%0 Clinical Trial, Phase I
%T Phase Ib Trial of Phenformin in Patients with V600-mutated Melanoma Receiving Dabrafenib and Trametinib.
%A Chapman PB
%A Klang M
%A Postow MA
%A Shoushtari AN
%A Sullivan RJ
%A Wolchok JD
%A Merghoub T
%A Budhu S
%A Wong P
%A Callahan MK
%A Zheng B
%A Zippin J
%J Cancer Res Commun
%V 3
%N 12
%D 2023 12 4
%M 37930123
暂无%R 10.1158/2767-9764.CRC-23-0296
%X 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.<BR>We used a 3+3 dose-escalation design which explored phenformin doses between 50 and 200 mg twice daily. Patients also received standard dose dabrafenib/trametinib. We measured phenformin pharmacokinetics and assessed the effect of treatment on circulating myeloid-derived suppressor cells (MDSC).<BR>A total of 18 patients were treated at dose levels ranging from 50 to 200 mg twice daily. The planned dose-escalation phase had to be cancelled because of the COVID 19 pandemic. The most common toxicities were nausea/vomiting; there were two cases of reversible lactic acidosis. Responses were seen in 10 of 18 patients overall (56%) and in 2 of 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 of 7 patients.<BR>We identified the recommended phase II dose of phenformin as 50 mg twice daily 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.<BR>This is the first trial using phenformin in combination with RAF/MEK inhibition in patients with BRAF V600-mutated melanoma. This is a novel strategy, based on preclinical data, to increase pAMPK while blocking the MAPK pathway in melanoma. Our data provide justification and a recommended dose for a phase II trial.