Phase Ib trial of phenformin in patients with V600-mutated melanoma receiving dabrafenib and trametinib.
Academic Article
Overview
abstract
PURPOSE: Preclinical studies show that activation of AMP kinase by phenformin can augment the cytotoxic effect and RAF inhibitors in BRAF V600-mutated melanoma. We conducted a phase Ib dose-escalation trial of phenformin with standard dose dabrafenib/trametinib in patients with metastatic BRAF V600-mutated melanoma. PATIENTS AND METHODS: We used a 3+3 dose escalation design which explored phenformin doses between 50 mg and 200 mg bid. Patients also received standard dose dabrafenib/trametinib. We measured phenformin pharmacokinetics and assessed the effect of treatment on circulating myeloid-derived suppressor cells (MDSCs). RESULTS: 18 patients were treated at dose levels ranging from 50 mg bid to 200 mg bid. The planned dose-escalation phase had to be cancelled because of the COVID 19 pandemic. The most common toxicities were nausea/vomiting; there were 2 cases of reversible lactic acidosis. Responses were seen in 10/18 patients overall (56%) and in 2/8 patients who had received prior therapy with RAF inhibitor. Pharmacokinetic data confirmed drug bioavailability. MDSCs were measured in 7 patients treated at the highest dose levels and showed MDSC levels declined on study drug in 6/7 patients. CONCLUSIONS: We identified the recommended phase 2 dose of phenformin as 50 mg bid when administered with dabrafenib/trametinib, although some patients will require short drug holidays. We observed a decrease in MDSCs, as predicted by preclinical studies, and may enhance immune recognition of melanoma cells.
