June 2003 9813-1 RTOG Protocol No: 9813 Protocol Status: ECOG Protocol No: R9813 Opened: June 16, 2000 NCCTG Protocol No: R9813 SWOG Protocol No: R9813 Title: A Phase / Randomized Study of Radiation Therapy and Temozolomide versus Radiation Therapy and BCNU for Anaplastic Astrocytoma (ND #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 F Y Age 1. <50 2. >50 KPS 1. 60-80 2. 90-100 Surgery 1. Biopsy only 2. Resection R A N D O M 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 ) 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)
June 2003 9813-2 Study Chairs: Statisticians: Research Associate: Dosimetrist: Protocol Associate: Susan M. Chang, M.D. Gregory J. Cairncross, M.D. Mark. R. Gilbert, M.D. Jean-Paul Bahary, M.D. Carol A. Dolinskas, M.D. Ken Aldape, M.D. Peter Bushunow, M.D. (ECOG) Paul Brown, M.D. (NCCTG) Jan Buckner, M.D. (NCCTG) Geoffrey R. Barger, M.D. (SWOG) Charles Scott, Ph.D. Rebecca Paulus, B.S. Barbara Kaiser, R.N., C.C.R.P. Elizabeth Martin, B.S., R.T.T. Linda Walters-Page, M.A.. 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, 2001. Fourteen patients were enrolled on Pilot #2, which closed January 25, 2002. The phase component was activated January 2003. The institutional accrual for the phase component is listed in Table 2.3. Pretreatment characteristics appear in Table 3.1. There were two grade 3 neurologic toxicities on Pilot #1 and none on Pilot #2. There were 5 grade 3-4 infections on Pilot #1 and one on Pilot #2 (Table 4.1). t has been determined that the combination of RT + Temozolomide + BCNU is not feasible, thus that arm has been discontinued.. Administrative nformation: Table 2.1 Patient Accrual Total Patients Entered on the Pilot Arms 29 Estimated number of patients needed to be randomized 454 Total randomized as of 5/1/03 17
June 2003 9813-3 Table 2.2 Patient Accrual by Participating nstitution RTOG (N=42) Thomas Jefferson University Hospital 6 Baptist Hospital of Miami 2 Dixie Medical Cancer Center 2 Foundation for Cancer Res. and Edu. 3 ngalls Memorial Hospital 2 Kansas City CCOP 2 Natalie Warren Bryant CC at St. Francis Hosp. 2 Notre Dame Hospital/University of Montreal 2 SE Cancer Control Consortium, nc. CCOP 2 University of Utah Health Science Center 2 University of Wisconsin Hospital 2 Cancer Research for the Ozarks 1 Central llinois CCOP 1 Cleveland Clinic Foundation 1 Dartmouth Hitchcock Medical Center 1 Dayton CCOP 1 Joe Arrington Cancer Res. & Treatment Ctr. 1 LDS Hospital 1 Lutheran General Hospital 1 Metro-MN CCOP 1 The Wendt Regional CC of the Finley Hosp. 1 Univ. of California Davis Medical Center 1 University of Rochester 1 University of Texas Medical Branch 1 Vanderbilt University Medical Center 1 Wake Forest Univ. Baptist Medical Center 1 SWOG (N=2) Oregon Health Sciences Center 1 University of Arkansas