Disulfiram in Recurrent Glioblastoma

NCT ID: NCT02678975

Last Updated: 2021-03-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 88 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-31
• Study Completion Date: 2021-01-15

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.

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

Conditions

Glioma; Glioblastoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Control

Alkylating chemotherapy

Group Type: ACTIVE_COMPARATOR

Alkylating Agents

Intervention Type: DRUG

Alkylating antineoplastic agent

Experimental

Alkylating chemotherapy + disulfiram + copper

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

Disulfiram 400 mg daily

Copper

Intervention Type: DIETARY_SUPPLEMENT

nutritional supplement with copper, 2 mg daily

Alkylating Agents

Intervention Type: DRUG

Alkylating antineoplastic agent

Interventions

Disulfiram

Disulfiram 400 mg daily

Intervention Type: DRUG

Copper

nutritional supplement with copper, 2 mg daily

Intervention Type: DIETARY_SUPPLEMENT

Alkylating Agents

Alkylating antineoplastic agent

Intervention Type: DRUG

Other Intervention Names

lomustine (CCNU), PCV or temozolomide

Eligibility Criteria

Inclusion Criteria

1. A previous diagnosis of glioblastoma (histologically verified) and presenting with a first progression/recurrence documented by MRI.

2. Indication for treatment with chemotherapeutic alkylating agents (i.e. temozolomide OR lomustine including PCV treatment).

3. Age 18 years or older.

4. Karnofsky performance status of 60 - 100 .

5. 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).

6. Able to take oral medications.

7. No known allergy to disulfiram or copper.

8. Absolute neutrophil count ≥ 1,500/mcL and platelets ≥ 100,000/mcL

9. 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.

10. 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

1. Earlier treatment for progression (e.g. "rescue therapy")

2. History of idiopathic seizure disorder, psychosis or schizophrenia.

3. History of uncontrolled hypertension (i.e. systolic BP > 180 mmHg) and a diagnosis of congestive heart failure

4. Received radiotherapy within the 3 months before the diagnosis of progression .

5. Addiction to alcohol or drugs.

6. Pregnant and/or breastfeeding.

7. Women of childbearing potential who do not have negative pregnancy test not older than 14 days before enrollment.

8. 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.

9. History of Wilson's disease or family member with Wilson's disease (unless excluded as a carrier by genetic test).

10. History of hemochromatosis or family member with hemochromatosis (unless excluded as a carrier by genetic test).

11. Nickel hypersensitivity (disulfiram mobilize nickel causing a brief increase in nickel concentrations before excretion. The initial increase may lead to hepatitis and predisposed patients).

12. Need for metronidazole, warfarin and/or theophylline medication (the metabolism may be influenced by disulfiram).

13. 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).

14. Unfit for participation for any other reason judged by the including physician.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

St. Olavs Hospital

OTHER

Sponsor Role: collaborator

Lund University Hospital

OTHER

Sponsor Role: collaborator

Karolinska University Hospital

OTHER

Sponsor Role: collaborator

University Hospital, Linkoeping

OTHER

Sponsor Role: collaborator

Region Örebro County

OTHER

Sponsor Role: collaborator

Ryhov County Hospital

OTHER

Sponsor Role: collaborator

Uppsala University Hospital

OTHER

Sponsor Role: collaborator

Sahlgrenska University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Asgeir S. Jakola

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Asgeir S Jakola, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Sahlgrenska University Hospital

Locations

Cancer Clinic, St.Olavs University Hospital

Trondheim, , Norway

Dept. of Oncology, Sahlgrenska University Hospital

Gothenburg, , Sweden

Ryhov County Hospital

Jönköping, , Sweden

Linköping University Hospital

Linköping, , Sweden

Lund University Hospital

Lund, , Sweden

Örebro University Hospital

Örebro, , Sweden

Karolinska University Hospital

Stockholm, , Sweden

Uppsala University Hospital

Uppsala, , Sweden

Countries

Norway; Sweden

References

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.

Reference Type: BACKGROUND

PMID: 21247389 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25777347 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25588723 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17026967 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8389572 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37000452 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30647912 (View on PubMed)

Other Identifiers

no ID yet

Identifier Type: -

Identifier Source: org_study_id