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

This study has been completed.
Sponsor:
Collaborator:
Yale University
Information provided by (Responsible Party):
Cavion LLC
ClinicalTrials.gov Identifier:
NCT02202993
First received: July 15, 2014
Last updated: March 30, 2017
Last verified: March 2017
  Purpose
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).

Condition Intervention Phase
Glioblastoma Multiforme (GBM)
Drug: Mibefradil with Radiation
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: TAU-2014-1: Phase I Trial of Mibefradil Dihydrochloride With Hypofractionated Re-Irradiation Therapy in Treating Patients With Recurrent Glioblastoma Multiforme (GBM)

Resource links provided by NLM:


Further study details as provided by Cavion LLC:

Primary Outcome Measures:
  • Dose limiting toxicities [ Time Frame: Monitored continuously, 27 months ]
  • Maximum tolerated dose [ Time Frame: Monitored continuously, 27 months ]

Secondary Outcome Measures:
  • Adverse events [ Time Frame: 27 months ]
  • Mibefradil dihydrochloride steady state plasma concentrations [ Time Frame: 27 months ]
  • Progression-free survival of treated patients [ Time Frame: 27 months ]
  • Overall survival of treated patients [ Time Frame: 27 months ]

Other Outcome Measures:
  • Intra-tumoral concentration of mibefradil dihydrochloride [ Time Frame: 27 months ]
  • Western blot characterization of resected tumor tissue following 5 days of mibefradil dihydrochloride [ Time Frame: 27 months ]

Estimated Enrollment: 24
Study Start Date: August 2014
Study Completion Date: March 31, 2017
Primary Completion Date: March 31, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • mibefradil
  • mibefradil dihydrochloride
  • Posicor
  • hypo fractionated radiation
  • intensity modulated radiation
  • IMRT

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02202993

Locations
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06520
Sponsors and Collaborators
Cavion LLC
Yale University
Investigators
Principal Investigator: Ranjit S Bindra, MD PhD Yale University
  More Information

Responsible Party: Cavion LLC
ClinicalTrials.gov Identifier: NCT02202993     History of Changes
Other Study ID Numbers: 1406014067
Study First Received: July 15, 2014
Last Updated: March 30, 2017

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Mibefradil
Antihypertensive Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 24, 2017