clolar™(clofarabine) pediatric subcommittee odac meeting 20 october 2005
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CLOLARCLOLAR™(clofarabine)™(clofarabine) Pediatric Subcommittee ODAC MeetingPediatric Subcommittee ODAC Meeting
20 October 200520 October 2005
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 22
• Rekha Abichandani, MDRekha Abichandani, MD Medical Director, Clinical Medical Director, Clinical
ResearchResearch
• Marie Bonneterre, MDMarie Bonneterre, MD Medical Director, Clinical Medical Director, Clinical
ResearchResearch
• Stephen Eckert, PhDStephen Eckert, PhD Senior Director, BiostatisticsSenior Director, Biostatistics
• Manny FernandezManny Fernandez Manager, Clinical ResearchManager, Clinical Research
• Mark Hayes, PhDMark Hayes, PhD Vice President, Regulatory Vice President, Regulatory AffairsAffairs
• Edda TschirhartEdda Tschirhart Associate, Regulatory AffairsAssociate, Regulatory Affairs
• Mike Vasconcelles, MDMike Vasconcelles, MD Vice President, Clinical Vice President, Clinical ResearchResearch
Genzyme participantsGenzyme participants
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 33
AgendaAgenda
• IntroductionIntroduction
• Pre-approval clinical development Pre-approval clinical development highlightshighlights
• Post-approval clinical development plansPost-approval clinical development plans
• Clinical development risks and Clinical development risks and challengeschallenges
• SummarySummary
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 44
• Treatments for newly diagnosed patients Treatments for newly diagnosed patients with ALL use aggressive multi-drug with ALL use aggressive multi-drug regimensregimens
• 21% ALL have relapsed/refractory disease21% ALL have relapsed/refractory disease
• Relapsed leukemia is the third most Relapsed leukemia is the third most common childhood cancercommon childhood cancer
Relapsed and refractory pediatric Relapsed and refractory pediatric leukemialeukemia
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 55
Annual incidence of pediatric ALL Annual incidence of pediatric ALL (SEER)(SEER)
2,4702,470Pediatric ALLPediatric ALL
2,3472,34795% CR95% CR
124 124 5% Refractory5% Refractory
37537516% Relapse16% Relapse
499 Pediatric ALL Patients499 Pediatric ALL Patients
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 66
• Heterogeneous populationHeterogeneous population• Multi-drug resistance is common in leukemia Multi-drug resistance is common in leukemia
cells, particularly at relapsecells, particularly at relapse• Dose intensification with combination therapies Dose intensification with combination therapies
has resulted in significant co-morbidities and has resulted in significant co-morbidities and organ dysfunctionorgan dysfunction
• Transplant is theTransplant is the best curative optionbest curative option but but requires requires disease controldisease control and time to identify and time to identify donordonor
Challenges in relapsed and refractoryChallenges in relapsed and refractoryPediatric leukemiaPediatric leukemia
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 77
• Clofarabine is the first drug specifically approved Clofarabine is the first drug specifically approved for pediatric leukemia in 20 yearsfor pediatric leukemia in 20 years
• Most commonly used agents approved many years Most commonly used agents approved many years agoago– methotrexate (1953) methotrexate (1953) – 6-mercaptopurine (1953)6-mercaptopurine (1953)– vincristine (1963)vincristine (1963)– Ara-C (1969)Ara-C (1969)– doxorubicin (1974) doxorubicin (1974)
• Development of new pediatric oncology agents has Development of new pediatric oncology agents has lagged behind adult oncology drug developmentlagged behind adult oncology drug development
Approved agents for relapsed or Approved agents for relapsed or Refractory pediatric leukemiaRefractory pediatric leukemia
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 88
deoxyadenosine cladribine fludarabine clofarabine
Nucleoside analogsNucleoside analogsdAdo and its analogsdAdo and its analogs
N
N N
NNH2
OHO
HO
N
N N
NNH2
OHO
HO
Cl
N
N N
NNH2
OHO
HO
F
HO
N
N N
NNH2
OHO
HO
Cl
F
