Harned and Gaynon or relapsed ALL at 52 mg/m2 for 5 days (Jeha et al 2006b). Patients were heavily pretreated, with a median of 3 prior induction regimens. Approximately one-third had received at least 1 prior transplantion, and 57% were refractory to the last therapeutic regimen. Twelve of 61 ALL patients achieved complete remission (CR) or complete remission without platelet recovery (CRp). Only 1 of 42 AML patients achieved CRp. Of those who were refractory to their most recent prior regimen, the overall response rate was 17%. There were an additional 10% of patients who achieved a partial response (PR). The median duration of response for patients with ALL who achieved at least a partial response was 9.7 weeks. Responses were observed in patients with both B-and T-lineage ALL, and in patients with various cyto- genetic abnormalities. Nine of the 61 ALL patients proceeded to HSCT, with no apparent increase in transplantation-related toxicity. The median duration of CR was 7 months in patients receiving transplants (Jeha et al 2006b; Jeha and Kantarjian 2007). The most common adverse events, grade 3 or higher, were fever with neutropenia, anorexia, hypotension, and nausea. Similar response rates were seen in a European phase II trial in pediatric patients with ALL, with a reported CR + CRp rate of 28% (Kearns et al 2006). Forty-two children with AML were reported in a separate pediatric phase II clofarabine trial. The overall response rate in the heavily pretreated pediatrics was 26% (1 CRp and 8 PRs) (Table 4). The median duration of remission was 16.2 weeks and reported toxicities were similar to patients with ALL (Jeha et al 2006b). Combination studies The pediatric phase I and phase II single agent trials deter- mined that clofarabine was active in pediatric patient with relapsed and refractory ALL with an acceptable toxicity proﬁle. Rational combinations of clofarabine with other agents are being investigated in order to optimize clinical Table 4 Response to clofarabine in phase II trials in United States Responses/Total (%) Response ALL AML CR 7/61 (12%) CRp 5/61 (8%) 1/35 (3%) PR 6/61 (10%) 8/35 (23%) CR + CRp 12/61 (20%) 1/35 (3%) CR + CRp + PR 18/61 (30%) 9/35 (26%) Derived from data of Jeha et al (2006 and 2004). Abbreviations: CR, complete remission; CRp, complete remission without full platelet recovery; PR, partial remission. 332 beneﬁt. In vitro data suggest that clofarabine, an inhibitor of DNA repair, may enhance the cytotoxicity of DNA-damaging agents such as cyclophosphamide (Yamauchi et al 2001). The combination of cyclophosphamide and etoposide is utilized during consolidation therapy for pediatric ALL patients with ALL in ﬁrst relapse (Children’s Oncology Group Protocol AALL01P2), and a similar ifosfamide/etoposide combina- tion is active in multiply relapsed ALL (Crooks and Sato 1995). A pilot phase I study of clofarabine used in combi- nation with cyclophosphamide and etoposide is ongoing to determine the MTD and the dose-limiting toxicities of the combination. Once etoposide and cyclophosphamide were escalated to their target doses (100 mg/m2/day and 440 mg/ m2/day, respectively in cohort 3), clofarabine was increased to 30 mg/m2/day in cohort 4 and would be increased to 40 mg/m2 in cohort 5 (Hijiya et al 2007). To date, 19 patients (15 ALL, 4 AML) have been enrolled in the ﬁrst 4 dose cohorts (Table 5). Seventeen patients (14 ALL, 3 AML) have response data available. The median number of prior regimens was 2. Seven of 14 evaluable ALL patients achieved a CR and 2 ALL patients achieved a CRp, for an overall response rate of 64% among pediatric patients with ALL. Three out of 3 patients with AML achieved a CRp. One patient in cohort 4 experienced a grade 3 elevation of lipase and possible veno-occlusive disease. Febrile neutropenia was a common toxicity. Phase 2 studies of this combination will take place once the MTD is determined (Hijiya et al 2007). Other studies are investigating whether clofarabine, a potent inhibitor of ribonucleotide reductase, will modulate intracellular cytarabine (Ara-c) triphosphate accumula- tion and increase the cytotoxicity of Ara-c (Cooper et al 2005; Faderl et al 2005b, 2006). A phase 1–2 adult study in 32 adults with relapsed and refractory acute leukemias demonstrated that the combination of clofarabine at the adult MTD dose level of 40 mg/m2/day for 5 days (days 2–6) followed 4 hours later by cytarabine 1 g/m2 administered as a 2-hour intravenous infusion for 5 days (days 1–5) was safe and effective (Faderl et al 2005b). The overall response rate was 38% with 1 death during induction. Adverse events were mainly less than or equal to grade 2, including transient liver enzyme elevations, nausea, diarrhea, skin rash, muco- sitis, and palmo-plantar erythrodysesthesias. A Children’s Oncology Group (COG) study (AAML0523) is underway to explore the safety and effecacy of this combination. Safety and tolerability Clofarabine is tolerated at 20 times higher doses in leukemia patients than in patients with solid tumors, where Therapeutics and Clinical Risk Management 2008:4(2)