A phase I and pharmacologic study of capecitabine and paclitaxel in breast cancer patients

Based on preclinical studies demonstrating that treatment with paclitaxel upregulates intratumoral thymidine phosphorylase (dTHdPase), which catalyzes the final step in the conversion of the oral fluoropyrimidine capecitabine to 5-fluorouracil (5-FU), as well as the overlapping spectra of activity for these agents, particularly in metastatic breast cancer, this phase I study evaluated the feasibility of administering capecitabine on an intermittent schedule in combination with paclitaxel in previously-treated patients with locally advanced or metastatic breast cancer. The study also sought to recommend doses for subsequent disease-specific studies, identify clinically significant pharmacokinetic interactions, and detect preliminary antitumor activity.

Nineteen previously treated women with metastatic breast cancer whose prior treatment included neither paclitaxel or capecitabine received one hundred one courses of capecitabine and paclitaxel. Paclitaxel was administered as a three-hour intravenous (i.v.) infusion at a fixed dose of 175 mg/m2 and capecitabine was administered as 2 divided daily doses for 14 days followed by a seven-day rest period every 3 weeks. The dose of capecitabine was increased from a starting dose of 1650 mg/m2/d. The plasma sampling scheme in the first course permitted characterization of the pharmacokinetics of each agent given alone and concurrently to detect major pharmacokinetic interactions.

Palmar plantar erythrodysesthesia (hand foot syndrome) and neutropenia were the principal dose-limiting toxicities (DLT). Other toxicities included diarrhea and transient hyperbilirubinemia. Three of eight new patients treated with capecitabine 2000 mg/m2/d and paclitaxel 175 mg/m2 experienced DLT in the first course, whereas none of eleven new patients treated with capecitabine 1650 mg/m2/d and paclitaxel 175 mg/m2 developed DLT. Pharmacokinetic studies indicated that capecitabine did not grossly affect the pharmacokinetics of paclitaxel, and there were no major effects of paclitaxel on the pharmacokinetics of capecitabine and capecitabine metabolites. However, AUC values for the major 5-FU catabolite, fluorobeta-alanine (FBAL), were significantly lower in the presence of paclitaxel. Two complete and seven partial responses (56% response rate) were observed in sixteen patients with measurable disease; four of six patients whose disease was previously treated with high-dose chemotherapy and hematopoietic stem-cell support had major responses. Seven of nineteen patients had stable disease as their best response.

Recommended combination doses of capecitabine on an intermittent schedule and paclitaxel are capecitabine 1650 mg/m2/d orally for 14 days and paclitaxel 175 mg/m2 i.v. every 3 weeks. The favorable preclinical interactions between capecitabine and paclitaxel, as well as the acceptable toxicity profile and antitumor activity in patients with metastatic breast cancer, support further clinical evaluations to determine an optimal role for the combination of capecitabine and paclitaxel in breast cancer and other relevant malignancies.