Disulfiram and Copper Gluconate With Temozolomide in Unmethylated Glioblastoma Multiforme

NCT ID: NCT03363659

Last Updated: 2024-10-03

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 15 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-28
• Study Completion Date: 2022-01-13

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 Disulfiram (DSF) + Copper (Cu) combination when added to standard Temozolomide in the treatment of unmethylated Glioblastoma Multiforme (GBM) patients.

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 Glioblastoma multiforme (GBM) patients.

Conditions

Glioblastoma; Glioblastoma Multiforme

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

Disulfiram is taken orally, twice daily.

Copper gluconate

Intervention Type: DIETARY_SUPPLEMENT

Copper gluconate is taken orally, twice daily

Temozolomide

Intervention Type: DRUG

Temozolomide is taken once daily

Interventions

Disulfiram

Disulfiram is taken orally, twice daily.

Intervention Type: DRUG

Copper gluconate

Copper gluconate is taken orally, twice daily

Intervention Type: DIETARY_SUPPLEMENT

Temozolomide

Temozolomide is taken once daily

Intervention Type: DRUG

Other Intervention Names

Antabuse; Temodar, Temodal, Temcad

Eligibility Criteria

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)
• Eastern Cooperative Oncology Group Performance Status (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 (microliter)
• Platelets ≥ 100,000/mcL
• Hemoglobin > 10.0 g/dL (grams/deciliter) (transfusion and/or ESA (erythropoiesis-stimulating agent) 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 international normalized ratio (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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Wake Forest University Health Sciences

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Asadullah Khan, MD

Role: PRINCIPAL_INVESTIGATOR

Wake Forest University Health Sciences

Locations

Aurora Health Care, Aurora St. Luke's Medical Center

Milwaukee, Wisconsin, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

17.56

Identifier Type: -

Identifier Source: org_study_id