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Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study.

ABSTRACT: Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter.Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT?TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability.Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated.Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT?TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.

SUBMITTER: Nabors LB

PROVIDER: S-EPMC4482861 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study.

Nabors L Burt LB Fink Karen L KL Mikkelsen Tom T Grujicic Danica D Tarnawski Rafal R Nam Do Hyun DH Mazurkiewicz Maria M Salacz Michael M Ashby Lynn L Zagonel Vittorina V Depenni Roberta R Perry James R JR Hicking Christine C Picard Martin M Hegi Monika E ME Lhermitte Benoit B Reardon David A DA

Neuro-oncology 20150311 5

<h4>Background</h4>Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter.<h4>Methods</h4>Overall, 265 p ...[more]

PMID: 25762461

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Project description:Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by chemo-radiation and temozolomide. An unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance and is strongly correlated with poor outcomes. Unmethylated MGMT represents the majority of newly diagnosed GBM tumors. VAL-083 is a first-in-class bi-functional DNA-targeting agent that has shown activity against GBM in NCI-sponsored clinical trials both as single agent and in combination with radiotherapy. VAL-083 induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083s unique mechanism-of-action circumvents MGMT-mediated chemoresistance, and it has demonstrated cytotoxicity in MGMT-unmethylated GBM cell-lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. We completed a dose-escalation trial of VAL-083 in recurrent GBM, and a generally well-tolerated dosing regimen was selected for further clinical development. The present trial is an ongoing open-label, biomarker-driven, Phase 1/2 study to evaluate the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study is being conducted in two parts: 1) a dose-escalation part (20, 30, and 40mg/m2/day IV infusion on days 1,2,3 of a 21-day cycle) in up to 10 patients; 2) an expansion part in up to 20 additional patients at the determined well-tolerated dose. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736.

Dataset Information

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study.

Publications

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study.

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