January Schema: S T R A T I F Y. Age 1. <50 2. >50

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1 January RTOG Protocol No: 9813 Protocol Status: ECOG Protocol No: R9813 Phase I: Opened June 16, 2000 NCCTG Protocol No: R9813 Closed January 25, 2002 SWOG Protocol No: R9813 Phase III: Opened October 15, 2002 Title: A Phase I/III Randomized Study of Radiation Therapy and Temozolomide versus Radiation Therapy and BCNU for Anaplastic Astrocytoma (IND #60,265) Patient Population: - Histologically confirmed anaplastic astrocytoma or mixed oligodendroglial/astrocytic tumors if the oligodroglial component is 25%. - No prior irradiation to the head, neck, or chemotherapy for any reason - Karnofsky performance status > 60 - Hgb > 10, absolute neutrophils > 1500, platelets > 150,000; liver function tests (AST/SGOT, alkaline phosphatase, total bilirubin < 2 x upper limit of normal); serum creatinine < 1.5 x normal. - Therapy must begin within 5 weeks after tissue diagnosis - No spinal cord tumors or spinal cord metastases - No prior invasive malignancy unless disease free > 5 years - No active infectious process - DLCO > 70% - Signed study-specific consent form prior to randomization Objective: 1. To compare overall survival. 2. To compare time to tumor progression. 3. To compare the relative toxicities of the two drug regimens. 4. To correlate molecular analyses with #1 and #2. Schema: S T R A T I F Y Age 1. <50 2. >50 KPS Surgery 1. Biopsy only 2. Resection R A N D O M I Z E Arm 1: Radiation Therapy: 59.4 Gy (1.8 Gy x 33 fractions, 5 days a week x 6 weeks) plus Temozolomide 200 mg/m 2 daily on days 1-5 of the first week of radiotherapy. Repeat Temozolomide every 28 days for a total of 12 cycles. Arm 2: Radiation Therapy: 59.4 Gy (1.8 Gy x 33 fractions, 5 days a week x 6 weeks) plus BCNU (80 mg/m 2 ) on days 1, 2, and 3 of the first week of radiotherapy and on days 56, 57, and 58 then every eight weeks for four cycles for a total of six cycles (maximum BCNU dose 1440 mg/m 2 ) Arm 3: (Radiation Therapy, BCNU, Temozolomide). Dropped; see section 1.3 Pilot #1, Arm 4: Pilot #2, Arm 5: Radiation Therapy: 59.4 (1.8 Gy x 33 fractions, 5 days a week x 6 weeks) plus BCNU 200 mg/m 2 on day 1 of radiotherapy and Temozolomide 150 mg/m 2 on days 1-5 of the first week of radiotherapy. Repeat every six weeks for a total of six cycles (maximum BCNU dose 1200 mg/m 2 ). (closed 3/15/01) Radiation Therapy: 59.4 (1.8 Gy x 33 fractions, 5 days a week x 6 weeks) plus BCNU 150 mg/m 2 on day 5 of radiotherapy and Temozolomide 150 mg/m 2 on days 1-5 of the first week of radiotherapy. Repeat every eight weeks for a total of six cycles. BCNU will be given on day 5 of Temozolomide in these cycles (maximum BCNU dose 900 mg/m 2 ). (closed 1/25/02)

2 January Study Chairs: Susan M. Chang, M.D. (Neuro-Oncology) Patients randomized as of: Gregory J. Cairncross, M.D. (Medical Oncology) 11/14/03 54 Mark R. Gilbert, M.D. (Medical Oncology) Jean-Paul Bahary, M.D. (Radiation Oncology) Carol A. Dolinskas, M.D. (Neuroradiology) Ken Aldape, M.D. (Neuropathology and Molecular Genetics) Peter Bushunow, M.D. (ECOG) Kurt Jaeckle, M.D. (NCCTG) Paul Brown, M.D. (NCCTG) Geoffrey R. Barger, M.D. (SWOG) Statisticians: Research Associate: Dosimetrist: Protocol Associate: Wendy Seiferheld, M.S. Minhee Won, M.A. Barbara Kaiser, R.N., C.C.R.P. Elizabeth Martin, B.S., R.T.T. Ellen Aiken, B.A. I. Summary: This study had two pilot arms in order to assess the toxicity and feasibility of combining BCNU and Temozolomide. Fifteen patients were enrolled on Pilot #1, which closed March 15, Fourteen patients were enrolled on Pilot #2, which closed January 25, Pilot arm toxicity data was presented at SNO 2002 and a manuscript reporting this data has been submitted. It was determined that the combination of RT + Temozolomide + BCNU is not feasible, thus arm 3 was dropped. The phase III component was activated October 15, 2002, and the tables in this report will address only the patients on the randomized component. Twenty-eight patients have toxicity data (Table 4). There were two grade 3 infections in RT + BCNU arm and none on RT+Temozolomide arm. One grade 4 dermatology/skin toxicity was reported in RT + BCNU arm. Only one late RT toxicity was reported (grade 2 skin within the irradiated field). The initial interim analysis of the primary endpoint is planned after the number of deaths has reached 36. II. Administrative Information: Table 2.1 Patient Accrual Estimated number of patients needed to be randomized 454 Patients randomized as of November 14, Average monthly accrual* 3.9 Average monthly accrual in the past 3 months 5.0 *The calculation is based on the date the study re-opened for randomization (October 15, 2002).

