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

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: L Burt Nabors, Karen L Fink, Tom Mikkelsen, Danica Grujicic, Rafal Tarnawski, Do Hyun Nam, Maria Mazurkiewicz, Michael Salacz, Lynn Ashby, Vittorina Zagonel, Roberta Depenni, James R Perry, Christine Hicking, Martin Picard, Monika E Hegi, Benoit Lhermitte, David A Reardon
• Journal: Neuro-oncology (Neuro Oncol) Vol. 17 Issue 5 Pg. 708-17 (May 2015) ISSN: 1523-5866 [Electronic] England
• PMID: 25762461 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents
• Snake Venoms
• Tumor Suppressor Proteins
• Cilengitide
• Dacarbazine
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes
• Temozolomide

Topics

• Adult
• Aged
• Antineoplastic Agents (adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Brain Neoplasms (drug therapy, genetics, mortality, radiotherapy)
• DNA Methylation
• DNA Modification Methylases (genetics)
• DNA Repair Enzymes (genetics)
• Dacarbazine (analogs & derivatives, therapeutic use)
• Female
• Glioblastoma (drug therapy, genetics, mortality, radiotherapy)
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Promoter Regions, Genetic
• Snake Venoms (adverse effects, therapeutic use)
• Temozolomide
• Treatment Outcome
• Tumor Suppressor Proteins (genetics)