Originally published as JCO Early Release 10.1200/JCO.2006.06.6209 on December 4 2006

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Phase I/II Study of Continuous-Infusion Troxacitabine in Refractory Acute Myeloid Leukemia

Gail J. Roboz, Francis J. Giles, Ellen K. Ritchie, Sandra Allen-Bard, Tania J. Curcio, Meredith A. Wilkes, S. Lani Park, Hagop M. Kantarjian, Stefan Faderl, Farhad Ravandi, Michael J. Kelner, Eric J. Feldman

From the Weill Medical College of Cornell University, New York, NY; Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Pathology, University of California–San Diego; and SGX Pharmaceuticals, San Diego, CA

Address reprint requests to Gail J. Roboz, MD, Weill Medical College of Cornell University, The New York Presbyterian Hospital, 520 East 70th St, Starr 340A, New York, NY 10021; e-mail: gar2001{at}med.cornell.edu

Purpose Troxacitabine is a non-natural nucleoside analog with unique structural and metabolic features. Bolus intravenous (IV) troxacitabine regimens have shown significant activity in patients with refractory acute myeloid leukemia (AML) and preclinical data suggest that administration via continuous infusion may result in enhanced antitumor activity.

Patients and Methods Patients with refractory AML initially received troxacitabine 10.1 mg/m² by continuous IV infusion (CIVI) for 48 hours. Infusion duration and daily dose were increased in subsequent patient cohorts.

Results Forty-eight patients, median age 58 years (range, 21 to 81 years), were treated. Dose-limiting toxicities were mucositis and hand-foot syndrome, and 12.0 mg/m²/d for 5 days was established as the maximum-tolerated dose. Seven patients (15%) achieved complete remission (CR) or CR with incomplete platelet recovery (CRp), with a median survival among responders of 12 months. Steady-state concentrations of troxacitabine were found to be linearly and inversely proportionally related to calculated creatinine clearance at doses of 10.1 and 12.0 mg/m²/d. All patients responding to troxacitabine had steady-state serum drug concentration of more than approximately 80 ng/mL. In 27 patients achieving target troxacitabine plasma concentrations (ie, approximately 80 ng/mL) the CR + CRp rate was 26%.

Conclusion Troxacitabine administered as a CIVI allows a significant increase in dose-intensity in comparison to IV bolus regimens, has antileukemic activity, and warrants additional investigation in patients with refractory AML. The recommended phase II study dose is 12.0 mg/m² daily CIVI for 5 days.

published online ahead of print at www.jco.org on December 4, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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