Mibefradil Dihydrochloride and Temozolomide in Treating Patients With Recurrent Glioma
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|ClinicalTrials.gov Identifier: NCT01480050|
Recruitment Status : Completed
First Posted : November 28, 2011
Last Update Posted : May 22, 2019
RATIONALE: Mibefradil dihydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.
PURPOSE: This phase I trial is studying the best dose of mibefradil dihydrochloride when given together with temozolomide in treating patients with glioma.
|Condition or disease||Intervention/treatment||Phase|
|Brain and Central Nervous System Tumors||Drug: temozolomide Other: 3'-deoxy-3'-[18F]fluorothymidine Other: pharmacological study Drug: Mibefradil||Phase 1|
- 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 dosing.
- Assess the severity and frequency of adverse events for tested mibefradil dihydrochloride dose levels including cumulative toxicity and/or tolerance to adverse effects.
- 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 dose-expansion study.
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 therapy.
After completion of study therapy, patients are followed up every 2 months.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||28 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||May 31, 2012|
|Actual Primary Completion Date :||August 2015|
|Actual Study Completion Date :||June 1, 2017|
Experimental: Dose Finding and Dose Expansion
DOSE FINDING 4 Levels
For all Levels:
Cycle 1 Mibefradil QID dosing, Days 1-8 (to accommodate PKs) (*2 doses on Days 1 and 8) Temozolomide daily at 150-200 mg/m2, Days 9-13;
Cycles 2+ Mibefradil QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
DOSE EXPANSION 28-day cycles FLT PET scans, Baseline x2, Day 7 Mibefradil MTD determined at Dose Finding QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
standard of care drug
tracer used for FLT PET CT
Other: pharmacological study
- Maximum-tolerated dose of mibefradil dihydrochloride [ Time Frame: 2 years ]Determine the maximum tolerated dose (MTD) of mibefradil administered prior to five days of temozolomide (TMZ) at 150-200 mg/m2 in subjects with progressive or recurrent high grade glioma.
- Dose-limiting toxicity [ Time Frame: 2 years ]
- Toxicity and adverse events according to CTCAE v. 4.0 [ Time Frame: 2 years ]Assess the severity and frequency of adverse events for tested mibefradil dose levels including cumulative toxicity and/or tolerance to adverse effects.
- Biological activity of treatment determined by radiographic response [ Time Frame: 3 years ]Estimate the number and type of radiographic responses to treatment with mibefradil and temozolomide.
- Pharmacokinetics of mibefradil dihydrochloride as measured by the steady-state maximum plasma concentration (Cmax) [ Time Frame: Day 8 ]Cmax (ng/mL) of mibefradil dihydrochloride at steady-state in plasma.
- Potential effect of mibefradil dihydrochloride on tumor metabolism as determined by [F-18]FLT PET scans in the dose-expansion cohort [ Time Frame: 6 months ]Assess the potential effect of mibefradil on tumor metabolism as determined by fluorothymidine positron emission tomography-computed tomography (FLT PETCT) scans with the radiotracer [18F]-3'-fluoro-3'-deoxy-L-thymidine.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01480050
|United States, Alabama|
|UAB Comprehensive Cancer Center|
|Birmingham, Alabama, United States, 35294-3410|
|United States, Georgia|
|Winship Cancer Institute of Emory University|
|Atlanta, Georgia, United States, 30322|
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21205|
|United States, Michigan|
|Henry Ford Hospital|
|Detroit, Michigan, United States, 48202|
|United States, North Carolina|
|Wake Forest University Comprehensive Cancer Center|
|Winston-Salem, North Carolina, United States, 27157-1096|
|United States, Pennsylvania|
|Abramson Cancer Center of the University of Pennsylvania|
|Philadelphia, Pennsylvania, United States, 19104-4283|
|Hillman Cancer Center at University of Pittsburgh Cancer Institute|
|Pittsburgh, Pennsylvania, United States, 15232|
|Principal Investigator:||Matthias Holdhoff, MD||Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins|