Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer

Study Overview
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Brief Summary
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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
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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

Official Title
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Phase II Open Labeled Trial of Disulfiram With Copper in Metastatic Breast Cancer

Conditions
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Breast Neoplasm Female, Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Disulfiram


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Disulfiram with copper<br>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<br>* 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.<br>* Other names: Copper;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response rate (RR) | sum of complete and partial responses (CR+PR) | 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 | 
| Clinical benefit rate (CBR) | sum of complete, partial responses and stable diseases (CR+PR)CR+PR+SD) | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression (TTP) | time to progression (TTP) in months | 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) | overall survival (OS) in months | 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 | 
| The pharmacokinetic (PK) characteristics | Cmax | Day 0 = at first administration of the drug | 
| The pharmacokinetic (PK) characteristic - Area Under Curve (AUC) | AUC - The area under the plasma concentration over the time | Day 0 = at first administration of the drug | 
| The pharmacokinetic (PK) characteristic - T-max | T-max - Time to reach maximum concentration | Day 0 = at first administration of the drug | 
| The pharmacokinetic (PK) characteristic - T1/2 | T1/2 - Apparent terminal elimination half-life time | Day 0 = at first administration of the drug | 
| 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 | Day 0 = at first administration of the drug | 
| 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic breast cancer, disulfiram, cooper