Phase I clinical and pharmacological study of thymidine (NSC 21548) and cis-diamminedichloroplatinum(II) in patients with advanced cancer.

Studies in cell culture systems have demonstrated synergistic cytotoxicity of thymidine and its in vivo metabolite thymine with cisplatin. We have conducted a Phase I trial to assess the toxic effects and tolerable doses of thymidine plus cisplatin in patients with advanced cancer. Twenty such patients were treated with varying doses of thymidine infused continuously during Days 1-5 of a 28-day cycle. Cisplatin at a dose of 100 mg/m2 was administered on Day 3 of the cycle. Using this schedule, the maximally tolerated dose of thymidine was 60 g/m2/day. Hematological toxicity was dose limiting with median granulocyte and platelet nadirs of 1,500/mm3 and 55,000/mm3, respectively. Central nervous system and gastrointestinal toxicity was also prominent. Plasma and urine thymidine and thymine concentrations were determined using a high-performance liquid chromatography assay. At the maximally tolerated thymidine dose, steady state plasma thymidine concentrations approached or exceeded 1 mM in all patients, and thymine levels of 1-2 mM were achievable. These concentrations approach those demonstrated to produce synergistic cytotoxicity with cisplatin in vitro. Further pharmacokinetic analysis revealed that there is a progressive fall in thymidine plasma clearance with increasing dose and that cisplatin administration is followed by a significant fall in plasma thymidine clearance. No clear-cut relationships between platelet nadir and thymidine pharmacokinetics could be found, although nonlinear regression analysis did reveal a significant correlation between steady-state plasma thymidine concentration and platelet nadir. The recommended thymidine dose for Phase II trials of this combination is 60 g/m2/day in patients with little or no prior therapy.