytogenetic abnormality if

preexisting abnormality was present

(Requires 20 analyzable metaphases using conventional

cytogenetic techniques)

Major Cytogenetic ResponseMajor Cytogenetic Response MDS-003MDS-003

Major Cytogenetic ResponseMajor Cytogenetic Response MDS-003MDS-003

Population Major ResponseN (%)

95% CI

ITT N=120

52 (43.3) 17.6, 33.7

FDA Evaluable N=58

26 (44.8) 31.7, 58.5

Major Platelet Response Major Platelet Response MDS-003MDS-003

Major Platelet Response Major Platelet Response MDS-003MDS-003

• Definition (IWG MDS Response criteria): For patients with pre-treatment platelet count less than

100,000/mm3 an absolute increase of 30,000 or more

for platelet transfusion-dependent patients, stabilization

of platelet counts and platelet transfusion independence

• Major platelet response rate: 0/14

• Definition (IWG MDS Response criteria): For patients with pre-treatment platelet count less than

100,000/mm3 an absolute increase of 30,000 or more

for platelet transfusion-dependent patients, stabilization

of platelet counts and platelet transfusion independence

• Major platelet response rate: 0/14

Major Neutrophil ResponseMajor Neutrophil Response MDS-003MDS-003

Major Neutrophil ResponseMajor Neutrophil Response MDS-003MDS-003

• Definition (IWG MDS Response Criteria):For ANC less than 1500/mm3 before therapy, at

least a 100% increase, or an absolute increase of more than 500/mm3,

whichever is greater

• Major neutrophil response: 1/6

• Definition (IWG MDS Response Criteria):For ANC less than 1500/mm3 before therapy, at

least a 100% increase, or an absolute increase of more than 500/mm3,

whichever is greater



• Dose-finding, phase 1/2, single-arm, single-center study

• Primary endpoint: patients with major or minor erythroid

response (modified from the IWG MDS Response Criteria)


• Doses:

• 25 mg daily (N=13)

• 10 mg q21 d/28 d (syncopated) (N=18)


• Dose-finding, phase 1/2, single-arm, single-center study

• Primary endpoint: patients with major or minor erythroid

response (modified from the IWG MDS Response Criteria)


• Doses:

• 25 mg daily (N=13)

• 10 mg q21 d/28 d (syncopated) (N=18)


Study EndpointsStudy EndpointsStudy EndpointsStudy Endpoints

• Primary

• Major or minor erythroid response

• Secondary

• cytogenetic response

• neutrophil response

• platelet count response

• Primary

• Major or minor erythroid response

• Secondary

• cytogenetic response

• neutrophil response

• platelet count response



• De novo MDS: RA, RARS, RAEB,

RAEB-t, CMML

• RBC transfusion- dependent anemia defined as

requiring ≥ 4 units of RBCs within 8 weeks of

study treatment, or

• Baseline mean hemoglobin < 10 g/dL

(untransfused)

• De novo MDS: RA, RARS, RAEB,

RAEB-t, CMML

• RBC transfusion- dependent anemia defined as

requiring ≥ 4 units of RBCs within 8 weeks of

study treatment, or

• Baseline mean hemoglobin < 10 g/dL

(untransfused)

Population (N=10)Population (N=10) MDS-001MDS-001

Population (N=10)Population (N=10) MDS-001MDS-001

• Transfusion dependent anemia (≥ 2 U/8 weeks)

low- or intermediate-1 risk MDS with del 5 q

• Transfusion dependent anemia (≥ 2 U/8 weeks)

low- or intermediate-1 risk MDS with del 5 q

Major Erythroid Response Major Erythroid Response MDS-001MDS-001

Major Erythroid Response Major Erythroid Response MDS-001MDS-001

• Major erythroid response 7/10 (70%) (95% CI [35, 93])

• Minor erythroid responsenone

• Major erythroid response 7/10 (70%) (95% CI [35, 93])

• Minor erythroid responsenone

Efficacy Analyses (cont’d)Efficacy Analyses (cont’d) MDS-001MDS-001

Efficacy Analyses (cont’d)Efficacy Analyses (cont’d) MDS-001MDS-001

• Duration of response (7 responders)

• Median: 41.4 weeks (Range: 31- 88.1 weeks)

• Median change in hemoglobin values : 5.3 g/dL

• Major cytogenetic response: 9/10

• Major platelet response: 1/1


• Duration of response (7 responders)

• Median: 41.4 weeks (Range: 31- 88.1 weeks)

• Median change in hemoglobin values : 5.3 g/dL

• Major cytogenetic response: 9/10

• Major platelet response: 1/1



• MDS-002 identical to MDS-003 except

• Study Population

Patients without del 5q cytogenetic abnormality


• 2 doses:

• Dose 10 mg syncopated (115)

• Dose 10 mg continuous (100)

