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Disulfiram and Copper Gluconate With Temozolomide in Unmethylated Glioblastoma Multiforme

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ClinicalTrials.gov Identifier: NCT03363659
Recruitment Status : Recruiting
First Posted : December 6, 2017
Last Update Posted : August 15, 2018
Sponsor:
Information provided by (Responsible Party):
Aurora Health Care

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 Type : Interventional
Estimated Enrollment : 40 participants
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 : January 21, 2026
Estimated Study Completion Date : January 21, 2027


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




Primary Outcome Measures :
  1. Objective Response Rate [ Time Frame: Percentage of patients at 6 months ]
    Complete or partial response using Response Assessment in Neuro-Oncology Criteria (RANO)

  2. Six months progression-free survival [ Time Frame: Proportion without progression at 6 months ]
    Response Assessment in Neuro-Oncology Criteria (RANO)


Secondary Outcome Measures :
  1. Toxicity [ Time Frame: 6 and 12 months ]
    Common Terminology Criteria for Adverse Events v4.0 (CTCAE)

  2. Quality of life (QOL) [ Time Frame: 12 months ]
    Edmonton Symptom Assessment System - Revised (ESAS-r) questionnaire

  3. Overall survival [ Time Frame: 12 months ]
    Proportion of alive participants



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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 unreseactable 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03363659


Contacts
Contact: Kate McPolin, RN 414-385-7125 kate.mcpolin@aurora.org
Contact: Carol Tutino, RN,MS,CCRC 414-649-5526 carol.tutino@aurora.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   
Principal Investigator: George Bobustuc, MD         
Sub-Investigator: Richard A Rovin, MD         
Sub-Investigator: Asad Khan, MD         
Sub-Investigator: Amin Kassam, MD         
Sub-Investigator: Santhi Konduri, PhD         
Sponsors and Collaborators
Aurora Health Care
Investigators
Principal Investigator: George Bobustuc, MD Aurora Health Care

Responsible Party: Aurora Health Care
ClinicalTrials.gov Identifier: NCT03363659     History of Changes
Other Study ID Numbers: 17.56
First Posted: December 6, 2017    Key Record Dates
Last Update Posted: August 15, 2018
Last Verified: August 2018
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
Glioma
Anaplastic Glioma
Unmethylated

Additional relevant MeSH terms:
Glioma
Glioblastoma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Copper
Disulfiram
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors
Enzyme Inhibitors