A randomized phase II trial of veliparib, radiotherapy, and temozolomide in patients with unmethylated MGMT glioblastoma: the VERTU study.

Antineoplastic Agents, Alkylating / therapeutic use Benzimidazoles Brain Neoplasms / genetics DNA Methylation DNA Modification Methylases / genetics DNA Repair Enzymes / genetics Glioblastoma / drug therapy Humans Male Middle Aged Radiation Oncology Temozolomide / therapeutic use Tumor Suppressor Proteins / genetics
MGMT DNA damage PARP glioblastoma veliparib

Journal

Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420

Informations de publication

Date de publication:
01 10 2021
Historique:
pubmed: 14 5 2021
medline: 6 10 2021
entrez: 13 5 2021
Statut: ppublish

Résumé

Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide. VERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm. A total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals. The veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.

Sections du résumé

BACKGROUND
Temozolomide offers minimal benefit in patients with glioblastoma with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status, hence, the need for novel therapies. This study evaluated whether veliparib, a brain-penetrant poly(ADP-ribose) polymerase (PARP) inhibitor, acts synergistically with radiation and temozolomide.
METHODS
VERTU was a multicenter 2:1 randomized phase II trial in patients with newly diagnosed glioblastoma and MGMT-unmethylated promotor status. The experimental arm consisted of veliparib and radiotherapy, followed by adjuvant veliparib and temozolomide. The standard arm consisted of concurrent temozolomide and radiotherapy, followed by adjuvant temozolomide. The primary objective was to extend the progression-free survival rate at six months (PFS-6m) in the experimental arm.
RESULTS
A total of 125 participants were enrolled, with 84 in the experimental arm and 41 in the standard arm. The median age was 61 years, 70% were male, 59% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, and 87% underwent macroscopic resection. PFS-6m was 46% (95% confidence interval [CI]: 36%-57%) in the experimental arm and 31% (95% CI: 18%-46%) in the standard arm. Median overall survival was 12.7 months (95% CI: 11.4-14.5 months) in the experimental arm and 12.8 months (95% CI: 9.5-15.8 months) in the standard arm. The most common grade 3-4 adverse events were thrombocytopenia and neutropenia, with no new safety signals.
CONCLUSION
The veliparib-containing regimen was feasible and well tolerated. However, there was insufficient evidence of clinical benefit in this population. Further information from correlative translational work and other trials of PARP inhibitors in glioblastoma are still awaited.

Identifiants

DOI: 10.1093/neuonc/noab111 PMID: 33984151 PMC: PMC8485443
pubmed: 33984151
pii: 6275307
doi: 10.1093/neuonc/noab111
pmc: PMC8485443
doi:

Substances chimiques

Antineoplastic Agents, Alkylating 0
Benzimidazoles 0
Tumor Suppressor Proteins 0
veliparib 01O4K0631N
DNA Modification Methylases EC 2.1.1.-
MGMT protein, human EC 2.1.1.63
DNA Repair Enzymes EC 6.5.1.-
Temozolomide YF1K15M17Y

Types de publication

Clinical Trial, Phase II Journal Article Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1736-1749

Subventions

Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States

Informations de copyright

© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

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Auteurs

Hao-Wen Sim (HW)

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
Department of Medical Oncology, The Kinghorn Cancer Centre, Sydney, Australia.
Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia.

Kerrie L McDonald (KL)

Cure Brain Cancer Neuro-Oncology Lab, University of New South Wales, Sydney, Australia.

Zarnie Lwin (Z)

School of Medicine, University of Queensland, Brisbane, Australia.
Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Elizabeth H Barnes (EH)

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.

Mark Rosenthal (M)

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
Department of Medical Oncology, Royal Melbourne Hospital, Melbourne, Australia.

Matthew C Foote (MC)

School of Medicine, University of Queensland, Brisbane, Australia.
Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Australia.

Eng-Siew Koh (ES)

South Western Sydney Clinical School, University of New South Wales, Sydney, Australia.
Ingham Institute for Applied Medical Research, Sydney, Australia.
Department of Radiation Oncology, Liverpool Hospital, Sydney, Australia.

Michael Back (M)

Department of Radiation Oncology, Royal North Shore Hospital, Sydney, Australia.

Helen Wheeler (H)

Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia.

Erik P Sulman (EP)

Department of Radiation Oncology, NYU Grossman School of Medicine and Brain and Spine Tumors, New York, New York, USA.
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA.

Michael E Buckland (ME)

Neuropathology Department, Royal Prince Alfred Hospital, Sydney, Australia.
Brain and Mind Centre, University of Sydney, Sydney, Australia.

Lauren Fisher (L)

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.

Robyn Leonard (R)

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.

Merryn Hall (M)

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
Duke University School of Medicine, Duke University, Durham, North Carolina, USA.

David M Ashley (DM)

Duke University School of Medicine, Duke University, Durham, North Carolina, USA.

Sonia Yip (S)

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.

John Simes (J)

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia.

Mustafa Khasraw (M)

NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
ORCID: 0000-0003-3249-9849

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions toxiques › Noxas › Agents alcoylants › Antinéoplasiques alcoylants › A randomized phase II trial of veliparib,...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzimidazoles › A randomized phase II trial of veliparib,...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › A randomized phase II trial of veliparib,...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › A randomized phase II trial of veliparib,...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › DNA modification methylases › A randomized phase II trial of veliparib,...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Enzymes de réparation de l'ADN › A randomized phase II trial of veliparib,...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Gliome › Astrocytome › Glioblastome › A randomized phase II trial of veliparib,...
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questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › A randomized phase II trial of veliparib,...
questionsmedicales.fr › Professions de santé › Médecine › Radiologie › Radio-oncologie › A randomized phase II trial of veliparib,...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Imidazoles › Dacarbazine › Témozolomide › A randomized phase II trial of veliparib,...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines suppresseurs de tumeurs › A randomized phase II trial of veliparib,...