ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 1 Temozolomide Oncology Drug Advisory Committee March 13,...

ODAC

SCHERING-PLOUGH RESEARCH INSTITUTE1

Temozolomide

Oncology Drug Advisory Committee

March 13, 2003

Craig L. Tendler, M.D.

Vice President, Oncology Clinical Research

ODAC


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

ODAC


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)

ODAC


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

ODAC


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

ODAC



•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%

ODAC



•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%)

ODAC


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

ODAC


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

ODAC


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

ODAC


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

ODAC


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

ODAC


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

ODAC


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

ODAC


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

ODAC


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)

ODAC


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



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)

ODAC


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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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

ODAC


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

ODAC


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

ODAC SCHERING-PLOUGH RESEARCH INSTITUTE 1 Temozolomide Oncology Drug Advisory Committee March 13,...

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