Mibefradil Dihydrochloride With Hypofractionated Radiation for Recurrent Glioblastoma: Preliminary Results of a Phase 1 Dose Expansion Trial

ATNT-15. MIBEFRADIL DIHYDROCHORIDE WITH HYPOFRACTIONATED RADIATION FOR RECURRENT GLIOBLASTOMA: PRELIMINARY RESULTS OF A PHASE I DOSE EXPANSION TRIAL Nataniel H. Lester-Coll1, Jeannie Kluytenaar1, Kira F. Pavlik2, James B. Yu1, Joseph N. Contessa1, Jennifer Moliterno3, Joseph M. Piepmeier3, Kevin P. Becker4, Joachim M. Baehring4, Anita J. Huttner5, Alexander O. Vortmeyer5, Ramachandran Ramani6, Rachel J. Lampert7, Xiaopan Yao8, and Ranjit S. Bindra1; Departmentof TherapeuticRadiology, YaleUniversity School of Medicine, New Haven, CT, USA; Yale University School of Medicine, New Haven, CT, USA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Department of Neurology, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA; Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA; Department of Cardiology, Yale University School of Medicine, New Haven, CT, USA; Yale Center for Analytical Sciences, Yale University School of Medicine, New Haven, CT, USA 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 mibefradildihydrochlorideas anovel radiosensitizer inpatientswith 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. Neuro-Oncology 17:v10–v17, 2015. doi:10.1093/neuonc/nov205.15 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.