Toxicity assessment
neutropenia, diarrhea, fever, toxicity, toxicities, thrombocytopenia, heart block, bone marrow disease, first-degree, dehydration, infection, weight gain, hyperglycemia, Toxicity, nausea,, anorexia
RECURRENCE, NEUTROPENIA, FEBRILE NEUTROPENIA, HEART BLOCK, THROMBOCYTOPENIA, BONE MARROW DISEASE, MOBITZ, DEHYDRATION, INFECTION, HYPERGLYCEMIA, PANCREATITIS, ANOREXIA
Toxicity was graded according to CTCAE version 4. DLT definitions included only toxicities deemed at least possibly related to therapy. For A1 and A2, hematologic DLT was defined as grade 4 thrombocytopenia or grade 4 neutropenia >7-day duration or a delay in the start of subsequent course by more than 14 days due to ongoing thrombocytopenia or neutropenia, in the absence of bone marrow disease progression seen on clinically indicated bone marrow biopsy (if performed). For cohort B2, hematological DLT is defined as a delay in the start of subsequent course by more than 14 days due to ongoing thrombocytopenia or neutropenia, in the absence of bone marrow disease progression seen on clinically indicated bone marrow biopsy after the first dose reduction of cyclophosphamide and topotecan. Non-hematologic DLT was defined as any non-hematologic toxicity that delayed the start of a subsequent cycle by more than 14 days or any grade ≥3 toxicity, with the exception of the following grade 3 toxicities: nausea, vomiting, anorexia or dehydration resolving to grade ≤2 within 72 hours; increase in hepatic transaminase or electrolyte abnormality resolving eligibility levels within 7 days; diarrhea persisting for less than 72 hours; fever; infection; febrile neutropenia; high cholesterol or triglycerides if responsive (to ≤grade 2) with statin treatment; weight gain; and hyperglycemia if responsive (to <grade 2) with dietary modification. Additional non-hematologic DLT included any grade 2 non-hematological toxicity that persists for more than 7 days and is considered sufficiently medically significant or sufficiently intolerable by patients that it requires treatment interruption; recurrence of grade 2 neuropsychological effects; grade 2 radiologically confirmed pancreatitis; recurrence of grade 2 first-degree symptomatic heart block; and grade 1 second-degree (Mobitz type 1 or 2) asymptomatic heart block.