title: Specifications of a continual reassessment method design for phase I trials of combined drugs.
abstract: In studies of combinations of agents in phase I oncology trials, the dose-toxicity relationship may not be monotone for all combinations, in which case the toxicity probabilities follow a partial order. The continual reassessment method for partial orders (PO-CRM) is a design for phase I trials of combinations that leans upon identifying possible complete orders associated with the partial order. This article addresses some practical design considerations not previously undertaken when describing the PO-CRM. We describe an approach in choosing a proper subset of possible orderings, formulated according to the known toxicity relationships within a matrix of combination therapies. Other design issues, such as working model selection and stopping rules, are also discussed. We demonstrate the practical ability of PO-CRM as a phase I design for combinations through its use in a recent trial designed at the University of Virginia Cancer Center.
authors.affiliation: Division of Translational Research and Applied Statistics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA. nwages@virginia.edu
authors.forename: Nolan A
authors.initials: NA
authors.lastname: Wages
authors.forename: Mark R
authors.initials: MR
authors.lastname: Conaway
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D008962:Models, Theoretical; D012107:Research Design
keywords: continual reassessment method; dose finding; drug combination; maximum tolerated dose; partial ordering; phase I trials