Resistant to DeaminationResistant to Deamination
Resistant Resistant to to
PhosphorolysisPhosphorolysis
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 99
clofarabine
dCK
dNTP poolDNAincorporation
Inhibition of DNA synthesis/ repair
CELL DEATH
clofarabine P P P
clofarabine
Polymerase , ε
Cytochrome C Release
5’NT
Mitochondria ΔΨm
RNR
Transporter
Mechanism of actionMechanism of action
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1010
AgendaAgenda
• IntroductionIntroduction
• Pre-approval clinical development Pre-approval clinical development highlightshighlights
• Post-approval clinical development plansPost-approval clinical development plans
• Clinical development risks and Clinical development risks and challengeschallenges
• SummarySummary
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1111
1999199919991999
2000200020002000
2001200120012001
2002200220022002
2003200320032003
2004200420042004
Pre-approval development timelinePre-approval development timeline
Adult studiesAdult studies
Phase I Solid/Hem Malignancies (DM93-036) (N=51) Phase I Solid/Hem Malignancies (DM93-036) (N=51)
Phase I CLL (DM99-225) (N=11)Phase I CLL (DM99-225) (N=11)
Phase II AML, ALL, MDS, CML (ID00-038) (N=62)Phase II AML, ALL, MDS, CML (ID00-038) (N=62)
Phase II AML (CLO 221) (N=40)Phase II AML (CLO 221) (N=40)
Phase I/II COMBO: CLO+ Ara-C, AML, MDS Phase I/II COMBO: CLO+ Ara-C, AML, MDS (CLO 141) (N=32)(CLO 141) (N=32)
Pediatric studiesPediatric studies
Phase I Hem Malignancies (ID99-383)(N=25)Phase I Hem Malignancies (ID99-383)(N=25)
Phase II AML (CLO 222) (N=35)Phase II AML (CLO 222) (N=35)
Phase II ALL (CLO 212) (N=49)Phase II ALL (CLO 212) (N=49)
Phase II AML (BIVN-121) Phase II AML (BIVN-121) (N=65)(N=65)
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1212
Key regulatory milestones forKey regulatory milestones forPediatric acute leukemiaPediatric acute leukemia
20032003
20032003
20042004
20042004
20042004
20042004
FebFeb
JulJul
MarMar
AugAug
Dec 01Dec 01
Dec 28Dec 28
Orphan drug designationOrphan drug designation
Fast track designationFast track designation
Rolling NDA submission completedRolling NDA submission completed
Efficacy update submittedEfficacy update submitted
ODAC recommends accelerated approvalODAC recommends accelerated approval (in relapsed and refractory pediatric ALL) (in relapsed and refractory pediatric ALL)
FDA grants approvalFDA grants approval
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1313
• EfficacyEfficacy– Single Phase II study of 49 patients (CLO 212)Single Phase II study of 49 patients (CLO 212)– Pediatric ALL: Second or subsequent relapse Pediatric ALL: Second or subsequent relapse
and/or refractoryand/or refractory– Clofarabine single agentClofarabine single agent– Endpoint: overall response (CR + CRp=20%)Endpoint: overall response (CR + CRp=20%)
• SafetySafety– 113 pediatric leukemia patients (includes 113 pediatric leukemia patients (includes
AML patients)AML patients)
Basis for approvalBasis for approval
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1414
Approved indicationApproved indication
• On 28 Dec 2004, FDA granted marketing On 28 Dec 2004, FDA granted marketing approval for clofarabine approval for clofarabine for the treatment of for the treatment of pediatric patients 1 to 21 years old with pediatric patients 1 to 21 years old with relapsed or refractory ALL after at least two relapsed or refractory ALL after at least two prior regimensprior regimens
• Approval wasApproval was– under provisions of accelerated approval under provisions of accelerated approval
regulations, andregulations, and– based on the induction of complete responsesbased on the induction of complete responses
• Sponsor required to conduct a randomized, Sponsor required to conduct a randomized, Phase III post-marketing study demonstrating Phase III post-marketing study demonstrating clinical benefitclinical benefit
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1515
AgendaAgenda
• IntroductionIntroduction
• Pre-approval clinical development Pre-approval clinical development highlightshighlights
• Post-approval clinical development plansPost-approval clinical development plans
