- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02678975
Disulfiram in Recurrent Glioblastoma
DIRECT (DIsulfiram REsponse as add-on to ChemoTherapy in Recurrent) Glioblastoma: A Randomized Controlled Trial
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.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
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Trondheim, Norway
- Cancer Clinic, St.Olavs University Hospital
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Gothenburg, Sweden
- Dept. of Oncology, Sahlgrenska University Hospital
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Jönköping, Sweden
- Ryhov County Hospital
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Linkoping, Sweden
- Linköping University Hospital
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Lund, Sweden
- Lund University Hospital
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Stockholm, Sweden
- Karolinska University Hospital
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Uppsala, Sweden
- Uppsala University Hospital
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Örebro, Sweden
- Orebro University Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Active Comparator: Control
Alkylating chemotherapy
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Alkylating antineoplastic agent
Other Names:
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Experimental: Experimental
Alkylating chemotherapy + disulfiram + copper
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Alkylating antineoplastic agent
Other Names:
Disulfiram 400 mg daily
nutritional supplement with copper, 2 mg daily
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Survival 6 mo
Time Frame: Proportion of alive participants at 6 months
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Proportion of alive participants at 6 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Progression free survival
Time Frame: Proportion without progression at 6 and 12 months
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Using RANO criteria applied by local investigators
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Proportion without progression at 6 and 12 months
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Survival 12 and 24 mo
Time Frame: Proportion of alive participants at 12 and 24 months
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Proportion of alive participants at 12 and 24 months
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Median overall survival
Time Frame: Median overall survival assessed at 6 months and 24 months after last included participant
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Using Kaplan Meier plots and log-rank test
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Median overall survival assessed at 6 months and 24 months after last included participant
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Health related quality of life
Time Frame: Assessed at baseline and month 3, 6, 9, 12, 15, 18, 21, 24
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EuroQol 5D (generic)
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Assessed at baseline and month 3, 6, 9, 12, 15, 18, 21, 24
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Volumetric tumor assessment
Time Frame: Baseline and first follow-up scan being scheduled at 3 months post-inclusion
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Tumor volumes are assessed using semi-automatic segmentation
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Baseline and first follow-up scan being scheduled at 3 months post-inclusion
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Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: 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
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Cumulative burden at 6 and 24 months
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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
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Asgeir S Jakola, MD, PhD, Sahlgrenska University Hospital, Sweden
Publications and helpful links
General Publications
- Wickstrom M, Danielsson K, Rickardson L, Gullbo J, Nygren P, Isaksson A, Larsson R, Lovborg H. Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients. Biochem Pharmacol. 2007 Jan 1;73(1):25-33. doi: 10.1016/j.bcp.2006.08.016. Epub 2006 Aug 26.
- Cvek B. Targeting malignancies with disulfiram (Antabuse): multidrug resistance, angiogenesis, and proteasome. Curr Cancer Drug Targets. 2011 Mar;11(3):332-7. doi: 10.2174/156800911794519806.
- Nechushtan H, Hamamreh Y, Nidal S, Gotfried M, Baron A, Shalev YI, Nisman B, Peretz T, Peylan-Ramu N. A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer. Oncologist. 2015 Apr;20(4):366-7. doi: 10.1634/theoncologist.2014-0424. Epub 2015 Mar 16.
- Triscott J, Rose Pambid M, Dunn SE. Concise review: bullseye: targeting cancer stem cells to improve the treatment of gliomas by repurposing disulfiram. Stem Cells. 2015 Apr;33(4):1042-6. doi: 10.1002/stem.1956.
- Dufour P, Lang JM, Giron C, Duclos B, Haehnel P, Jaeck D, Jung JM, Oberling F. Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study. Biotherapy. 1993;6(1):9-12. doi: 10.1007/BF01877380.
- Jakola AS, Werlenius K, Mudaisi M, Hylin S, Kinhult S, Bartek J Jr, Salvesen O, Carlsen SM, Strandeus M, Lindskog M, Lofgren D, Rydenhag B, Carstam L, Gulati S, Solheim O, Bartek J, Solheim T. Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial. F1000Res. 2018 Nov 15;7:1797. doi: 10.12688/f1000research.16786.1. eCollection 2018.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms, Glandular and Epithelial
- Astrocytoma
- Glioma
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Glioblastoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Antineoplastic Agents, Alkylating
- Trace Elements
- Micronutrients
- Alcohol Deterrents
- Acetaldehyde Dehydrogenase Inhibitors
- Copper
- Temozolomide
- Disulfiram
- Lomustine
- Alkylating Agents
Other Study ID Numbers
- no ID yet
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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