• MDS-002 identical to MDS-003 except

• Study Population

Patients without del 5q cytogenetic abnormality


• 2 doses:

• Dose 10 mg syncopated (115)

• Dose 10 mg continuous (100)

Efficacy AnalysesEfficacy AnalysesMDS-002MDS-002

Efficacy AnalysesEfficacy AnalysesMDS-002MDS-002

ITT Population Results

RBC Transfusion Independence (N=215)

46 (21.4 %)

Change in Hgb in responders (N=46) 3 g/dL (Range: 1.3-8.3)

Duration in responders (N=46)18.9 weeks(Range: 8-36)

Integrated Safety SummaryIntegrated Safety SummaryIntegrated Safety SummaryIntegrated Safety Summary

Patient ExposurePatient ExposurePatient ExposurePatient Exposure

Data Sources• 408 MDS patients• 13 patients 25 mg/day starting dose• 215 patients 10 mg/day starting dose• 180 patients 10 mg x 21 days q28 day cycle

Data Sources• 408 MDS patients• 13 patients 25 mg/day starting dose• 215 patients 10 mg/day starting dose• 180 patients 10 mg x 21 days q28 day cycle

Dose Modifications due to Adverse EventsDose Modifications due to Adverse EventsDose Modifications due to Adverse EventsDose Modifications due to Adverse Events

Dose reducedor interrupted

MDS-00310 mgN = 148

MDS-00125 mgN = 13

MDS-00110 mgN = 32

MDS-00210 mgN = 215

Any dose reduced or interrupted

118 (80%) 8 (62%) 12 (38%) 102 (47%)

≥ 2 doses reduced or interrupted

50 (34%) 7 (54%) 0 49 (23%)

Grade 3 and 4 Adverse Events (AEs)Grade 3 and 4 Adverse Events (AEs)10 mg Starting Dose 10 mg Starting Dose

Grade 3 and 4 Adverse Events (AEs)Grade 3 and 4 Adverse Events (AEs)10 mg Starting Dose 10 mg Starting Dose

• Are AEs due to MDS or lenalidomide or both?

• All patients had grade 1 to 4 AEs • 80% had one or more grade 3 or 4 AEs

• Neutropenia - 39%• Thrombocytopenia - 34%• Pneumonia, Sepsis and Other Infections – 9%• Anemia – 7%• Fatigue – 6%• Rash – 5%• Diarrhea – 4%• Febrile neutropenia – 3%• DVTs – 2%• Single grade 4 bleeding events – subarachnoid, subdural,

GI, hematuria

• Are AEs due to MDS or lenalidomide or both?

• All patients had grade 1 to 4 AEs • 80% had one or more grade 3 or 4 AEs

• Neutropenia - 39%• Thrombocytopenia - 34%• Pneumonia, Sepsis and Other Infections – 9%• Anemia – 7%• Fatigue – 6%• Rash – 5%• Diarrhea – 4%• Febrile neutropenia – 3%• DVTs – 2%• Single grade 4 bleeding events – subarachnoid, subdural,

GI, hematuria

Confounding IssueConfounding IssueConfounding IssueConfounding Issue

Neutropenia or thrombocytopenia due to MDS or to lenalidomide, especially in a trial without a control?

Neutropenia or thrombocytopenia due to MDS or to lenalidomide, especially in a trial without a control?

Serious Adverse Events (SAEs) with 10 mg DoseSerious Adverse Events (SAEs) with 10 mg DoseSerious Adverse Events (SAEs) with 10 mg DoseSerious Adverse Events (SAEs) with 10 mg Dose

SAEs occurred in 38% in all 3 studies

• Blood (13%)• Infections (8%)• General (4%)• Respiratory (3%)• Cardiac (3%)• GI (2%)• Metabolic (2%)• Vascular (1%)

SAEs occurred in 38% in all 3 studies

• Blood (13%)• Infections (8%)• General (4%)• Respiratory (3%)• Cardiac (3%)• GI (2%)• Metabolic (2%)• Vascular (1%)

DeathsDeathsDeathsDeaths

In the 3 studies, 28 on-study deaths, and 14 deaths in patients with continuing toxicity

• Pneumonia/sepsis with neutropenia (9)• AML (9)• Bleeding with thrombocytopenia (5)• Cardiac (5)• Liver failure (2)• Perforated bowel & sepsis (2)• Multiorgan failure with pancytopenia (1)• Lung cancer (1)• Angiodysplasia and bleeding (1) • Cause unknown (7)

In the 3 studies, 28 on-study deaths, and 14 deaths in patients with continuing toxicity

• Pneumonia/sepsis with neutropenia (9)• AML (9)• Bleeding with thrombocytopenia (5)• Cardiac (5)• Liver failure (2)• Perforated bowel & sepsis (2)• Multiorgan failure with pancytopenia (1)• Lung cancer (1)• Angiodysplasia and bleeding (1) • Cause unknown (7)

