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Phase I Assessment of the Pharmacokinetics, Metabolism, and Safety of Emitefur in Patients With Refractory Solid Tumors

From the US Oncology; Sammons Cancer Center, Baylor University Medical Center; and Mary Crowley Medical Research Center, Dallas; and M.D. Anderson Cancer Center, Houston, TX; Otsuka America Pharmaceutical, Inc., Palo Alto, CA; Otsuka America Pharmaceutical, Inc., and United States Food and Drug Administration, Division of Oncology Drug Products, Rockville; University of Maryland Greenbaum Cancer Center, Baltimore, MD; and University of Washington Medical Center, Seattle, WA.

Address reprint requests to John Nemunaitis, MD, US Oncology, 3535 Worth St, Collins Bldg, 5th Floor, Dallas, TX 75246; email john.nemunaitis{at}usoncology.com

PURPOSE: To determine the toxicities, dose-limiting toxicities (DLT), maximum-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in patients with advanced solid tumors.

METHODS: This was a phase I dose-escalating trial in which cohorts of patients received BOF-A2 (cohort 1, 300 mg/m² orally [PO] tid; cohort 2, 200 mg/m² PO tid; cohort 3, 200 mg/m² bid; and cohort 4, 250 mg/m² bid) for 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetics, 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) was observed in cohorts 1, 2, and 4. Pharmacokinetics indicated that prolonged systemic expression of fluorouracil (5-FU) is maintained after administration of BOF-A2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was 24 ng/mL, which was 184-fold greater than the minimum effective cytotoxic concentration in vitro. Lack of variation of 5-FU trough levels within a day at steady-state indicates suppression 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 days of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidence of circadian variation. Furthermore, evidence of antitumor activity is suggested.

The views expressed in this article are the result of independent work and do not represent the views of the United States Food and Drug Administration or the United States Government.

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