Journal of Clinical Oncology, Vol 15, 1511-1517, Copyright © 1997 by American Society of Clinical Oncology
Phase I trial of PN401, an oral prodrug of uridine, to prevent toxicity from fluorouracil in patients with advanced cancer
DP Kelsen, D Martin, J O'Neil, G Schwartz, L Saltz, MT Sung, R von Borstel and J Bertino
Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, NY 10021, USA. kelsend@mskcc.org
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 than 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 > or = 50 mumol/L. In
the first phase of the study, all patients received a fixed dose of FU 600
mg/m2 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 greater than 50 mumol/L. In the
second phase of the study, FU doses were escalated from 600 to 1,000 mg/m2.
FU was given as a rapid intravenous bolus weekly for 6 weeks with a 2-week
rest. The MTD of FU given in this fashion with PN401 rescue was 1,000
mg/m2, at which level two of six patients had neutropenic fever. FU at
doses of 800 mg/m2 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 mumol/L. The MTD of FU with PN401 rescue is
1,000 mg/m2 and the recommended dose for phase II trials is 800 mg/m2 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.
