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2011 Background: Angiogenesis is a hallmark of GBM, making the tumor vasculature an attractive therapeutic target. In gliomas, vascular endothelial growth factor (VEGF) promotes both angiogenesis and invasion of tumor cells. Bevacizumab is a humanized monoclonal antibody against VEGF-A that rapidly reduces the concentration of VEGF in the circulation. Irinotecan may enhance efficacy by synergistic tumor endothelial cell death or improved tumor delivery of the chemotherapy via “normalized” tumor vasculature. Prior studies of this combination demonstrated high radiographic response and 6-month progression free (6-mPFS) rates. This study was designed to determine the efficacy and safety of this regimen in the cooperative group setting. Methods: Eligibility included age ≥ 18, centrally confirmed GBM or gliosarcoma, progressive or recurrent disease. Enzyme-inducing anticonvulsants were not allowed. Treatment was intravenous bevacizumab 10 mg/kg and irinotecan 200 mg/m2 every 2 weeks. Accrual goal was 57 eligible patients. Primary endpoint was 6-mPFS rate where an estimate of ≥ 35% would define efficacy (15% improvement over historical data). Results: Full enrollment (57) was achieved, median age was 57, median KPS was 80; all had prior radiation and temozolomide treatment. The 6m-PFS rate was 37% (95% CI: 24–50%), with 21 of 57 patients progression-free at 6 months. Moderate toxicity was noted with 21(37%) grade 3, seven (12%) grade 4, and one (<2%) treatment-related death (intracranial hemorrhage). There were six episodes of venous thrombosis, 14 episodes of grade 3 or 4 hematologic toxicity, predominantly lymphopenia (7), and neutropenia (4), no opportunistic infections or febrile neutropenia were noted. Other toxicities included fatigue (9), diarrhea (2), and hypertension (2). Conclusions: These results, in the cooperative group context, corroborate the efficacy of the bevacizumab and irinotecan combination for recurrent GBM with the 6m-PFS surpassing the predetermined efficacy threshold. Previously described toxicities were confirmed with a moderately high rate of venous thrombosis, one intracranial hemorrhage, and moderate hypertension. Studies to determine the contribution of the cytotoxic agent to efficacy and the role of bevacizumab in newly diagnosed GBM are planned. [Table: see text]