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Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer (DISC)

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ClinicalTrials.gov Identifier: NCT03323346
Recruitment Status : Recruiting
First Posted : October 27, 2017
Last Update Posted : May 14, 2021
Sponsor:
Collaborator:
University Hospital Olomouc
Information provided by (Responsible Party):
The Institute of Molecular and Translational Medicine, Czech Republic

Tracking Information
First Submitted Date  ICMJE September 29, 2017
First Posted Date  ICMJE October 27, 2017
Last Update Posted Date May 14, 2021
Actual Study Start Date  ICMJE September 29, 2017
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 25, 2017)
  • Clinical response rate (RR) [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months ]
    sum of complete and partial responses (CR+PR)
  • Clinical benefit rate (CBR) [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months ]
    sum of complete, partial responses and stable diseases (CR+PR)CR+PR+SD)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 25, 2017)
  • Time to progression (TTP) [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months ]
    time to progression (TTP) in months
  • Overall survival (OS) [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months ]
    overall survival (OS) in months
  • The pharmacokinetic (PK) characteristics [ Time Frame: Day 0 = at first administration of the drug ]
    Cmax
  • The pharmacokinetic (PK) characteristic - Area Under Curve (AUC) [ Time Frame: Day 0 = at first administration of the drug ]
    AUC - The area under the plasma concentration over the time
  • The pharmacokinetic (PK) characteristic - T-max [ Time Frame: Day 0 = at first administration of the drug ]
    T-max - Time to reach maximum concentration
  • The pharmacokinetic (PK) characteristic - T1/2 [ Time Frame: Day 0 = at first administration of the drug ]
    T1/2 - Apparent terminal elimination half-life time
  • The pharmacokinetic (PK) characteristic - λz [ Time Frame: Day 0 = at first administration of the drug ]
    λz (Lambda-z) - Individual estimate of the terminal elimination rate constant, calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months ]
    Number of participants with treatment-related adverse events analyzed as cumulative burden at every 6 months until study termination.
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 Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer
Official Title  ICMJE Phase II Open Labeled Trial of Disulfiram With Copper in Metastatic Breast Cancer
Brief Summary

The aim of the study is to establish clinical evidence for introducing disulfiram and cooper as an active therapy for metastatic breast cancer upon failure of conventional systemic and/or locoregional therapies.

Analyses of the following objectives will be performed in the population of patients with metastatic breast cancer:

Primary efficacy objective:

To evaluate the efficacy of the treatment by assessment of:

  • clinical response rate (RR)
  • clinical benefit rate (CBR)

Secondary efficacy objectives:

To evaluate the efficacy of the treatment by assessment of:

  • time to progression (TTP)
  • overall survival (OS)

Pharmacokinetic objectives:

• to determine pharmacokinetic parameters for disulfiram and its active metabolites administered in combination with copper supplements in cancer patient population

Safety objectives:

• to describe safety profile of disulfiram administered in combination with copper supplements

Exploratory objectives:

Parallel analysis to assess (identify) potential candidate surrogate biomarkers of disulfiram efficacy, as well as identification (using proteomic, biochemical and molecular genetic studies) of potential predictive biomarkers of disulfiram sensitivity or resistance will be performed. Surrogate biomarker analysis will focus on in vivo ubiquitin-proteosomal system inhibition, cell cycle and DNA damage.

Detailed Description

Inclusion criteria:

  1. Patients with stage IV breast cancer with metastases demonstrated by appropriate imaging techniques
  2. Histologically or cytologically confirmed tumor
  3. Age of 18 years or more
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
  5. Patients have failed, untolerated or refused standard therapeutic modalities
  6. Not received systemic anticancer therapy or radiation or had major surgery in last 2 weeks
  7. Not currently participating in another study
  8. Anticipated survival of at least 2 months
  9. Baseline aspartate aminotransferase (AST) and alanine aminotransferase (ALT) not greater than 2.5 X upper institutional limit
  10. Serum copper within normal limits
  11. Serum ceruloplasmin > 17 mg/dL
  12. Able and willing to sign informed consent and to comply with study procedures
  13. Able to ingest oral medications
  14. No known allergy to disulfiram or copper
  15. Willing to refrain from ingestion of alcoholic beverages while on the study

Exclusion criteria:

