Mibefradil Dihydrochloride and Temozolomide in Treating Patients With Recurrent Glioma

Phase 1

Completed

• Conditions: Brain and Central Nervous System Tumors
• Interventions: Drug: temozolomide; Other: 3'-deoxy-3'-[18F]fluorothymidine; Other: pharmacological study; Drug: Mibefradil

• Registration Number: NCT01480050
• Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary

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.

Detailed Description

OBJECTIVES:

Primary

* 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.

Secondary

* 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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2011-11-23
• Study First Submitted QC: 2011-11-23
• Study First Posted: 2011-11-28
• Study Start: 2012-05-31
• Primary Completion: 2015-08
• Study Completion: 2017-06-01
• Status Verified: 2019-05
• Last Update Submitted: 2019-05-21
• Last Update Posted: 2019-05-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dose Finding and Dose Expansion	Mibefradil	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
Dose Finding and Dose Expansion	3'-deoxy-3'-[18F]fluorothymidine	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
Dose Finding and Dose Expansion	pharmacological study	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
Dose Finding and Dose Expansion	temozolomide	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

Primary Outcome Measures

Name	Time	Method
Dose-limiting toxicity	2 years
Maximum-tolerated dose of mibefradil dihydrochloride	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.

Secondary Outcome Measures

Name	Time	Method
Toxicity and adverse events according to CTCAE v. 4.0	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	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)	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	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.

Trial Locations

Locations (7)

UAB Comprehensive Cancer Center; 🇺🇸 Birmingham, Alabama, United States

Wake Forest University Comprehensive Cancer Center; 🇺🇸 Winston-Salem, North Carolina, United States

Henry Ford Hospital; 🇺🇸 Detroit, Michigan, United States

Hillman Cancer Center at University of Pittsburgh Cancer Institute; 🇺🇸 Pittsburgh, Pennsylvania, United States

Abramson Cancer Center of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Winship Cancer Institute of Emory University; 🇺🇸 Atlanta, Georgia, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States