ATNT-15MIBEFRADIL DIHYDROCHORIDE WITH HYPOFRACTIONATED RADIATION FOR RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS OF A PHASE I DOSE EXPANSION TRIAL

Abstract

BACKGROUND: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Our group recently performed a high-throughput drug screen for novel DNA repair inhibitors which identified mibefradil dihydrochloride, a T-type calcium channel blocker. Follow-up studies by our group and others subsequently revealed that mibefradil is active as a glioma radiosensitizer. Based on these findings, we sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and hypofractionated radiation (RT), in a Phase I study of patients with recurrent GBM. A subset of patients are enrolled on a molecular biomarker sub-study, in which the drug is administered prior to surgical re-resection, and the tissue is analyzed for tumor penetration and in situ activity. METHODS: The inclusion criteria are histologically proven GBM progressive or recurrent following RT and temozolomide treatment. Patients receive mibefradil, in escalating dose from 150mg/day until the maximum tolerated dose (MTD) or a dose of 350 mg/day is reached using a standard 3 + 3 design. RT consists of 5 fractions of 600 cGy each, delivered over 2 weeks for a total of 3,000 cGy using stereotactic, intensity-modulated RT. RESULTS: To date, eight patients have been enrolled including two patients on the molecular biomarker sub-study, and seven have been successfully treated. The first dose level cohort has completed accrual. Median progression-free survival was 2.5 months. One patient experienced a complete radiographic response on MRI and one had grade 3 or higher drug-related toxicity. CONCLUSIONS: This Phase I dose-escalation study assesses the safety and determines the MTD of mibefradil dihydrochloride as a novel radiosensitizer in patients with recurrent GBM. Our preliminary data suggest that mibefradil and RT can be safely co-administered with the potential to improve disease response as a novel radiosensitizer.