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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE1
Temozolomide
Oncology Drug Advisory Committee
March 13, 2003
Craig L. Tendler, M.D.
Vice President, Oncology Clinical Research
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE2
Agenda
• Basis for the accelerated approval of Temozolomide in refractory Anaplastic Astrocytoma (94-123)
• Post-approval commitment study (98-13)– Design
– Key study milestones
– Current status
• Ongoing challenges associated with post-approvalcommitment study
• Initiatives to expedite completion of post approval commitment
• Schering-Plough development programs with temozolomide in primary brain tumors
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE3
Temozolomide NDA Submission for Recurrent Glioma (at first relapse)
•Recurrent Glioblastoma Multiforme– Phase 2 randomized study temozolomide vs procarbazine
(94-091)– Phase 2 single arm study
(94-122)
•Recurrent Anaplastic Astrocytoma– Phase 2 single arm study Anaplastic Astrocytoma
(94-123)
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE4
Temozolomide
Indication (August 1999)
Adult patients with refractory anaplastic astrocytoma, i.e. patients at first relapse who have experienced disease progression on a regimen containing a nitrosourea and procarbazine
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE5
Basis for Temozolomide Accelerated Approval for Refractory Anaplastic Astrocytoma
•Study Design (94-123)–single arm study (n=162)–adult anaplastic astrocytoma patients at first
relapse •≤ 1 prior chemotherapy regimen
•Study conduct –32 institutions–February 1995 – April 1998
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE6
Basis for Temozolomide Accelerated Approval for Refractory Anaplastic Astrocytoma
•Primary endpoint – PFS at 6 months assessed by Gd MRI (confirmed by
central review)
•Secondary endpoints– response rate– overall survival
•Objective– to show 6 month PFS rate lower boundary of 95% CI of
at least 10%
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE7
Basis for Temozolomide Accelerated Approval for Refractory Anaplastic Astrocytoma
•Overall results: ITT Population (94-123)
–PFS 6 Months: 51% (95% CI: 43-59%)
–Median Survival: 13.6 months
–Response Rate: 33% (CR + PR: 5%+28%)
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE8
Basis for Temozolomide Accelerated Approval
for Refractory Anaplastic Astrocytoma•Results: Patients Refractory to Procarbazine Plus a Nitrosourea (n = 54)
– Objective Response Rate: 22% (CR = 9%)
– Median Duration of Response: 50 weeks (16-114 weeks)
– Duration of Response inComplete Responders: 52-114 weeks
– Median Survival: 15.9 months
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE9
Temozolomide Safetyin Malignant Glioma
• Safety database: 1,017 temozolomide treated patients (400 GBM & AA)
• Temozolomide was administered with few dose reductions or dose delays
• Most adverse events were mild to moderate in severity
• Study treatment discontinuation due to adverse events was infrequent
• Grade 3/4 myelosuppression was also infrequent and non-cumulative
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE10
Unanimous ODAC Opinion
•Patients with relapsed anaplastic astrocytoma after procarbazine and a nitrosourea are considered unresponsive to other therapies– Unmet medical need
•Objective response in this setting could be an adequate surrogate for clinical benefit if well defined and of sufficient magnitude
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE11
Unanimous ODAC Opinion
•Efficacy:– Temozolomide is effective for the treatment of
anaplastic astrocytoma in patients previously treated with a nitrosourea and procarbazine
•Safety:– Safety of Temozolomide is acceptable for this indication
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE12
Temozolomide Anaplastic Astrocytoma Post Approval Commitment
• Planning for first-line study with RTOG already underway at time of the ODAC accelerated approval recommendation
• Design (98-13)– Population: First-line anaplastic astrocytoma
– Primary endpoint: Overall Survival RT + TMZ
Randomization RT + BCNU
RT + TMZ/BCNU
• Rationale for TMZ/BCNU Combination– AGAT depletion
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE13
FDA Agreed Commitments
Commitment Date
Status
• Randomized phase III (98-13) to be preceded by additional safety assessment of TMZ/BCNU in the study population
June ’01 Submitted July ‘01
• Submission of pediatric study reports -I93-125 -H97-017
Dec. ‘02 SubmittedSept. ‘02
• Submission of final study report(Anaplastic Astrocytoma first-line study 98-13)
June ‘07 Project ongoing
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE14
Temozolomide Anaplastic Astrocytoma Post Approval Commitment: Key Milestones
• 6/99 Protocol first submitted to FDA
• 8/99 Accelerated approval granted
• 10/99 Revised protocol incorporating FDA comments submitted to FDA
• 12/99 FDA indicated that the protocol should not proceed until additional safety data on the TMZ + BCNU in the study population was submitted
• 2/00 Agreement on design of phase I safety assessment
• 4/00 IND filed by RTOG
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE15
Key Milestones - Continued
• 6/00 Initiation of Phase I safety assessment with TMZ/BCNU
• 3/01 Completion of enrollment for safety assessment
• 7/01 Submission of safety data to FDA
• 9/01 Enrollment initiated for second safety cohort
• 1/02 Completion of enrollment for 2nd safety cohort
• 6/02 Combination arm discontinued due to safety profile
• 1/03 Randomized Phase 3 opened
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE16
RTOG 98-13: Status March ‘03
RT + TMZ
• Study design RT + BCNU
• Phase 3 opened to enrollment Jan. ‘03
• Projected enrollment 24 patients/month for total of 454 patients
• Inter-group study infrastructure provides broadest access to U.S. and Canadian investigators– RTOG, ECOG, SWOG, NCCTG (>300 sites)
(HR target 1.5; median OS 36 vs. 54 months)
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE17
Temozolomide Post-Approval Commitment:Estimates of Interim Analyses and Study Completion
• Protocol-specified objective: survival HR = 1.5
ProtocolSpecifiedAnalyses
Projected Time from Study Initiation
(Jan. ’03)
SurvivalHR Required to
Cross Boundary*
Interim 1: 63 events ’04 1.95
Interim 2: 126 events ’05 1.47
Interim 3: 188 events ’06 1.32
Final: 251 events ’07 1.25
*Boundaries at interims are one sided p values 0.0041, 0.0158, 0.0285, final analysis 0.0405 Overall significance levels .05 (one sided)
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE18
Challenges of Survival Trial in First-Line Anaplastic Astrocytoma
•Low and declining annual incidence
(~3,000 newly diagnosed U.S.patients/year)
•Long median survival (3-4 years)
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE19
Schering-Plough and RTOG Initiatives to Expedite Study Completion
• Communications:– Investigators: investigator meetings, target neuro-surgeons,
monthly teleconference with the lead investigators at each cooperative group, cooperative group newsletters
– Patients: internet listing, patient brochures, patient brain tumor support groups (National Brain Tumor Foundation and American Brain Tumor Foundation)
• Project Management:– RTOG HQ staff– Monthly progress reviews (SPRI / Inter-group PIs)– Institutional data management support
• International Sites
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE20
Temozolomide Additional Initiatives in Malignant Gliomas
•SPRI-supported EORTC/NCIC phase 3 study of Temozolomide plus radiation versus radiation in newly diagnosed Glioblastoma Multiforme
•Enrollment completed March ‘02 (573 patients)
•Primary endpoint is overall survival
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ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE21
Temozolomide Development Programs in Primary Brain Cancer
• Phase 3 Newly diagnosed Anaplastic Astrocytoma (98-13)
• Phase 3 Newly diagnosed Glioblastoma Multiforme
• Phase 2 Anaplastic Oligodendroglioma-RTOG
• Phase 3 Low Grade Glioma-EORTC
• Phase 1/2 studies in recurrent pediatric CNS tumors