Phase I dose-escalation trial of clofarabine followed by escalating doses of fractionated cyclophosphamide in children with relapsed or refractory acute leukemias

Background By inhibiting DNA repair, clofarabine (CLO) may augment cyclophosphamide (CY)-induced DNA damage and apoptosis. We performed a Phase I study for refractory and/or relapsed (R/R) leukemia in children to determine maximum-tolerated dose (MTD) of time-sequential CLO followed by CY. Procedure Thirteen patients with (R/R) ALL (n?=?8) and AML (N?=?5), median age 9 years (range: 212 years), were treated with escalating doses of CLO on days 1, 2, 3 and 8, 9, 10 and CY 200?mg/m2/day on days 0 and 1 then 400?mg/m2/day on days 2, 3, 8, 9, and 10. Ten patients were treated at dose level 1 (DL1) (CLO 20?mg/m2/day) and three patients at DL2 (CLO 30?mg/m2/day). The average number of prior chemotherapies was 8.9. DNA damage testing was performed before treatment on day 0, and 2?hours after CY on day 0, before sequential CLO, CY treatment on day 1, and 2?hours after CLO followed by CY on day 1. Results Two patients at DL2 had dose-limiting toxicities (DLTs) that included hypotension with cardio-respiratory failure (1) and hepato-renal failure (1). Complete remission (CR) was achieved in 2/11 (18.2%) and partial remission (PR) in 2/11 (18.2%) for an overall response (OR) of 36.4%. The use of CLO before CY augmented CY-induced DNA damage in leukemic blasts compared to CY alone. Conclusion In pediatric patients with R/R leukemia, 20?mg/m2/day is the MTD for CLO in timed sequential combination with CY. Increased DNA damage with the use of this combination suggests a mechanism for the sequential timing of these two chemotherapeutic agents. Pediatr Blood Cancer 2012; 59: 12521258. (C) 2012 Wiley Periodicals, Inc.