Abstract P6-11-02: Final Analysis of NO16853, a Randomized Phase II Non-Inferiority Study of Two Different Doses of Capecitabine in Combination with Docetaxel for Locally Advanced/Metastatic Breast Cancer (LA/MBC)
Authors: Buzdar A , Tjulandin S , Xu B , Digumarti R , Goedhals L , Hu X , Semiglazov V , Cheporov S , Gotovkin E , Gilberg F , Rittweger K , Schaedeli Stark F. 
Published: April 2011

Abstract
Background: In the phase III registration trial of capecitabine (X) plus docetaxel (T) in MBC (SO14999), a higher proportion of pts treated with XT vs T alone experienced grade 3/4 AEs (78% vs 64%, respectively), and dose reductions (65% vs 36%, respectively). Previously, it has been shown that dose reductions of X allow pts to continue therapy without compromising efficacy. Thus, this open-label, multicenter, phase II study was requested by the FDA, to investigate whether a lower dose of XT would be at least equivalent to standard-dose XT in LA/MBC.
Methods: Females aged ≥18 years with LA/MBC resistant to an anthracycline-based regimen in the (neo)adjuvant, 1st-or 2nd-line metastatic setting were eligible. Pts had ≥1 target lesion and ≥2 prior regimens in the metastatic setting. Following stratification (region; age; anthracycline status; prior taxane use), pts were randomized to 3-weekly cycles of standard XT (X 1,250mg/m2 b.i.d., d1-14 + T 75mg/m2, d1), or low-dose XT (X 825mg/m2 b.i.d., d1-14 + T 75mg/m2, d1) up to 16 cycles. Pts without PD entered a post-study treatment phase until PD or unacceptable toxicity. Primary endpoint: non-inferiority of low-dose vs standard XT in terms of PFS. Secondary endpoints: safety; ORR; duration of response; time to treatment failure; OS.
Results: Between 2003 and 2008, 470 pts, median age 51 years (range 22-75), were enrolled. Most pts (∼60%) received XT in the 1st-line setting. The primary analysis was based on the per-protocol population: standard XT (n=230), low-dose XT (n=229). Median PFS was 7.9 vs 6.0 months (HR 1.13, 95% CI: 0.93-1.37) in the standard and low-dose XT arms, respectively. As the upper limit of the 95% CI was above the predefined non-inferiority margin (1.35), the primary endpoint was not met. Secondary efficacy endpoints were consistent with PFS: median OS was 18.5 vs 15.2 months (HR 1.21, 95% CI: 0.96-1.52); ORR was 46.1% vs 38.4% (odds ratio 0.73, 95% CI: 0.50-1.06) with standard and low-dose XT, respectively. Median total dose intensity for X was 0.82 for standard dose and 0.91 for the lower dose. Exploratory analyses using established modelling and simulation methods show that 1,000mg/m2 X in combination with T would have demonstrated non-inferiority to standard XT with 80% power. The frequency of AEs was similar across the two groups: 94.9% standard XT (n=206) vs 94.4% low-dose XT (n=234), as was the incidence of serious AEs: 18.9% vs 21.4%, respectively. Differences were noted between the standard and low-dose XT group, respectively, in terms of the incidence of grade 3 hand-foot syndrome (16.1% vs 7.3%) and grade 3/4 neutropenia (32.7% vs 23.8%).
Conclusions: Non-inferiority of low-dose XT to standard XT was not demonstrated, yet superiority of the standard dose could not be established. Exploratory analyses suggest that X 1,000mg/m2 plus T would demonstrate non-inferiority to standard XT. Though not directly comparable, the efficacy of low-dose XT was similar to that of standard XT in study SO14999. A lower incidence of serious AEs was noted as compared with study SO14999 (43%) possibly reflecting improvements in dose modification, AE management and pt selection over time.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-02.