Clinical trial NCT03323346: Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer
Official title: Phase II Open Labeled Trial of Disulfiram With Copper in Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Neoplasm Female
Metastatic Breast Cancer
Keywords: metastatic breast cancer
disulfiram
cooper
Lead sponsor: The Institute of Molecular and Translational Medicine, Czech Republic
Sponsor class: OTHER
Collaborators: name: University Hospital Olomouc
First posted: 2017-10-27
Enrollment: 150
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility 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

Primary outcomes:
measure: Clinical response rate (RR)
timeFrame: 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
measure: Clinical benefit rate (CBR)
timeFrame: 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 outcomes:
measure: Time to progression (TTP)
timeFrame: 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
measure: Overall survival (OS)
timeFrame: 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
measure: The pharmacokinetic (PK) characteristics
timeFrame: Day 0 = at first administration of the drug
measure: The pharmacokinetic (PK) characteristic - Area Under Curve (AUC)
timeFrame: Day 0 = at first administration of the drug
measure: The pharmacokinetic (PK) characteristic - T-max
timeFrame: Day 0 = at first administration of the drug
measure: The pharmacokinetic (PK) characteristic - T1/2
timeFrame: Day 0 = at first administration of the drug
measure: The pharmacokinetic (PK) characteristic - λz
timeFrame: Day 0 = at first administration of the drug
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 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
Other outcomes:
Locations:
city: Olomouc
country: Czechia
facility: University Hospital Olomouc
Study officials:
affiliation: Palacky University
name: Marian Hajduch, MD., PhD.
role: STUDY_CHAIR
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