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Phase I and Pharmacologic Study of PN401 and Fluorouracil in Patients With Advanced Solid Malignancies

From the Institute for Drug Development, Cancer Therapy and Research Center and the University of Texas Health Science Center, San Antonio, TX; and Pro-Neuron, Inc, Gaithersburg, MD.

Address reprint requests to Manuel Hidalgo, MD, Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Dr, Suite 700, San Antonio, TX, 78229; email mhidalgo{at}saci.org

PURPOSE: To assess the feasibility of administering PN401, an oral uridine prodrug, as a rescue agent for the toxic effects of fluorouracil (5-FU), and to determine the maximum-tolerated dose of 5-FU when given with PN401, with an 8-hour treatment interval between these agents.

PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of 5-FU, given as a rapid intravenous infusion weekly for 3 consecutive weeks every 4 weeks. PN401 was administered orally 8 hours after 5-FU administration, to achieve sustained plasma uridine concentrations of at least 50 µmol/L. Initially, patients received 6 g of PN401 orally every 8 hours for eight doses (schedule 1). When dose-limiting toxicity (DLT) was consistently noted, patients then received 6 g of PN401 every 2 hours for three doses and every 6 hours thereafter for 15 doses (schedule 2).

RESULTS: Twenty-three patients received 50 courses of 5-FU and PN401. Among patients on schedule 1, DLT (grade 4 neutropenia complicated by fever and diarrhea) occurred in those receiving 5-FU 1,250 mg/m²/wk. Among patients on schedule 2, 5-FU 1,250 mg/m²/wk was well tolerated, but grade 4, protracted (> 5 days) neutropenia was consistently noted in those treated with higher doses of the drugs. Nonhematologic effects were uncommon and rarely severe. The pharmacokinetics of 5-FU, assessed in 12 patients on schedule 2, were nonlinear, with the mean area under the time-versus-concentration curve (AUC) increasing from 298 ± 44 to 962 ± 23 µmol/L and mean clearance decreasing from 34 ± 4 to 15.6 ± 0.38 L/h/m² as the dose of 5-FU was increased from 1,250 to 1,950 mg/m²/wk. 5-FU AUCs achieved with 5-FU 1,250 mg/m²/wk for 6 weeks along with the intensified PN401 dose schedule were approximately five-fold higher than those achieved with 5-FU alone. Plasma uridine concentrations increased with each of the three PN401 doses given every 2 hours, and uridine steady-state concentrations were greater than 50 µmol/L.

CONCLUSION: Treatment with oral PN401 beginning 8 hours after 5-FU administration is well tolerated and results in sustained plasma uridine concentrations above therapeutic-relevant levels. The recommended 5-FU dosage for phase II evaluations is 1,250 mg/m²/wk for 3 weeks every 4 weeks with the intensified PN401 dose schedule (schedule 2). At this dose, systemic exposure to 5-FU as measured by AUC was five-fold higher than that observed after administration of a conventional 5-FU bolus.

Some patients were treated at the Frederic C. Barter Clinical Research Unit of the Audie Murphy Veterans Administration Hospital; that part of the study was supported in part by National Institutes of Health grant no. MO1 RR01346. M.H. was supported in part by grant no. PF 97 52273279 from the Ministerio de Educación y Cultura, Spain, and is the recipient of a National Cancer Institute–European Organization for Research and Treatment of Cancer Fellowship Award.

Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.

M.H and M.A.V.C. contributed equally to this work and should both be considered first authors.

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