TAU-2014-1: Mibefradil and Hypofractionated Re-Irradiation Therapy in Recurrent GBM

TAU-2014-1: Phase I Trial of Mibefradil Dihydrochloride With Hypofractionated Re-Irradiation Therapy in Treating Patients With Recurrent Glioblastoma Multiforme (GBM)

This is a dose-escalation study that will assess the safety and determine the maximum tolerated dose (MTD) of mibefradil dihydrochloride, a partially selective T-type calcium channel blocker, combined with hypofractionated radiation therapy (RT) in subjects with recurrent glioblastoma multiforme (GBM).

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme (GBM)
• Intervention / Treatment: Drug: Mibefradil with Radiation

Detailed Description

Patients will receive mibefradil dihydrochloride, which will be dose escalated from 150mg/day until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day is reached using a standard 3 + 3 design. Mibefradil dihydrochloride will be dosed orally in 4 divided doses per day for 17 consecutive days to the MTD. The MTD will be determined according to dose-limiting toxicities (DLTs) graded using the Common Terminology Criteria for Adverse Events version 4.0. Radiation therapy (RT) consists of 5 fractions of 600 centigray (cGy) each, delivered over 2 consecutive weeks for a total dose of 3,000 cGy, using stereotactic, intensity-modulated radiation therapy (IMRT).

The primary endpoint of the study is to determine the MTD of mibefradil dihydrochloride when given with concurrent hypofractionated RT. Secondary and tertiary endpoints include evaluating the efficacy of mibefradil dihydrochloride and RT in terms of progression-free survival (PFS) and overall survival (OS), and to perform translational research on resected tumor tissue.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Sign written informed consent.
• Histologically proven glioblastoma multiforme (GBM) that is progressive or recurrent following standard radiation therapy (RT) and temozolomide (i.e., at least "biopsy-proven" recurrent disease). Previous salvage therapies after first recurrence are permitted.
• Measurable contrast-enhancing progressive or recurrent GBM (single or multiple lesions) by MRI imaging with an interval of greater than or equal to 6 months between recurrence and completion of prior radiotherapy.
• Patients who have not passed an interval of at least 6 months 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.
• 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%
• Clinical laboratory:
• absolute neutrophil count >1,500/microliter (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
• Women of childbearing potential and men must agree to use adequate contraception.
• Women of childbearing potential must have a negative pregnancy test prior to treatment.
• Recovered to Common Toxicity Criteria for Adverse Effects (CTCAE) grade ≤ 2 from prior therapy toxicities
• 30 days since previous treatment of brain tumor with any other agents.
• Stable or decreasing corticosteroid regimen (no increase for 7 days) prior to the start of treatment.
• >18 years of age

Exclusion Criteria:

• Concurrent malignancy except curatively treated non-melanoma skin cancer or carcinoma in situ of the cervix, breast, or bladder. Subjects with prior malignancies must be disease-free for ≥ five years.
• Biopsy-confirmed exclusive radionecrosis after initial GBM therapy.
• Receipt of other investigational agents or anti-cancer agents within 30 days
• Serious concurrent infection or medical illness, which would jeopardize the ability of the subject to receive treatment safely.
• Systolic blood pressure <100 mm Hg, diastolic <60 mm Hg.
• Requirement for 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.
• Known, active hepatitis.
• corrected QT (QTc) interval ≥ 450 milliseconds (mSec) for males or ≥470 mSec for females. PR interval > 250 mSec for males and females
• High-grade (second degree or above) atria-ventricular (AV) block or persistent sinus bradycardia of less than 50 beats per minute (BPM).
• Known HIV-positivity
• Pregnant and/or lactating women
• Anti-arrhythmia medication other than beta-blockers or digoxin.
• Treatment with concurrent enzyme-inducing anti-epileptic drugs (EIAEDs).
• Treatment with unfractionated heparin. Patients taking an anticoagulant must use warfarin or a low molecular weight heparin.
• Treatment with specified drugs that are substrates of cytochrome 3A4 (CYP3A4), cytochrome 2D6 (CYP2D6), cytochrome 1A2 (CYP1A2)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Mibefradil with Radiation; Patients will receive mibefradil dihydrochloride, which will be dose escalated from 150mg/day until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day is reached using a standard 3 + 3 design. Mibefradil dihydrochloride will be dosed orally in 4 divided doses per day for 17 consecutive days to the MTD. This will be given concurrently with hypofractionated radiation therapy.

Drug: Mibefradil with Radiation; Patients will receive mibefradil dihydrochloride, which will be dose escalated from 150mg/day until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day is reached using a standard 3 + 3 design. Mibefradil dihydrochloride will be dosed orally in 4 divided doses per day for 17 consecutive days to the MTD. This will be given concurrently with hypofractionated radiation therapy.; Other Names: IMRT; mibefradil; mibefradil dihydrochloride; Posicor; hypo fractionated radiation; intensity modulated radiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Dose limiting toxicities	Monitored continuously, 27 months
Maximum tolerated dose	Monitored continuously, 27 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse events	27 months
Mibefradil dihydrochloride steady state plasma concentrations	27 months
Progression-free survival of treated patients	27 months
Overall survival of treated patients	27 months

Other Outcome Measures

Outcome Measure	Time Frame
Intra-tumoral concentration of mibefradil dihydrochloride	27 months
Western blot characterization of resected tumor tissue following 5 days of mibefradil dihydrochloride	27 months

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals
• Collaborators: Yale University
• Investigators: Principal Investigator: Ranjit S Bindra, MD PhD, Yale University

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): September 29, 2017
• Study Completion (Actual): September 29, 2017

Study Registration Dates

• First Submitted: July 15, 2014
• First Submitted That Met QC Criteria: July 25, 2014
• First Posted (Estimate): July 29, 2014

Study Record Updates

• Last Update Posted (Actual): July 24, 2019
• Last Update Submitted That Met QC Criteria: July 22, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Cytochrome P-450 Enzyme Inhibitors; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Cytochrome P-450 CYP1A2 Inhibitors; Mibefradil
• Other Study ID Numbers: 1406014067