ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
1
Temozolomide
Oncology Drug Advisory Committee
March 13, 2003
Craig L. Tendler, M...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
2
Agenda
• Basis for the accelerated approval of Temozolomide
in refractory Anapla...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
3
Temozolomide NDA Submission for
Recurrent Glioma (at first relapse)
•Recurrent G...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
4
Temozolomide
Indication (August 1999)
Adult patients with refractory anaplastic
...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
5
Basis for Temozolomide Accelerated Approval
for Refractory Anaplastic Astrocytom...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
6
Basis for Temozolomide Accelerated Approval
for Refractory Anaplastic Astrocytom...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
7
Basis for Temozolomide Accelerated Approval
for Refractory Anaplastic Astrocytom...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
8
Basis for Temozolomide Accelerated Approval
for Refractory Anaplastic Astrocytom...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
9
Temozolomide Safety
in Malignant Glioma
• Safety database: 1,017 temozolomide tr...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
10
Unanimous ODAC Opinion
•Patients with relapsed anaplastic astrocytoma
after pro...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
11
Unanimous ODAC Opinion
•Efficacy:
– Temozolomide is effective for the treatment...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
12
Temozolomide Anaplastic Astrocytoma
Post Approval Commitment
• Planning for fir...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
13
FDA Agreed Commitments
Commitment
Date
Status
• Randomized phase III (98-13)
to...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
14
Temozolomide Anaplastic Astrocytoma
Post Approval Commitment: Key Milestones
• ...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
15
Key Milestones - Continued
• 6/00 Initiation of Phase I safety assessment
with ...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
16
RTOG 98-13: Status March ‘03
RT + TMZ
• Study design
RT + BCNU
• Phase 3 opened...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
17
Temozolomide Post-Approval Commitment:
Estimates of Interim Analyses and Study ...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
18
Challenges of Survival Trial in First-
Line Anaplastic Astrocytoma
•Low and dec...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
19
Schering-Plough and RTOG Initiatives
to Expedite Study Completion
• Communicati...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
20
Temozolomide
Additional Initiatives in Malignant Gliomas
•SPRI-supported EORTC/...
ODAC
SCHERING-PLOUGH RESEARCH INSTITUTE
21
Temozolomide Development
Programs in Primary Brain Cancer
• Phase 3 Newly diagn...
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PPT - US Food and Drug Administration Home Page

  1. 1. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 1 Temozolomide Oncology Drug Advisory Committee March 13, 2003 Craig L. Tendler, M.D. Vice President, Oncology Clinical Research
  2. 2. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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-approval commitment study • Initiatives to expedite completion of post approval commitment • Schering-Plough development programs with temozolomide in primary brain tumors
  3. 3. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 4. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 5. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 6. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 7. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 8. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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 in Complete Responders: 52-114 weeks – Median Survival: 15.9 months
  9. 9. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 9 Temozolomide Safety in 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. 10. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 11. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 12. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 13. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 13 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 Submitted Sept. ‘02 • Submission of final study report (Anaplastic Astrocytoma first-line study 98-13) June ‘07 Project ongoing
  14. 14. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 14 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
  15. 15. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 16. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 16 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)
  17. 17. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 17 Temozolomide Post-Approval Commitment: Estimates of Interim Analyses and Study Completion • Protocol-specified objective: survival HR = 1.5 Protocol Specified Analyses Projected Time from Study Initiation (Jan. ’03) Survival HR 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)
  18. 18. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 19. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 20. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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. 21. ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 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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