SPOC-2012-001, Phase 1 Dose-escalating Study of MM-398 (Irinotecan Sucrosofate Liposome Injection) plus Intravenous Cyclophosphamide in Recurrent or Refractory Pediatric Solid Tumors

a dose escalating phase 1 study of intravenous MM-398 (given once per three week cycle) together with intravenous cyclophosphamide (daily x 5 doses) in patients with recurrent or refractory pediatric solid tumors. all patients will participate in up to 28 days of screening, during which they will be assessed for eligibility and screened for the uGT1a1*28 allele. intravenous Cyclophosphamide Dosing: all patients will receive cyclophosphamide 250 mg/m2 intravenously (given over 30 minutes) daily for 5 days. MM-398 Dosing: MM-398 will be administered intravenously over 90 minutes on the 3rd day of the 5 day course of cyclophosphamide. The MM-398 + cyclophosphamide regimen will be administered every 3 weeks, unless precluded by progressive disease (radiologic or clinical deterioration) or unacceptable toxicity. The MM-398 will be dose-escalated as follows: Dose Level: 1a (30 mg/m2), 1 (60 mg/m2), 2 (90 mg/m2), 3 (120 mg/m2), 4 (150 mg/m2), 5 (180 mg/m2), 6 (210 mg/m2) adverse events (aes) will be evaluated according to the national Cancer institute's Common Terminology Criteria for adverse events version 4 (CTCae v4). a dose limiting toxicity (DLT) is defined as a toxicity during the first cycle consisting of one or more of the following events: --Grade 3 or 4 non-hematological toxicity (except grade 3 nausea and vomiting, grade 3 diarrhea lasting less than 4 days) --Grade 4 neutropenia [Greater Than]7 days (stated elsewhere in study) --Dose delay of [Greater Than]2 weeks due to drug-related toxicity --Fever with neutropenia is not a DLT (stated elsewhere in study) Subjects will be enrolled in cohorts of 3 for each dose level. Dose escalation will proceed between each cohort and no intrapatient dose escalation will be allowed. if none of the first 3 subjects experience DLT, then dose escalation will proceed to the next cohort. if 1 of 3 subjects develops DLT, the cohort will be expanded to 6 subjects. if no more than 1 subject of the 6 experience DLT, then escalation to the next dose level will proceed. if 2 subjects in any dose level experience DLT, the dose escalation will be stopped and the prior dose level declared the MTD. a minimum of 6 evaluable subjects will be treated at the MTD dose level and no more than one of the 6 subjects may experience DLT at this dose level. Tumor responses will be measured and recorded according to institutional guidelines, approximately every 6 to 8 weeks by using the ReCiST guidelines (version 1.1). The local radiologist and/or Pi assessment will determine disease progression. Pharmacokinetic (PK) studies Plasma samples for PK will be collected in Cycle 1, from all patients randomized in this study, at the following time points: Just prior to infusion, and then the following times after infusion completes: 4 hours, 24 hours, 48 hours, 120 hours and 168 hours ( all PK are required except the 168 hour time point which is optional). exploratory Research To explore biomarkers associated with toxicity and efficacy following treatment with MM-398 plus cyclophosphamide, analysis of patient Dna from patient blood will be collected for metabolic genotype information (e.g. uGT1a1 genotypes). in addition, if archived biopsies are available, exploratory protein and mRna biomarkers will be measured (in particular, SFLn11 expression, as SLFn11 expression may be associated with the cytotoxic response to topoisomerase inhibitors).