title: Simulations to Assess Phase II Noninferiority Trials of Different Doses of Capecitabine in Combination With Docetaxel for Metastatic Breast Cancer.
abstract: A phase II trial in metastatic breast cancer (MBC) (NO16853) failed to show noninferiority (progression-free survival, PFS) of capecitabine 825 mg/m(2) plus docetaxel 75 mg/m(2) to the registered capecitabine dose of 1,250 mg/m(2) plus docetaxel 75 mg/m(2). 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/m(2). Simulation showed NO16853 had little power to demonstrate noninferiority (69%). The power reached 80% with a 1,000 mg/m(2) starting dose and an increased number of PFS events. A starting dose of 1,000 mg/m(2) 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.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e19; doi:10.1038/psp.2012.20; advance online publication 26 December 2012.
authors.affiliation: Pharsight Consulting Services, Pharsight, part of Certara, St. Louis, Missouri, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bruno
authors.forename: L
authors.initials: L
authors.lastname: Lindbom
authors.forename: F
authors.initials: F
authors.lastname: Schaedeli Stark
authors.forename: P
authors.initials: P
authors.lastname: Chanu
authors.forename: F
authors.initials: F
authors.lastname: Gilberg
authors.forename: N
authors.initials: N
authors.lastname: Frey
authors.forename: L
authors.initials: L
authors.lastname: Claret