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Clinical Trials (PDQ®)

Phase I Study of Mibefradil Dihydrochloride in Patients With Recurrent High-Grade Glioma Receiving Temozolomide
First Published: 11/22/2011     Last Modified: 5/16/2012  

Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Mibefradil Dihydrochloride and Temozolomide in Treating Patients With Recurrent Glioma

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IBiomarker/Laboratory analysis, Diagnostic, TreatmentActive18 and overNCIABTC-1101
ABTC-1101, NCT01480050

Objectives

Primary

  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.

Secondary

  1. 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.
  2. Determine the pharmacokinetic profile of mibefradil.
  3. Determine the steady state levels of mibefradil dihydrochloride on the last day of dosing.
  4. Assess the severity and frequency of adverse events for tested mibefradil dihydrochloride dose levels including cumulative toxicity and/or tolerance to adverse effects.
  5. Estimate the number and type of radiographic responses to treatment with mibefradil dihydrochloride and temozolomide.
  6. 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).

Entry Criteria

Disease Characteristics:

  • Histologically proven high-grade glioma (glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, mixed anaplastic oligoastrocytoma, anaplastic ependymoma) that is progressive or recurrent following standard upfront radiation therapy + temozolomide

  • Measurable contrast-enhancing progressive or recurrent high-grade glioma (single or multiple lesions) by MRI within 30 days of starting treatment

  • Must have a plan for retreatment with temozolomide at 150-200 mg/m² for 5 days per cycle; each cycle = 28 days
    • Must have previously tolerated at least one cycle of adjuvant temozolomide therapy in the prior treatment of the glioma

Prior/Concurrent Therapy:

  • See Disease Characteristics
  • Recovered to CTCAE grade < 2 from toxicities related to prior therapy
  • An interval of at least 3 months must have elapsed since the completion of the most recent course of radiation therapy, the last dose of temozolomide (TMZ), or placement of Gliadel wafers
    • No prior cytotoxic therapies other than temozolomide and Gliadel wafers
  • Prior anti-VEGF therapies are allowed if more than four months have elapsed from the end of prior treatment
  • 30 days must have elapsed since previous treatment of the brain tumor with any other agents
  • Must be maintained on a stable or decreasing corticosteroid regimen (no increase for 7 days) prior to the start of treatment
  • Patients may not be receiving any other investigational agents or chemotherapeutic agents other than temozolomide
  • No anti-arrhythmia medication other than beta-blockers or digoxin
  • No requirement for a calcium channel blocker for blood pressure control that cannot be switched to an antihypertensive with an alternative mechanism of action
    • Permitted anti-hypertensive medications include: chlorothiazide, hydrochlorothiazide, atenolol, nadolol, enalapril, lisinopril, eprosartan, and irbesartan
  • Patients cannot receive any statin while on trial except pravastatin
  • No treatment with an H2 blocker, other than famotidine
    • If the patient requires a proton pump inhibitor (PPI), then esomeprazole, pantoprazole, or rabeprazole may be given
  • No concurrent enzyme-inducing anti-epileptic drugs (EIAEDs)
    • Patients 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
  • Patients taking an anticoagulant must use warfarin or a low molecular weight heparin
    • Unfractionated heparin is not permitted
  • No drugs that are substrates of CYP3A4, CYP2D6, and CYP1A2 except for the ones that are explicitly permitted
  • No drugs that are known to interact adversely with metabolism or excretion of mibefradil
  • Patients who are taking and cannot discontinue over-the-counter (OTC) medications and nutritional supplements, including herbal or “Chinese” medications, are not eligible, except for the following:
    • OTC medications that are allowed at labeled doses during dosing with mibefradil are acetaminophen, aspirin, diphenhydramine, calcium carbonate antacids, branded multiple vitamin supplements and pseudoephedrine
    • Topical preparations and decongestant nasal sprays are allowed

Patient Characteristics:

  • Karnofsky performance status ≥ 60%
  • Hemoglobin > 9 g/dL
  • Absolute neutrophil count > 1,500/µL
  • Platelets > 100,000/µL
  • Total bilirubin < 3 times institutional upper limit of normal (ULN)
  • AST(SGOT)/ALT(SGPT) < 3 times ULN
  • Creatinine normal OR creatinine clearance > 50 mL/min
  • Serum potassium, magnesium, and calcium levels normal (may be corrected to those levels by supplementation during screening period)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Women of childbearing potential and men must agree to use adequate contraception
  • Able to tolerate MRIs
    • CT scans cannot be substituted for MRIs in this study
  • No concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder
    • Subjects with prior malignancies must be disease-free for ≥ five years
  • Patients must identify a caregiver/support person who will agree to assist with the remote cardiac monitor and taking/recording blood pressure at home
  • No serious concurrent infection or medical illness, which would jeopardize the ability of the subject to receive the treatment outlined in this protocol with reasonable safety
  • No 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
  • No history of known, active hepatitis
  • No screening QTc interval ≥ 450 mSec for males or 470 mSec for females
  • No PR interval > 250 mSec
  • No systolic blood pressure < 100 mm Hg at baseline
  • No history (within six months) of myocardial infarction, unstable angina, uncontrolled hypertension, or congestive heart failure
  • No high-grade (second degree or above) AV block or persistent sinus bradycardia of less than 50 BPM
  • No known HIV-positivity

Expected Enrollment

58

Outcomes

Primary Outcome(s)

Maximum-tolerated dose of mibefradil dihydrochloride
Dose-limiting toxicity

Secondary Outcome(s)

Toxicity and adverse events according to CTCAE v. 4.0
Biological activity of treatment determined by radiographic response
Pharmacokinetics of mibefradil dihydrochloride
Potential effect of mibefradil dihydrochloride on tumor metabolism as determined by [F-18]FLT PET scans in the dose-expansion cohort

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.

Trial Contact Information

Trial Lead Organizations

Adult Brain Tumor Consortium

Matthias Holdhoff, MD, Principal investigator
Ph: 410-287-0337

Trial Sites

U.S.A.
Maryland
  Baltimore
 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
 Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Center at John Hopkins
Ph: 410-955-8804
  Email: jhcccro@jhmi.edu

Registry Information
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
Trial Start Date 2012-04-18
Trial Completion Date 2013-01-01 (estimated)
Registered in ClinicalTrials.gov NCT01480050
Date Submitted to PDQ 2011-11-07
Information Last Verified 2012-06-25
NCI Grant/Contract Number CA-137443

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.