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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 : July 2, 2020
Sponsor:
Information provided by (Responsible Party):
Aurora Health Care

Tracking Information
First Submitted Date  ICMJE November 30, 2017
First Posted Date  ICMJE December 6, 2017
Last Update Posted Date July 2, 2020
Actual Study Start Date  ICMJE March 28, 2018
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 11, 2019)
  • Progression Free Survival (PFS) [ Time Frame: 6 months ]
  • Overall Survival [ Time Frame: 1 and 2 years ]
Original Primary Outcome Measures  ICMJE
 (submitted: November 30, 2017)
  • Objective Response Rate [ Time Frame: Percentage of patients at 6 months ]
    Complete or partial response using RANO criteria
  • Progression-free survival [ Time Frame: Proportion without progression at 6 months ]
    Using RANO criteria applied by local investigators
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 11, 2019)
Quality of life (QOL) [ Time Frame: 1 year ]
Edmonton Symptom Assessment System - Revised (ESAS-r) questionnaire
Original Secondary Outcome Measures  ICMJE
 (submitted: November 30, 2017)
  • Toxicity [ Time Frame: 6 and 12 months ]
    NCI CTCAE version 4.0 - type and grade
  • Quality of life (QOL) [ Time Frame: 1 month ]
    Edmonton Symptom Assessment System - Revised (ESAS-r) questionnaire
  • Overall survival [ Time Frame: 12 months ]
    Proportion of alive participants
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Disulfiram and Copper Gluconate With Temozolomide in Unmethylated Glioblastoma Multiforme
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Glioblastoma Multiforme
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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
Interventions:
  • Drug: Disulfiram
  • Dietary Supplement: Copper gluconate
  • Drug: Temozolomide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 30, 2017)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kate McPolin, RN 414-385-7125 kate.mcpolin@aurora.org
Contact: Carol Tutino, RN,MS,CCRC 414-649-5526 carol.tutino@aurora.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03363659
Other Study ID Numbers  ICMJE 17.56
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Aurora Health Care
Study Sponsor  ICMJE Aurora Health Care
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: George Bobustuc, MD Aurora Health Care
PRS Account Aurora Health Care
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP