VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor specific immune response. This phase I/II study evaluated the safety, tolerability and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM).Patients with rGBM (n=72) received VB-111 in 4 treatment groups: Sub-Therapeutic (VB-111 dose escalation), Limited Exposure (LE, VB-111 monotherapy until progression), Primed Combination (VB-111 monotherapy continued upon progression with combination of bevacizumab) and Unprimed Combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS).VB-111 was well-tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the Primed Combination group compared to both LE (414 vs 223 days; HR 0.48; p=0.043), and Unprimed Combination (414 vs. 141.5 days; HR 0.24; p=0.0056); Patients in the combination phase of the Primed Combination group had a median PFS time of 90 days compared to 60 in the LE group (HR 0.36; p=0.032), and 63 in the Unprimed Combination group (p=0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease.Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab, showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.