Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers

Purpose: To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia. Patients and Methods: The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia. Results: The starting dose of clofarabine (15 mg/m²) was myelosuppressive, requiring several dose de-escalations to 2 mg/m², the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m², with several escalations to 55 mg/m². The DLT was reversible hepatotoxicity at 55 mg/m². The recommended dose for acute leukemia phase II studies was 40 mg/m². Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m², the median plasma clofarabine level was 1.5 μmol/L (range, 0.42 to 3.2 μmol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate. Conclusion: This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m² for solid tumors, the DLT being myelosuppression; and 40 mg/m² for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.