Background: Disulfiram, when complexed with metal ions, is capable of inactivating key oncoproteins. It is thought to accomplish this via glutathionylation of sulfhydryl residues. In human experience thus far is limited. Despite recent advances in treatment including immunologic checkpoint blockade, and b-raf inhibition Stage IV melanoma remains a near-uniformly fatal disease. This study was designed to determine the response rate following treatment with disulfiram and chelated Zn in patients with stage IV melanoma with secondary endpoints of progression free survival, overall survival, pharmacodynamics and toxicity of the combination.

Methods: Eligible patients had biopsy proven Stage IV melanoma. Patients with brain metastases were allowed provided the brain metastases were treated, and the patient was on stable doses of steroids. Disulfiram was dosed at 250 mg orally at bedtime, while chelated Zn was given thrice daily at 50 mg elemental Zn orally with each meal. A treatment cycle consisted of 28 days. Patients were scheduled for response evaluation after two cycles of therapy. Serum was sampled at baseline, and at 1 week from the start of therapy for pharmacodynamic analysis.

Results: Enrollment for this study began 8/3/2010, with the final patient enrolling on 1/16/2013. In total, 12 patients were enrolled, with ten being evaluable for response for this interim futility analysis. 10 of the 12 patients were tested for b-raf mutation status, with three patients harboring a b-raf mutation. One patient experienced a partial response not meeting RECIST criteria with one target lesion decreasing 27% from baseline measurements. Average time on treatment for evaluable patients was 55 days (range 20-168). Progression free survival and overall survival of evaluable patients was 53 days and 203 days respectively. Overall safety data has shown this regimen to be well tolerated with only one Gr 3 or greater drug related adverse event recorded consisting of a confusional episode which resolved following discontinuation of study medication. Other Gr 1 and 2 toxicities have included fatigue, dysgeusia, nausea, vomiting, diarrhea, ataxia, renal insufficiency, and LFT elevations. Pharmacodynamic analysis is pending.

Conclusions: Disulfiram dosed at 250 mg daily together with chelated Zn at doses of 50 mg three times daily is well tolerated in patients with advanced stage IV melanoma; the combination is capable of producing tumor shrinkage. The interim futility analysis endpoint of one responding patient was not met and the study will not expand to the full Phase II cohort of 29 patients. Future work with this combination may be warranted in other cancers given the favorable safety profile, and may also be considered in combination with other therapies actively in use for stage IV melanoma.

Citation Format: Kenneth F. Grossmann, Moesis Terrazas, Hung T. Khong, Wallace Akerley, Ken Kosak, Ken Boucher, Thomas P. Kennedy, Paul J. Shami. Phase II study of disulfiram and chelated Zn for the treatment of disseminated metastatic melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-175. doi:10.1158/1538-7445.AM2013-LB-175