Phase I trial of PN401, an oral prodrug of uridine, to prevent toxicity from fluorouracil in patients with advanced cancer

Purpose: We performed a phase I study to determine the appropriate dose of PN401, a uridine (URD) prodrug, to use as a rescue agent for fluorouracil (FU) and then to determine the maximum-tolerated dose (MTD) of FU when given with PN401. Patients and Methods: Patients with advanced cancer received oral PN401 as either a suspension or a tablet in escalating doses. A pharmacokinetic analysis was performed to determine which dose best achieved a target value of sustained levels of URD greater than or equal to 50 mu mol/L. In the first phase of the study, all patients received a fixed dose of FU 600 mg/m(2) as a rapid intravenous bolus followed by 10 doses of PN401 given at 6-hour intervals. PN401 therapy commenced 24 hours after FU. After determination of the appropriate dose of PN401, a second group of patients received escalating doses of FU with a fixed dose of PN401. Results: Thirty-eight patients with advanced cancer received PN401 and FU. Pharmacokinetic analysis indicated that either 6.6 g of PN401 as an oral suspension or 6 g given in tablet form resulted in high bioavailability of URD, with sustained plasma concentrations greeter than 50 mu mol/L. In the second phase of the study, FU doses were escalated from 600 to 1,000 mg/m(2). FU was given as a rapid intravenous bolus weekly for 6 weeks with a 5-week rest. The MTD of FU given in this fashion with PN401 rescue was 1,000 mg/m(2), at which level two of six patients had neutropenic fever. FU at doses of 800 mg/m(2) for 6 weeks was well tolerated without significant toxicity when given with PN401 rescue. Conclusion: Oral PN401 is well tolerated and total doses of 6 g every 6 hours yield sustained levels of URD in the target range of 50 mu mol/L. The MTD of FU with PN401 rescue is 1,000 mg/m(2) and the recommended dose for phase II trials is 800 mg/m(2) given weekly for 6 weeks with dose escalation. Further studies to define better the appropriate interval for PN401 rescue and the appropriate dose of FU when given with biochemical modulation, such as with leucovorin, are indicated. (C) 1997 by American Society of Clinical Oncology.