Phase I study of paclitaxel and uracil plus tegafur combination in patients with pretreated metastatic breast cancer: drug sequencing based on preclinical modelling studies

Abstract

Objective: Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC.

Methods: Pacl was infused at a fixed dose of 150 mg/m2 on day 1. UFT, at doses escalated by 50 mg/m2 starting from 200 mg/m2 . day, and LV, at a fixed dose of 90 mg/day, were given orally every 8 h for 11 days (days 3-13). Cohorts of at least 3 patients were treated at each dose level, and if 1 experienced dose-limiting toxicity (DLT), a maximum of 3 additional patients were added at the same dose level. MTD was reached if 2 out of the 6 patients experienced DLT.

Results: Sixteen patients were enrolled in the study. The most important toxicity observed was hematological. Nonhematological toxicities were paresthesia and myalgia, asthenia, nausea, and mucositis. DLT occurred in only 1 patient (grade 3 hepatic toxicity).

Conclusions: The recommended dose for a subsequent phase II trial is Pacl 150 mg/m2 on day 1, and UFT 300 mg/m2 and LV 90 mg on days 3-13, every 2 weeks.