Lenalidomide (REVLIMID

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Lenalidomide (REVLIMID)Celgene CorporationNew
Drug Application (021880)

• Oncology Drug Advisory Committee
• Sept 14, 2005
• Lenalidomide Review Team
• Division of Drug Oncology Products

Center for Drug Evaluation and Research
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NDA 21880 Review Team

• Medical
• Efficacy Maitreyee Hazarika, MD
• Safety Edvardas Kaminskas, MD
• Ann Farrell, MD
• Statistics
• Yuan Li Shen, DrPH
• Rajeshwari Sridhara, PhD
• Pharmacology/Toxicology
• Pharm Tox Anwar Goheer, PhD
• Reproductive Safety Kimberly Benson, PhD
• John Leighton, PhD

• Clinical Pharmacology
• Gene Williams, PhD
• Brian Booth, PhD
• Chemistry
• Hari Sarker, PhD
• Nallaperumal Chidambaram, PhD
• Project Manager
• Carl Huntley, RPh, MBA

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Proposed 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

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Issues 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

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Outline

• Drug Approvals for MDS
• Reproductive Safety Assessment
• Clinical Review Efficacy
• Integrated Safety Summary
• Risk Management
• Summary

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FDA Approval for MDS Azacitidine (Vidaza)
injection

• MDS subtypes RA, RARS, RAEB, RAEB-t, CMML
• 1 randomized, controlled trial comparing
  azacitidine supportive care (SC) vs. SC (N191)
• 2 single-arm studies
• Response rate (16) 4 weeks duration (plt0.0001)
  based on complete or partial response (CR PR)
  of
• bone marrow
• peripheral blood (all cell counts)

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Structural Comparison

• Lenalidomide
• Thalidomide

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Clinical 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

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Reproductive Safety Assessment
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Embryo-Fetal Development Study Requirements

• Study in first species
• Conduct confirmatory study in second species

If results are negative - No evidence of
drug-induced embryo-fetal development adverse
events
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Lenalidomide Embryo-Fetal Development Studies
Rat 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

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Lenalidomide Embryo-Fetal Development Studies
Rat 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

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Lenalidomide Embryo-Fetal Development
StudiesRabbit 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

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Lenalidomide Embryo-Fetal Development
StudiesRabbit Study

• 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

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Conclusion

• Structural similarities of lenalidomide and
  thalidomide suggests risk
• Insufficient information to fully determine the
  effects on embryo-fetal development for
  lenalidomide
• The rat is not an appropriate model for full
  assessment of embryo-fetal effects of this drug
• The rabbit study was inadequate

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Recommendations

• If approved, Pregnancy Category D is recommended,
  similar to most other oncologic agents
• Additional studies to fully assess potential
  developmental effects should be conducted

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Clinical Review
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Efficacy Studies
Study Study Design Evaluable patients/N Doses Primary Endpoint
MDS-003 Single-arm Open-label Multicenter Phase 2 96/148 10 mg daily 10 mg x21d/q28d RBC transfusion independence
MDS-001 Pilot, phase 1/2, single-arm, 2-stage, dose-finding 10/45 25 mg daily 10 mg daily 10 mg x21d/q28d Major and minor erythroid response
MDS-002 Single-arm Open-label Multicenter Phase 2 118/215 10 mg daily 10 mg x21d/q28d RBC transfusion independence
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MDS-003 Efficacy
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MDS-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)

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Study 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

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Eligibility CriteriaMDS-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

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MDS-003

• Enrolled 148 patients
• Doses Oral lenalidomide
• 10 mg x21 d/q28 d (syncopated) (N45)
• 10 mg daily (continuous) (N103)

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Disease CharacteristicsCytogenetics MDS-003
Cytogenetics ITT N148 ()
5q deletion 148 (100)
Isolated 5q del 110 (74.3)
Del 5q with other abnormality 38 (25.7)
20 metaphases 119 (80.4)
lt 20 metaphases 29 (19.6)
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Disease CharacteristicsIPSS Risk Score MDS-003
Risk Category 10 mg sync N45 () 10 mg cont N103 () ITT N148 ()
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)
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Patient CharacteristicsRBC Transfusion Dependent
Anemia MDS-003
Transfusion Dependence At Baseline ITT N148
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
Median Min, Max 6 0-18
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Patient Populations MDS-003
Population Sponsor N () FDA N ()
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)
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FDA Evaluable for EfficacyMDS-003
Reasons for Exclusions Patients N148 ()
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)
lt 20 metaphases analyzed at baseline 29 (19.6)
Total FDA Evaluable 96 (64.9)
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IWG Response Criteria for MDSCheson et al,
Blood, 2000

