Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer

Metastatic Breast Cancer Clinical Trial

— DISC  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03323346
• Other study ID #: 2016-1-DSF-MBC
• Status: Recruiting
• Phase: Phase 2
• Start date: September 29, 2017
• Est. completion date: December 31, 2023

Study information

• Verified date: March 2023
• Source: The Institute of Molecular and Translational Medicine, Czech Republic
• Contact: Marian Hajduch, MD., PhD.
• Phone: +420 585632111
• Email: marian.hajduch[@]upol.cz
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: December 31, 2023
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Neoplasm Female
• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

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.

Locations

Country	Name	City	State
Czechia	University Hospital Olomouc	Olomouc

Sponsors (2)

Lead Sponsor	Collaborator
The Institute of Molecular and Translational Medicine, Czech Republic	University Hospital Olomouc

Country where clinical trial is conducted

Czechia, 

References & Publications (11)

Askgaard G, Friis S, Hallas J, Thygesen LC, Pottegard A. Use of disulfiram and risk of cancer: a population-based case-control study. Eur J Cancer Prev. 2014 May;23(3):225-32. doi: 10.1097/CEJ.0b013e3283647466. — View Citation

Brar SS, Grigg C, Wilson KS, Holder WD Jr, Dreau D, Austin C, Foster M, Ghio AJ, Whorton AR, Stowell GW, Whittall LB, Whittle RR, White DP, Kennedy TP. Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. Mol Cancer Ther. 2004 Sep;3(9):1049-60. — View Citation

Chen D, Cui QC, Yang H, Dou QP. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 2006 Nov 1;66(21):10425-33. doi: 10.1158/0008-5472.CAN-06-2126. — View Citation

Cvek B, Milacic V, Taraba J, Dou QP. Ni(II), Cu(II), and Zn(II) diethyldithiocarbamate complexes show various activities against the proteasome in breast cancer cells. J Med Chem. 2008 Oct 23;51(20):6256-8. doi: 10.1021/jm8007807. Epub 2008 Sep 25. — View Citation

Cvek B. Nonprofit drugs as the salvation of the world's healthcare systems: the case of Antabuse (disulfiram). Drug Discov Today. 2012 May;17(9-10):409-12. doi: 10.1016/j.drudis.2011.12.010. Epub 2011 Dec 16. — View Citation

Lewison EF. Spontaneous regression of breast cancer. Prog Clin Biol Res. 1977;12:47-53. No abstract available. — View Citation

Lin J, Haffner MC, Zhang Y, Lee BH, Brennen WN, Britton J, Kachhap SK, Shim JS, Liu JO, Nelson WG, Yegnasubramanian S, Carducci MA. Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth. Prostate. 2011 Mar 1;71(4):333-43. doi: 10.1002/pros.21247. Epub 2010 Aug 31. — View Citation

Robinson TJ, Pai M, Liu JC, Vizeacoumar F, Sun T, Egan SE, Datti A, Huang J, Zacksenhaus E. High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: interaction with IQ motif-containing factors. Cell Cycle. 2013 Sep 15;12(18):3013-24. doi: 10.4161/cc.26063. Epub 2013 Aug 12. — View Citation

Schweizer MT, Lin J, Blackford A, Bardia A, King S, Armstrong AJ, Rudek MA, Yegnasubramanian S, Carducci MA. Pharmacodynamic study of disulfiram in men with non-metastatic recurrent prostate cancer. Prostate Cancer Prostatic Dis. 2013 Dec;16(4):357-61. doi: 10.1038/pcan.2013.28. Epub 2013 Aug 20. — View Citation

Suh JJ, Pettinati HM, Kampman KM, O'Brien CP. The status of disulfiram: a half of a century later. J Clin Psychopharmacol. 2006 Jun;26(3):290-302. doi: 10.1097/01.jcp.0000222512.25649.08. — View Citation

Wickstrom M, Danielsson K, Rickardson L, Gullbo J, Nygren P, Isaksson A, Larsson R, Lovborg H. Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients. Biochem Pharmacol. 2007 Jan 1;73(1):25-33. doi: 10.1016/j.bcp.2006.08.016. Epub 2006 Aug 26. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	The pharmacokinetic (PK) characteristics	Cmax	Day 0 = at first administration of the drug
Secondary	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
Secondary	The pharmacokinetic (PK) characteristic - T-max	T-max - Time to reach maximum concentration	Day 0 = at first administration of the drug
Secondary	The pharmacokinetic (PK) characteristic - T1/2	T1/2 - Apparent terminal elimination half-life time	Day 0 = at first administration of the drug
Secondary	The pharmacokinetic (PK) characteristic - ?z	?z (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
Secondary	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

External Links

•   The trial status on regulator's website.
•   The trial status on sponsor's website.