Mibefradil Dihydrochloride and Temozolomide in Treating Patients With Recurrent Glioma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01480050
Recruitment Status : Completed
First Posted : November 28, 2011
Last Update Posted : June 26, 2018
National Cancer Institute (NCI)
Cavion, Inc.
Information provided by (Responsible Party):
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.

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

Detailed Description:



  • 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)
Primary Purpose: Treatment
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 : April 2012
Actual Primary Completion Date : August 2015
Actual Study Completion Date : June 1, 2017

Arm Intervention/treatment
Experimental: Dose Finding

Dose Escalation of Mibefradil for 7 days followed by TMZ (150-200mg/m2) every 28 days. At MTD 10 additional pts treated with an addition FLT PET-CT scan.

Mibefradil Temozolomide (TMZ) FLT PET CT '3'-deoxy-3'-[18F]fluorothymidine' Pharmacology Studies

Drug: temozolomide
Other: 3'-deoxy-3'-[18F]fluorothymidine
tracer used for FLT PET CT

Other: pharmacological study
Drug: Mibefradil

Primary Outcome Measures :
  1. Maximum-tolerated dose of mibefradil dihydrochloride [ Time Frame: 2 years ]
  2. Dose-limiting toxicity [ Time Frame: 2 years ]

Secondary Outcome Measures :
  1. Toxicity and adverse events according to CTCAE v. 4.0 [ Time Frame: 2 years ]
  2. Biological activity of treatment determined by radiographic response [ Time Frame: 3 years ]
  3. Pharmacokinetics of mibefradil dihydrochloride [ Time Frame: 2 years ]
  4. 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 ]

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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 imaging 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


  • Karnofsky performance status ≥ 60%
  • Hemoglobin ≥ 9 g/dL
  • Absolute neutrophil count ≥ 1,500/µL
  • Platelets ≥ 100,000/µL
  • Total bilirubin < or equal to 3 times institutional upper limit of normal (ULN)
  • AST(SGOT)/ALT(SGPT) < or equal to 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
  • Mini-Mental State Exam score of ≥ 15
  • 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 < or equal 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


  • See Disease Characteristics
  • Recovered to CTCAE grade < or equal 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 have potential to interfere 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

Information from the National Library of Medicine

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 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
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Cavion, Inc.
Principal Investigator: Matthias Holdhoff, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Identifier: NCT01480050     History of Changes
Other Study ID Numbers: ABTC-1101 CDR0000716313
First Posted: November 28, 2011    Key Record Dates
Last Update Posted: June 26, 2018
Last Verified: June 2018

Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
adult giant cell glioblastoma
adult glioblastoma
adult anaplastic astrocytoma
adult anaplastic ependymoma
adult anaplastic oligodendroglioma
adult mixed glioma
recurrent adult brain tumor

Additional relevant MeSH terms:
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents
Antihypertensive Agents
Calcium Channel Blockers