Phase I/Randomized Phase II Trial of Either Dasatinib or Placebo Combined with Standard Chemo-Radiotherapy for Newly Diagnosed Glioblastoma Multiforme (GBM) Purpose of - Phase I Study: 1) To establish a maximum tolerable dose of dasatinib combined with radiation and temozolomide in this patient population. - Phase II 1) To determine the efficacy of dasatinib in combination with RT and concomitant and adjuvant TMZ in patients with newly diagnosed glioblastoma multiforme, and compare it with the standard of care approach in the treatment of these patients consisting of RT and TMZ, followed by adjuvant TMZ (Stupp regimen). - Translational (Phase II only) 1) To determine the relationship between tumor biomarkers and clinical outcome of patients treated with the dasatinib/rt/tmz combination. 2) s part of ongoing research for NCCTG studies, we are banking paraffin-embedded tissue blocks/slides and blood products for furture studies. 3) Evaluate potential mechanisms of therapy resistance in recurrent tumor samples obtained at the time of surgery for recurrent disease. - QOL (Phase II only) 1) ssess the impact of the addition of dasatinib to RT/TMZ on quality of life (QOL) using both FCT-Br (50 items) and EORTC QLQ-C15-PL plus BN20 (35 items). 2) To compare the results of the two most commonly used QOL tools, FCT- Br (50 items) and EORTC QLQ-C15-PL plus BN20 (35 items) and validate the use of EORTC QLQ-C15-PL plus BN20 (35 items) in newly diagnosed GBM patients. Study Chairs: Nadia Nicole Laack M.D. Francois J. Geoffroy M.D. Clinton H. Leinweber M.D. QC Specialist: Butch K. Kvittem CCRP Statistician: Wenting Wu Ph.D. Nurse Resource: Wanda L. DeKrey R.N., OCN Status: 06/05/2009 ctivated Projected Number of Patients: 223 Excluded: None Final ccrual: N Stratification (For Phase II Only) ge: >70 vs. <=70 Factors: Schema: Reg Phase I Dasatinib + RT + Temozolomide N0877 - Page 1 of 5
Treating Schedule: NCCTG Status Report for Study N0877 - May 2010 Dasatinib + Temozolomide Dasatinib Phase II Group : Placebo + RT + Temozolomide Placebo + Temozolomide Placebo Group B: Dasatinib + RT + Temozolomide Dasatinib + Temozolomide Dasatinib gent Dose Route Days Freq Phase I - Dasatinib s assigned by Registration Office - RT 6000 cgy (200 cgy x 30 fx) - Temozolomide 75 mg/m2/d Daily (starting on 28-42 day Rest Period - djuvant Temozolomide lone until progression Phase II - Dasatinib or Placebo Continue same dose as end of previous 150 mg/m2/d (for 3)/ 200 mg/ m2/d (for s 4-8) Continue same as end of previous Dose Level determined in Phase I - RT 6000 cgy (200 cgy x 30 fx) daily as assigned (starting on same day as RT) 5 days/week 1-5 - Temozolomide 75 mg/m2 Daily (starting on 28-42 day Rest Period or Placebo Continue at same dose as end or previous daily (starting on 5 days/week N0877 - Page 2 of 5
gent Dose Route Days Freq 1-5 - djuvant Temozolomide or Placebo lone until progression 150 mg/m2/d (for 3)/ 200 mg/ m2/d (for s 4-8) Continue same as end of previous daily Study Design: This trial includes a phase I dose-escalation study (Study 1) and a double-blind randomized phase II trial (Study 2) for patients with newly diagnosed glioblastoma multiforme (GBM). Study 1 will be a phase I cohort of 3 dose-escalation trial of dasatinib in combination with radiation and concomitant TMZ. Study 2 will be a randomized phase II trial with two arms. Patients will be randomized at the time of registration at a ratio of 1:2 respectively to either: standard therapy arm (continuous daily placebo prior, during and after standard RT/TMZ followed by TMZ alone), or the experimental arm (continuous dialy dasatinib prior, during and after standard RT/TMZ followed by TMZ). ccrual: This study was activated on 06/05/2009. s of 03/23/2010, four patients have been enrolled to the phase I portion (three at dose level 0 and one at dose level 0-) of this study. Patient Characteristics: vailable baseline information is summarized in the Baseline Characteristics Table below. The 4 patients are 2 (50%) male and 2 (50%) female ranging in age from 49 to 58 (median age=54.5). No one is classified as a minority. vailable Information: s of 03/23/2010, all 4 patients are alive with 3 still on-study. No patients have been declared ineligible. No patients have been replaced. Three patients have response data available. dverse Events: With adverse event data available for 3 patients (see dverse Events Table below), four grade 4 events (1 leukopenia, 1 lymphopenia, 1 thrombocytopenia, 1 neutrophil count decreased) have been seen in 2 patients. No grade 5 events have been seen. One DLT has been seen (grade 4 neutrophil count decreased, leukopenia, and thrombocytopenia) at dose level 0. Study Status: s of 03/23/2010, this study is open to accrue an additional 2 patients at dose level 0-. ccrual Table: N0877 - Page 3 of 5
Randomizing Membership Total Entered Past 6 Months Past 12 Months Florida 2 0 2 Mayo 2 1 2 Total Membership ccrual 4 1 4 Baseline Characteristics Table: ge Group Characteristics B Missing 4 0 0 Corticosteroid Therapy at stud Yes 2 0 0 Dose level 0 3 0 0 0-1 0 0 Extent Resection Subtotal Resection 1 0 0 Gross Total Resection 1 0 0 Family History Brain No 2 0 0 Gender Female 2 0 0 Male 2 0 0 Group Phase I 4 0 0 Primary Neoplasm Frontal 1 0 0 Temporal 1 0 0 Race White 3 0 0 Not reported: patient refused or not ava 1 0 0 Side Lesion Right 1 0 0 Left 1 0 0 Site of Tumor Thalamus 1 0 0 C N0877 - Page 4 of 5
Characteristics B Other 1 0 0 C Grade 4/5 and Most Frequent dverse Event Table: Evaluable Patients: 3 Body System dverse Event R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Hematology LEUKOPENI 0 0 1 33 1 33 0 0 LYMPHOPENI 0 0 2 67 1 33 0 0 THROMBOCYTOPENI 2 67 0 0 1 33 0 0 NEMI 1 33 2 67 0 0 0 0 NEUTROPHIL COUNT 1 33 1 33 1 33 0 0 DECRESED Cardiovascular TRIL FIBRILLTION 1 33 0 0 0 0 0 0 Constitutional Symptoms FTIGUE 1 33 0 0 0 0 0 0 Dermatology/Skin RSH 2 67 0 0 0 0 0 0 Gastrointestinal NUSE 1 33 0 0 0 0 0 0 Hemorrhage INTRCRNIL HEMOR- 1 33 0 0 0 0 0 0 RHGE Hepatic SGOT (ST) 1 33 0 0 0 0 0 0 Maximum Grade dverse Event 0 0 1 33 2 67 0 0 N0877 - Page 5 of 5