Simulations to Assess Phase 2 Non-inferiority Trials of Different Doses of Capecitabine in Combination with Docetaxel for Metastatic Breast Cancer

A phase II trial in metastatic breast cancer (MBC) (NO16853) failed to show noninferiority (progression-free survival, PFS) of capecitabine 825 mg/m² plus docetaxel 75 mg/m² to the registered capecitabine dose of 1,250 mg/m² plus docetaxel 75 mg/m² . We developed a modeling framework based on NO16853 and the pivotal phase III MBC study, SO14999, to characterize the link between capecitabine dose, tumor growth, PFS, and survival to simulate response to a range of capecitabine doses and determine a minimum capecitabine dose noninferior to 1,250 mg/m² . Simulation showed NO16853 had little power to demonstrate noninferiority (69%). The power reached 80% with a 1,000 mg/m² starting dose and an increased number of PFS events. A starting dose of 1,000 mg/m² could be established as noninferior in terms of efficacy to the registered dose in the second-line MBC setting, with a potentially improved safety, in line with medical practice.