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Mibefradil Dihydrochloride and Hypofractionated Radiation Therapy in Treating Patients with Progressive or Recurrent Glioblastoma Multiforme

Trial Status: Complete

This phase I trial studies the side effects and best dose of mibefradil dihydrochloride when given together with hypofractionated radiation therapy in treating patients with glioblastoma multiforme that is growing, spreading, or getting worse (progressive), or has come back (recurrent). Mibefradil dihydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Mibefradil dihydrochloride may also make tumor cells more sensitive to radiation therapy. Hypofractionated radiation therapy is a radiation treatment in which the total dose of radiation is divided into large doses over a shorter period of time. Giving mibefradil dihydrochloride with hypofractionated radiation therapy may be a better treatment for patients with glioblastoma multiforme.

Inclusion Criteria

  • Patients must consent to be in the study and sign an approved consent form conforming with institutional guidelines
  • Patients must have histologically proven GBM that is progressive or recurrent following standard RT and temozolomide (i.e., at least “biopsy-proven” recurrent disease); previous salvage therapies after first recurrence do not exclude subjects from this trial (e.g., anti-angiogenesis therapies, second- and third-line chemotherapies); patients will be eligible if the original histology was lower-grade glioma and a subsequent diagnosis of GBM is made; for subjects who have tumor resection within the translation sub-study, the pathology results will be reviewed post-surgery and prior to treatment on the main study
  • There must be measurable contrast-enhancing progressive or recurrent GBM (single or multiple lesions) by magnetic resonance imaging (MRI) imaging with an interval of greater than or equal to 6 months between recurrence and completion of prior radiotherapy; while there is no defined maximum tumor volume for eligibility in this study, patients with diffuse, multifocal recurrences may be excluded at the discretion of the study principle investigator (PI); there must be an MRI performed within 4 weeks prior to any therapy
  • If subjects have not passed an interval of at least 6 months, they may still be eligible if they meet the following criteria: convincing histologic evidence of disease recurrence which is not thought to predominantly represent radionecrosis, standard focal external beam radiation therapy (EBRT) treatment with acceptable doses to tumor and normal tissue which suggest re-irradiation is feasible; these cases of early recurrence must be reviewed and approved by the study PI for enrollment into the trial
  • Prior history of standard dose focal RT to 60 Gy in 30 fractions or 59.4 Gy in 1.8 Gy fractions, or equivalent or lower doses; patients who have received prior treatment with non-standard RT dose and fractionation schemes are still eligible, provided they have only received a single course of RT; however, subjects treated with interstitial brachytherapy or single-fraction stereotactic radiosurgery are not eligible for this trial
  • Karnofsky performance status >= 60% within 4 weeks prior to start of any therapy
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dL
  • Serum bilirubin < 1.5 times the upper limit of normal (ULN); unless due to Gilbert’s syndrome (in which < 2 times ULN acceptable)
  • Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.5 times ULN
  • Serum creatinine < 1.5 times ULN
  • Serum potassium, magnesium, and calcium levels normal per current Yale-New Haven Hospital (YNHH) lab medicine standards (may be corrected to those levels by supplementation during screening period) within 2 weeks prior to start of any therapy
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; women of childbearing potential must have a negative pregnancy test prior to treatment
  • Ability to understand and the willingness to sign a written informed consent document
  • Recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade < or equal to 2 from toxicities related to prior therapy within 4 weeks prior to start of any therapy
  • 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

