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

Author(s): Kantarjian HM, Gandhi V, Kozuch P, Faderl S, Giles F, Cortes J, O'Brien S, Ibrahim N, Khuri F, Du M, Rios MB, Jeha S, McLaughlin P, Plunkett W, Keating M

Affiliation(s): Departments of Leukemia, Experimental Therapeutics, and Breast and Head and Neck, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. hkantarj@mdanderson.org

Publication date & source: 2003-03-15, J Clin Oncol., 21(6):1167-73.

Publication type: Clinical Trial; Clinical Trial, Phase I; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.

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/m(2)) was myelosuppressive, requiring several dose de-escalations to 2 mg/m(2), the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m(2), with several escalations to 55 mg/m(2). The DLT was reversible hepatotoxicity at 55 mg/m(2). The recommended dose for acute leukemia phase II studies was 40 mg/m(2). 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/m(2), the median plasma clofarabine level was 1.5 micro mol/L (range, 0.42 to 3.2 micro mol/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/m(2) for solid tumors, the DLT being myelosuppression; and 40 mg/m(2) for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.

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