Phase I and Pharmacokinetic Study of Cisplatin and Troxacitabine Administered Intravenously Every 28 Days in Patients with Advanced Solid Malignancies

PURPOSE: To assess the feasibility of administering troxacitabine, an L- nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity. METHODS: Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m(2)) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin. RESULTS: Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m(2), respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196-396 L and 7.2-9.8 L/ h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42% reduction in extent of disease for 6 months. CONCLUSIONS : The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75 /6.4 and 50/4.8 mg/m(2), every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine