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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 : October 27, 2017
Sponsor:
Collaborator:
University Hospital Olomouc
Information provided by (Responsible Party):
Marian Hajduch, M.D., Ph.D., The Institute of Molecular and Translational Medicine, Czech Republic

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.


Condition or disease Intervention/treatment Phase
Breast Neoplasm Female Metastatic Breast Cancer Drug: Disulfiram Phase 2

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Open Labeled Trial of Disulfiram With Copper in Metastatic Breast Cancer
Actual Study Start Date : September 29, 2017
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : September 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Disulfiram

Arm Intervention/treatment
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.

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




Primary Outcome Measures :
  1. 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)

  2. 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)


Secondary Outcome Measures :
  1. 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

  2. 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

  3. The pharmacokinetic (PK) characteristics [ Time Frame: Day 0 = at first administration of the drug ]
    Cmax

  4. 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

  5. The pharmacokinetic (PK) characteristic - T-max [ Time Frame: Day 0 = at first administration of the drug ]
    T-max - Time to reach maximum concentration

  6. The pharmacokinetic (PK) characteristic - T1/2 [ Time Frame: Day 0 = at first administration of the drug ]
    T1/2 - Apparent terminal elimination half-life time

  7. 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

  8. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03323346


Contacts
Contact: Marian Hajduch, MD., PhD. +420 585632111 marian.hajduch@upol.cz

Locations
Czechia
University Hospital Olomouc Recruiting
Olomouc, Czechia, 77900
Contact: Bohuslav Melichar, MD., PhD.    +420588444295    bohuslav.melichar@fnol.cz   
Contact: Lucie Stejskalova, MSc.    +420588444295    lucie.stejskalova@fnol.cz   
Principal Investigator: Bohuslav Melichar, MD., PhD.         
Sponsors and Collaborators
Marian Hajduch, M.D., Ph.D.
University Hospital Olomouc
Investigators
Study Chair: Marian Hajduch, MD., PhD. Palacky University

Additional Information:
Publications:

Responsible Party: Marian Hajduch, M.D., Ph.D., Director, Principal Investigator, The Institute of Molecular and Translational Medicine, Czech Republic
ClinicalTrials.gov Identifier: NCT03323346     History of Changes
Other Study ID Numbers: 2016-1-DSF-MBC
First Posted: October 27, 2017    Key Record Dates
Last Update Posted: October 27, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Marian Hajduch, M.D., Ph.D., The Institute of Molecular and Translational Medicine, Czech Republic:
metastatic breast cancer
disulfiram
cooper

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Copper
Disulfiram
Trace Elements
Micronutrients
Growth Substances
Physiological Effects of Drugs
Alcohol Deterrents
Acetaldehyde Dehydrogenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action