• Cancer Chemother. Pharmacol. · Dec 2009

    Phase I and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies.

    • Chia-Chi Lin, Muralidhar Beeram, Eric K Rowinsky, Chris H Takimoto, Chee M Ng, Charles E Geyer, Louis J Denis, Johann S De Bono, Desiree Hao, Anthony W Tolcher, Sun-Young Rha, Jacques Jolivet, and Amita Patnaik.
    • The Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA.
    • Cancer Chemother. Pharmacol. 2009 Dec 1; 65 (1): 167-75.

    PurposeTo 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.MethodsPatients 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.ResultsThirty-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.ConclusionsThe 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.

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