Disulfiram and Copper Gluconate With Temozolomide in Unmethylated Glioblastoma Multiforme
Condition: Glioblastoma; Glioblastoma Multiforme
MeSH terms: Glioblastoma
Intervention: Disulfiram; Copper gluconate; Temozolomide
Intervention description: Disulfiram is taken orally, twice daily.; Copper gluconate is taken orally, twice daily; Temozolomide is taken once daily
Intervention MeSH terms: Copper; Temozolomide; Disulfiram
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Glioblastoma; Glioblastoma Multiforme; Anaplastic Glioma; Unmethylated

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.
    

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