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| Name | Class |
|---|---|
| University Hospital Olomouc | OTHER |
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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:
Secondary efficacy objectives:
To evaluate the efficacy of the treatment by assessment of:
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:
Exclusion criteria:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Disulfiram with copper | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Disulfiram | Drug | 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. |
| 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 |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Marian Hajduch, MD., PhD. | Palacky University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Olomouc | Olomouc | 77900 | Czechia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23863824 | Background | 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. | |
| 17026967 | Background | 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. |
| Label | URL |
|---|---|
| The trial status on sponsor's website. | View source |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D004221 | Disulfiram |
| D003300 | Copper |
| ID | Term |
|---|---|
| D004050 | Ditiocarb |
| D013859 | Thiocarbamates |
| D002219 | Carbamates |
| D000144 | Acids, Acyclic |
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|
|
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 |
| 23958896 | Background | 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. |
| 15367699 | Background | 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. |
| 918117 | Background | Lewison EF. Spontaneous regression of breast cancer. Prog Clin Biol Res. 1977;12:47-53. No abstract available. |
| 20809552 | Background | 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. |
| 23974104 | Background | 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. |
| 18816109 | Background | 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. |
| 17079463 | Background | 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. |
| 22192884 | Background | 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. |
| 16702894 | Background | 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. |
| D017437 |
| Skin and Connective Tissue Diseases |
| D002264 |
| Carboxylic Acids |
| D009930 | Organic Chemicals |
| D004220 | Disulfides |
| D013440 | Sulfides |
| D013457 | Sulfur Compounds |
| D019216 | Metals, Heavy |
| D004602 | Elements |
| D007287 | Inorganic Chemicals |
| D028561 | Transition Elements |
| D008670 | Metals |