  1. Participation in another clinical trial of a therapeutic drug during the past 14 days
  2. Addiction to alcohol or drugs
  3. Baseline AST or ALT greater than 2.5 X upper institutional limit
  4. Unable to ingest oral medications
  5. Unable to undergo CT/SPECT scanning because of inability to lie recumbent in the scanner
  6. Actively receiving cytotoxic cancer chemotherapy agents
  7. Anticipated survival of less than 2 months
  8. Women of child-bearing potential who are not using a commonly accepted effective means of contraception; women of child-bearing potential will have negative pregnancy test before enrollment
  9. History of active liver disease, including chronic active hepatitis, viral hepatitis (hepatitis B, C and CMV), cholestatic jaundice of any etiology, toxic hepatitis, or cholestatic hepatitis or jaundice with bilirubin greater than 2.0 X upper institutional limit
  10. History of Wilson's disease or family member with Wilson's disease
  11. History of hemochromatosis or family member with hemochromatosis
  12. History of other iron overload syndrome such as hemochromatosis
  13. Need for metronidazole, warfarin and/or theophylline medication, the metabolism of which is likely influenced by disulfiram
  14. Pregnant women and nursing mothers are not allowed to enroll on this study
  15. Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Neoplasm Female
  • Metastatic Breast Cancer
Intervention  ICMJE Drug: Disulfiram

Patients will take one pill of disulfiram (Antabus) daily at a dose of 400 mg continually during the treatment phase (from day 0 till End of treatment Visit). In case of intolerance, lower dose up to 200 mg per day is allowed.

Copper supplementation will be given separately from disulfiram; in the morning with patients´breakfast. Patients will take one pill of copper dietary supplement (for instance Copper Star, STARLIFE) corresponding to 2 mg of elementary copper.

Other Name: Copper
Study Arms  ICMJE Experimental: Disulfiram with copper

Patients will take one pill of disulfiram (Antabus) daily at a dose of 400 mg continually during the treatment phase (from day 0 till End of treatment Visit). In case of intolerance, lower dose up to 200 mg per day is allowed. Patients will take disulfiram after their evening meal.

Patients will avoid alcohol and other disulfiram-drug interactions will be considered.

Copper supplementation will be given separately from disulfiram; in the morning with patients´breakfast. Patients will take one pill of copper dietary supplement (for instance Copper Star, STARLIFE) corresponding to 2 mg of elementary copper.

Intervention: Drug: Disulfiram
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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 25, 2017)
150
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients with stage IV breast cancer with metastases demonstrated by appropriate imaging techniques (computer tomography - CT, positron emission tomography - PET or PET/CT, MRI, ultrasound, etc.)
  2. Histologically or cytologically confirmed tumor
  3. Age of 18 years or more
  4. ECOG performance status of 0 - 2
  5. Patients have failed, untolerated or refused standard therapeutic modalities
  6. Not received systemic anticancer therapy or radiation or had major surgery in last 2 weeks
  7. Not currently participating in another study
  8. Anticipated survival of at least 2 months
  9. Baseline AST and ALT not greater than 2.5 X upper institutional limit
  10. Serum copper within normal limits
  11. Serum ceruloplasmin > 17 mg/dL
  12. Able and willing to sign informed consent and to comply with study procedures
  13. Able to ingest oral medications
  14. No known allergy to disulfiram or copper
  15. Willing to refrain from ingestion of alcoholic beverages while on the study

Exclusion Criteria:

  1. Participation in another clinical trial of a therapeutic drug during the past 14 days
  2. Addiction to alcohol or drugs
  3. Baseline AST or ALT greater than 2.5 X upper institutional limit
  4. Unable to ingest oral medications
  5. Unable to undergo CT/SPECT scanning because of inability to lie recumbent in the scanner
  6. Actively receiving cytotoxic cancer chemotherapy agents
  7. Anticipated survival of less than 2 months
  8. Women of child-bearing potential who are not using a commonly accepted effective means of contraception; women of child-bearing potential will have negative pregnancy test before enrollment
  9. History of active liver disease, including chronic active hepatitis, viral hepatitis (hepatitis B, C and CMV), cholestatic jaundice of any etiology, toxic hepatitis, or cholestatic hepatitis or jaundice with bilirubin greater than 2.0 X upper institutional limit
  10. History of Wilson's disease or family member with Wilson's disease
  11. History of hemochromatosis or family member with hemochromatosis
  12. History of other iron overload syndrome such as hemochromatosis
  13. Need for metronidazole, warfarin and/or theophylline medication, the metabolism of which is likely influenced by disulfiram
  14. Pregnant women and nursing mothers are not allowed to enroll on this study
  15. Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Marian Hajduch, MD., PhD. +420 585632111 marian.hajduch@upol.cz
Listed Location Countries  ICMJE Czechia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03323346
Other Study ID Numbers  ICMJE 2016-1-DSF-MBC
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party The Institute of Molecular and Translational Medicine, Czech Republic
Study Sponsor  ICMJE The Institute of Molecular and Translational Medicine, Czech Republic
Collaborators  ICMJE University Hospital Olomouc
Investigators  ICMJE
Study Chair: Marian Hajduch, MD., PhD. Palacky University
PRS Account The Institute of Molecular and Translational Medicine, Czech Republic
Verification Date May 2021

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