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

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.

EXPERIMENTAL DESIGN:

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).

RESULTS:

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.

CONCLUSIONS:

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.

SIGNIFICANCE:

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.

• Authors: 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
• Journal: Cancer research communications (Cancer Res Commun) Vol. 3 Issue 12 Pg. 2447-2454 (12 04 2023) ISSN: 2767-9764 [Electronic] United States
• PMID: 37930123 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2023 The Authors; Published by the American Association for Cancer Research.

Chemical References

• trametinib
• dabrafenib
• Phenformin
• Proto-Oncogene Proteins B-raf

Topics

• Humans
• Melanoma (drug therapy)
• Skin Neoplasms (drug therapy)
• Phenformin (adverse effects)
• Proto-Oncogene Proteins B-raf (genetics)