Safety SummarySafety SummarySafety SummarySafety Summary

• 408 MDS patients treated with starting doses of 25

mg/day or 10 mg/day lenalidomide

• Excessive toxicity observed - 10 mg/day dose

reduced and/or interrupted in 80%

• Single-arm trial does not permit attribution of AEs to

MDS or to the drug or to both

• 80% of patients had grade 3 or 4 AEs

• 38% of patients had SAEs

• 408 MDS patients treated with starting doses of 25

mg/day or 10 mg/day lenalidomide

• Excessive toxicity observed - 10 mg/day dose

reduced and/or interrupted in 80%

• Single-arm trial does not permit attribution of AEs to

MDS or to the drug or to both

• 80% of patients had grade 3 or 4 AEs

• 38% of patients had SAEs

Safety Summary (cont’d) Safety Summary (cont’d) Safety Summary (cont’d) Safety Summary (cont’d)

• Most common gr. 3/4 AEs and SAEs were neutropenia, thrombocytopenia, and infections.

• Most common reasons for discontinuations from studies were adverse events: hematologic, GI, and dermatologic.

• Most deaths were due to: infections, AML, bleeding, and cardiac.

• Benefits of RBC transfusion independence vs. risks of neutropenia and thrombocytopenia need to be assessed.

• Most common gr. 3/4 AEs and SAEs were neutropenia, thrombocytopenia, and infections.

• Most common reasons for discontinuations from studies were adverse events: hematologic, GI, and dermatologic.

• Most deaths were due to: infections, AML, bleeding, and cardiac.

• Benefits of RBC transfusion independence vs. risks of neutropenia and thrombocytopenia need to be assessed.

Ongoing Phase 3 StudyOngoing Phase 3 StudyOngoing Phase 3 StudyOngoing Phase 3 Study

Planned Phase 3 StudyPlanned Phase 3 StudyPlanned Phase 3 StudyPlanned Phase 3 Study

• Ongoing in Europe

• Del 5q patients

• Randomized, double-blind, 3-arm trial

5 mg daily

10 mg x21d/q28 d

placebo

• Primary endpoint

RBC transfusion independence for ≥26 weeks

• Ongoing in Europe

• Del 5q patients

• Randomized, double-blind, 3-arm trial

5 mg daily

10 mg x21d/q28 d

placebo

• Primary endpoint

RBC transfusion independence for ≥26 weeks

Risk Management Risk Management Risk Management Risk Management

Risk ManagementRisk ManagementRisk ManagementRisk Management

• Major safety concernTeratogenicity

• Major goalPrevention of fetal exposure to lenalidomide

• Major safety concernTeratogenicity

• Major goalPrevention of fetal exposure to lenalidomide

Risk Management PlanRisk Management PlanRisk Management PlanRisk Management Plan

• Examples of other drugs with teratogenic

potential and risk management plans

Thalidomide/ S.T.E.P.S® Program

Isotretinoin/ iPLEDGE®

• Examples of other drugs with teratogenic

potential and risk management plans

Thalidomide/ S.T.E.P.S® Program

Isotretinoin/ iPLEDGE®

SummarySummaryComparisonComparison

SummarySummaryComparisonComparison

Azacitidine Lenalidomide

Study Design randomized single-arm

Population RA, RARS, RAEB, RAEB-t, CMML

low or int-1 risk MDS, transfusion dependent anemia, del 5q

Response Criteria

CR + PR (Bone marrow, peripheral blood)

transfusion independence, change in hemoglobin

SummarySummarySummarySummary

• Embryo-fetal development not adequately addressed

• Single arm study for efficacy

transfusion entry criteria; median 6 units/8 weeks

a rolling 56 day transfusion free period

• RBC transfusion independence response (67%) with ≥ 1 g/dL increase in

hemoglobin

• Median duration of transfusion independence in responders (52 wks)

• Major cytogenetic response (43%)

• Embryo-fetal development not adequately addressed

• Single arm study for efficacy

transfusion entry criteria; median 6 units/8 weeks

a rolling 56 day transfusion free period

• RBC transfusion independence response (67%) with ≥ 1 g/dL increase in

hemoglobin

• Median duration of transfusion independence in responders (52 wks)

• Major cytogenetic response (43%)

SummarySummarySummarySummary

• All patients had AEs, 80% grade 3/4 AEs

• Dosing reduced in 80% patients

• Excessive toxicity at 10 mg

• Absence of control arm makes attribution of AEs

and deaths difficult

• All patients had AEs, 80% grade 3/4 AEs

• Dosing reduced in 80% patients

• Excessive toxicity at 10 mg

• Absence of control arm makes attribution of AEs

and deaths difficult

Lenalidomide (REVLIMID ® ) Celgene Corporation New Drug Application (021880) Oncology Drug Advisory...

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