This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kantarjian, H. M. Articles by Keating, M. Search for Related Content PubMed PubMed Citation Articles by Kantarjian, H. M. Articles by Keating, M. Social Bookmarking                            What's this?

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

From the Departments of Leukemia, Experimental Therapeutics, and Breast and Head and Neck, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Hagop M. Kantarjian, MD, Department of Leukemia, Box 428, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: hkantarj{at}mdanderson.org.

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.

Supported in part by grants CA32839, CA57629, and CA81534 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD, grant FD-R-001972 from the Food and Drug Administration, and Bioenvision, Inc.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. Jeha, B. Razzouk, M. Rytting, S. Rheingold, E. Albano, R. Kadota, L. Luchtman-Jones, L. Bomgaars, P. Gaynon, S. Goldman, et al. Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia J. Clin. Oncol., September 10, 2009; 27(26): 4392 - 4397. [Abstract] [Full Text] [PDF]

				J. STYCZYNSKI, L. GIL, K. DERWICH, J. WACHOWIAK, W. BALWIERZ, W. BADOWSKA, M. KRAWCZUK-RYBAK, M. MATYSIAK, M. WIECZOREK, A. BALCERSKA, et al. Comparison of Clofarabine Activity in Childhood and Adult Acute Leukemia: Individual Tumor Response Study Anticancer Res, May 1, 2009; 29(5): 1643 - 1650. [Abstract] [Full Text] [PDF]

				J. Laubach and A. V. Rao Current and Emerging Strategies for the Management of Acute Myeloid Leukemia in the Elderly Oncologist, October 1, 2008; 13(10): 1097 - 1108. [Abstract] [Full Text] [PDF]

				J. E. Karp, R. M. Ricklis, K. Balakrishnan, J. Briel, J. Greer, S. D. Gore, B. D. Smith, M. A. McDevitt, H. Carraway, M. J. Levis, et al. A phase 1 clinical-laboratory study of clofarabine followed by cyclophosphamide for adults with refractory acute leukemias Blood, September 15, 2007; 110(6): 1762 - 1769. [Abstract] [Full Text] [PDF]

				V. Gandhi, W. Plunkett, P. L. Bonate, M. Du, B. Nowak, S. Lerner, and M. J. Keating Clinical and Pharmacokinetic Study of Clofarabine in Chronic Lymphocytic Leukemia: Strategy for Treatment. Clin. Cancer Res., July 1, 2006; 12(13): 4011 - 4017. [Abstract] [Full Text] [PDF]

				S. Faderl, S. Verstovsek, J. Cortes, F. Ravandi, M. Beran, G. Garcia-Manero, A. Ferrajoli, Z. Estrov, S. O'Brien, C. Koller, et al. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older Blood, July 1, 2006; 108(1): 45 - 51. [Abstract] [Full Text] [PDF]

				S. Jeha, P. S. Gaynon, B. I. Razzouk, J. Franklin, R. Kadota, V. Shen, L. Luchtman-Jones, M. Rytting, L. R. Bomgaars, S. Rheingold, et al. Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia J. Clin. Oncol., April 20, 2006; 24(12): 1917 - 1923. [Abstract] [Full Text] [PDF]

				E. J. Jabbour, E. Estey, and H. M. Kantarjian Adult Acute Myeloid Leukemia Mayo Clin. Proc., February 1, 2006; 81(2): 247 - 260. [Abstract] [Full Text] [PDF]

				E. J. Jabbour, S. Faderl, and H. M. Kantarjian Adult Acute Lymphoblastic Leukemia Mayo Clin. Proc., November 1, 2005; 80(11): 1517 - 1527. [Abstract] [PDF]

				P. L. Bonate, L. Arthaud, J. Stuhler, P. Yerino, R. J. Press, and J. Q. Rose THE DISTRIBUTION, METABOLISM, AND ELIMINATION OF CLOFARABINE IN RATS Drug Metab. Dispos., June 1, 2005; 33(6): 739 - 748. [Abstract] [Full Text] [PDF]

				S. Faderl, V. Gandhi, S. O'Brien, P. Bonate, J. Cortes, E. Estey, M. Beran, W. Wierda, G. Garcia-Manero, A. Ferrajoli, et al. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias Blood, February 1, 2005; 105(3): 940 - 947. [Abstract] [Full Text] [PDF]

				P. L. Bonate, A. Craig, P. Gaynon, V. Gandhi, S. Jeha, R. Kadota, G. N. Lam, W. Plunkett, B. Razzouk, M. Rytting, et al. Population Pharmacokinetics of Clofarabine, a Second-Generation Nucleoside Analog, in Pediatric Patients With Acute Leukemia J. Clin. Pharmacol., November 1, 2004; 44(11): 1309 - 1322. [Abstract] [Full Text] [PDF]

				S. Jeha, V. Gandhi, K. W. Chan, L. McDonald, I. Ramirez, R. Madden, M. Rytting, M. Brandt, M. Keating, W. Plunkett, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia Blood, February 1, 2004; 103(3): 784 - 789. [Abstract] [Full Text] [PDF]

				J. C. Byrd, S. Stilgenbauer, and I. W. Flinn Chronic Lymphocytic Leukemia Hematology, January 1, 2004; 2004(1): 163 - 183. [Abstract] [Full Text] [PDF]

				V. Gandhi, H. Kantarjian, S. Faderl, P. Bonate, M. Du, M. Ayres, M. B. Rios, M. J. Keating, and W. Plunkett Pharmacokinetics and Pharmacodynamics of Plasma Clofarabine and Cellular Clofarabine Triphosphate in Patients with Acute Leukemias Clin. Cancer Res., December 15, 2003; 9(17): 6335 - 6342. [Abstract] [Full Text] [PDF]

				M. R. Litzow PNAs for AML Blood, October 1, 2003; 102(7): 2315 - 2315. [Full Text] [PDF]

				H. Kantarjian, V. Gandhi, J. Cortes, S. Verstovsek, M. Du, G. Garcia-Manero, F. Giles, S. Faderl, S. O'Brien, S. Jeha, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia Blood, October 1, 2003; 102(7): 2379 - 2386. [Abstract] [Full Text] [PDF]