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 Giles, F. J. Articles by Kantarjian, H. M. Search for Related Content PubMed PubMed Citation Articles by Giles, F. J. Articles by Kantarjian, H. M.

Troxacitabine, A Novel Dioxolane Nucleoside Analog, Has Activity in Patients With Advanced Leukemia

From the Departments of Leukemia and Biomathematics, The University of Texas M.D. Anderson Cancer Center, Houston; Department of Clinical Research, Institute for Drug Development, San Antonio, TX; and BioChem Pharma Inc, Laval, Quebec, Canada.

Address reprint requests to Francis J. Giles, MD, The University of Texas M.D. Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd, Box 61, Houston, TX 77030-4095; email: frankgiles@ aol.com.

PURPOSE: To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia.

PATIENTS AND METHODS: Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m²/d (3.6 mg/m²/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined.

RESULTS: Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m²/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m². Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease.

CONCLUSION: Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.

This article has been cited by other articles:

				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]

				A. Jimeno, W. A. Messersmith, C. K. Lee, W. W. Ma, D. Laheru, R. C. Donehower, S. D. Baker, and M. Hidalgo Phase I study of troxacitabine administered by continuous infusion in subjects with advanced solid malignancies Ann. Onc., February 1, 2008; 19(2): 374 - 379. [Abstract] [Full Text] [PDF]

				A. Sparreboom, A. C. Wolff, R. H.J. Mathijssen, E. Chatelut, E. K. Rowinsky, J. Verweij, and S. D. Baker Evaluation of Alternate Size Descriptors for Dose Calculation of Anticancer Drugs in the Obese J. Clin. Oncol., October 20, 2007; 25(30): 4707 - 4713. [Abstract] [Full Text] [PDF]

				G. J. Roboz, F. J. Giles, E. K. Ritchie, S. Allen-Bard, T. J. Curcio, M. A. Wilkes, S. L. Park, H. M. Kantarjian, S. Faderl, F. Ravandi, et al. Phase I/II Study of Continuous-Infusion Troxacitabine in Refractory Acute Myeloid Leukemia J. Clin. Oncol., January 1, 2007; 25(1): 10 - 15. [Abstract] [Full Text] [PDF]

				C. K. K. Lee, E. K. Rowinsky, J. Li, F. Giles, M. J. Moore, M. Hidalgo, E. Capparelli, J. Jolivet, and S. D. Baker Population pharmacokinetics of troxacitabine, a novel dioxolane nucleoside analogue. Clin. Cancer Res., April 1, 2006; 12(7): 2158 - 2165. [Abstract] [Full Text] [PDF]

				R. Lapointe, R. Letourneau, W. Steward, R. E. Hawkins, G. Batist, M. Vincent, R. Whittom, M. Eatock, J. Jolivet, and M. Moore Phase II study of troxacitabine in chemotherapy-naive patients with advanced cancer of the pancreas: Gastrointestinal tumors Ann. Onc., February 1, 2005; 16(2): 289 - 293. [Abstract] [Full Text] [PDF]

				H. Gourdeau, L. Leblond, B. Hamelin, K. Dong, F. Ouellet, C. Boudreau, D. Custeau, A. Richard, M.-J. Gilbert, and J. Jolivet Species Differences in Troxacitabine Pharmacokinetics and Pharmacodynamics: Implications for Clinical Development Clin. Cancer Res., November 15, 2004; 10(22): 7692 - 7702. [Abstract] [Full Text] [PDF]

				T. E. Kim, S.-Y. Park, C.-H. Hsu, G. E. Dutschman, and Y.-C. Cheng Synergistic Antitumor Activity of Troxacitabine and Camptothecin in Selected Human Cancer Cell Lines Mol. Pharmacol., August 1, 2004; 66(2): 285 - 292. [Abstract] [Full Text] [PDF]

				P. Gilbar Palmar-plantar erythrodysesthesia Journal of Oncology Pharmacy Practice, December 1, 2003; 9(4): 137 - 150. [Abstract] [PDF]

				F. J. Giles, H. M. Kantarjian, J. E. Cortes, G. Garcia-Manero, S. Verstovsek, S. Faderl, D. A. Thomas, A. Ferrajoli, S. O'Brien, J. K. Wathen, et al. Adaptive Randomized Study of Idarubicin and Cytarabine Versus Troxacitabine and Cytarabine Versus Troxacitabine and Idarubicin in Untreated Patients 50 Years or Older With Adverse Karyotype Acute Myeloid Leukemia J. Clin. Oncol., May 1, 2003; 21(9): 1722 - 1727. [Abstract] [Full Text] [PDF]

				C.A. Townsley, K. Chi, D.S. Ernst, K. Belanger, I. Tannock, G.A. Bjarnason, D. Stewart, R. Goel, J.D. Ruether, L.L. Siu, et al. Phase II Study of Troxacitabine (BCH-4556) in Patients With Advanced and/or Metastatic Renal Cell Carcinoma: A Trial of the National Cancer Institute of Canada-Clinical Trials Group J. Clin. Oncol., April 15, 2003; 21(8): 1524 - 1529. [Abstract] [Full Text] [PDF]

