A phase 1b open-label, dose-escalating study of safety and efficacy of disulfiram, copper and vinorelbine in advanced solid tumors

Disulfiram (DSF) is an inhibitor of acetaldehyde dehydrogenase and is currently used for the treatment of alcoholism. Preclinical studies have shown that the DSF metabolite dithiocarbamate, can bind to copper (Cu) and form bis-(diethyldithiocarbamate)-copper (CuET) that has anti-tumor effects. In the present clinical phase Ib study we investigated DSF in combination with Cu and vinorelbine in cancer patients. This dose escalating phase 1b trial, registered in EudraCT 2019-001972-12 on 23 Oct 2019, included patients with treatment-refractory advanced solid tumors. The treatment combination consisted of chemotherapy with vinorelbine, DSF and Cu. The primary endpoints were dose limiting toxicity (DLT) and to establish the maximal tolerated dose (MTD) of the treatment combination. A total of 16 patients were enrolled in the trial. Two of 16 patients had a dose limiting toxicity (DLT). Three dose levels (DLs) were tested and the MTD was found in DL3: DSF 400 mg once per day (QD) for day 1-7, DSF 200 mg QD day 8-14, Cu 2 mg QD, day 1-15 and vinorelbine (30 mg/m2) day 4 and 11 every third week (Q3W). In this phase 1b trial, an MTD for the treatment combination of DSF, Cu and vinorelbine was found. Even though the drug combination DSF, Cu and vinorelbine was safe and an MTD found, further studies are warranted to investigate whether DSF can be used as an anti-neoplastic repurpose drug.