A phase I and pharmacologic study of capecitabine and paclitaxel in breastcancer patients

Background: Based on preclinical studies demonstrating that treatment with paclitaxel upregulates intratumoral thymidine phosphorylase (dTHdPase), whi ch catalyzes the final step in the conversion of the oral fluoropyrimidine capecitabine to 5-fluorouracil (5-FU), as well as the overlapping spectra o f activity for these agents, particularly in metastatic breast cancer, this phase I study evaluated the feasibility of administering capecitabine on a n intermittent schedule in combination with paclitaxel in previously-treate d patients with locally advanced or metastatic breast cancer. The study als o sought to recommend doses for subsequent disease-specific studies, identi fy clinically significant pharmacokinetic interactions, and detect prelimin ary antitumor activity. Patients and methods: Nineteen previously treated women with metastatic bre ast cancer whose prior treatment included neither paclitaxel or capecitabin e received one hundred one courses of capecitabine and paclitaxel. Paclitax el was administered as a three-hour intravenous (i.v.) infusion at a fixed dose of 175 mg/m(2) and capecitabine was administered as 2 divided daily do ses 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/m(2)/d. The plasma sampling scheme in the first course permitted characterization of th e pharmacokinetics of each agent given alone and concurrently to detect maj or pharmacokinetic interactions. Results: Palmar-plantar erythrodysesthesia (hand-foot syndrome) and neutrop enia were the principal dose-limiting toxicities (DLT). Other toxicities in cluded diarrhea and transient hyperbilirubinemia. Three of eight new patien ts treated with capecitabine 2000 mg/m(2)/d and paclitaxel 175 mg/m(2) expe rienced DLT in the first course, whereas none of eleven new patients treate d with capecitabine 1650 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLT . Pharmacokinetic studies indicated that capecitabine did not grossly affec t the pharmacokinetics of paclitaxel, and there were no major effects of pa clitaxel on the pharmacokinetics of capecitabine and capecitabine metabolit es. However, AUC values for the major 5-FU catabolite, fluoro-beta-alanine (FBAL), were significantly lower in the presence of paclitaxel. Two complet e and seven partial responses (56% response rate) were observed in sixteen patients with measurable disease; four of six patients whose disease was pr eviously treated with high-dose chemotherapy and hematopoietic stem-cell su pport had major responses. Seven of nineteen patients had stable disease as their best response. Conclusions: Recommended combination doses of capecitabine on an intermitte nt schedule and paclitaxel are capecitabine 1650 mg/m(2)/d orally for 14 da ys and paclitaxel 175 mg/m(2) i.v. every 3 weeks. The favorable preclinical interactions between capecitabine and paclitaxel, as well as the acceptabl e toxicity profile and antitumor activity in patients with metastatic breas t cancer, support further clinical evaluations to determine an optimal role for the combination of capecitabine and paclitaxel in breast cancer and ot her relevant malignancies.