CLOLAR™(clofarabine) Pediatric Subcommittee ODAC Meeting 20 October 2005

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


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


• 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


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


• 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


• 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


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


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


AgendaAgenda





• SummarySummary


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)


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


• 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


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


AgendaAgenda





• SummarySummary


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


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


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


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


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


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


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)


AgendaAgenda





• SummarySummary


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


AgendaAgenda





• SummarySummary


• 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


CLOLARCLOLAR™(clofarabine)™(clofarabine) Pediatric Subcommittee ODAC MeetingPediatric Subcommittee ODAC Meeting

20 October 200520 October 2005

Documents

CLOLAR™(clofarabine) Pediatric Subcommittee ODAC Meeting 20 October 2005