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

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...

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Autores principales: Cloughesy, Timothy F, Brenner, Andrew, de Groot, John F, Butowski, Nicholas A, Zach, Leor, Campian, Jian L, Ellingson, Benjamin M, Freedman, Laurence S, Cohen, Yael C, Lowenton-Spier, Noa, Rachmilewitz Minei, Tamar, Fain Shmueli, Shifra, Wen, Patrick Y
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229248/
https://www.ncbi.nlm.nih.gov/pubmed/31844890
http://dx.doi.org/10.1093/neuonc/noz232
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author Cloughesy, Timothy F
Brenner, Andrew
de Groot, John F
Butowski, Nicholas A
Zach, Leor
Campian, Jian L
Ellingson, Benjamin M
Freedman, Laurence S
Cohen, Yael C
Lowenton-Spier, Noa
Rachmilewitz Minei, Tamar
Fain Shmueli, Shifra
Wen, Patrick Y
author_facet Cloughesy, Timothy F
Brenner, Andrew
de Groot, John F
Butowski, Nicholas A
Zach, Leor
Campian, Jian L
Ellingson, Benjamin M
Freedman, Laurence S
Cohen, Yael C
Lowenton-Spier, Noa
Rachmilewitz Minei, Tamar
Fain Shmueli, Shifra
Wen, Patrick Y
author_sort Cloughesy, Timothy F
collection PubMed
description 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 10(13) 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
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spelling pubmed-72292482020-05-21 A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE) Cloughesy, Timothy F Brenner, Andrew de Groot, John F Butowski, Nicholas A Zach, Leor Campian, Jian L Ellingson, Benjamin M Freedman, Laurence S Cohen, Yael C Lowenton-Spier, Noa Rachmilewitz Minei, Tamar Fain Shmueli, Shifra Wen, Patrick Y Neuro Oncol Clinical Investigations 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 10(13) 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 Oxford University Press 2020-05 2019-12-07 /pmc/articles/PMC7229248/ /pubmed/31844890 http://dx.doi.org/10.1093/neuonc/noz232 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Investigations
Cloughesy, Timothy F
Brenner, Andrew
de Groot, John F
Butowski, Nicholas A
Zach, Leor
Campian, Jian L
Ellingson, Benjamin M
Freedman, Laurence S
Cohen, Yael C
Lowenton-Spier, Noa
Rachmilewitz Minei, Tamar
Fain Shmueli, Shifra
Wen, Patrick Y
A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)
title A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)
title_full A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)
title_fullStr A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)
title_full_unstemmed A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)
title_short A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)
title_sort randomized controlled phase iii study of vb-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (globe)
topic Clinical Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229248/
https://www.ncbi.nlm.nih.gov/pubmed/31844890
http://dx.doi.org/10.1093/neuonc/noz232
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