1. No category

Lenalidomide (REVLIMID®)
Celgene Corporation
New Drug Application (021880)
Oncology Drug Advisory Committee
Sept 14, 2005
Lenalidomide Review Team
Division of Drug Oncology Products
Center for Drug Evaluation and Research
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
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
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
Outline
• Drug Approvals for MDS
• Reproductive Safety Assessment
• Clinical Review Efficacy
• Integrated Safety Summary
• Risk Management
• Summary
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 (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 Comparison
Lenalidomide
O
O
NH
N
O
NH2
O
O
Thalidomide
NH
N
O
O
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
Reproductive
Safety Assessment
Embryo-Fetal Development
Study Requirements
• Study in first species
If results are negative No evidence of druginduced embryo-fetal
development adverse
events
• Conduct confirmatory study in
second species
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
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
Lenalidomide Embryo-Fetal
Development Studies
Rabbit 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
Lenalidomide Embryo-Fetal
Development Studies
Rabbit 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
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
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
Clinical Review
Efficacy Studies
Study
Study Design Evaluable Doses
patients/N
Primary
Endpoint
MDS-003
Single-arm
Open-label
Multicenter
Phase 2
96/148
10 mg daily
RBC
10 mg x21d/q28d transfusion
independence
MDS-001
Pilot, phase 1/2,
single-arm, 2stage, dosefinding
10/45
25 mg daily
Major and
minor
10 mg daily
10 mg x21d/q28d erythroid
response
MDS-002
Single-arm
Open-label
Multicenter
Phase 2
118/215
10 mg daily
RBC
10 mg x21d/q28d transfusion
independence
MDS-003 Efficacy
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)
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
Eligibility Criteria
MDS-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
MDS-003
• Enrolled 148 patients
• Doses: Oral lenalidomide
• 10 mg x21 d/q28 d (syncopated) (N=45)
• 10 mg daily (continuous) (N=103)
Disease Characteristics
Cytogenetics
MDS-003
Cytogenetics
ITT
N=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 Characteristics
IPSS Risk Score
MDS-003
Risk Category 10 mg sync 10 mg cont
N=45 (%)
N=103 (%)
ITT
N=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 Characteristics
RBC Transfusion Dependent Anemia
MDS-003
Transfusion Dependence
At Baseline
ITT
%
N=148
≥ 2 RBC units within 8 weeks of
start of study drug
≥ 3 RBC units
141
95
106
71.6
0-2 units within 8 weeks
42
28.4
Median
Min, Max
6
0-18
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)
FDA Evaluable for Efficacy
MDS-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 MDS
Cheson et al, Blood, 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
IWG Response Criteria for MDS
Cheson et al, Blood, 2000
Hematologic Improvement
 Improvements must last at least 2 months in
the absence of ongoing cytotoxic therapy
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
RBC Transfusion Independence
Response
Population
Transfusion
Independent
95% CI
N (%)
ITT
99 (66.9)
0.59, 0.74
64 (66.7)
0.56, 0.76
N=148
FDA Evaluable
N=96
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
≥50% Decrease in Transfusion
Requirements
Population
≥ 50% decrease
95% CI
N (%)
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
in Responders (weeks) (N=99)
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)
Relapsed Patients
• Relapses from transfusion independent to
transfusion dependent : 32/99 patients
• Relapses occurred within treatment period: 13/32
patients
IWG Response Criteria for MDS
Cheson 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)
Major Cytogenetic Response
MDS-003
Population
Major Response
95% CI
N (%)
ITT
N=120
52 (43.3)
17.6, 33.7
FDA Evaluable
N=58
26 (44.8)
31.7, 58.5
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
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
MDS-001 Efficacy
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 (N=13)
• 10 mg q21 d/28 d (syncopated) (N=18)
• 10 mg daily (continuous) (N=12)
Study Endpoints
• Primary
• Major or minor erythroid response
• Secondary
• cytogenetic response
• neutrophil response
• platelet count response
Eligibility Criteria
MDS-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 < 10 g/dL
(untransfused)
Population (N=10)
MDS-001
• Transfusion dependent anemia (≥ 2 U/8 weeks)
low- or intermediate-1 risk MDS with del 5 q
Major Erythroid Response
MDS-001
• Major erythroid response
 7/10 (70%) (95% CI [35, 93])
• Minor erythroid response
 none
Efficacy Analyses (cont’d)
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
MDS-002 Efficacy
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)
Efficacy Analyses
MDS-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 Summary
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
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%)
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
Confounding Issue
Neutropenia or thrombocytopenia due to
MDS or to lenalidomide, especially in a
trial without a control?
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%)
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)
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
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.
Ongoing Phase 3 Study
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
Risk Management
Risk Management
• Major safety concern
 Teratogenicity
• Major goal
 Prevention of fetal exposure to lenalidomide
Risk Management Plan
• Examples of other drugs with teratogenic
potential and risk management plans
 Thalidomide/ S.T.E.P.S® Program
 Isotretinoin/ iPLEDGE®
Summary
Comparison
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
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%)
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