Background: Pre-clinical data suggest BEV may sensitize tumor endothelia to RT and disrupt vascular niches harboring cancer stem cells. Due to radioprotective effects, BEV also allows for more aggressive RT schedules such as HFSRT. We initiated a phase II trial in newly diagnosed GBM utilizing HFSRT, BEV and TMZ. Methods: Pts with tumor volume under 60cc were eligible. HFSRT was given in 6 treatments over 2 weeks: 6x6 Gy to contrast-enhancing tumor and 6x4 Gy to FLAIR hypersignal, with dose painting, concomitant with BEV (10 mg/kg every 2 weeks) and TMZ (75mg/m2 daily), followed by adjuvant BEV/ TMZ (150-200 mg/m2 in 5/28 days). Followup included perfusion MRI (PWI) and comprehensive neuropsychological assessment (NPA) in all patients. Primary endpoint was 1y overall survival (OS): single-stage binomial design; promising: 70%, non-promising: 50%; α and β=0.1). Results: Accrual was completed (N=40 evaluable pts; 14 women; median age: 55y; median KPS: 90). The frequency of methylated MGMT promoter was low (methylated: 8 pts, unmethylated: 26, not done: 6). Grades 3/4 non-hematologic toxicities included pulmonary embolism (2), thrombotic microangiopathy/renal failure (1), wound infection (1), colitis (1). The median PFS was 11m (95% CI 9-15). No pt had pseudo progression. Among 30 evaluable pts, response (Macdonald criteria) was complete in 27%, partial in 63%; disease was stable in 3% and 7% progressed. Fifteen pts have died; the 1-y OS is 90% (CI 73-97); median followup: 13m. NPA at baseline showed decreased verbal memory, but no statistically significant changes at 4 and 8m followup. PWI showed early decreases in relative cerebral blood volume (rCBV): mean rCBV at baseline=2.77 versus 1.65 at 6 weeks (p=0.01); rCBV anticipated achieved responses. Conclusions: Despite a more aggressive RT schedule, the regimen was safe and more convenient for pts (shorter treatment, high response rates, preserved cognitive function throughout and following RT). Compared to historical controls, prolonged PFS and 1y OS were observed. While evaluation of late survival endpoints requires longer followup, the primary endpoint was met, indicating a randomized study is warranted.