30 Sep Mibefradil Dihydrochoride with Hypofractionated Radiation for Recurrent Glioblastoma
MedicalResearch.com Interview with:
Nataniel Lester-Coll, MD
Chief Resident in Radiation Oncology at Yale
New Haven, Connecticut
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Mibefradil diydrochloride was identified using a high-throughput compound screen for DNA double stranded break repair inhibitors. Mibefradil was found to radiosensitize GBM tumor cells in vitro and in vivo. Based on these findings, we sought to determine the maximum tolerated dose of mibefradil and radiation therapy in a Phase I recurrent GBM study. Eligible patients with recurrent Glioblastoma Multiforme received Mibefradil over a 17 day period, with hypofractionated radiation (600 cGy x 5 fractions). There are 18 patients currently enrolled who have completed treatment. Thus far, there is no clear evidence of radionecrosis. A final dose level of 200 mg/day was reached as the maximum tolerated dose. The drug was very well tolerated at this dose. We saw intriguing evidence of enhanced local control in selected cases. Patients enrolled in a translational substudy who received Mibefradil prior to surgery were found to have adequate levels of Mibefradil in resected brain tumor tissue.
MedicalResearch.com: What should readers take away from your report?
Response: Our preliminary data suggest Mibefradil can be safely co-administered with RT over a 17 day period at 200 mg/day. We observed promising local control signals apparent in a selection of patients, and we have demonstrated adequate levels of the drug directly in resected brain tumor tissue
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Based on the positive results of this study, we are now collaborating with Cavion LLC, the IND holder for Mibefradil, to design a Phase I trial testing the efficacy of this drug in front-line Glioblastoma Multiforme. Mibefradil is a partially selective T-type calcium channel inhibitor and we are conducting laboratory research to dissect out the mechanism of action of DNA repair inhibition. Cavion also has a medicinal chemistry/discovery program that has developed follow-on T-type calcium channel inhibitors that have improved pharmacological properties and greater potency than Mibefradil that will be interesting to move into clinical trials.
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Mibefradil Dihydrochoride with Hypofractionated Radiation for Recurrent Glioblastoma: Preliminary Results of a Phase I Dose Expansion Trial
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