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 dos e of PN401, a uridine (URD) prodrug, to use as a rescue agent for fluo rouracil (FU) and then to determine the maximum-tolerated dose (MTD) o f FU when given with PN401. Patients and Methods: Patients with advanc ed cancer received oral PN401 as either a suspension or a tablet in es calating doses. A pharmacokinetic analysis was performed to determine which dose best achieved a target value of sustained levels of URD gre ater than or equal to 50 mu mol/L. In the first phase of the study, al l patients received a fixed dose of FU 600 mg/m(2) as a rapid intraven ous bolus followed by 10 doses of PN401 given at 6-hour intervals. PN4 01 therapy commenced 24 hours after FU. After determination of the app ropriate dose of PN401, a second group of patients received escalating doses of FU with a fixed dose of PN401. Results: Thirty-eight patient s with advanced cancer received PN401 and FU. Pharmacokinetic analysis indicated that either 6.6 g of PN401 as an oral suspension or 6 g giv en in tablet form resulted in high bioavailability of URD, with sustai ned plasma concentrations greeter than 50 mu mol/L. In the second phas e 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-wee k rest. The MTD of FU given in this fashion with PN401 rescue was 1,00 0 mg/m(2), at which level two of six patients had neutropenic fever. F U at doses of 800 mg/m(2) for 6 weeks was well tolerated without signi ficant toxicity when given with PN401 rescue. Conclusion: Oral PN401 i s 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 P N401 rescue is 1,000 mg/m(2) and the recommended dose for phase II tri als is 800 mg/m(2) given weekly for 6 weeks with dose escalation. Furt her 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.