				F. J. Giles, S. Faderl, D. A. Thomas, J. E. Cortes, G. Garcia-Manero, D. Douer, A. M. Levine, C. A. Koller, S. S. Jeha, S. M. O'Brien, et al. Randomized Phase I/II Study of Troxacitabine Combined With Cytarabine, Idarubicin, or Topotecan in Patients With Refractory Myeloid Leukemias J. Clin. Oncol., March 15, 2003; 21(6): 1050 - 1056. [Abstract] [Full Text] [PDF]

				J.-Y. Liou, P. Krishnan, C.-C. Hsieh, G. E. Dutschman, and Y.-c. Cheng Assessment of the Effect of Phosphorylated Metabolites of Anti-Human Immunodeficiency Virus and Anti-Hepatitis B Virus Pyrimidine Analogs on the Behavior of Human Deoxycytidylate Deaminase Mol. Pharmacol., January 1, 2003; 63(1): 105 - 110. [Abstract] [Full Text] [PDF]

				P. Krishnan, J.-Y. Liou, and Y.-C. Cheng Phosphorylation of Pyrimidine L-Deoxynucleoside Analog Diphosphates. KINETICS OF PHOSPHORYLATION AND DEPHOSPHORYLATION OF NUCLEOSIDE ANALOG DIPHOSPHATES AND TRIPHOSPHATES BY 3-PHOSPHOGLYCERATE KINASE J. Biol. Chem., August 23, 2002; 277(35): 31593 - 31600. [Abstract] [Full Text] [PDF]

				H. M. Kantarjian, S. O'Brien, J. E. Cortes, T. L. Smith, M. B. Rios, J. Shan, Y. Yang, F. J. Giles, D. A. Thomas, S. Faderl, et al. Treatment of Philadelphia Chromosome-positive, Accelerated-phase Chronic Myelogenous Leukemia with Imatinib Mesylate Clin. Cancer Res., July 1, 2002; 8(7): 2167 - 2176. [Abstract] [Full Text] [PDF]

				K. Belanger, M. Moore, S. D. Baker, J. Dionne, M. Maclean, J. Jolivet, L. Siu, D. Soulieres, N. Wainman, and L. Seymour Phase I and Pharmacokinetic Study of Novel L-Nucleoside Analog Troxacitabine Given as a 30-Minute Infusion Every 21 Days J. Clin. Oncol., May 15, 2002; 20(10): 2567 - 2574. [Abstract] [Full Text] [PDF]

				H. M. Kantarjian, J. Cortes, S. O'Brien, F. J. Giles, M. Albitar, M. B. Rios, J. Shan, S. Faderl, G. Garcia-Manero, D. A. Thomas, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase Blood, May 15, 2002; 99(10): 3547 - 3553. [Abstract] [Full Text] [PDF]

				J.-Y. Liou, G. E. Dutschman, W. Lam, Z. Jiang, and Y.-C. Cheng Characterization of Human UMP/CMP Kinase and Its Phosphorylation of D- and L-Form Deoxycytidine Analogue Monophosphates Cancer Res., March 1, 2002; 62(6): 1624 - 1631. [Abstract] [Full Text] [PDF]

				P. Krishnan, Q. Fu, W. Lam, J.-Y. Liou, G. Dutschman, and Y.-C. Cheng Phosphorylation of Pyrimidine Deoxynucleoside Analog Diphosphates. SELECTIVE PHOSPHORYLATION OF L-NUCLEOSIDE ANALOG DIPHOSPHATES BY 3-PHOSPHOGLYCERATE KINASE J. Biol. Chem., February 8, 2002; 277(7): 5453 - 5459. [Abstract] [Full Text] [PDF]

				F. J. Giles, G. Garcia-Manero, J. E. Cortes, S. D. Baker, C. B. Miller, S. M. O'Brien, D. A. Thomas, M. Andreeff, C. Bivins, J. Jolivet, et al. Phase II Study of Troxacitabine, a Novel Dioxolane Nucleoside Analog, in Patients With Refractory Leukemia J. Clin. Oncol., February 1, 2002; 20(3): 656 - 664. [Abstract] [Full Text] [PDF]

				J. S. de Bono, J. Stephenson Jr, S. D. Baker, M. Hidalgo, A. Patnaik, L. A. Hammond, G. Weiss, A. Goetz, L. Siu, C. Simmons, et al. Troxacitabine, an L-Stereoisomeric Nucleoside Analog, on a Five-Times-Daily Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies J. Clin. Oncol., January 1, 2002; 20(1): 96 - 109. [Abstract] [Full Text] [PDF]

				F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian Acute Myeloid Leukemia Hematology, January 1, 2002; 2002(1): 73 - 110. [Abstract] [Full Text]

				B. J. Druker, S. G. O'Brien, J. Cortes, and J. Radich Chronic Myelogenous Leukemia Hematology, January 1, 2002; 2002(1): 111 - 135. [Abstract] [Full Text]