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; Jian Campian; Jose Carrillo; 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 Y. Wen; Shlomit Youst

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, 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, Jian Campian, Jose CarrilloJohn 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 Y. Wen, Shlomit Youst

Research output: Contribution to journal › Article › peer-review

51 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.

Original language	English
Pages (from-to)	705-717
Number of pages	13
Journal	Neuro-Oncology
Volume	22
Issue number	5
DOIs	https://doi.org/10.1093/neuonc/noz232
State	Published - 15 May 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Funding

are employees of VBL Therapeutics. LSF is a statistical consultant to VBL Therapeutics and his institute (Gertner Institute for Epidemiology and Health Policy Research) received payment for the statistical advice and analysis provided. TFC is a paid consultant for VBL, Trizel, Medscape, Bayer, Amgen, Odonate Therapeutics, Pascal Biosciences, Bayer, Del Mar Pharmaceuticals, Tocagen, Karyopharm, GW Pharma, Kiyatec, Abbvie, Boehinger Ingelheim, VBI, Deciphera, Agios, Merck, Roche, Genocea, Celgene, Puma, Lilly, BMS, Cortice, Wellcome Trust, Novocure, Novogen, Boston Biomedical, Sunovion, Human Longevity, Insys, ProNai, Pfizer, Notable labs, and Medqia; stock options for Notable Labs; board member for 501c3 Global Coalition for Adaptive Research and has a provisional patent on compositions and methods for treating cancer with UCLA. AB has no conflicts. JFG has grant and research support through Grant or Research Support: Sanofi-Aventis, Astrazeneca, EMD-Serono, Eli Lilly, Novartis, Deciphera Pharmaceuticals, and Mundipharma; paid consultant for Celldex, Deciphera Pharmaceuticals, AbbVie, FivePrime Therapeutics, Inc., GW Pharma, Carthera, Eli Lilly, Kadmon, Boston Biomedical Inc., Taiho Pharmaceuticals, Kairos Venture Investments, Syneos Health, Monteris, Agios, Mundipharma Research, GenomiCare, Blue Earth Diagnostics, Del Mar Pharmaceuticals, Insightec, E-Health Now; advisory boards for Genentech, Celldex, Foundation Medicine, Inc., Novogen, Deciphera, Astrazeneca, Insys Therapeutics, Merck, Eli Lilly, Novella Clinical, Kiyatec, Blue Earth Diagnostics, Vanquish Oncology, Orsenix, Insightec, Prelude Therapeutics; stock ownership in Ziopharm Oncology, and Gilead; company employment with Ziopharm Oncology (spouse); other financial interests include DSMB memebership for VBL Therapeutics, Novella, and VBI Vaccines, Inc. NAB is a paid consultant for VBL Bayer, Amgen, Del Mar Pharmaceuticals, Tocagen, GW Pharma, Kiyatec, Abbvie, Boehinger Ingelheim, Deciphera, Merck, Roche, Lilly, BMS, Cortice, Wellcome Trust, Novocure, Boston Biomedical, Insys. LSF has no conflicts. JLC paid consultant for Alexion, Abbvie, Arbor Pharmaceuticals, Dova Pharmaceuticals, Inovio Pharmaceuticals, Incyte, Novocure. BME paid consultant for MedQIA, Agios Pharmaceuticals, Siemens Healthcare, Janssen Pharmaceuticals, Medicenna, Imaging Endpoints, Genentech, Novogen, Northwest Biopharmaceuticals, Image Analysis Group, Oncoceutics, BeiGene, and VBL. PYW has research support from Agios, Astra Zeneca, Beigene, Eli Lily, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines; consulting with Agios, Bayer, Astra Zeneca, Blue Earth Diagnostics, Eli Lilly, Genentech/Roche, Immunomic Therapeutics, Karyopharm, Kiyatec, Puma, Vascular Biogenics, Taiho, Tocagen, Deciphera, VBI Vaccines; Speaker honorarium from Merck and Prime Oncology. This work was supported by VBL Therapeutics. Data presented within this article were previously presented in part at SNO 2018 and ASCO 2019.

