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Clinical Trial
. 2020 May 15;22(5):705-717.
doi: 10.1093/neuonc/noz232.

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)

Timothy F Cloughesy  1 , Andrew Brenner  2 , John F de Groot  3 , Nicholas A Butowski  4 , Leor Zach  5 , Jian L Campian  6 , Benjamin M Ellingson  7 , Laurence S Freedman  8 , Yael C Cohen  9 , Noa Lowenton-Spier  9 , Tamar Rachmilewitz Minei  9 , Shifra Fain Shmueli  9 ; GLOBE Study Investigators; Patrick Y Wen  10
Collaborators, Affiliations
Clinical Trial

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)

Timothy F Cloughesy et al. Neuro Oncol. .

Abstract

Background: Ofranergene obadenovec (VB-111) is an anticancer 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.

Methods: 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 every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).

Results: Enrolled were 256 patients 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 versus control arm (hazard ratio, 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 grades 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 posttreatment febrile reaction.

Conclusions: 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.

Clinical trials registration: NCT02511405.

Keywords: VB-111; anti-angiogenesis; gene therapy; glioblastoma; viral immuno-oncology.

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Figures

Fig. 1
Fig. 1
VB-111 dual mechanism of action: (1) Targeting tumor vasculature by apoptosis of angiogenic endothelial cells. (2) Induction of an antitumor immune response.
Fig. 2
Fig. 2
Study disposition CONSORT diagram.
Fig. 3
Fig. 3
Efficacy endpoints Kaplan–Meier curves. (A) OS; (B) PFS; (C) OS of patients with tumors <25 mL in phase II primed combination, GLOBE unprimed combination, and bevacizumab control
See this image and copyright information in PMC

Comment in

  • Way to Go/No-Go!
    Lesser GJ. Lesser GJ. Neuro Oncol. 2020 May 15;22(5):596-597. doi: 10.1093/neuonc/noaa061. Neuro Oncol. 2020. PMID: 32188987 Free PMC article. No abstract available.

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