Mibefradil Dihydrochloride and Temozolomide in Treating Patients With Recurrent Glioma

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Collaborators:
Tau Therapeutics LLC
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01480050
First received: November 23, 2011
Last updated: August 11, 2014
Last verified: August 2014

November 23, 2011
August 11, 2014
April 2012
January 2015   (final data collection date for primary outcome measure)
  • Maximum-tolerated dose of mibefradil dihydrochloride [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Dose-limiting toxicity [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Maximum-tolerated dose of mibefradil dihydrochloride [ Designated as safety issue: Yes ]
  • Dose-limiting toxicity [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01480050 on ClinicalTrials.gov Archive Site
  • Toxicity and adverse events according to CTCAE v. 4.0 [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Biological activity of treatment determined by radiographic response [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Pharmacokinetics of mibefradil dihydrochloride [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Toxicity and adverse events according to CTCAE v. 4.0 [ Designated as safety issue: Yes ]
  • Biological activity of treatment determined by radiographic response [ Designated as safety issue: No ]
  • Pharmacokinetics of mibefradil dihydrochloride [ Designated as safety issue: No ]
  • Potential effect of mibefradil dihydrochloride on tumor metabolism as determined by [F-18]FLT PET scans in the dose-expansion cohort [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Mibefradil Dihydrochloride and Temozolomide in Treating Patients With Recurrent Glioma
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

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.

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.

Interventional
Phase 1
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Brain and Central Nervous System Tumors
  • Drug: mibefradil dihydrochloride
  • Drug: temozolomide
  • Other: 3'-deoxy-3'-[18F]fluorothymidine
  • Other: pharmacological study
Not Provided
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
34
Not Provided
January 2015   (final data collection date for primary outcome measure)

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 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

PATIENT CHARACTERISTICS:

  • 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

PRIOR CONCURRENT THERAPY:

  • 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
Both
18 Years and older
No
Contact: Joy Fisher, MA 410-955-3657 jfisher@jhmi.edu
Contact: Serena Desideri, MD 410-614-4400 sdeside1@jhmi.edu
United States
 
NCT01480050
ABTC-1101 CDR0000716313, ABTC-1101
Not Provided
Sidney Kimmel Comprehensive Cancer Center
Sidney Kimmel Comprehensive Cancer Center
  • National Cancer Institute (NCI)
  • Tau Therapeutics LLC
Principal Investigator: Matthias Holdhoff, MD Sidney Kimmel Comprehensive Cancer Center
Sidney Kimmel Comprehensive Cancer Center
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP