A phase I study of clofarabine in combination with cyclophosphamide and etoposide: A new regimen in pediatric patients with refractory or relapsed acute leukemia

Abstract

9529 Background: Clofarabine is a promising new agent in the treatment of childhood leukemia as evidenced by single agent activity in previous phase I and II studies. We conducted a pilot phase I study of clofarabine used in combination with cyclophosphamide and etoposide to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: Patients between 1 and 21 years old with relapsed or refractory acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) were enrolled. A standard 3+3 design was followed to determine the safe dose when used in combination. All drugs were administered by IV infusion daily for 5 consecutive days in induction and 4 days in consolidation. Patients received up to 2 induction cycles depending on the response, followed by consolidation cycles (maximum of 8 total cycles). The initial doses (cohort 1) were as follows: clofarabine: 20 mg/m2/day, etoposide 75 mg/m2/day and cyclophosphamide 340 mg/m2/day. Once etoposide and cyclophosphamide were escalated to their target dose (100 mg/m2/day and 440 mg/m2/day respectively in cohort 3), clofarabine was then increased to 30 mg/m2/day in cohorts 4 and would be increased to 40 mg/m2/day in cohort 5. Results: Thirteen patients (10 ALL; 3 AML) were enrolled in the first 4 dose cohorts to this date. The median number of prior regimens was 2. Response data (based on investigator assessment) are available for the first 8 patients: 6 patients (including 1 patient with AML) achieved either complete remission (CR) or complete remission without platelet recovery (CRp), for an overall response rate of 75%. Four patients proceeded to HSCT. One patient in cohort 4 experienced a DLT which resolved (grade 3 elevation of lipase) and possible veno-occlusive disease leading to cohort expansion. Common toxicities noted include febrile neutropenia and fever. Conclusions: The phase I study is ongoing until determination of MTD for this combination but these early results indicate that this combination shows significant activity in children with refractory or relapsed acute leukemias and is well-tolerated. No significant financial relationships to disclose.