Disulfiram and Copper Gluconate With Temozolomide in Unmethylated Glioblastoma Multiforme

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.

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