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).

Participant Eligibility

* Histologically or cytologically-confirmed Ewing sarcoma with confirmation of diagnosis by molecular assessment of t(11:22), breakapart of the EWSR1 gene by FISH translocation or similar translocation in the tumor; rhabdomyosarcoma, neuroblastoma, or osteosarcoma.

* Patients in the expansion cohort must have Ewing sarcoma as defined above.

* Documented disease progression after prior therapy in locally advanced or metastatic setting.

* Disease Status: Patients must have either measurable or evaluable disease based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria from the NCI for assessment of radiographic response. Age 12 months to <21 years

* Adequate bone marrow reserves as evidenced by:
o Peripheral absolute neutrophil count (ANC) >= 1000/mm3
o Platelet count >= 100,000/mm3 (transfusion independent),
o Patients with known bone marrow disease will be eligible for study provided they meet the blood counts following transfusion

* Adequate hepatic function as evidenced by:
o Serum total bilirubin less than or equal to 1.5 x ULN
o SGPT (Alanine aminotransferase [ALT]) < 3 x ULN
o Serum albumin > 2 g/dL

* Adequate Renal Function Defined As
o Creatinine clearance or radioisotope GFR >70ml/min/1.73 m2
o or a serum creatinine based on age/gender

* Recovered from the effects of any prior surgery, radiotherapy or other anti-neoplastic therapy and at least 21 days after the last treatment with systemic cytotoxic chemotherapy.

* Patients 18 years or older will provide written consent. A parent or legal guardian of a patient <18 years of age will provide informed consent and patients 11 to 18 years of age will provide written assent or as per participating institutional policy.

* Although the potential of MM-398 crossing the blood-brain barrier is unknown, patients with brain metastases who meet all other eligibility criteria will not be excluded.