Disulfiram and Copper Gluconate With Temozolomide in Unmethylated Glioblastoma Multiforme

Sponsor

Aurora Health Care (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03363659

Collaborator

(none)

Enrollment

Location

Arm

57.1

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

One of Disulfiram antitumor effects suggested in preclinical studies is MGMT (methyl-guanine-methyl-transferase) inhibition. Disulfiram MGMT inhibitory effect is enhanced by addition of Copper. This study evaluates the impact of DSF + Cu combination when added to standard Temozolomide in the treatment of unmethylated GBM patients.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Glioblastoma Multiforme	Drug: Disulfiram Dietary Supplement: Copper gluconate Drug: Temozolomide	Phase 2

Detailed Description

Glioblastoma is the most common malignant primary brain tumor and one of the most devastating cancers. The current standard of care for glioblastoma includes maximal safe resection followed by radiotherapy and temozolomide, which results in a median progression-free survival of less than 7 months, and median overall survival (OS) of less than 15 months. Moreover, patients with unmethylated glioblastoma respond poorly to this current standard treatment. This clinical trial evaluates the potential role of continuous, upfront use of Disulfiram in combination with Copper gluconate in enhancing temozolomide effect in the treatment of unmethylated GBM patients.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II, Open-Label Study to Evaluate the Safety, Tolerability, and Efficacy of Disulfiram and Copper Gluconate When Added to Standard Temozolomide Treatment in Patients With Newly Diagnosed Resected Unmethylated Glioblastoma Multiforme

Actual Study Start Date :

Mar 28, 2018

Anticipated Primary Completion Date :

Dec 31, 2021

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DSF-Cu with temozolomide and radiation Disulfiram (DSF; oral) / copper gluconate (Cu; oral) dosed at 125 mg / 2 mg, twice daily. Temozolomide will be administered following the standard Stupp protocol at a dose of 75 mg/m2 for 42 days with concurrent radiation therapy. Temozolomide maintenance dose will be 150 mg/m2 once daily on Days 1-5 of every 28-day cycle while DSF-Cu is continued twice daily, as tolerated, for the duration of the Temozolomide adjuvant treatment. Patients demonstrating continued benefit from the adjuvant temozolomide after 6 cycles can continue treatment to a maximum of 12 cycles	Drug: Disulfiram Disulfiram is taken orally, twice daily. Other Names: Antabuse Dietary Supplement: Copper gluconate Copper gluconate is taken orally, twice daily Drug: Temozolomide Temozolomide is taken once daily Other Names: Temodar, Temodal, Temcad

Arm

Intervention/Treatment

Experimental: DSF-Cu with temozolomide and radiation

Disulfiram (DSF; oral) / copper gluconate (Cu; oral) dosed at 125 mg / 2 mg, twice daily. Temozolomide will be administered following the standard Stupp protocol at a dose of 75 mg/m2 for 42 days with concurrent radiation therapy. Temozolomide maintenance dose will be 150 mg/m2 once daily on Days 1-5 of every 28-day cycle while DSF-Cu is continued twice daily, as tolerated, for the duration of the Temozolomide adjuvant treatment. Patients demonstrating continued benefit from the adjuvant temozolomide after 6 cycles can continue treatment to a maximum of 12 cycles

Drug: Disulfiram

Disulfiram is taken orally, twice daily.

Other Names:

Antabuse

Dietary Supplement: Copper gluconate

Copper gluconate is taken orally, twice daily

Drug: Temozolomide

Temozolomide is taken once daily

Other Names:

Temodar, Temodal, Temcad

Outcome Measures

Primary Outcome Measures

Progression Free Survival (PFS) [6 months]
Overall Survival [1 and 2 years]

Secondary Outcome Measures

Quality of life (QOL) [1 year]
Edmonton Symptom Assessment System - Revised (ESAS-r) questionnaire

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18 or older
Diagnosis of histologically confirmed glioblastoma (WHO grade IV). Subjects with an original histologic diagnosis of low grade glioma or anaplastic glioma (WHO grade II or III) are eligible if a subsequent histological diagnosis of glioblastoma is made
Patients whose tumor is determined to be unmethylated
Patients with incomplete resection as determined by residual, measurable gadolinium or contrast-enhancing lesion or lesions
Recent resection of glioblastoma within 4 weeks of study entry. Patients who have only had a tumor biopsy and who are considered unresectable are eligible (but based on the study accrual this subset of patients with unresectable tumor may be considered for separate analysis)
ECOG PS of ≤ 2 (see appendix A)
Willing to remain abstinent from consuming alcohol while on DSF
No prior radiation or chemotherapy
Meets the following laboratory criteria:
Absolute neutrophil count ≥ 1,500/mcL
Platelets ≥ 100,000/mcL
Hemoglobin > 10.0 g/dL (transfusion and/or ESA allowed)
Total bilirubin and alkaline phosphatase ≤ 2x institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN
Blood urea nitrogen (BUN) and creatinine < 1.5 x ULN
Able to take oral medication
Able to understand and willing to sign an institutional review board (IRB)-approved written informed consent document (legally authorized representative permitted)

Exclusion Criteria:

Radiographic evidence of leptomeningeal dissemination, extensive intraparenchymal dissemination, infratentorial tumor, or metastatic disease to sites remote from the supratentorial brain
Enrolled in another clinical trial testing a novel therapy or drug
Received prior radiation therapy or chemotherapy for glioblastoma
History of allergic reaction/hypersensitivity to DSF (without alcohol) or copper.
Treatment with the following medications that may interfere with metabolism of DSF: warfarin (unless otherwise chosen by the study PI who will actively adjust Coumadin dose to consistently maintain a safe, therapeutic INR < 3), theophylline, amitriptyline, isoniazid, metronidazole, phenytoin, phenobarbital, chlorzoxazone, halothane, imipramine, chlordiazepoxide, diazepam. (Note: lorazepam and oxazepam are not affected by the P450 system and are not contraindicated with DSF).
Active severe hepatic or renal disease
Grade 2 or higher peripheral neuropathy or ataxia per NCI CTCAE version 4.0 (2009)
History of idiopathic seizure disorder schizophrenia, or psychosis unrelated to glioblastoma, corticosteroid, or anti-epileptic medications
History of Wilson's or Gilbert's disease
Current excessive use of alcohol