PRELIMINARY STUDIES OF A NOVEL ORAL FLUOROPYRIMIDINE CARBAMATE - CAPECITABINE

Purpose: To evaluate the toxicology and pharmacology of an orally acti ve fluoropyrimidine given as a continuous daily dose divided into two portions for 6 weeks, and to determine the maximal-tolerated daily dos e (MTD) and the suggested phase II daily dose. Patients and Methods: S olid-tumor patients with a Karnofsky performance status greater than 7 0 who had normal organ function and resolution of the effects of prior therapy, and who gave informed written consent, were enrolled, Oral c apecitabine, as a divided morning and evening dose, was administered t o cohorts of ct minimum of 3 patients starling at 110 mg/m(2) and esca lating by means of a modified Fibonacci scheme to 1,657 mg/m(2)/d. Pha rmacologic samples were obtained on days 1 and 15, Toxicity evaluation s were performed approximately every 3 days for the first 43 days. Ant itumor effect was evaluated at day 42 of therapy. Results: Thirty-thre e 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, abdomin al pain, diarrhea, and thrombocytopenia. All toxicities were reversibl e. A mixed response was seen in one breast cancer patient, Pharmacolog ic studies showed rapid and extensive metabolism of the parent drug in to cytotoxic metabolites with a maximum plasma concentration (C-max) 1 hour after ingestion. Linear increases in the area under the concentm tion-time curve (AUC) and C-max were seen with linear increases in adm inistered dose. Conclusion: The suggested phase II dose on a continuou s 42-day dosing schedule is 1,331 mg/m(2)/d. Linear pharmacologic para meters of the parent compound and metabolites are demonstrated. (C) 19 98 by American Society of Clinical Oncology.