Recruitment

Recruitment Status
Completed
Estimated Enrollment
24

Inclusion Criteria

Stable or decreasing corticosteroid regimen (no increase for 7 days) prior to the start of treatment.
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)
...
Stable or decreasing corticosteroid regimen (no increase for 7 days) prior to the start of treatment.
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)
>18 years of age
serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.5 times ULN
Recovered to Common Toxicity Criteria for Adverse Effects (CTCAE) grade ≤ 2 from prior therapy toxicities
Women of childbearing potential and men must agree to use adequate contraception.
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.
Women of childbearing potential must have a negative pregnancy test prior to treatment.
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.
Clinical laboratory:
Karnofsky performance status ≥60%
serum Creatinine < 1.5 times ULN
Sign written informed consent.
30 days since previous treatment of brain tumor with any other agents.
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.
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.
absolute neutrophil count >1,500/microliter (mcL)

Exclusion Criteria

Treatment with specified drugs that are substrates of cytochrome 3A4 (CYP3A4), cytochrome 2D6 (CYP2D6), cytochrome 1A2 (CYP1A2)
Treatment with concurrent enzyme-inducing anti-epileptic drugs (EIAEDs).
Known HIV-positivity
...
Treatment with specified drugs that are substrates of cytochrome 3A4 (CYP3A4), cytochrome 2D6 (CYP2D6), cytochrome 1A2 (CYP1A2)
Treatment with concurrent enzyme-inducing anti-epileptic drugs (EIAEDs).
Known HIV-positivity
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.
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.
Receipt of other investigational agents or anti-cancer agents within 30 days
High-grade (second degree or above) atria-ventricular (AV) block or persistent sinus bradycardia of less than 50 beats per minute (BPM).
Treatment with unfractionated heparin. Patients taking an anticoagulant must use warfarin or a low molecular weight heparin.
Pregnant and/or lactating women
Biopsy-confirmed exclusive radionecrosis after initial GBM therapy.
Anti-arrhythmia medication other than beta-blockers or digoxin.
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.
corrected QT (QTc) interval ≥ 450 milliseconds (mSec) for males or ≥470 mSec for females. PR interval > 250 mSec for males and females
Known, active hepatitis.

Summary

Conditions
Glioblastoma Multiforme (GBM)
Type
Interventional
Phase
Phase 1
Design
  • Allocation: N/A
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label)
  • Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 80 years
Gender
Both males and females

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 1...

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.

Inclusion Criteria

Stable or decreasing corticosteroid regimen (no increase for 7 days) prior to the start of treatment.
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)
...
Stable or decreasing corticosteroid regimen (no increase for 7 days) prior to the start of treatment.
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)
>18 years of age
serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.5 times ULN
Recovered to Common Toxicity Criteria for Adverse Effects (CTCAE) grade ≤ 2 from prior therapy toxicities
Women of childbearing potential and men must agree to use adequate contraception.
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.
Women of childbearing potential must have a negative pregnancy test prior to treatment.
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.
Clinical laboratory:
Karnofsky performance status ≥60%
serum Creatinine < 1.5 times ULN
Sign written informed consent.
30 days since previous treatment of brain tumor with any other agents.
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.
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.
absolute neutrophil count >1,500/microliter (mcL)

Exclusion Criteria

Treatment with specified drugs that are substrates of cytochrome 3A4 (CYP3A4), cytochrome 2D6 (CYP2D6), cytochrome 1A2 (CYP1A2)
Treatment with concurrent enzyme-inducing anti-epileptic drugs (EIAEDs).
Known HIV-positivity
...
Treatment with specified drugs that are substrates of cytochrome 3A4 (CYP3A4), cytochrome 2D6 (CYP2D6), cytochrome 1A2 (CYP1A2)
Treatment with concurrent enzyme-inducing anti-epileptic drugs (EIAEDs).
Known HIV-positivity
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.
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.
Receipt of other investigational agents or anti-cancer agents within 30 days
High-grade (second degree or above) atria-ventricular (AV) block or persistent sinus bradycardia of less than 50 beats per minute (BPM).
Treatment with unfractionated heparin. Patients taking an anticoagulant must use warfarin or a low molecular weight heparin.
Pregnant and/or lactating women
Biopsy-confirmed exclusive radionecrosis after initial GBM therapy.
Anti-arrhythmia medication other than beta-blockers or digoxin.
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.
corrected QT (QTc) interval ≥ 450 milliseconds (mSec) for males or ≥470 mSec for females. PR interval > 250 mSec for males and females
Known, active hepatitis.

Tracking Information

NCT #
NCT02202993
Collaborators
Yale University
Investigators
  • Principal Investigator: Ranjit S Bindra, MD PhD Yale University
  • Ranjit S Bindra, MD PhD Yale University
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