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

Timothy F. Cloughesy*, Andrew Brenner, John F. De Groot, Nicholas A. Butowski, Leor Zach, Jian L. Campian, Benjamin M. Ellingson, Laurence S. Freedman, Yael C. Cohen, Noa Lowenton-Spier, Tamar Rachmilewitz Minei, Shifra Fain Shmueli, Nicholas Avgeropoulos, Joseph Beck, Tara Benkers, Felix Bokstein, Andrew Brenner, Eric Burton, Nicholas Butowski, Jian CampianJose Carrillo, Timothy Cloughesy, John De Groot, Paula De Robles, Jan Drappatz, Irine Dunbar, Karen Fink, Morris Groves, Xiaosi Han, Hormigo Adila, Randy Jensen, Agnieszka Kowalska, Pyriya Kumthekar, Mijung Lee, Glenn Lesser, Alexander Lossos, Rimas Lukas, David Macdonald, Aaron Mammoser, Laszlo Mechtler, Nimish Mohile, Seema Nagpal, Garth Nicholas, Teri Kreisl, Edward Pan, Scott Peak, Michael Pearlman, James Perry, Richard Peterson, David Piccioni, Henry Robins, Lara Ronan, Michael Salacz, David Schiff, David Tran, Leor Zach, Tzahala Tzuk-Shina, Tobias Walbert, Patrick Wen, Shlomit Youst, Patrick Y. Wen

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)705-717
Number of pages13
JournalNeuro-oncology
Volume22
Issue number5
DOIs
StatePublished - May 15 2020

Keywords

  • VB-111
  • anti-angiogenesis
  • gene therapy
  • glioblastoma
  • viral immuno-oncology

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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    Cloughesy, T. F., Brenner, A., De Groot, J. F., Butowski, N. A., Zach, L., Campian, J. L., Ellingson, B. M., Freedman, L. S., Cohen, Y. C., Lowenton-Spier, N., Rachmilewitz Minei, T., Fain Shmueli, S., Avgeropoulos, N., Beck, J., Benkers, T., Bokstein, F., Brenner, A., Burton, E., Butowski, N., ... Wen, P. Y. (2020). A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE). Neuro-oncology, 22(5), 705-717. https://doi.org/10.1093/neuonc/noz232