Disulfiram in Recurrent Glioblastoma

• ClinicalTrials.gov Identifier: NCT02678975
• Recruitment Status: Active, not recruiting
• First Posted: February 10, 2016
• Last Update Posted: November 9, 2020
• Sponsor: Sahlgrenska University Hospital, Sweden
• Collaborators: St. Olavs Hospital; Lund University Hospital; Karolinska University Hospital; University Hospital, Linkoeping; Region Örebro County; Ryhov County Hospital; Uppsala University Hospital
• Information provided by (Responsible Party): Asgeir S. Jakola, Sahlgrenska University Hospital, Sweden

Tracking Information

• First Submitted Date: January 31, 2016
• First Posted Date: February 10, 2016
• Last Update Posted Date: November 9, 2020
• Study Start Date: January 2017
• Estimated Primary Completion Date: January 15, 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 5, 2016): Survival 6 mo [ Time Frame: Proportion of alive participants at 6 months ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 5, 2016)

• Progression free survival [ Time Frame: Proportion without progression at 6 and 12 months ]
  Using RANO criteria applied by local investigators
• Survival 12 and 24 mo [ Time Frame: Proportion of alive participants at 12 and 24 months ]
• Median overall survival [ Time Frame: Median overall survival assessed at 6 months and 24 months after last included participant ]
  Using Kaplan Meier plots and log-rank test
• Health related quality of life [ Time Frame: Assessed at baseline and month 3, 6, 9, 12, 15, 18, 21, 24 ]
  EuroQol 5D (generic)
• Volumetric tumor assessment [ Time Frame: Baseline and first follow-up scan being scheduled at 3 months post-inclusion ]
  Tumor volumes are assessed using semi-automatic segmentation
• 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 ]
  Cumulative burden at 6 and 24 months

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment

Condition

• Glioma
• Glioblastoma

Intervention

• Drug: Disulfiram
  Disulfiram 400 mg daily
• Dietary Supplement: Copper
  nutritional supplement with copper, 2 mg daily
• Drug: Alkylating Agents
  Alkylating antineoplastic agent
  Other Name: lomustine (CCNU), PCV or temozolomide

Study Arms

• Active Comparator: Control
  Alkylating chemotherapy
  Intervention: Drug: Alkylating Agents
• Experimental: Experimental
  Alkylating chemotherapy + disulfiram + copper
  Interventions:

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

Publications *

• Cvek B. Targeting malignancies with disulfiram (Antabuse): multidrug resistance, angiogenesis, and proteasome. Curr Cancer Drug Targets. 2011 Mar;11(3):332-7. Review.
• 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. Review.
• 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.
• 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.
• Jakola AS, Werlenius K, Mudaisi M, Hylin S, Kinhult S, Bartek J Jr, Salvesen Ø, Carlsen SM, Strandéus M, Lindskog M, Löfgren 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 6, 2020): 88
• Original Estimated Enrollment (submitted: February 5, 2016): 142
• Estimated Study Completion Date: January 15, 2021
• Estimated Primary Completion Date: January 15, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Norway, Sweden

Administrative Information

• NCT Number: NCT02678975
• Other Study ID Numbers: no ID yet
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Asgeir S. Jakola, Sahlgrenska University Hospital, Sweden
• Study Sponsor: Sahlgrenska University Hospital, Sweden

Collaborators

• St. Olavs Hospital
• Lund University Hospital
• Karolinska University Hospital
• University Hospital, Linkoeping
• Region Örebro County
• Ryhov County Hospital
• Uppsala University Hospital

Investigators

• Principal Investigator: Asgeir S Jakola, MD, PhD; Sahlgrenska University Hospital, Sweden

• PRS Account: Sahlgrenska University Hospital, Sweden
• Verification Date: November 2020