Exclusion Criteria

  • A 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
  • A history of biopsy-confirmed exclusive radionecrosis after initial GBM therapy
  • Patients receiving any other investigational agents or anti-cancer agents within 30 days other than mibefradil dihydrochloride, hypofractionated RT, or corticosteroids as described in this clinical protocol during treatment
  • A 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; an uncontrolled intercurrent illness including, but not limited to, hypertension (> 140/90 mm Hg or above, with or without medication), 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
  • Systolic blood pressure =< 100 mm Hg at baseline, diastolic =< 60 mm Hg at baseline within 4 weeks prior to start of any therapy
  • A 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
  • A history of known, active hepatitis
  • Screening corrected QT (QTc) interval >= 450 msec for males or >= 470 msec for females; PR interval > 250 msec for males and females within 4 weeks prior to start of any therapy
  • High-grade (second degree or above) atrioventricular (AV) block or persistent sinus bradycardia of less than 50 beats per minute (BPM)
  • Known human immunodeficiency virus (HIV)-positivity
  • Pregnant and/or lactating women are excluded
  • Anti-arrhythmia medication other than beta-blockers or digoxin
  • Patients receiving any statin except pravastatin or rosuvastatin
  • Treatment with an H2 blocker, other than famotidine; if the subject requires a proton pump inhibitor (PPI), then esomeprazole, pantoprazole, or rabeprazole may be given
  • Treatment with 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 (mibefradil dihydrochloride)
  • Treatment with unfractionated heparin; patients taking an anticoagulant must use warfarin or a low molecular weight heparin
  • Treatment with drugs that are substrates of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), and cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) except for the ones that are explicitly permitted; prohibited medications include but are not necessarily limited to alfuzosin, amiodarone, astemizole, bepridil, “Chinese” (herbal) medicines, cisapride, cyclosporine, cyclophosphamide, desipramine, erythromycin, etoposide, fentanyl, flecainide, flutamide, grapefruit and grapefruit juice, halofantrine, ifosfamide, imipramine, lovastatin, mexiletine, modafinil, oxycodone, pimozide, propafenone, quetiapine, quinidine, simvastatin, tacrolimus, tamoxifen, terfenadine, thioridazine, vinblastine and vincristine; exception: those patients who are in the translational sub-study will receive a low dose of fentanyl (a substrate of CYP3A4) during the surgical procedure (100-200 mcg) for pain, along with ultra-short acting remifentanil (the latter has 8-10 min half-life)
  • Treatment with drugs that have the 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 if using the following OTC medications that are allowed at labeled doses, acetaminophen, aspirin, diphenhydramine, calcium carbonate antacids, branded multiple vitamin supplements and pseudoephedrine; topical preparations and decongestant nasal sprays are allowed

Connecticut

New Haven
Yale University
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Ranjit S. Bindra
Phone: 203-200-3673

PRIMARY OBJECTIVES:

I. Determine the maximum-tolerated dose (MTD) of mibefradil dihydrochloride when administered with concurrent hypofractionated radiation therapy (RT), 600 cGy x 5 fractions, in subjects with progressive or recurrent glioblastoma multiforme (GBM).

SECONDARY OBJECTIVES:

I. Assess the safety of mibefradil dihydrochloride administered continuously daily with hypofractionated RT when the drug dose is escalated from a starting dose of 150 mg/day, given in 4 divided doses per day for 17 consecutive days to the MTD.

II. Determine the steady state levels of mibefradil dihydrochloride at the time of surgical intervention in selected subjects, as well as baseline, pre-dose and post-dose levels twice during RT for all subjects.

III. Evaluate the preliminary efficacy of mibefradil dihydrochloride and RT in terms of progression-free and overall survival (progression-free survival [PFS] and overall survival [OS], respectively), calculated using the Kaplan-Meier method. Patients from both the dose escalation and MTD expansion cohorts will be evaluated.

TERTIARY OBJECTIVES:

I. Determine whether intratumoral concentrations of mibefradil dihydrochloride can be detected in resected tumor tissue in selected subjects who receive the drug prior to surgery.

II. Assess the effects of mibefradil dihydrochloride on the cleavage of selected proteins in vivo in resected tumor tissue, including poly (adenosine phosphate [ADP]-ribose) polymerase-1 (PARP-1), caspase-3, and deoxyribonucleic acid (DNA) protein kinase, catalytic subunit (DNA-PKcs).

III. Create primary spheroid cultures from resected tumor to test and compare mibefradil sensitivity in vitro.

OUTLINE: This is a dose-escalation study of mibefradil dihydrochloride.

Patients receive mibefradil dihydrochloride orally (PO) four times daily (QID) on days 1-17 and undergo hypofractionated radiation therapy on Monday, Wednesday, and Friday of week 2 and Tuesday and Thursday of week 3 (days 4-14) in the absence of disease progression or unacceptable toxicity. Selected patients undergoing surgery receive mibefradil dihydrochloride PO QID for 5 days prior to surgical intervention.

After completion of study treatment, patients are followed up every 6 weeks for 30 weeks, and then every 12 weeks for 24 weeks.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Yale University

Principal Investigator
Ranjit S. Bindra

  • Primary ID 1406014067
  • Secondary IDs NCI-2014-01558, TAU-2014-1
  • Clinicaltrials.gov ID NCT02202993