Disulfiram in Recurrent Glioblastoma

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02678975
• Other study ID #: no ID yet
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: January 2017
• Est. completion date: January 15, 2021

Study information

• Verified date: March 2021
• Source: Sahlgrenska University Hospital, Sweden
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: January 15, 2021
• Est. primary completion date: January 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Glioblastoma
• Glioma

Intervention

Drug:
• Disulfiram
Disulfiram 400 mg daily

Dietary Supplement:
• Copper
nutritional supplement with copper, 2 mg daily

Drug:
• Alkylating Agents
Alkylating antineoplastic agent

Locations

Country	Name	City	State
Norway	Cancer Clinic, St.Olavs University Hospital	Trondheim
Sweden	Dept. of Oncology, Sahlgrenska University Hospital	Gothenburg
Sweden	Ryhov County Hospital	Jönköping
Sweden	Linköping University Hospital	Linkoping
Sweden	Lund University Hospital	Lund
Sweden	Örebro University Hospital	Örebro
Sweden	Karolinska University Hospital	Stockholm
Sweden	Uppsala University Hospital	Uppsala

Sponsors (8)

Lead Sponsor	Collaborator
Sahlgrenska University Hospital, Sweden	Karolinska University Hospital, Lund University Hospital, Region Örebro County, Ryhov County Hospital, St. Olavs Hospital, University Hospital, Linkoeping, Uppsala University Hospital

Countries where clinical trial is conducted

Norway,  Sweden, 

References & Publications (5)

Cvek B. Targeting malignancies with disulfiram (Antabuse): multidrug resistance, angiogenesis, and proteasome. Curr Cancer Drug Targets. 2011 Mar;11(3):332-7. Review. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

Wickström M, Danielsson K, Rickardson L, Gullbo J, Nygren P, Isaksson A, Larsson R, Lövborg 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. Epub 2006 Aug 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival 6 mo		Proportion of alive participants at 6 months
Secondary	Progression free survival	Using RANO criteria applied by local investigators	Proportion without progression at 6 and 12 months
Secondary	Survival 12 and 24 mo		Proportion of alive participants at 12 and 24 months
Secondary	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
Secondary	Health related quality of life	EuroQol 5D (generic)	Assessed at baseline and month 3, 6, 9, 12, 15, 18, 21, 24
Secondary	Volumetric tumor assessment	Tumor volumes are assessed using semi-automatic segmentation	Baseline and first follow-up scan being scheduled at 3 months post-inclusion
Secondary	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