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.