Definition of MTD and DLT
Toxicities were graded according to version 4.0 of the NCI Common Terminology Criteria for Adverse Events. A non-hematologic DLT was defined as any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity (except for grade 3 nausea and vomiting <5 days, grade 3 diarrhea or electrolyte disturbance that has not been maximally treated, or grade 3 AST/ALT elevation that resolves within 7 days and does not recur), or any grade 2 non-hematologic toxicity that persists for >7 days and is considered medically significant or sufficiently intolerable by patients and requires treatment interruption. A hematologic DLT was defined as grade 3 neutropenia with fever and sepsis, any grade 4 hematologic toxicity with the exception of lymphopenia, grade 3 thrombocytopenia, or requiring a platelet transfusion on 2 separate days in a 7 day span.
MTD was defined based on the Rolling-6 design as the highest dose studied where no more than 1/6 patients experienced a DLT and the next higher dose level was determined to be intolerable. Patients were evaluable for MTD estimation if they received at least one dose of the study drug and were taken off treatment for toxicity during the first course (dose-finding period). In the absence of toxicity, patients needed to receive 17 or more doses of prescribed therapy during the dose-finding period to be evaluable for MTD estimation.