Mibefradil Dihydrochloride and Temozolomide in Treating Patients With Recurrent Glioma

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