Clinical Trial Design
Toxicities, nausea/vomiting, neurologic toxicity, DLTs, fatigue, diarrhea, toxicity, toxicities, melanoma, liver or renal disease, hypoglycemic agents, bundle branch block, laboratory abnormalities, DLT, diabetes
ADVERSE EVENT, MELANOMA, BRAIN METASTASES, BUNDLE BRANCH BLOCK, LACTIC ACIDOSIS, ONCOLOGY, G6PD DEFICIENCY, DIABETES
In this phase Ib trial, patients with metastatic or stage III inoperable BRAF V600-mutated melanoma were treated with standard dose dabrafenib (150 mg orally twice daily), trametinib (2 mg orally every day) plus phenformin at escalating dose levels. The first cohort received 50 mg orally twice daily of phenformin. Subsequent cohorts were to be treated at 100 mg twice daily, 200 mg twice daily, 300 mg twice daily according to a standard 3+3 dose-escalation design. Cohorts could be accrued to intermediate dose levels (e.g., 150 mg twice daily) based on toxicities observed. Patients could be de-escalated a maximum of two dose levels if necessary for toxicity. Toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE) 4.0. Dose-limiting toxicities (DLT) were defined as lactic acidosis, any grade 2 neurologic toxicity, most grade 3 toxicities (except transient fatigue, nausea/vomiting, or diarrhea, asymptomatic laboratory abnormalities), or any grade 4 toxicity. Additional toxicities not listed were considered DLTs at the discretion of the principal investigator. Once a recommended phase II dose (RP2D) was identified, we planned to accrue 10 additional patients to the RP2D in a dose-expansion cohort. Clinical responses were assessed using RECIST 1.1.Patients were eligible if they had stage IV (or inoperable stage III) melanoma with a BRAF V600 mutation. Patients had to be at least 18 years old, have an Eastern Cooperative Oncology Group performance status of at least 2, and have adequate organ and marrow function. In the dose-escalation phase, prior therapy with RAF inhibitors was allowed. In the 10-patient dose-expansion cohort, patients had to be RAF inhibitor-naïve. Aside from standard exclusion criteria, other exclusion criteria included: brain metastases unless asymptomatic and stable for at least 6 weeks on the equivalent of 2 mg/day of dexamethasone or less; type 1 or 2 diabetes, or Hgb A1c >6.5% (the Hgb A1c exclusion was removed in later amendments); concurrent use of hypoglycemic agents; chronic liver or renal disease; known G6PD deficiency; and QTc interval >500 ms unless a bundle branch block was present.The protocol was approved by the Institutional Review Boards at MSKCC and Massachusetts General Hospital. All patients provided written informed consent prior to participating on this trial.