Toxicity
nausea, neutropenia, fever, fatigue, dose-limiting, toxicities, nausea and vomiting, vomiting, anion-gap acidosis, weight loss
NEUTROPENIA, ADVERSE EVENTS, EVENT, ADVERSE EVENT, EVENTS
The treatment-related adverse events (AE) thought to be at least possibly related to study treatment are recorded in AEs attributable to study drugNOTE: Each dot represents a patient. If a patient had an adverse event multiple times, only the worst grade event was scored. Red dots indicate adverse events that were considered dose-limiting.Abbreviation: bid, twice daily.In the first dose level (50 mg twice daily), 1 patient developed neutropenia that qualified as a DLT and required a total of 6 patients to be treated. Three patients were then treated at 100 mg twice daily without a DLT. The next 3 patients were treated at 200 mg twice daily but this was not tolerable due to GI toxicities. We observed two cases of anion-gap acidosis. Patient 13 (150 mg twice daily dose level) presented for day 8 of the first cycle with nausea and vomiting. The patient was found to have an anion gap and mildly elevated creatinine. He was admitted, treated with intravenous fluids and anti-nausea drugs and was discharged 2 days later fully recovered. Patient 18 (100 mg twice daily dose level) developed fever, nausea, and vomiting (cycle 1 day 27). She was admitted to a local hospital with elevated creatinine and elevated lactic acid. She was treated with intravenous fluids and after 9 days, she was discharged fully recovered.Constitutional/inflammatory AEs as well as skin/mucosal events were also observed, presumably due primarily to dabrafenib/trametinib, but constituted only one DLT (fatigue). We also saw hematologic AEs at the lower dose levels including 1 DLT (neutropenia). It is unclear why these AEs were not seen at the higher dose levels, but it could be related to the fact that patients on the lower dose levels were on treatment longer.Because many studies with metformin, but not all, have reported weight loss, we assessed changes in body weight in our patients on phenformin. In almost all patients, body weight decreased on study (At the completion of the dose-escalation phase (