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Temozolomide. Oncology Drug Advisory Committee March 13, 2003 Craig L. Tendler, M.D. Vice President, Oncology Clinical Research. Agenda. Basis for the accelerated approval of Temozolomide in refractory Anaplastic Astrocytoma (94-123) Post-approval commitment study (98-13) Design
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Temozolomide Oncology Drug Advisory Committee March 13, 2003 Craig L. Tendler, M.D. Vice President, Oncology Clinical Research
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
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)
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
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
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%
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%)
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
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
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
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
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
Temozolomide Anaplastic Astrocytoma Post Approval Commitment: Key Milestones • 6/99 Protocol first submitted to FDA • 8/99 Accelerated approval granted • 10/99Revised 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
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
RTOG 98-13: Status March ‘03 RT + TMZ • Study designRT + 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)
Temozolomide Post-Approval Commitment:Estimates of Interim Analyses and Study Completion
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)
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
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
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