# Presentation: 671872

## 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-approval****commitment 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 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**

## 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**

## 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 |

## 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 ****	****	****      ****                             **** **

## 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 2****nd**** 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 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)**

## 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)          |  |  |

## 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**