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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

Phase 1
18 Years
Open (Enrolling)
Brain and Central Nervous System Tumors

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Trial Information

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



- 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

- Assess the severity and frequency of adverse events for tested mibefradil
dihydrochloride dose levels including cumulative toxicity and/or tolerance to adverse

- 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

After completion of study therapy, patients are followed up every 2 months.

Inclusion Criteria


- 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

- 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

- 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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose of mibefradil dihydrochloride

Safety Issue:


Principal Investigator

Matthias Holdhoff, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:

ABTC-1101 CDR0000716313



Start Date:

April 2012

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult giant cell glioblastoma
  • adult glioblastoma
  • adult anaplastic astrocytoma
  • adult anaplastic ependymoma
  • adult anaplastic oligodendroglioma
  • adult mixed glioma
  • recurrent adult brain tumor
  • Glioma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms



Johns Hopkins University Baltimore, Maryland  21205
Abramson Cancer Center of the University of Pennsylvania Philadelphia, Pennsylvania  19104-4283
Henry Ford Hospital Detroit, Michigan  48202
Hillman Cancer Center at University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania  15236
Winship Cancer Institute of Emory University Atlanta, Georgia  30322
Wake Forest University Comprehensive Cancer Center Winston-Salem, North Carolina  27157-1096