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

NCT02202993 | Completed Phase 1 DMC

• 1 other identifier: 1406014067
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Glioblastoma Multiforme (GBM)

Outcome Measures

Primary Outcomes (2)

• Dose limiting toxicities

  Monitored continuously, 27 months

• Maximum tolerated dose

  Monitored continuously, 27 months

Secondary Outcomes (4)

• 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 Outcomes (2)

• Intra-tumoral concentration of mibefradil dihydrochloride

  27 months

• Western blot characterization of resected tumor tissue following 5 days of mibefradil dihydrochloride

  27 months

Study Arms (1)

Mibefradil with Radiation

EXPERIMENTAL

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

Interventions

Mibefradil with Radiation DRUG

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.

Also known as: mibefradil, mibefradil dihydrochloride, Posicor, hypo fractionated radiation, intensity modulated radiation, IMRT

Mibefradil with Radiation

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Cavion, Inc.: lead
• Yale University: collaborator

Study Sites (1)

Yale University

New Haven, Connecticut, 06520, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

Mibefradil; Radiation

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Polycyclic Compounds; Physical Phenomena

Study Officials

• Ranjit S Bindra, MD PhD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2014
• First Posted: July 29, 2014
• Study Start: August 1, 2014
• Primary Completion: September 29, 2017
• Study Completion: September 29, 2017
• Last Updated: July 24, 2019

Record last verified: 2019-04

Locations

US (1)