Discussion
DLTs, melanoma, toxicity, cancer, toxicities, acute myelogenous leukemia, neurotoxicity, lactic acidosis, weight loss, anorexia, nausea, vomiting
MELANOMA, CANCER, ACUTE MYELOGENOUS LEUKEMIA, SOLID TUMORS, SECONDARY, HOLIDAY, LACTIC ACIDOSIS, TYPE 2 DIABETES, ANOREXIA
Preclinical observations indicated that biguanide treatment would be expected to enhance the effects of RAF inhibitors on the inhibition of the MAPK pathway. Although metformin penetrates melanoma cells poorly due to lack of expression of organic cation transporters, phenformin can be taken up by melanoma cells in a transporter-independent manner. As such, we were interested in combining phenformin with dabrafenib/trametinib. For this phase Ib trial, we produced and encapsulated phenformin and carried out a dose-escalation trial with dabrafenib/trametinib to establish a RP2D. We had initially planned a dose-expansion cohort in treatment-naïve patients but due to the COVID19 pandemic, we were unable to keep the trial open to accrual. To our knowledge, our trial represents the first human phenformin trial in cancer.Dose escalation showed that, as expected, the most common AEs and the most common DLTs were GI toxicities—nausea, vomiting, and anorexia. We were especially observant for lactic acidosis because this was the toxicity that led the FDA to remove phenformin from the U.S. market. We found lactic acidosis in 2 patients associated with severe nausea/vomiting. Both patients recovered with discontinuation of phenformin and supportive care. Overall, we recommend 50 mg twice daily as the RP2D for phenformin when combined with dabrafenib/trametinib. However, we recognize that this is based on a small number of patients and that even at this dose, some patients will require a drug holiday. It should be noted that this dose is within the range used previously to treat type 2 diabetes (We observed 8 responders among 10 treatment-naïve patients (80% response rate). Among the 8 patients who had previously progressed on RAFi/MEKi therapy, there were 2 responders; one of which was a CR. Response rate was a secondary endpoint of this phase I trial and these response rates, although relatively high, could be consistent with the effects of dabrafenib/trametinib alone. We did observe initial signs of pharmacodynamic effects of phenformin such as increased phospho-AMPK in PBMCs, decreased MDSCs, and weight loss in patients. Because of technical limitation and patient specimen restraint, we opted to measure number of circulating MDSCs from patients without investigating their functional status. MDSCs have been suggested to contribute to resistance to targeted therapies, including RAF inhibitor, in preclinical studies (The toxicity profile of phenformin contrasts with observations from a recent phase I trial with IACS-010759, a potent and selective mitochondrial complex I inhibitor. A dose-escalation trial in patients with acute myelogenous leukemia or other advanced solid tumors was discontinued because of intolerable and dose-limiting neurotoxicity and lactic acidosis (