Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies

Purpose: To evaluate the feasibility of administering the oral fluoropyrimi dine capecitabine in combination with paclitaxel, to characterize the princ ipal toxicities of the combination, to recommend doses for subsequent disea se-directed studies, and to determine whether significant pharmacokinetic i nteractions 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. Paclitaxe l wets administered as a 3-hour intravenous (IV) infusion every 3 weeks, an d capecitabine was administered continuously as two divided daily doses. Du ring stage I, capecitabine was escalated to a target dose of 1,657 mg/m(2)/ d, whereas the paclitaxel dose was fixed at 135 mg/m(2). In stage II, pacli taxel was increased to a target dose of 175 mg/m(2), and the capecitabine d ose was the maximum established in stage I. Pharmacokinetics were character ized for each drug when given alone and concurrently. Results: Myelosuppression, predominately neutropenia, was the principal dos e-limiting toxicity (DLT). Other toxicities included hand-foot syndrome, di arrhea, hyper-bilirubinemia, skin rash, myalgia, and arthralgia. Two patien ts treated with capecitabine 1,657 mg/m(2)/d and paclitaxel 175 mg/m(2) dev eloped DLTs, whereas none of six patients treated with capecitabine 1,331 m g/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs during course 1. Pharmac okinetic studies indicated that capecitabine and paclitaxel did not affect the pharmacokinetic behavior of each other. No major antitumor responses we re noted. Conclusion: Recommended combination doses of continuous capecitabine and pa clitaxel are capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2)/d IV e very 3 weeks, favorable preclinical mechanistic interactions between capeci tabine and paclitaxel, as well as an acceptable toxicity profile without cl inically relevant pharmacokinetic interactions, supper, the performance of disease-directed evaluations of this combination. (C) 1999 by American Society of Clinical Oncology.