PHASE-I AND PLASMA PHARMACOKINETIC STUDY OF INFUSIONAL FLUOROURACIL COMBINED WITH RECOMBINANT INTERFERON-ALFA-2B IN PATIENTS WITH ADVANCED CANCER

Purpose: Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated. Portents and Methods: FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 × 106 U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography. Results: The maximum-tolerated dose of rIFN-a was 10 × 106 U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Casi; range, 0.77 ± 0.35 μmol/L to 1.85 ± 0.48 μmol/L), elimination half-life (t1/2; mean, 9.7 ± 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 μmol/L × hours), total-body clearance (Cl; range, 1,172 to 3,236 ml/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 μmol/l.) was greater than that before rIFN-a administration (1.02 μmol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20% to 35% compared with use of FUra alone (P < .0001). Patients with a greater than 20% decrease in FUra Cl had a fourfold greater incidence of diarrhea. Conclusion: rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted. © 1993 by American Society of Clinical Oncology.