Funders	Funder number
Mundipharma
VBI Vaccines, Inc.
VBL Therapeutics
National Cancer Institute	P30CA016672
Eli Lilly and Company
Gilead Sciences
AbbVie
Boston Biomedical
Foundation Medicine

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/neuonc/noz232

Cite this

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., Campian, J., ... Youst, S. (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

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

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.",

keywords = "VB-111, anti-angiogenesis, gene therapy, glioblastoma, viral immuno-oncology",

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

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.",

year = "2020",

month = may,

day = "15",

doi = "10.1093/neuonc/noz232",

language = "אנגלית",

volume = "22",

pages = "705--717",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "5",

}

Cloughesy, TF, Brenner, A, De Groot, JF, Butowski, NA, Zach, L, Campian, JL, Ellingson, BM, Freedman, LS, Cohen, YC, Lowenton-Spier, N, Rachmilewitz Minei, T, Fain Shmueli, S, Avgeropoulos, N, Beck, J, Benkers, T, Bokstein, F, Brenner, A, Burton, E, Campian, J, Carrillo, J, De Groot, J, De Robles, P, Drappatz, J, Dunbar, I, Fink, K, Groves, M, Han, X, Adila, H, Jensen, R, Kowalska, A, Kumthekar, P, Lee, M, Lesser, G, Lossos, A, Lukas, R, Macdonald, D, Mammoser, A, Mechtler, L, Mohile, N, Nagpal, S, Nicholas, G, Kreisl, T, Pan, E, Peak, S, Pearlman, M, Perry, J, Peterson, R, Piccioni, D, Robins, H, Ronan, L, Salacz, M, Schiff, D, Tran, D, Zach, L, Tzuk-Shina, T, Walbert, T, Wen, PY & Youst, S 2020, 'A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)', Neuro-Oncology, vol. 22, no. 5, pp. 705-717. https://doi.org/10.1093/neuonc/noz232

TY - JOUR

T1 - A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)

AU - Cloughesy, Timothy F.

AU - Brenner, Andrew

AU - De Groot, John F.

AU - Butowski, Nicholas A.

AU - Zach, Leor

AU - Campian, Jian L.

AU - Ellingson, Benjamin M.

AU - Freedman, Laurence S.

AU - Cohen, Yael C.

AU - Lowenton-Spier, Noa

AU - Rachmilewitz Minei, Tamar

AU - Fain Shmueli, Shifra

AU - Avgeropoulos, Nicholas

AU - Beck, Joseph

AU - Benkers, Tara

AU - Bokstein, Felix

AU - Brenner, Andrew

AU - Burton, Eric

AU - Campian, Jian

AU - Carrillo, Jose

AU - De Groot, John

AU - De Robles, Paula

AU - Drappatz, Jan

AU - Dunbar, Irine

AU - Fink, Karen

AU - Groves, Morris

AU - Han, Xiaosi

AU - Adila, Hormigo

AU - Jensen, Randy

AU - Kowalska, Agnieszka

AU - Kumthekar, Pyriya

AU - Lee, Mijung

AU - Lesser, Glenn

AU - Lossos, Alexander

AU - Lukas, Rimas

AU - Macdonald, David

AU - Mammoser, Aaron

AU - Mechtler, Laszlo

AU - Mohile, Nimish

AU - Nagpal, Seema

AU - Nicholas, Garth

AU - Kreisl, Teri

AU - Pan, Edward

AU - Peak, Scott

AU - Pearlman, Michael

AU - Perry, James

AU - Peterson, Richard

AU - Piccioni, David

AU - Robins, Henry

AU - Ronan, Lara

AU - Salacz, Michael

AU - Schiff, David

AU - Tran, David

AU - Zach, Leor

AU - Tzuk-Shina, Tzahala

AU - Walbert, Tobias

AU - Wen, Patrick Y.

AU - Youst, Shlomit

PY - 2020/5/15

Y1 - 2020/5/15

N2 - 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.

AB - 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.

KW - VB-111

KW - anti-angiogenesis

KW - gene therapy

KW - glioblastoma

KW - viral immuno-oncology

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SN - 1522-8517

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EP - 717

JO - Neuro-Oncology

JF - Neuro-Oncology

IS - 5

ER -

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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