• Johann S de Bono, Joseph Stephenson, Sharyn D Baker, Manuel Hidalgo, Amita Patnaik, Lisa A Hammond, Geoffrey Weiss, Andrew Goetz, Lillian Siu, Cecelia Simmons, Jacques Jolivet, and Eric K Rowinsky.
• Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, 8122 Datapoint Drive, Suite 700, San Antonio, TX 78229, USA.
• J. Clin. Oncol. 2002 Jan 1; 20 (1): 96-109.

PurposeTo 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 MethodsPatients 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.ResultsThirty-nine patients received 124 courses of troxacitabine at eight dose levels ranging from 0.12 to 1.8 mg/m(2)/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/m(2)/d, respectively. At troxacitabine doses > or = 1.2 mg/m(2)/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.ConclusionRecommended 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/m(2)/d for MP and HP patients, respectively. Broad disease-directed evaluations of troxacitabine on this schedule and possibly less frequent schedules are warranted.

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