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Timed-sequential therapy with mibefradil and temozolomide in patients with recurrent high-grade gliomas: A phase I Adult Brain Tumor Consortium study.
Background: Mibefradil (MIB) is a selective T-type calcium channel blocker that had previously been approved for treatment of hypertension. MIB has shown significant preclinical activity in many cancers, including high-grade gliomas (HGG). MIB was found to impact cell cycle activity with arrest at G1/S in tumor cells, suggesting a possible chemo-sensitizing effect of the drug if given prior to cytotoxic therapy. This was a multi-center open label phase I study to determine the maximum tolerated dose (MTD) of MIB followed by temozolomide (TMZ) in recurrent HGG and to assess the safety and tolerability of MIB, particularly its myelosuppressive effects, in a timed-sequential combination with TMZ. Methods: Adult patients with recurrent HGG (WHO grade III and IV) who were selected to likely have a benefit from repeat treatment with TMZ (no progression ≥ 3 months from their last dose of TMZ) were eligible. MIB was given in 4 daily doses (QID) for 7 days followed 24 hours later by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. Dose escalation of MIB was done using a modified 3+3 design, followed by an extension cohort of 10 patients at the MTD. Results: 27 eligible patients with recurrent HGG participated (at time of enrollment, 21 with WHO grade IV, 6 with grade III; median age 50y; median KPS 90). The MTD of MIB was determined as 87.5 mg po QID. Most common side effects (grade 1 and 2) were fatigue, nausea, constipation and anorexia. Grade 3 elevation of ALT/AST was observed in one patient. Dose limiting toxicities were elevation of ALT/AST and sinus bradycardia. 5 partial and 1 complete responses were observed based on review by the sites (response rate 22%; 95% CI:9-42%). Plasma concentrations of MIB achieved a steady-state after 4 days of dosing with a mean peak concentration of approximately 1,700 ng/mL and a peak-to-trough ratio of 1.1 at the MTD. Conclusions: MIB followed by TMZ was well tolerated in patients with recurrent HGG. The MTD for MIB in this setting was determined as 87.5 mg po QID. The lack of toxicity, including extensive myelosuppression, and the presence of responses in this selected patient population suggests that this regimen deserves further investigation. Clinical trial information: NCT01480050
Abstracts by Matthias Holdhoff:
- Meeting: 2016 ASCO Annual Meeting | Abstract No: 2054
Inter-interpreter reliability of neuropathological assessment of disease status after early repeat resection for suspected recurrent glioblastoma.Meeting: 2016 ASCO Annual Meeting | Abstract No: 2050
Phase I study of procaspase activating compound -1 (PAC-1) in the treatment of advanced malignancies.Meeting: 2016 ASCO Annual Meeting | Abstract No: TPS2605