Disulfiram and Copper Gluconate With Temozolomide in Unmethylated Glioblastoma Multiforme

• ClinicalTrials.gov Identifier: NCT03363659
• Recruitment Status: Recruiting
• First Posted: December 6, 2017
• Last Update Posted: September 28, 2020
• Sponsor: Aurora Health Care
• Information provided by (Responsible Party): Aurora Health Care

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 (Clinical Trial)
• Estimated 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: March 28, 2018
• Estimated Primary Completion Date: December 31, 2021
• Estimated Study Completion Date: December 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 Name: Antabuse; Dietary Supplement: Copper gluconate; Copper gluconate is taken orally, twice daily; Drug: Temozolomide; Temozolomide is taken once daily; Other Name: Temodar, Temodal, Temcad

Outcome Measures

Primary Outcome Measures :

1. Progression Free Survival (PFS) [ Time Frame: 6 months ]
2. Overall Survival [ Time Frame: 1 and 2 years ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)
• 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

Contacts and Locations

Contacts

Contact: Kate McPolin, RN; 414-385-7125; kate.mcpolin@aurora.org

Contact: Lynda Yanny; 414-649-6685; Lynda.Yanny@aah.org

Locations

United States, Wisconsin

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

Milwaukee, Wisconsin, United States, 53215

Contact: Lynda Yanny 414-649-6685 lynda.yanny@aurora.org

Sub-Investigator: Richard A Rovin, MD

Sub-Investigator: Asad Khan, MD

Sub-Investigator: Amin Kassam, MD

Sub-Investigator: Santhi Konduri, PhD

Principal Investigator: Asadullah Khan, MD

Sponsors and Collaborators

Aurora Health Care

Investigators

• Principal Investigator: George Bobustuc, MD; Aurora Health Care

More Information

• Responsible Party: Aurora Health Care
• ClinicalTrials.gov Identifier: NCT03363659
• Other Study ID Numbers: 17.56
• First Posted: December 6, 2017
• Last Update Posted: September 28, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Aurora Health Care:

Glioblastoma; Glioblastoma Multiforme; Anaplastic Glioma; Unmethylated

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; Copper; Temozolomide; Disulfiram; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Trace Elements; Micronutrients; Nutrients; Growth Substances; Physiological Effects of Drugs; Alcohol Deterrents; Acetaldehyde Dehydrogenase Inhibitors; Enzyme Inhibitors