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Troxacitabine, an L-Stereoisomeric Nucleoside Analog, on a Five-Times-Daily Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Malignancies

From the Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio; and Brooke Army Medical Center, San Antonio, TX; and Biochem Pharma Inc, Laval, Canada.

Address reprint request to Eric K. Rowinsky, MD, Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Dr, Ste 700, San Antonio, TX, 78229; email: erowinsk{at}saci.org

PURPOSE: To assess the feasibility of administering troxacitabine, a unique L-nucleoside that is not a substrate for deoxycytidine deaminase–mediated catabolism, as a 30-minute intravenous (IV) infusion daily for 5 days.

PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of troxacitabine as a 30-minute IV infusion daily for 5 days. Plasma and urine sampling was performed to characterize the pharmacokinetics and pharmacodynamics of troxacitabine.

RESULTS: Thirty-nine patients received 124 courses of troxacitabine at eight dose levels ranging from 0.12 to 1.8 mg/m²/d. Severe neutropenia that was protracted (> 5 days) and/or associated with fever, and skin rashes were consistently experienced by heavily (HP) and minimally pretreated (MP) patients at doses exceeding 1.2 and 1.5 mg/m²/d, respectively. At troxacitabine doses 1.2 mg/m²/d, treatment was often delayed 1 additional week for complete resolution of hematologic effects, resulting in lengthening of the treatment interval from every 3 to 4 weeks. Skin rash, palmar-plantar erythrodysesthesia, and thrombocytopenia were also observed and were occasionally severe, particularly at the highest doses. A patient with metastatic ocular melanoma experienced a partial response. Pharmacokinetics of troxacitabine were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance (Cl_s) were 60 (32) L and 161 (33) mL/min, respectively, on day 1. After treatment on the fifth day, terminal half-life values averaged 39 (63) hours, and Cl_s was reduced by approximately 20%, averaging 127 (27) mL/min. The principal mode of drug elimination was renal.

CONCLUSION: Recommended doses for phase II studies of troxacitabine as a 30-minute infusion daily for 5 days every 4 weeks are 1.5 and 1.2 mg/m²/d for MP and HP patients, respectively. Broad disease-directed evaluations of troxacitabine on this schedule and possibly less frequent schedules are warranted.

Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.

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