3 January Table 2.2 Randomized Accrual by Participating Institution (Arms 1 & 2) ECOG (N=2) Lankenau Hospital 1 West Virginia Univ Med Center 1 NCCTG (N=4) Cedar Rapids 1 Rochester Methodist Hospital 1 RTOG (N=40) Foundation for Cancer Res. and Edu. 4 LDS Hospital 4 Notre Dame Hospital/Univ. of Montreal 4 Partners/Dana Farber Cancer Institute 4 Univ. of Texas-MD Anderson Can. Ctr. 3 Fox Chase Cancer Center 2 Univ. of California Davis Med. Ctr. 2 University of Miami 2 University of Rochester 2 Dartmouth Hitchcock Medical Center 1 H. Lee Moffitt Cancer Center 1 SWOG (N=8) Kaiser Permante Medical Center 2 University of Utah 2 Oregon Health Sciences Center 1 Saskatchewan 1 Siouxland Regional Cancer Center 1 Johns Hopkins Hospital 1 Kansas City CCOP 1 Mayo Clinic 1 Medical College of Wisconsin 1 Metro-MN CCOP 1 Natalie Warren Bryant Can.Ctr. at St.Francis Hosp. 1 Roswell Park Cancer Institute 1 SUNY Health Science Center/Brooklyn 1 Thomas Jefferson University Hospital 1 University of Kentucky Hospital 1 West Michigan Cancer Center CCOP 1 Scott and White Clinic and Hospital 1 Univ. of Arkansas Medical Center 1 Univ. of Washington Medical Center 1 Table 2.3 Status of Cases RT + Temozolomide RT + BCNU Total Patients Entered Ineligible* 0 1 Eligible/Pending** No On-Study Form Analyzable *Arm CN Status Reason RT+BCNU 43 Ineligible Randomized 41 days after tissue diagnosis **Arm CN Status Reason RT+BCNU 67 Pending KPS in query

4 January III. Pretreatment Characteristics: Table 3 Pretreatment Characteristics RT + Temozolomide (N=16) RT + BCNU (N=15) Age <50 10 (63%) 7 (47%) 50 6 (37%) 8 (53%) Gender Male 11 (69%) 7 (47%) Female 5 (31%) 8 (53%) Race White 15 (94%) 13 (86%) Hispanic 0 1 ( 7%) African American 1 ( 6%) 1 ( 7%) KPS (44%) 4 (27%) (56%) 10 (66%) Pending 0 1 ( 7%) Surgery Biopsy 5 (31%) 5 (33%) Partial Resection 6 (38%) 6 (40%) Total Resection 5 (31%) 4 (27%) Neurologic Function No Symptoms 3 (19%) 6 (40%) Minor Symptoms 8 (50%) 9 (60%) Moderate Symptoms 5 (31%) 0

5 January IV. Toxicities: Table 4 Toxicities RT + Temozolomide (N=13) Grade RT + BCNU (N=8) Grade Allergy/immunology Auditory/Hearing Blood/Bone Marrow Cardiovascular (General) Constitutional Symptoms (Fatigue) Constitutional Symptoms (Other) Dermatology/Skin * Gastrointestinal (Constipation) Gastrointestinal (N/V) Gastrointestinal (Other) 6 0 1* Hemorrhage Hepatic Infection/Febrile Neutropenia * 0 Metabolic/Laboratory Neurology Ocular/Visual Pain (Headache) Pain (Other) Pulmonary Renal/Genitourinary Maximum Toxicity per Patient Maximum Non-Hematologic Toxicity per Patient Most Recent Days from Arm CN Toxicity Grade Description/Comment Cycle of CT Start of RT RT + Temozolomide 35 Gastrointestinal (Other) 3 Dehydration 4 85 RT + BCNU 31 Dermatology/Skin 4 Alopecia 2 77 Infection/febrile neutropenia 3 Infection w/neutropenia Infection/febrile neutropenia 3 Infection w/neutropenia 1 26