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Phase I and Pharmacokinetic Study of the Oral Fluoropyrimidine Capecitabine in Combination With Paclitaxel in Patients With Advanced Solid Malignancies

From the Institute for Drug Development, Cancer Therapy and Research Center, and The University of Texas Health Science Center at San Antonio, San Antonio; Brooke Army Medical Center, Fort Sam Houston, TX; and Hoffmann-LaRoche, Inc, Nutley, NJ.

Address reprint requests to Miguel A. Villalona-Calero, MD, Division of Hematology Oncology, Ohio State University, B406 Starling-Louing Hall, Columbus, OH 43210; email villalona-1{at}medctr.osu.edu

PURPOSE: To evaluate the feasibility of administering the oral fluoropyrimidine capecitabine in combination with paclitaxel, to characterize the principal toxicities of the combination, to recommend doses for subsequent disease-directed studies, and to determine whether significant pharmacokinetic interactions occur between these agents when combined.

PATIENTS AND METHODS: Sixty-six courses of capecitabine and paclitaxel were administered to 17 patients in a two-stage dose-escalation study. Paclitaxel was administered as a 3-hour intravenous (IV) infusion every 3 weeks, and capecitabine was administered continuously as two divided daily doses. During stage I, capecitabine was escalated to a target dose of 1,657 mg/m²/d, whereas the paclitaxel dose was fixed at 135 mg/m². In stage II, paclitaxel was increased to a target dose of 175 mg/m², and the capecitabine dose was the maximum established in stage I. Pharmacokinetics were characterized for each drug when given alone and concurrently.

RESULTS: Myelosuppression, predominately neutropenia, was the principal dose-limiting toxicity (DLT). Othertoxicities included hand-foot syndrome, diarrhea, hyperbilirubinemia, skin rash, myalgia, and arthralgia. Two patients treated with capecitabine 1,657 mg/m²/d and paclitaxel 175 mg/m² developed DLTs, whereas none of six patients treated with capecitabine 1,331 mg/m²/d and paclitaxel 175 mg/m² developed DLTs during course 1. Pharmacokinetic studies indicated that capecitabine and paclitaxel did not affect the pharmacokinetic behavior of each other. No major antitumor responses were noted.

CONCLUSION: Recommended combination doses of continuous capecitabine and paclitaxel are capecitabine 1,331 mg/m²/d and paclitaxel 175 mg/m²/d IV every 3 weeks. Favorable preclinical mechanistic interactions between capecitabine and paclitaxel, as well as an acceptable toxicity profile without clinically relevant pharmacokinetic interactions, support the performance of disease-directed evaluations of this combination.

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