• Clinical development risks and Clinical development risks and challengeschallenges
• SummarySummary
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1616
Initial pediatric ALL post-approval Initial pediatric ALL post-approval Clinical development planClinical development plan
• Step 1Step 1– Phase I / II dose-escalation study of CLO plus Phase I / II dose-escalation study of CLO plus
Ara-C and L-asparaginase (L-asp) in Ara-C and L-asparaginase (L-asp) in refractory or relapsed ALLrefractory or relapsed ALL
• Step 2Step 2– Randomized Phase III study of Randomized Phase III study of
(Ara-C + L-asp) (Ara-C + L-asp) ± CLO in pediatric ALL in first ± CLO in pediatric ALL in first relapserelapse• Concepts from COG protocol AALL01P2 Concepts from COG protocol AALL01P2 • Innovative, yet complicated, multi-agent designInnovative, yet complicated, multi-agent design
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1717
Original proposed Phase III designOriginal proposed Phase III designFirst relapseFirst relapse
Block 1Block 1vincristinevincristineprednisoneprednisonePEG-asparaginasePEG-asparaginasedoxorubicindoxorubicinIT cytarabineIT cytarabineIT methotrexateIT methotrexate
MRDMRD
Block 3-Block 3-AAAra-CAra-CL-aspL-asp
Block 3-BBlock 3-BclofarabinclofarabineeAra-CAra-CL-aspL-asp
Block 2Block 2etoposideetoposidecyclophosphamidecyclophosphamideIT methotrexate IT methotrexate
MRDMRD
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1818
FDA comments on FDA comments on Proposed development planProposed development plan
• Agreed to step 1 (Phase I / II combination)Agreed to step 1 (Phase I / II combination)• Stated that step 2 (Phase III) “does not appear Stated that step 2 (Phase III) “does not appear
to have a realistic chance of showing a clinical to have a realistic chance of showing a clinical benefit of clofarabine in children with ALL in benefit of clofarabine in children with ALL in first relapse”first relapse”
• COG AALL01P2 designed to identify optimal COG AALL01P2 designed to identify optimal combination therapies for patients with ALLcombination therapies for patients with ALL
• Genzyme’s understanding is that the complex Genzyme’s understanding is that the complex multi-agent design would make it difficult to multi-agent design would make it difficult to isolate the clinical benefit of clofarabineisolate the clinical benefit of clofarabine
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 1919
Additional issue with Additional issue with Proposed development planProposed development plan
• Combination CLO + Ara-C + L-asp did not Combination CLO + Ara-C + L-asp did not have wide investigator supporthave wide investigator support– Potential toxicity concernsPotential toxicity concerns
• Ara-C + L-asp already “maximally toxic”Ara-C + L-asp already “maximally toxic”• Thus, may not be able to effectively dose-escalate Thus, may not be able to effectively dose-escalate
clofarabineclofarabine
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 2020
Revised pediatric ALL post-approvalRevised pediatric ALL post-approvalClinical development planClinical development plan
• Step 1 Step 1 – Conduct at least two Phase I / II combination Conduct at least two Phase I / II combination
studiesstudies• CLO + cyclophosphamide + etoposideCLO + cyclophosphamide + etoposide
(protocol CLO 21800205)(protocol CLO 21800205)• CLO + Ara-CCLO + Ara-C
(protocol COG AAML0523)(protocol COG AAML0523)
• Step 2Step 2– Build from Phase II results to design Build from Phase II results to design
appropriate randomized Phase III study to appropriate randomized Phase III study to demonstrate clinical benefitdemonstrate clinical benefit
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 2121
Potential Phase III study designPotential Phase III study design
• Randomized Phase III Study of combination selected Randomized Phase III Study of combination selected based on the results of the Phase I/II studiesbased on the results of the Phase I/II studies
• Patient populationPatient population– 11stst relapse relapse– 22ndnd/Subsequent relapse /Subsequent relapse