• Hematologic Improvement-Erythroid Response
• Major response
• for RBC transfusion-dependent patients,
  transfusion independence
• For patients with pretreatment hemoglobin lt 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 lt 11
  g/dL, 1-2 g/dL increase in hemoglobin

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IWG Response Criteria for MDSCheson et al,
Blood, 2000

• Hematologic Improvement
• Improvements must last at least 2 months in the
  absence of ongoing cytotoxic therapy

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Definition of Response (Protocol) RBC
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

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RBC Transfusion Independence Response
Population Transfusion Independent N () 95 CI
ITT N148 99 (66.9) 0.59, 0.74
FDA Evaluable N96 64 (66.7) 0.56, 0.76
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Change in Hemoglobin from Baseline MDS-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

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50 Decrease in Transfusion Requirements
Population 50 decrease N () 95 CI
ITT N148 112 (75.7) 0.68, 0.82
FDA Evaluable N96 73 (76.0) 0.66, 0.84
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Duration of Transfusion Independence in
Responders (weeks) (N99)MDS-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)

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Relapsed Patients

• Relapses from transfusion independent to
  transfusion dependent 32/99 patients
• Relapses occurred within treatment period 13/32
  patients

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IWG Response Criteria for MDSCheson et al,
Blood, 2000

• Major Cytogenetic Response
• Major No detectable cytogenetic abnormality if
  preexisting abnormality was present
• (Requires 20 analyzable metaphases using
  conventional
  cytogenetic techniques)

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Major Cytogenetic Response MDS-003
Population Major Response N () 95 CI
ITT N120 52 (43.3) 17.6, 33.7
FDA Evaluable N58 26 (44.8) 31.7, 58.5
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Major Platelet Response MDS-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

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Major Neutrophil Response MDS-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

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MDS-001 Efficacy
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MDS-001 Study Design

• 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)
• Enrolled 45 patients
• Doses
• 25 mg daily (N13)
• 10 mg q21 d/28 d (syncopated) (N18)
• 10 mg daily (continuous) (N12)

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Study Endpoints

• Primary
• Major or minor erythroid response
• Secondary
• cytogenetic response
• neutrophil response
• platelet count response

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Eligibility CriteriaMDS-001

• 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 lt 10 g/dL (untransfused)

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Population (N10) MDS-001

• Transfusion dependent anemia ( 2 U/8 weeks) low-
  or intermediate-1 risk MDS with del 5 q

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Major Erythroid Response MDS-001

• Major erythroid response
• 7/10 (70) (95 CI 35, 93)
• Minor erythroid response
• none

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Efficacy Analyses (contd) MDS-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
• Major neutrophil response 1/2

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MDS-002 Efficacy
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MDS-002 Study Design

• MDS-002 identical to MDS-003 except
• Study Population
• Patients without del 5q cytogenetic abnormality
• Enrolled 215 patients
• 2 doses
• Dose 10 mg syncopated (115)
• Dose 10 mg continuous (100)

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Efficacy AnalysesMDS-002
ITT Population Results
RBC Transfusion Independence (N215) 46 (21.4 )
Change in Hgb in responders (N46) 3 g/dL (Range 1.3-8.3)
Duration in responders (N46) 18.9 weeks (Range 8-36)
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Integrated Safety Summary
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Patient 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

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Dose Modifications due to Adverse Events
Dose reduced or interrupted MDS-003 10 mg N 148 MDS-001 25 mg N 13 MDS-001 10 mg N 32 MDS-002 10 mg N 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)
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Grade 3 and 4 Adverse Events (AEs)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

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Confounding Issue

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

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Serious 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)

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Deaths

• 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)

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Safety 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

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Safety Summary (contd)

• 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.

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Ongoing Phase 3 Study
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Planned 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

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Risk Management
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Risk Management

• Major safety concern
• Teratogenicity
• Major goal
• Prevention of fetal exposure to lenalidomide

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Risk Management Plan

• Examples of other drugs with teratogenic
  potential and risk management plans
• Thalidomide/ S.T.E.P.S Program
• Isotretinoin/ iPLEDGE

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SummaryComparison
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
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Summary

• 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)

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Summary

• 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