A Phase 1B Clinical Trial of Trametinib Plus Digoxin in Patients With Unresectable or Metastatic BRAF Wild-type Melanoma

Primary Objectives: * To describe the toxicities and estimate the frequency of dose limiting toxicities (DLTs) of digoxin in combination with trametinib in advanced melanoma patients and estimate the frequency of DLTs. * To measure the response rate, response duration and progression free survival (PFS) of digoxin plus trametinib in advanced melanoma. Secondary Objectives: * To correlate NSG xenograft sensivity to the drug combination with clinical response in the same patient. * To compare response rates in MAPK inhibitor naive versus refractory patients and NRAS mutant versus wild-type patients and for sodium pump 3 subunit high tumor expression versus low tumor expression patients. Rationale: Having established cell culture and xenograft systems for studying patient melanoma samples, the researchers were able to grow tumors in vitro and in vivo from single cells and found a correlation of tumor metastatic behavior in immunocompromised mice and in patients. Recently they have extended the experiments to examine melanoma sensitivity to novel compounds. In screens of FDA approved drugs, they found several cardenolides including digoxin that reproducibly exhibited greater toxicity to primary human melanomas as compared to a range of normal human cells. They then examined the anti-tumor efficacy against primary human melanomas growing in vivo as xenografts. While trametinib, vemurafenib, and digoxin and digitoxin individually slowed the growth of human melanomas xenografts, they did not cause tumor regression. However, the combination of digoxin or digitoxin and trametinib caused substantial tumor regression using melanomas obtained from multiple patients, some with BRAF mutations and some without. The effects were dramatically better than trametinib, digoxin, digitoxin or vemurafenib alone. No difference in efficacy for the combination was seen in BRAF mutant and BRAF wild-type samples.