Anglo-Celtic IV: First results of a UK National Cancer Research Network randomized phase III pharmacogenetic trial of weekly compared to 3 weekly paclitaxel in patients with locally advanced or metastatic breast cancer (ABC)

Abstract

LBA1005 Background: Phase II studies of weekly paclitaxel (P) confirm this to be a well tolerated regimen in ABC with potentially superior efficacy to standard q3w schedules. This was tested in the phase III CALGB 9840 trial, which used a “patient resource conserving” design, combining randomised patients with imported control data from a previous CALGB study of predominantly 2nd line treatment. This and the higher total dose of P in the weekly arm, left many unsure if there really was superior activity for the weekly schedule. Methods: The primary efficacy objective was to detect a 2 month improvement (6 to 8 months, HR = 1.33) in time to progression (TTP) by the giving the same total dose of P weekly (wP) vs. 3 weekly (3wP). 560 randomised patients were required to give 90% power to detect this difference at the 0.05 significance level. A single analysis was planned six months after study closure. Secondary endpoints include overall survival, toxicity and quality of life. The primary translational endpoint is a pharmacogenetic (PG) study of the effect of MDR and CYP single nucleotide polymorphisms. Between Sept. 2002 and July 2006, 569 patients were randomized to receive either wP 90 mg/m 2 for 12 weeks or 3wP 175 mg/m 2 for 6 cycles. Patients were stratified for measurable disease, prior treatment for ABC and Trastuzumab use. Results: The investigator reported response rates were 27% (3wP) and 42% (wP), p=0.002. Median TTP was 22.0 weeks for 3wP (95% CI 19.7–24.6) and 23.9 weeks for wP (95% CI 20.7–26.7), HR=0.92, p=0.06. Both schedules were well tolerated. PG samples from 325 patients are being matched to the unblinded efficacy data. Conclusions: This phase III trial shows that, for a matched total dose, wP produces a higher response rate than 3wP. This confirms the result from CALGB 9840. The mismatch in treatment duration in this trial may explain why TTP with wP was superior in CALGB 9840 while in the current study we have failed to detect superiority despite a higher response rate. Combining the trial results supports the hypothesis that total dose and schedule of P are important. Our results support the widespread adoption of wP as the standard schedule. No significant financial relationships to disclose.