Preliminary studies of a novel oral fluoropyrimidine carbamate: Capecitabine

Purpose: To evaluate the toxicology and pharmacology of an orally active fluoropyrimidine given as a continuous daily dose divided into two portions for 6 weeks, and to determine the maximal-tolerated daily dose (MTD) and the suggested phase II daily dose. Patients and Methods: Solid-tumor patients with a Karnofsky performance status greater than 70 who had normal organ function and resolution of the effects of prior therapy, and who gave informed written consent, were enrolled, Oral capecitabine, as a divided morning and evening dose, was administered to cohorts of ct minimum of 3 patients starling at 110 mg/m(2) and escalating by means of a modified Fibonacci scheme to 1,657 mg/m(2)/d. Pharmacologic samples were obtained on days 1 and 15, Toxicity evaluations were performed approximately every 3 days for the first 43 days. Antitumor effect was evaluated at day 42 of therapy. Results: Thirty-three patients entered the study. Few side effects occurred at or below 1,331 mg/m(2)/d. The MTD was 1,657 mg/m(2)/d with limiting toxicities of palmar-plantar erythrodysesthesia, nausea, vomiting, vertigo, abdominal pain, diarrhea, and thrombocytopenia. All toxicities were reversible. A mixed response was seen in one breast cancer patient, Pharmacologic studies showed rapid and extensive metabolism of the parent drug into cytotoxic metabolites with a maximum plasma concentration (C-max) 1 hour after ingestion. Linear increases in the area under the concentmtion-time curve (AUC) and C-max were seen with linear increases in administered dose. Conclusion: The suggested phase II dose on a continuous 42-day dosing schedule is 1,331 mg/m(2)/d. Linear pharmacologic parameters of the parent compound and metabolites are demonstrated. (C) 1998 by American Society of Clinical Oncology.