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

Primary Purpose

Breast Neoplasm Female, Metastatic Breast Cancer

Status
Recruiting
Phase
Phase 2
Locations
Czechia
Study Type
Interventional
Intervention
Disulfiram
Sponsored by
The Institute of Molecular and Translational Medicine, Czech Republic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Neoplasm Female focused on measuring metastatic breast cancer, disulfiram, cooper

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • University Hospital OlomoucRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Disulfiram with copper

Arm Description

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.

Outcomes

Primary Outcome Measures

Clinical response rate (RR)
sum of complete and partial responses (CR+PR)
Clinical benefit rate (CBR)
sum of complete, partial responses and stable diseases (CR+PR)CR+PR+SD)

Secondary Outcome Measures

Time to progression (TTP)
time to progression (TTP) in months
Overall survival (OS)
overall survival (OS) in months
The pharmacokinetic (PK) characteristics
Cmax
The pharmacokinetic (PK) characteristic - Area Under Curve (AUC)
AUC - The area under the plasma concentration over the time
The pharmacokinetic (PK) characteristic - T-max
T-max - Time to reach maximum concentration
The pharmacokinetic (PK) characteristic - T1/2
T1/2 - Apparent terminal elimination half-life time
The pharmacokinetic (PK) characteristic - λz
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
Number of participants with treatment-related adverse events analyzed as cumulative burden at every 6 months until study termination.

Full Information

First Posted
September 29, 2017
Last Updated
March 7, 2023
Sponsor
The Institute of Molecular and Translational Medicine, Czech Republic
Collaborators
University Hospital Olomouc
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1. Study Identification

Unique Protocol Identification Number
NCT03323346
Brief Title
Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer
Acronym
DISC
Official Title
Phase II Open Labeled Trial of Disulfiram With Copper in Metastatic Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 29, 2017 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Institute of Molecular and Translational Medicine, Czech Republic
Collaborators
University Hospital Olomouc

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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: Patients with stage IV breast cancer with metastases demonstrated by appropriate imaging techniques Histologically or cytologically confirmed tumor Age of 18 years or more Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 Patients have failed, untolerated or refused standard therapeutic modalities Not received systemic anticancer therapy or radiation or had major surgery in last 2 weeks Not currently participating in another study Anticipated survival of at least 2 months Baseline aspartate aminotransferase (AST) and alanine aminotransferase (ALT) not greater than 2.5 X upper institutional limit Serum copper within normal limits Serum ceruloplasmin > 17 mg/dL Able and willing to sign informed consent and to comply with study procedures Able to ingest oral medications No known allergy to disulfiram or copper Willing to refrain from ingestion of alcoholic beverages while on the study Exclusion criteria: Participation in another clinical trial of a therapeutic drug during the past 14 days Addiction to alcohol or drugs Baseline AST or ALT greater than 2.5 X upper institutional limit Unable to ingest oral medications Unable to undergo CT/SPECT scanning because of inability to lie recumbent in the scanner Actively receiving cytotoxic cancer chemotherapy agents Anticipated survival of less than 2 months 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 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 History of Wilson's disease or family member with Wilson's disease History of hemochromatosis or family member with hemochromatosis History of other iron overload syndrome such as hemochromatosis Need for metronidazole, warfarin and/or theophylline medication, the metabolism of which is likely influenced by disulfiram Pregnant women and nursing mothers are not allowed to enroll on this study Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Neoplasm Female, Metastatic Breast Cancer
Keywords
metastatic breast cancer, disulfiram, cooper

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Disulfiram with copper
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
Disulfiram
Other Intervention Name(s)
Copper
Intervention Description
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.
Primary Outcome Measure Information:
Title
Clinical response rate (RR)
Description
sum of complete and partial responses (CR+PR)
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
Title
Clinical benefit rate (CBR)
Description
sum of complete, partial responses and stable diseases (CR+PR)CR+PR+SD)
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
Secondary Outcome Measure Information:
Title
Time to progression (TTP)
Description
time to progression (TTP) in months
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
Title
Overall survival (OS)
Description
overall survival (OS) in months
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
Title
The pharmacokinetic (PK) characteristics
Description
Cmax
Time Frame
Day 0 = at first administration of the drug
Title
The pharmacokinetic (PK) characteristic - Area Under Curve (AUC)
Description
AUC - The area under the plasma concentration over the time
Time Frame
Day 0 = at first administration of the drug
Title
The pharmacokinetic (PK) characteristic - T-max
Description
T-max - Time to reach maximum concentration
Time Frame
Day 0 = at first administration of the drug
Title
The pharmacokinetic (PK) characteristic - T1/2
Description
T1/2 - Apparent terminal elimination half-life time
Time Frame
Day 0 = at first administration of the drug
Title
The pharmacokinetic (PK) characteristic - λz
Description
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
Time Frame
Day 0 = at first administration of the drug
Title
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Description
Number of participants with treatment-related adverse events analyzed as cumulative burden at every 6 months until study termination.
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

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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.) Histologically or cytologically confirmed tumor Age of 18 years or more ECOG performance status of 0 - 2 Patients have failed, untolerated or refused standard therapeutic modalities Not received systemic anticancer therapy or radiation or had major surgery in last 2 weeks Not currently participating in another study Anticipated survival of at least 2 months Baseline AST and ALT not greater than 2.5 X upper institutional limit Serum copper within normal limits Serum ceruloplasmin > 17 mg/dL Able and willing to sign informed consent and to comply with study procedures Able to ingest oral medications No known allergy to disulfiram or copper Willing to refrain from ingestion of alcoholic beverages while on the study Exclusion Criteria: Participation in another clinical trial of a therapeutic drug during the past 14 days Addiction to alcohol or drugs Baseline AST or ALT greater than 2.5 X upper institutional limit Unable to ingest oral medications Unable to undergo CT/SPECT scanning because of inability to lie recumbent in the scanner Actively receiving cytotoxic cancer chemotherapy agents Anticipated survival of less than 2 months 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 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 History of Wilson's disease or family member with Wilson's disease History of hemochromatosis or family member with hemochromatosis History of other iron overload syndrome such as hemochromatosis Need for metronidazole, warfarin and/or theophylline medication, the metabolism of which is likely influenced by disulfiram Pregnant women and nursing mothers are not allowed to enroll on this study Patients who are taking medications metabolized by cytochrome P450 2E1, including chlorzoxazone or halothane and its derivatives
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marian Hajduch, MD., PhD.
Phone
+420 585632111
Email
marian.hajduch@upol.cz
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marian Hajduch, MD., PhD.
Organizational Affiliation
Palacky University
Official's Role
Study Chair
Facility Information:
Facility Name
University Hospital Olomouc
City
Olomouc
ZIP/Postal Code
77900
Country
Czechia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bohuslav Melichar, MD., PhD.
Phone
+420588444295
Email
bohuslav.melichar@fnol.cz
First Name & Middle Initial & Last Name & Degree
Lucie Stejskalova, MSc.
Phone
+420588444295
Email
lucie.stejskalova@fnol.cz
First Name & Middle Initial & Last Name & Degree
Bohuslav Melichar, MD., PhD.

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
23863824
Citation
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Results Reference
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Results Reference
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23958896
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Links:
URL
http://imtm.cz/clinical-trials
Description
The trial status on sponsor's website.
URL
http://www.sukl.eu/modules/evaluation/detail.php?id=42666&lang=2
Description
The trial status on regulator's website.

Learn more about this trial

Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer

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