Phase I and pharmacokinetic study of novel L-nucleoside analog troxacitabine given as a 30-minute infusion every 21 days

Purpose: Troxacitabine (Troxatyl, BCH-4556; BioChem Pharma Inc, Basingstoke, United Kingdom) is a novel synthetic L-nucleoside analog with activity against a broad range of human tumors in preclinical models. Preclinical toxicity suggested a predictable toxicity profile consistent with an agent of this class, with evidence of interspecies differences. We conducted a phase I study of troxacitabine given as a 30-minute infusion once every 21 days. Patients and Methods: The starting dose of troxacitabine was 0.025 mg/m(2), based on toxicology data from the most sensitive species studied (cynomolgus monkey). Doses were doubled until grade I skin or mucosal or grade 2 other toxicity was encountered. A modified Fibonacci scale was used. Results: A total of 45 patients were enrolled at 13 dose levels. Most common nonhematologic side effects were skin rash (44%), lethargy (29%), nausea (24%), alopecia, dry skin (18%), anorexia (13%), neurosensory symptoms (13%), and hand-foot syndrome (13%). In patients treated with prednisone 25 mg/d orally for 5 days, starting on day 1, skin rash was less problematic. Two patients at 12.5 mg/ml experienced close-limiting (grade 4) granulocytopenia. Confirmed partial responses were documented in one patient with previously untreated renal cell carcinoma with metastatic lung and bone lesions and in one patient with an unknown primary tumor. Eighteen patients had a best response of stable disease with a median duration of 5.1 months (range, 2.1 to 18.7 months). Conclusion: When given in this schedule, the maximum-tolerated dose of troxacitabine is 12.5 mg/m(2), and the recommended dose for additional phase 11 studies is 10 mg/m(2) once every 21 days with steroid premedication. E) 2002 by American Society of Clinical Oncology.