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FIGURE 2 from Phase Ib Trial of Phenformin in Patients with V600-mutated Melanoma Receiving Dabrafenib and Trametinib

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posted on 2023-12-04, 14:20 authored by Paul B. Chapman, Mark Klang, Michael A. Postow, Alexander Noor Shoushtari, Ryan J. Sullivan, Jedd D. Wolchok, Taha Merghoub, Sadna Budhu, Phillip Wong, Margaret K. Callahan, Bin Zheng, Jonathan Zippin

Pharmacokinetics of phenformin. Pharmacokinetic results are shown for the 50 mg bid cohort (A), 100 mg bid cohort (B), 150 mg bid cohort (C), and the 200 mg bid cohort (D). Data for patients who missed a substantial number of doses due to toxicity are not shown. For the patients in the 200 mg bid cohort (D), red bars indicate days on which phenformin was held due to toxicity. The arrows indicate dose reductions. E, Box and whiskers plot of day 7 phenformin plasma concentrations by dose level. The mean is indicated by the horizontal lines. Each box indicates 25%–75% quartiles; whiskers indicate the range. For the 200 mg dose level, there were data on only 2 patients and so no box is shown. bid, twice daily.

Funding

HHS | NIH | National Cancer Institute (NCI)

History

ARTICLE ABSTRACT

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. 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). 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. 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. 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.