Mibefradil Dihydrochloride and Temozolomide in Treating Patients With Recurrent Glioma

NCT ID: NCT01480050

Last Updated: 2019-05-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-05-31
• Study Completion Date: 2017-06-01

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.

Conditions

Brain and Central Nervous System Tumors

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

temozolomide

Intervention Type: DRUG

standard of care drug

3'-deoxy-3'-[18F]fluorothymidine

Intervention Type: OTHER

tracer used for FLT PET CT

pharmacological study

Intervention Type: OTHER

Mibefradil

Intervention Type: DRUG

Interventions

temozolomide

standard of care drug

Intervention Type: DRUG

3'-deoxy-3'-[18F]fluorothymidine

tracer used for FLT PET CT

Intervention Type: OTHER

pharmacological study

Intervention Type: OTHER

Mibefradil

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Subjects may not be receiving any other investigational agents or chemotherapeutic agents other than temozolomide.
• Uncontrolled intercurrent illness including, but not limited to, hypertension, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women or those who are breastfeeding are ineligible.
• Subjects with a history of known, active hepatitis are ineligible.
• Subjects with a screening QTc interval greater than or equal to 450 mSec for males, 470 mSec for females are ineligible.
• Subjects with a PR interval >250 mSec are ineligible.
• Subjects with a systolic blood pressure <100 mmHg at baseline are ineligible.
• Subjects taking any anti-arrhythmia medication other than beta-blockers or digoxin or with a history (within six months) of myocardial infarction, unstable angina, uncontrolled hypertension, or congestive heart failure are ineligible.
• Subjects with high grade (second degree or above) AV block or persistent sinus bradycardia of less than 50 BPM are ineligible.
• Subjects who require a calcium channel blocker for blood pressure control and who cannot be switched to an antihypertensive with an alternative mechanism of action will be excluded from the study. Permitted anti-hypertensive medications include:

• chlorothiazide
• hydrochlorothiazide
• atenolol
• nadolol
• enalapril
• lisinopril,
• eprosartan
• irbesartan.
• Subjects cannot receive any statin while on trial except pravastatin.
• Subjects who require treatment with an H2 blocker, other than famotidine, are ineligible. If the subject requires a proton pump inhibitor (PPI), then esomeprazole, pantoprazole, or rabeprazole may be given.
• Known HIV-positive subjects are ineligible because of potential CNS conditions associated with HIV and the possibility of unexpected drug-drug interactions.
• Subjects on enzyme-inducing anti-epileptic drugs (EIAEDs) are not eligible for treatment on this protocol. Subjects previously treated with EIAEDs may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of mibefradil.
• Subjects taking an anticoagulant must use warfarin or a low molecular weight heparin. Unfractionated heparin is not permitted. Appropriate monitoring of the effect of anticoagulation is required by guidelines.
• All subjects who require drugs that are substrates of CYP 3A4, CYP 2D6, and CYP 1A2 are ineligible except for the ones that are explicitly permitted
• Subjects who require any drugs that are known to interact adversely with metabolism or excretion of mibefradil are ineligible.
• Subjects who are taking and cannot discontinue over-the-counter (OTC) medications and nutritional supplements, including herbal or "Chinese" medications are ineligible.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Cavion, Inc.

INDUSTRY

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Matthias Holdhoff, MD

Role: PRINCIPAL_INVESTIGATOR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Locations

UAB Comprehensive Cancer Center

Birmingham, Alabama, United States

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States

Johns Hopkins University

Baltimore, Maryland, United States

Henry Ford Hospital

Detroit, Michigan, United States

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, United States

Abramson Cancer Center of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Hillman Cancer Center at University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, United States

Countries

United States

References

Holdhoff M, Ye X, Supko JG, Nabors LB, Desai AS, Walbert T, Lesser GJ, Read WL, Lieberman FS, Lodge MA, Leal J, Fisher JD, Desideri S, Grossman SA, Wahl RL, Schiff D. Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas. Neuro Oncol. 2017 Jun 1;19(6):845-852. doi: 10.1093/neuonc/nox020.

Reference Type: RESULT

PMID: 28371832 (View on PubMed)

Other Identifiers

NA_00068561

Identifier Type: OTHER

Identifier Source: secondary_id

M1 CA137443

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

ABTC-1101 CDR0000716313

Identifier Type: -

Identifier Source: org_study_id