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Temozolomide

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

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  1. Temozolomide Oncology Drug Advisory Committee March 13, 2003 Craig L. Tendler, M.D. Vice President, Oncology Clinical Research

  2. 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

  3. 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)

  4. 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

  5. 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

  6. 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%

  7. 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%)

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. FDA Agreed Commitments

  14. 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

  15. 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

  16. 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)

  17. Temozolomide Post-Approval Commitment:Estimates of Interim Analyses and Study Completion

  18. 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)

  19. 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

  20. 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

  21. 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

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