lenalidomide (revlimid ® ) celgene corporation new drug application (021880) oncology drug advisory...
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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
Lenalidomide Embryo-Fetal Lenalidomide Embryo-Fetal Development StudiesDevelopment Studies
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
Lenalidomide Embryo-Fetal Lenalidomide Embryo-Fetal Development StudiesDevelopment Studies
Rat StudyRat Study
Lenalidomide Embryo-Fetal Lenalidomide Embryo-Fetal Development StudiesDevelopment Studies
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
Lenalidomide Embryo-Fetal Lenalidomide Embryo-Fetal Development StudiesDevelopment Studies
Rabbit StudyRabbit Study
Lenalidomide Embryo-Fetal Lenalidomide Embryo-Fetal Development StudiesDevelopment Studies
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
Lenalidomide Embryo-Fetal Lenalidomide Embryo-Fetal Development StudiesDevelopment Studies
Rabbit StudyRabbit Study
Lenalidomide Embryo-Fetal Lenalidomide Embryo-Fetal Development StudiesDevelopment Studies
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
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)
• Enrolled 148 patients
• Doses: Oral lenalidomide
• 10 mg x21 d/q28 d (syncopated) (N=45)
• 10 mg daily (continuous) (N=103)
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
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
IWG Response Criteria for MDSIWG Response Criteria for MDSCheson et al,Cheson et al, Blood, 2000Blood, 2000
IWG Response Criteria for MDSIWG Response Criteria for MDSCheson et al,Cheson et al, Blood, 2000Blood, 2000
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
IWG Response Criteria for MDSIWG Response Criteria for MDSCheson et al,Cheson et al, Blood, 2000Blood, 2000
IWG Response Criteria for MDSIWG Response Criteria for MDSCheson et al,Cheson et al, Blood, 2000Blood, 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
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
• Major neutrophil response: 1/6
MDS-001 EfficacyMDS-001 EfficacyMDS-001 EfficacyMDS-001 Efficacy
MDS-001 Study DesignMDS-001 Study DesignMDS-001 Study DesignMDS-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)
• 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 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
Eligibility CriteriaEligibility CriteriaMDS-001MDS-001
Eligibility CriteriaEligibility CriteriaMDS-001MDS-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)
• 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
• Major neutrophil response: 1/2
• 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 EfficacyMDS-002 EfficacyMDS-002 EfficacyMDS-002 Efficacy
MDS-002 Study DesignMDS-002 Study DesignMDS-002 Study DesignMDS-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)
• 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 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