Medical Center 1 ECOG (N=1) Rochester General Hospital 1 NCCTG (N=1) Cedar Rapids 1 Table 2.3 Randomized Accrual by Participating nstitution RTOG (N=14) Baptist Hospital of Miami 2 Notre Dame Hospital/University of Montreal 2 Dartmouth Hitchcock Medical Center 1 Dixie Medical Cancer Center 1 Foundation for Cancer Res. and Edu. 1 Kansas City CCOP 1 LDS Hospital 1 Natalie Warren Bryant CC at St. Francis Hosp. 1 The Wendt Regional CC of the Finley Hosp. 1 Thomas Jefferson University Hospital 1 University of Rochester 1 University of Utah Health Science Center 1 SWOG (N=2) Oregon Health Sciences Center 1 University of Arkansas Medical Center 1 NCCTG (N=1) Cedar Rapids 1
June 2003 9813-4 Table 2.4 Status of Cases Pilot #1 Pilot #2 RT + Temozolomide RT + BCNU Total Patients Entered 15 14 10 7 Cancelled 0 1* 0 0 No On-study Form 0 0 9 5 Eligible and Analyzable 15 13 1 2 *CN Arm Reason 27 Pilot #2 Cancelled: Patient progressed prior to receiving treatment, refused any treatment. Pretreatment Characteristics: Table 3.1 Pretreatment Characteristics Pilot #1 (N=15) Pilot #2 (N=13) RT + Temozolomide (N=1) RT + BCNU (N=2) Age <50 8 (53%) 10 (77%) 0 1 (50%) 50 7 (47%) 3 (23%) 1(100%) 1 (50%) Gender Male 10 (67%) 7 (54%) 1(100%) 1 (50%) Female 5 (33%) 6 (46%) 0 1 (50%) Race White 13 (87%) 11 (85%) 1(100%) 2(100%) Hispanic 2 (13%) 1 ( 8%) 0 0 African American 0 1 ( 8%) 0 0 KPS 60 2 (13%) 0 0 0 70-80 8 (53%) 3 (23%) 1(100%) 1 (50%) 90-100 5 (33%) 10 (77%) 0 1 (50%) Surgery Biopsy 7 (47%) 5 (38%) 0 1 (50%) Partial Resection 5 (33%) 3 (23%) 1(100%) 1 (50%) Total Resection 3 (20%) 5 (38%) 0 0 Neurologic Function No Symptoms 4 (27%) 4 (31%) 0 0 Minor Symptoms 5 (33%) 7 (54%) 1(100%) 2(100%) Moderate Symptoms 6 (40%) 2 (15%) 0 0
June 2003 9813-5 V. Toxicities: Table 4.1 Toxicities Pilot #1 N=15 Grade Pilot #2 N=13 Grade 1 2 3 4 1 2 3 4 Auditory/Hearing 0 1 0 0 1 0 0 0 Blood/Bone Marrow 3 4 1 5 5 3 1 4 Thrombocytopenia 2 3 4 2 2 2 8 0 Cardiovascular (General) 0 0 0 1* 2 0 0 0 Constitutional Symptoms 5 4 0 0 6 3 0 0 Dermatology/Skin 4 4 1* 0 2 7 0 0 Gastrointestinal 6 4 0 0 7 1 0 0 Hepatic 4 1 0 0 3 1 0 0 nfection/febrile Neutropenia 0 0 3 2 0 0 1 0 Lymphatics 0 0 0 0 1 0 0 0 Metabolic/Laboratory 4 1 1 0 2 2 0 0 Musculoskeletal 0 1 0 0 2 0 0 0 Neurology 2 2 2* 0 2 4 0 0 Ocular/Visual 1 1 0 0 1 2 0 0 Pain 2 1 0 0 5 2 0 0 Pulmonary 1 3 1* 0 1 7 0 0 Renal/Genitourinary 4 0 0 0 1 1 0 0 Maximum Toxicity per Patient 0 5 3 6 1 4 4 4 Maximum Non-Hematologic Toxicity per Patient 1 6 4 3 1 10 1 0 *CN Arm Toxicity Grade Most Recent Cycle of Chemotherapy Days from Start of RT 3 Pilot #1 Pulmonary: Dyspnea 3 1 28 7 Pilot #1 Dermatology: Rash/desquamation 3 2 45 13 Pilot #1 Neurology: Confusion 3 6 259 14 Pilot #1 Cardiovascular (General): Thrombosis/embolism 4 2 Unknown 15 Pilot #1 Neurology: Vertigo 3 6 199