DISCUSSION
DLTs, neutropenia, diarrhea, toxicity, toxicities, thrombocytopenia, GI toxicity, Toxicity, type 2 diabetes mellitus
PEDIATRIC ALL, THROMBOCYTOPENIA, TYPE 2 DIABETES MELLITUS, NEUTROPENIA
This Phase I trial found the MTD was exceeded at Dose Level 5, 2000 mg/mRecommended metformin dosing for newly‐diagnosed type 2 diabetes mellitus in children 10 years and older is initially 500–1000 mg daily with escalation as high as 1000 mg twice daily.This study collected all Grade 3 and 4 toxicities and assessed attribution to metformin, but did not assess attribution to VIT. The toxicities attributed to metformin may have overlapping attribution to VIT or may represent interactions between VIT and metformin. The initial design of this trial adding metformin to VIT in the second cycle was designed to assist in determining additive and overlapping toxicities. For hematologic toxicity, rates of Grade 3 and 4 thrombocytopenia appear higher in the VIT‐only cycles (20% VIT alone vs. 9.6% VIT‐metformin), while Grade 3 and 4 neutropenia was increased in metformin containing cycles (6.7% for VIT alone vs. 29.8%% for VIT‐metformin). Notably, for GI toxicity, rates of Grade 3 and 4 diarrhea appear higher in the VIT‐metformin cycles (0% for VIT alone vs. 6.4% for VIT‐metformin). This increased frequency along with two DLTs of diarrhea requiring prolonged hospitalization with IV fluids indicate diarrhea was an important additional toxicity from VIT‐metformin. Toxicity comparisons between VIT and VIT‐metformin cycles, especially hematologic, must be interpreted with caution, as the dosing of temozolomide was lowered with an amendment after the 11th patient.An exact toxicity comparison in the literature using the VIT backbone identical to our trial is unavailable, as our study utilized a decrease dose of temozolomide for most patients. Multiple other prior trials and retrospective experiences of VIT have used varying doses, dosing schedules, and administration routes of these agents (e.g. IV vs. oral irinotecan, five‐ vs ten‐day irinotecan dosing schedule, dosing heterogeneity of temozolomide), making direct comparisons to our trial challenging.Comparable to our previous study of metformin in pediatric ALL patients, reported AUC was within 6% at the same dosing cohort (1000 mg/mOur trial has several limitations. First, because of feasibility difficulties during early enrollment, the dose of temozolomide was lowered from 100 mg/mIn conclusion, the addition of metformin to VIT chemotherapy with modified‐dose temozolomide was found to be tolerable, and our RP2D is metformin 1666 m/m