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

Hagop M. Kantarjian*, Varsha Gandhi, Peter Kozuch, Stefan Faderl, Francis Giles, Jorge Cortes, Susan O'Brien, Nuhad Ibrahim, Fadlo Khuri, Min Du, Mary Beth Rios, Sima Jeha, Peter McLaughlin, William Plunkett, Michael Keating

*Corresponding author for this work

Research output: Contribution to journalArticle

169 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1167-1173
Number of pages7
JournalJournal of Clinical Oncology
Volume21
Issue number6
DOIs
StatePublished - Mar 15 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kantarjian, H. M., Gandhi, V., Kozuch, P., Faderl, S., Giles, F., Cortes, J., O'Brien, S., Ibrahim, N., Khuri, F., Du, M., Rios, M. B., Jeha, S., McLaughlin, P., Plunkett, W., & Keating, M. (2003). Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. Journal of Clinical Oncology, 21(6), 1167-1173. https://doi.org/10.1200/JCO.2003.04.031