Disulfiram in Recurrent Glioblastoma

NCT02678975 | Completed Phase 2 DMC

• 1 other identifier: no ID yet
• Study Type: interventional
• Target: 88
• Locations: 2 countries
• Sites: 8

Brief Summary

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.

Conditions

Glioma; Glioblastoma

Outcome Measures

Primary Outcomes (1)

• Survival 6 mo

  Proportion of alive participants at 6 months

Secondary Outcomes (6)

• Progression free survival

  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

  Median overall survival assessed at 6 months and 24 months after last included participant

• Health related quality of life

  Assessed at baseline and month 3, 6, 9, 12, 15, 18, 21, 24

• Volumetric tumor assessment

  Baseline and first follow-up scan being scheduled at 3 months post-inclusion

Study Arms (2)

Control

ACTIVE COMPARATOR

Alkylating chemotherapy

Drug: Alkylating Agents

Experimental

EXPERIMENTAL

Alkylating chemotherapy + disulfiram + copper

Drug: Disulfiram; Dietary Supplement: Copper; Drug: Alkylating Agents

Interventions

Disulfiram DRUG

Disulfiram 400 mg daily

Experimental

Copper DIETARY_SUPPLEMENT

nutritional supplement with copper, 2 mg daily

Experimental

Alkylating Agents DRUG

Alkylating antineoplastic agent

Also known as: lomustine (CCNU), PCV or temozolomide

Control; Experimental

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 .
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sahlgrenska University Hospital: lead
• St. Olavs Hospital: collaborator
• Lund University Hospital: collaborator
• Karolinska University Hospital: collaborator
• University Hospital, Linkoeping: collaborator
• Region Örebro County: collaborator
• Ryhov County Hospital: collaborator
• Uppsala University Hospital: collaborator

Study Sites (8)

Cancer Clinic, St.Olavs University Hospital

Trondheim, Norway

Location

Dept. of Oncology, Sahlgrenska University Hospital

Gothenburg, Sweden

Location

Ryhov County Hospital

Jönköping, Sweden

Location

Linköping University Hospital

Linköping, Sweden

Location

Lund University Hospital

Lund, Sweden

Location

Örebro University Hospital

Örebro, Sweden

Location

Karolinska University Hospital

Stockholm, Sweden

Location

Uppsala University Hospital

Uppsala, Sweden

Location

Related Publications (7)

• 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.

  PMID: 21247389 BACKGROUND

• 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.

  PMID: 25777347 BACKGROUND

• 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.

  PMID: 25588723 BACKGROUND

• 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.

  PMID: 17026967 BACKGROUND

• 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.

  PMID: 8389572 BACKGROUND

• Werlenius K, Kinhult S, Solheim TS, Magelssen H, Lofgren D, Mudaisi M, Hylin S, Bartek J Jr, Strandeus M, Lindskog M, Rashid HB, Carstam L, Gulati S, Solheim O, Bartek J, Salvesen O, Jakola AS. Effect of Disulfiram and Copper Plus Chemotherapy vs Chemotherapy Alone on Survival in Patients With Recurrent Glioblastoma: A Randomized Clinical Trial. JAMA Netw Open. 2023 Mar 1;6(3):e234149. doi: 10.1001/jamanetworkopen.2023.4149.

  PMID: 37000452 DERIVED

• 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.

  PMID: 30647912 DERIVED

MeSH Terms

Conditions

Glioma; Glioblastoma

Interventions

Disulfiram; Copper; Alkylating Agents; Lomustine; Temozolomide

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Astrocytoma

Intervention Hierarchy (Ancestors)

Ditiocarb; Thiocarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Disulfides; Sulfides; Sulfur Compounds; Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Noxae; Toxic Actions; Nitrosourea Compounds; Urea; Amides; Nitroso Compounds; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Asgeir S Jakola, MD, PhD

  Sahlgrenska University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: January 31, 2016
• First Posted: February 10, 2016
• Study Start: January 1, 2017
• Primary Completion: January 15, 2021
• Study Completion: January 15, 2021
• Last Updated: March 18, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

NO (1); SE (7)