Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas

Abstract

Background: Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG.

Methods: Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB.

Results: Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 ± 287 ng/mL (mean ± SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB.

Conclusions: MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.

Keywords: anaplastic glioma; glioblastoma; mibefradil; temozolomide; timed sequential therapy.

© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Figures

Fig. 1

Mean plasma concentration–time profiles of mibefradil (solid circles) and its alcohol metabolite (solid squares) for the group of 6 patients receiving oral mibefradil 87.5 mg q.i.d. Pharmacokinetic sampling was performed over single dosing intervals on day 2 after administration of the fourth consecutive dose, on day 5 after the sixteenth dose, and for 48 h after the final dose on day 8. The error bars represent 1 SD of the mean concentrations.

Fig. 2

Progression-free and overall survival.

Fig. 3

18F-FLT PET imaging. (A) Synopsis of SUVpeak values of double-baseline and values after 7 days of treatment with mibefradil. (B and C) Examples of a patient with significant decline in SUV after 7 days of MIB (B) and a patient without a decline (C). MRI T1 contrast-enhanced image corresponding to the images of 18F-FLT PET imaging shown. Double baseline scans (left, 2 18F-FLT PET images), followed by 7 days on mibefradil and repeat imaging on day 7 (right, 18F-FLT PET images). Far right: changes in SUV values.