title: A two-stage patient enrichment adaptive design in phase II oncology trials.
abstract: Illustrated is the use of a patient enrichment adaptive design in a randomized phase II trial which allows the evaluation of treatment benefits by the biomarker expression level and makes interim adjustment according to the pre-specified rules. The design was applied to an actual phase II metastatic hepatocellular carcinoma (HCC) trial in which progression-free survival (PFS) in two biomarker-defined populations is evaluated at both interim and final analyses. As an extension, a short-term biomarker is used to predict the long-term PFS in a Bayesian model in order to improve the precision of hazard ratio (HR) estimate at the interim analysis. The characteristics of the extended design are examined in a number of scenarios via simulations. The recommended adaptive design is shown to be useful in a phase II setting. When a short-term maker which correlates with the long-term PFS is available, the design can be applied in smaller early phase trials in which PFS requires longer follow-up. In summary, the adaptive design offers flexibility in randomized phase II patient enrichment trials and should be considered in an overall personalized healthcare (PHC) strategy.
authors.affiliation: 100 Tice Blvd, Woodcliff Lake, NJ 07677, USA. Electronic address: james_song@eisai.com.
authors.forename: James X
authors.initials: JX
authors.lastname: Song
mesh_terms: D001499:Bayes Theorem; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D018572:Disease-Free Survival; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015233:Models, Statistical; D016016:Proportional Hazards Models; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor
keywords: Adaptive design; Oncology; Phase II trials; Predictive marker