A Phase I Open Label Safety Study to Evaluate the Pharmacokinetic Profile and Tolerance of Mibefradil Dose Finding in Subjects With Recurrent High-Grade Glioma Undergoing Standard, Repeated Temozolomide Treatment
- Determine the maximum-tolerated dose (MTD) of mibefradil dihydrochloride administered
prior to five days of temozolomide (TMZ) at 150-200 mg/m² in subjects with progressive
or recurrent high-grade glioma.
- Assess the safety of mibefradil dihydrochloride administered prior to five days of TMZ
at 150-200 mg/m² when the mibefradil dihydrochloride dose is escalated from a starting
dose of 100 mg/day, given four times a day for seven consecutive days.
- Determine the pharmacokinetic profile of mibefradil.
- Determine the steady state levels of mibefradil dihydrochloride on the last day of
- Assess the severity and frequency of adverse events for tested mibefradil
dihydrochloride dose levels including cumulative toxicity and/or tolerance to adverse
- Estimate the number and type of radiographic responses to treatment with mibefradil
dihydrochloride and temozolomide.
- Assess the potential effect of mibefradil dihydrochloride on tumor metabolism as
determined by Fluorothymidine Positron Emission Tomography (FLT PET) scans with the
radiotracer [18F]-3'-fluoro-3'-deoxy-L-thymidine (dose-expansion cohort only).
OUTLINE: This is a dose-escalation study of mibefradil dihydrochloride followed by a
Patients receive mibefradil dihydrochloride orally (PO) 4 times a day on days 1-7 (days 1-8
on first course) and temozolomide PO on days 8-12 (days 9-13 on first course). Treatment
repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Blood samples are collected during the first course for pharmacokinetic studies.
Patients in the dose-expansion cohort undergo [18F]-3'-fluoro-3'-deoxy-L-thymidine
(FLT)-positron emission tomography (PET) at baseline and on day 7 of the first course of
After completion of study therapy, patients are followed up every 2 months.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum-tolerated dose of mibefradil dihydrochloride
Matthias Holdhoff, MD
Sidney Kimmel Comprehensive Cancer Center
United States: Food and Drug Administration
|Johns Hopkins University||Baltimore, Maryland 21205|
|Abramson Cancer Center of the University of Pennsylvania||Philadelphia, Pennsylvania 19104-4283|
|Henry Ford Hospital||Detroit, Michigan 48202|
|Hillman Cancer Center at University of Pittsburgh Cancer Institute||Pittsburgh, Pennsylvania 15236|
|Winship Cancer Institute of Emory University||Atlanta, Georgia 30322|
|Wake Forest University Comprehensive Cancer Center||Winston-Salem, North Carolina 27157-1096|