A Novel Therapy of Clofarabine in Combination with Etoposide and Cyclophosphamide Shows Activity in Pediatric Patients with Refractory or Relapsed Acute Leukemia.

Clofarabine as a single agent has demonstrated activity in childhood acute leukemia. In the current phase I/II study, clofarabine was added to the widely used combination of etoposide and cyclophosphamide. The phase I component of the study is completed. Patients between 1 and 21 years old with refractory or relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) were enrolled in phase I. A standard 3+3 design was followed to determine the safest dose when used in combination. All 3 drugs were administered via IV infusion daily for 5 consecutive days in induction and 4 consecutive days in consolidation. Patients received up to 2 induction cycles (depending on the response following cycle 1), followed by consolidation (up to a maximum of 8 cycles, including induction). The initial doses (cohort 1) were: clofarabine 20 mg/m²/day, etoposide 75 mg/m²/day and cyclophosphamide 340 mg/m²/day. Clofarabine was increased to 30 mg/m²/day in cohort 4 and 40 mg/m²/day in cohort 5 after cyclophosphamide and etoposide were escalated to their respective target dose levels (440 mg/m²/day and 100 mg/m²/day) in cohorts 2 and 3. Twenty-five patients (ALL: 20 patients; AML: 5 patients) were enrolled in the 5 cohorts, and response data based on investigator’s assessment are available on the first 22 patients (ALL: 18 patients; AML: 4 patients). The median number of prior induction regimens was 2, and 3 patients had a prior hematopoietic stem cell transplant (HSCT). Data show complete remission (CR) in 7 patients (ALL: 7 patients; AML: 0 patients) and complete remission without platelet recovery (CRp) in 6 patients (ALL: 2 patients; AML: 4 patients) for an overall response rate of 59% (ALL: 50%; AML: 100%). Four patients proceeded to HSCT after treatment. One patient in cohort 4 experienced a dose-limiting toxicity (DLT) that resolved (grade 3 elevation of lipase and abdominal pain). In addition, a second patient in cohort 4 experienced a lipase elevation that did not meet DLT criteria, leading to a cohort expansion to 10 total patients. One patient in cohort 5 (n=6) experienced a DLT of prolonged bone marrow aplasia leading to cohort expansion. Common toxicities observed in ≥20% of patients included febrile neutropenia, abdominal pain, diarrhea, nausea, vomiting, pyrexia, anorexia, hypokalemia, headache, anxiety and rash. As determined by the independent data monitoring committee, the recommended phase II doses of clofarabine, cyclophosphamide, etoposide 40mg/m²/day, 440 mg/m²/day, and 100 mg/m²/day, respectively. Encouraging preliminary efficacy results and an acceptable safety profile of the combination regimen warrants continuation of the phase II portion of the study, which is actively enrolling patients.