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GliomaPhase 2/3NCT02678975

Disulfiram in Recurrent Glioblastoma

A Phase 2/3 study testing Disulfiram, Copper and Alkylating Agents in people with Glioma and Glioblastoma, run by Sahlgrenska University Hospital at 8 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Glioma, Glioblastoma
What is being tested?
Disulfiram, Copper and Alkylating Agents
Could I receive a placebo?
No, everyone receives an active treatment
How many people
88 participants
Where
8 sitesin 2 countries
Study dates
Jan 2017to 15 Jan 2021
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.
  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

8 sites in 2 countries.

8 sites in 2 countries

Sweden7 sites

  • Dept. of Oncology, Sahlgrenska University Hospital

    Gothenburg

  • Ryhov County Hospital

    Jönköping

  • Linköping University Hospital

    Linköping

  • Lund University Hospital

    Lund

  • Örebro University Hospital

    Örebro

  • Karolinska University Hospital

    Stockholm

  • Uppsala University Hospital

    Uppsala

Other trials in Sweden

Norway1 site

  • Cancer Clinic, St.Olavs University Hospital

    Trondheim

Other trials in Norway

About this study

Official title: 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.

Read the 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
Being tested
Disulfiram, Copper, Alkylating Agents
Medical subject headings
Glioma, Glioblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DisulfiramDrug

    Disulfiram 400 mg daily

  • CopperDietary supplement

    nutritional supplement with copper, 2 mg daily

  • Alkylating AgentsDrug

    Also called lomustine (CCNU), PCV or temozolomide

    Alkylating antineoplastic agent

Study groups in NCT02678975
Study groupRoleWhat they receive
ControlActive comparatorAlkylating chemotherapy
Receives: Drug: Alkylating Agents
ExperimentalExperimentalAlkylating chemotherapy + disulfiram + copper
Receives: Drug: Disulfiram; Dietary Supplement: Copper; Drug: Alkylating Agents

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Survival 6 mo

    Measured: Proportion of alive participants at 6 months

Secondary outcomes (6)

  1. Progression free survival

    Using RANO criteria applied by local investigators

    Measured: Proportion without progression at 6 and 12 months

  2. Survival 12 and 24 mo

    Measured: Proportion of alive participants at 12 and 24 months

  3. Median overall survival

    Using Kaplan Meier plots and log-rank test

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

  4. Health related quality of life

    EuroQol 5D (generic)

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

  5. Volumetric tumor assessment

    Tumor volumes are assessed using semi-automatic segmentation

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

  6. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

    Cumulative burden at 6 and 24 months

    Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Feb 2016 (estimated)
  2. Study startJan 2017
  3. Primary completion15 Jan 2021
  4. Study completion15 Jan 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
88 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02678975
Sponsor's protocol ID
no ID yet
Status last verified
Mar 2021
First submitted
31 Jan 2016
Last updated
18 Mar 2021
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • 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.

    PubMed 21247389

  • 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.

    PubMed 25777347

  • 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.

    PubMed 25588723

  • 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.

    PubMed 17026967

  • 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.

    PubMed 8389572

  • 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.

    PubMed 37000452

  • 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.

    PubMed 30647912

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Disulfiram, Copper and Alkylating Agents in people with Glioma and Glioblastoma, run by Sahlgrenska University Hospital at 8 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in Sweden, Norway. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Survival 6 mo (time frame: Proportion of alive participants at 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02678975, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2021.

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