• Potential endpointsPotential endpoints– Event free survivalEvent free survival– Remission rate/duration of remissionRemission rate/duration of remission– Overall survivalOverall survival
• FDA/Genzyme to discuss details of the Phase III study FDA/Genzyme to discuss details of the Phase III study design once data available from the Phase I/II studiesdesign once data available from the Phase I/II studies
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 2222
Pediatric leukemia development timelinePediatric leukemia development timelinePost-approvalPost-approval
20052005200520052006200620062006
2007200720072007
Phase I / II CLO+etoposide+cyclophosphamide (CLO 21800205) (N=39)Phase I / II CLO+etoposide+cyclophosphamide (CLO 21800205) (N=39)
Phase II CLO+Ara-C (COG AAML0523) (N=70)Phase II CLO+Ara-C (COG AAML0523) (N=70)
Phase III comparator Phase III comparator ±± CLO (N=TBD) CLO (N=TBD)
New pediatric studiesNew pediatric studies
New adult studiesNew adult studies Phase 3 Ara-C +/- CLO (CLO 34100405) (N=~360)Phase 3 Ara-C +/- CLO (CLO 34100405) (N=~360)
Phase 3 CLO vs low dose Ara-C (CLO-34200505) (N=~360)Phase 3 CLO vs low dose Ara-C (CLO-34200505) (N=~360)
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 2323
AgendaAgenda
• IntroductionIntroduction
• Pre-approval clinical development Pre-approval clinical development highlightshighlights
• Post-approval clinical development plansPost-approval clinical development plans
• Clinical development risks and Clinical development risks and challengeschallenges
• SummarySummary
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 2424
Risks and challenges withRisks and challenges withPediatric ALL development proposalPediatric ALL development proposal
• No standard chemotherapeutic options in second or No standard chemotherapeutic options in second or subsequent relapsed or refractory diseasesubsequent relapsed or refractory disease– Challenge: No standard comparator armChallenge: No standard comparator arm
• Defining an appropriate primary endpoint for a Phase III Defining an appropriate primary endpoint for a Phase III studystudy– Allogeneic SCT only potentially curative optionAllogeneic SCT only potentially curative option– Challenge: SCT may confound remission duration and Challenge: SCT may confound remission duration and
potentially other endpointspotentially other endpoints
• Small patient population (~500 per year)Small patient population (~500 per year)– Competing clinical trialsCompeting clinical trials– Challenge: Difficult to enroll Phase III trial in reasonable Challenge: Difficult to enroll Phase III trial in reasonable
timeframetimeframe
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 2525
AgendaAgenda
• IntroductionIntroduction
• Pre-approval clinical development Pre-approval clinical development highlightshighlights
• Post-approval clinical development plansPost-approval clinical development plans
• Clinical development risks and Clinical development risks and challengeschallenges
• SummarySummary
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 2626
• In the 10 months since receiving approval, In the 10 months since receiving approval, Genzyme has made progress toward meeting Genzyme has made progress toward meeting post-marketing commitmentspost-marketing commitments– Initial plan proposed and required revisionInitial plan proposed and required revision– One Phase I / II trial initiated: CLO 21800205One Phase I / II trial initiated: CLO 21800205– Second Phase II protocol (collaboration with COG) Second Phase II protocol (collaboration with COG)
finalized: AAML0523finalized: AAML0523• Many challenges to designing an appropriate Many challenges to designing an appropriate
confirmatory trial, particularly in relapsed or confirmatory trial, particularly in relapsed or refractory ALLrefractory ALL
• Genzyme looks forward to collaborating with Genzyme looks forward to collaborating with FDA and COG to face these challengesFDA and COG to face these challenges
SummarySummary
20 Oct 200520 Oct 2005 ODAC Pediatric Subcommittee: ClofarabineODAC Pediatric Subcommittee: Clofarabine 2727
CLOLARCLOLAR™(clofarabine)™(clofarabine) Pediatric Subcommittee ODAC MeetingPediatric Subcommittee ODAC Meeting
20 October 200520 October 2005