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Disulfiram in Recurrent Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02678975
Recruitment Status : Active, not recruiting
First Posted : February 10, 2016
Last Update Posted : November 9, 2020
Sponsor:
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  ICMJE January 31, 2016
First Posted Date  ICMJE February 10, 2016
Last Update Posted Date November 9, 2020
Study Start Date  ICMJE January 2017
Estimated Primary Completion Date January 15, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 5, 2016)
Survival 6 mo [ Time Frame: Proportion of alive participants at 6 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Disulfiram in Recurrent Glioblastoma
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioma
  • Glioblastoma
Intervention  ICMJE
  • 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  ICMJE
  • 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 *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 6, 2020)
88
Original Estimated Enrollment  ICMJE
 (submitted: February 5, 2016)
142
Estimated Study Completion Date  ICMJE January 15, 2021
Estimated Primary Completion Date January 15, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Norway,   Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02678975
Other Study ID Numbers  ICMJE no ID yet
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Asgeir S. Jakola, Sahlgrenska University Hospital, Sweden
Study Sponsor  ICMJE Sahlgrenska University Hospital, Sweden
Collaborators  ICMJE
  • St. Olavs Hospital
  • Lund University Hospital
  • Karolinska University Hospital
  • University Hospital, Linkoeping
  • Region Örebro County
  • Ryhov County Hospital
  • Uppsala University Hospital
Investigators  ICMJE
Principal Investigator: Asgeir S Jakola, MD, PhD Sahlgrenska University Hospital, Sweden
PRS Account Sahlgrenska University Hospital, Sweden
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP