title: Effect of design specifications in dose-finding trials for combination therapies in oncology.
abstract: Model-based dose-finding methods for a combination therapy involving two agents in phase I oncology trials typically include four design aspects namely, size of the patient cohort, three-parameter dose-toxicity model, choice of start-up rule, and whether or not to include a restriction on dose-level skipping. The effect of each design aspect on the operating characteristics of the dose-finding method has not been adequately studied. However, some studies compared the performance of rival dose-finding methods using design aspects outlined by the original studies. In this study, we featured the well-known four design aspects and evaluated the impact of each independent effect on the operating characteristics of the dose-finding method including these aspects. We performed simulation studies to examine the effect of these design aspects on the determination of the true maximum tolerated dose combinations as well as exposure to unacceptable toxic dose combinations. The results demonstrated that the selection rates of maximum tolerated dose combinations and UTDCs vary depending on the patient cohort size and restrictions on dose-level skipping However, the three-parameter dose-toxicity models and start-up rules did not affect these parameters. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Biostatistics and Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirakawa
authors.affiliation: Biostatistics Group, Center for Product Evaluation, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Clinical Trial and Clinical Epidemiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Gosho
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy; D012107:Research Design
keywords: combination therapy; dose finding; maximum tolerated dose; phase I