Mibefradil dihydrochoride with hypofractionated radiation for recurrent glioblastoma: A phase I dose expansion trial.

Abstract

e14046 Background: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options. We performed a high-throughput screen for DNA repair inhibitors and identified mibefradil dihydrochloride, a T-type calcium channel blocker. We and others revealed that mibefradil acts as a glioma radiosensitizer. Recent studies in our laboratory indicate that mibefradil blocks non-homologous end joining. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and radiation therapy (RT), in a Phase I recurrent GBM study. Methods: The Primary objective was to determine mibefradil MTD with concurrent hypofractionated RT. Secondary objectives included safety, pharmacokinetics, progression-free survival (PFS) and overall survival (OS). A tertiary objective included assessing intra-tumoral drug concentrations. In this novel translational sub-study, patients were given mibefradil for 5 days prior to surgery, followed by a re-resection. Resected tissues were analyzed for the presence of drug in situ. Inclusion criteria included histologically proven GBM progressive following RT and temozolomide. Patients received mibefradil, dose escalated from 150mg/day using a 3 + 3 design. RT consisted of 5 fractions of 600 cGy each, delivered over 2 weeks. Results: Nineteen patients enrolled from 9/2014 - 12/2016. There were 4 DLTs; a final dose level of 200 mg/day was reached. Median PFS and OS were 3 months and 9 months, respectively. Four patients (22%) achieved a PFS interval of ≥4 months (longest 8 months). One patient had a complete radiographic response. Intriguingly, mibefradil was detected at micromolar levels in GBM tumor tissue in 2 patients enrolled in the translational sub-study. We detected drug levels in biopsies from T1-post contrast and FLAIR regions on MRI and these levels correlate with that required for tumor cell radiosensitization in vitro. Conclusions: Our data suggest mibefradil can be safely co-administered with RT over a 17 day period at 200 mg/day. Promising local control signals apparent in a selection of patients, and we have demonstrated that pharmacologically effective concentrations of the drug are achieved in resected brain tumor tissue. Clinical trial information: NCT02202993.