Ofranergene obadenovec (VB-111) is an anti-cancer viral therapy that demonstrated in a Phase-II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.This pivotal phase-III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles q8W in combination with bevacizumab 10mg/Kg q2W (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS) and secondary endpoints were objective response rate (ORR) by RANO and Progression Free Survival (PFS).256 patients were enrolled at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination vs control arm (HR 1.20 [95% CI 0.91-1.59, p=0.19) and ORR was 27.3% versus 21.9% (P=0.26). A higher rate of grade 3-5 Adverse Events was reported in the combination arm (67% vs 40%) mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a post treatment febrile reaction.In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase-II results.