Clinical trial NCT03363659: Disulfiram and Copper Gluconate With Temozolomide in Unmethylated Glioblastoma Multiforme
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Glioblastoma
Glioblastoma Multiforme
Keywords: Glioblastoma
Glioblastoma Multiforme
Anaplastic Glioma
Unmethylated
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
First posted: 2017-12-06
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 Disulfiram (DSF) + Copper (Cu) combination when added to standard Temozolomide in the treatment of unmethylated Glioblastoma Multiforme (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 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

Primary outcomes:
measure: 6 Months Progression Free Survival (PFS)
timeFrame: 6 months
measure: Overall Survival
timeFrame: 1 and 2 years
Secondary outcomes:
measure: Quality of Life (QOL)
timeFrame: 1 year
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Aurora Health Care, Aurora St. Luke's Medical Center
state: Wisconsin
Study officials:
affiliation: Wake Forest University Health Sciences
name: Asadullah Khan, MD
role: PRINCIPAL_INVESTIGATOR
References: