Phase I assessment of the pharmacokinetics, metabolism, and safety of emitefur in patients with refractory solid tumors

Purpose: To determine the toxicities, dose-limiting toxicities (DLT), maxim um-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in pati ents with advanced solid tumors. Methods: This was a phase I dose-escalating trial in which cohorts of patie nts received BOF-A2 (cohort 1, 300 mg/m(2) orally [PO] tid; cohort 2, 200 m g/m(2) PO tid; cohort 3, 200 mg/m(2) bid; and cohort 4, 250 mg/m(2) bid) fo r 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetic s, toxicity, and tumor response were monitored. Results: Nineteen patients received 110 cycles (three patients in cohort 1, three patients in cohort 2, 10 patients in cohort 3, and three patients in cohort 4), DLT (grade 3 stomatitis, diarrhea, leukopenia) wets observed in cohorts 1, 2, and 4, pharmacokinetics indicated that prolonged systemic ex pression of fluorouracil (5-FU) is maintained after administration of BOF-A 2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was greater than or equal to 24 ng/mL, which wets 184-fold g reater than the minimum effective cytotoxic concentration in vitro. Lack of variation of 5-FU trough levels within a day at steady-state indicates sup pression of circadian variation. One patient in cohort 3 achieved a partial response and five patients maintained stable disease in excess of 6 months . Conclusion: BOF-A2 at a dose of 200 mg PO bid for 14 days followed by 7 day s of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidenc e of circadian variation. Furthermore, evidence of antitumor activity is su ggested. J Clin Oncol 18:3423-3434. (C) 2000 by American Society of Clinica l Oncology.