Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer
Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer
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.
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
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