Disulfiram in Recurrent Glioblastoma

Study Overview
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Brief Summary
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Disulfiram (Antabuse®) is a well-tolerated, cheap, generic drug that has been in use since the 1950s to treat alcoholism. There is now an increasing amount of independent preclinical data to support disulfiram as an anticancer agent. The potency of disulfiram as an anticancer agent seems strengthened by copper. The investigators aim is to investigate disulfiram and copper-supplement as add-on treatment in glioblastoma patients with recurrence receiving alkylating chemotherapy.

Detailed Description
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Disulfiram (Antabuse®) is a well-tolerated, cheap, generic drug that has been in use since the 1950s to treat alcoholism. There is now an increasing amount of independent preclinical data to support disulfiram as an anticancer agent. The potency of disulfiram as an anticancer agent seems strengthened by copper. There is now anecdotal clinical evidence of disulfiram as an anticancer agent. So far no clinical studies have been published in glioma patients, but two small, uncontrolled studies are planned according to clinicaltrials.gov. with search 1st November 2015. The investigators aim to investigate disulfiram and copper-supplement as add-on treatment in glioblastoma patients with recurrence receiving alkylating chemotherapy. The study will be performed as a multicenter RCT including patients in Norway and Sweden. This will serve as a proof-of concept study. The primary end-point is survival at 6 months

Official Title
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DIRECT (DIsulfiram REsponse as add-on to ChemoTherapy in Recurrent) Glioblastoma: A Randomized Controlled Trial

Conditions
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Glioma, Glioblastoma

Intervention / Treatment
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* Drug: Disulfiram
* Dietary Supplement: Copper
* Drug: Alkylating Agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A previous diagnosis of glioblastoma (histologically verified) and presenting with a first progression/recurrence documented by MRI. Indication for treatment with chemotherapeutic alkylating agents (i.e. temozolomide OR lomustine including PCV treatment). Age 18 years or older. Karnofsky performance status of 60 - 100 . Not receiving another experimental treatment for glioblastoma at the moment of inclusion or during active treatment within the assigned group (i.e. control or disulfiram group). Able to take oral medications. No known allergy to disulfiram or copper. Absolute neutrophil count ≥ 1,500/mcL and platelets ≥ 100,000/mcL Serum/plasma copper and serum ceruloplasmin within institutional limits. a. However increased levels are seen together with ongoing acute phase reaction as determined by elevated C-reactive protein (ceruloplasmin is elevated as part of the same process) it is possible to retest after normalization of C-reactive protein. Willing to refrain from ingestion of alcoholic beverages while on the study is a criteria to be randomized. However, once randomized alcohol abstinence only affects the group treated with disulfiram, and in this group it includes the entire period and one month after last dosage of disulfiram. Exclusion Criteria: Earlier treatment for progression (e.g. rescue therapy) History of idiopathic seizure disorder, psychosis or schizophrenia. History of uncontrolled hypertension (i.e. systolic BP > 180 mmHg) and a diagnosis of congestive heart failure Received radiotherapy within the 3 months before the diagnosis of progression . Addiction to alcohol or drugs. Pregnant and/or breastfeeding. Women of childbearing potential who do not have negative pregnancy test not older than 14 days before enrollment. History of active liver disease, including chronic active hepatitis, viral hepatitis (hepatitis B, C and CMV), cholestatic jaundice of any etiology or toxic hepatitis or inadequate hepatic function, defined as baseline ASAT and ALAT > 2.5 X upper institutional limit and/or bilirubin > 2.0 X upper institutional limit. History of Wilson's disease or family member with Wilson's disease (unless excluded as a carrier by genetic test). History of hemochromatosis or family member with hemochromatosis (unless excluded as a carrier by genetic test). Nickel hypersensitivity (disulfiram mobilize nickel causing a brief increase in nickel concentrations before excretion. The initial increase may lead to hepatitis and predisposed patients). Need for metronidazole, warfarin and/or theophylline medication (the metabolism may be influenced by disulfiram). Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives (phenytoin, phenobarbital, chlordiazepoxide, imipramine, diazepam, isoniazid, metronidazole, warfarin, amitriptyline within 14 days prior to the first dose of disulfiram. Of note, lorazepam and oxazepam are not affected by the P450 system and are not contraindicated with disulfiram). Unfit for participation for any other reason judged by the including physician.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>Alkylating chemotherapy | Drug: Alkylating Agents<br>* Alkylating antineoplastic agent<br>* Other names: lomustine (CCNU), PCV or temozolomide;|
| Experimental: Experimental<br>Alkylating chemotherapy + disulfiram + copper | Drug: Disulfiram<br>* Disulfiram 400 mg daily<br>Dietary Supplement: Copper<br>* nutritional supplement with copper, 2 mg daily<br>Drug: Alkylating Agents<br>* Alkylating antineoplastic agent<br>* Other names: lomustine (CCNU), PCV or temozolomide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival 6 mo |  | Proportion of alive participants at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Using RANO criteria applied by local investigators | Proportion without progression at 6 and 12 months | 
| Survival 12 and 24 mo |  | Proportion of alive participants at 12 and 24 months | 
| Median overall survival | Using Kaplan Meier plots and log-rank test | Median overall survival assessed at 6 months and 24 months after last included participant | 
| Health related quality of life | EuroQol 5D (generic) | Assessed at baseline and month 3, 6, 9, 12, 15, 18, 21, 24 | 
| Volumetric tumor assessment | Tumor volumes are assessed using semi-automatic segmentation | Baseline and first follow-up scan being scheduled at 3 months post-inclusion | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Cumulative burden at 6 and 24 months | Assessed month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, but analyzed as cumulative burden at 6 and 24 months |