Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer

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.

Timeline

Start

2017-09-29

Primary completion

2025-10-30

Completion

2025-12-30

Publications

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

Drugs

Indications