title: Nonparametric overdose control with late-onset toxicity in phase I clinical trials.
abstract: Under the framework of Bayesian model selection, we propose a nonparametric overdose control (NOC) design for dose finding in phase I clinical trials. Each dose assignment is guided via a feasibility bound, which thereby can control the number of patients allocated to excessively toxic dose levels. Several aspects of the NOC design are explored, including the coherence property in dose assignment, calibration of design parameters, and selection of the maximum tolerated dose (MTD). We further propose a fractional NOC (fNOC) design in conjunction with a so-called fractional imputation approach, to account for late-onset toxicity outcomes. Extensive simulation studies have been conducted to show that both the NOC and fNOC designs have robust and satisfactory finite-sample performance compared with the existing dose-finding designs. The proposed methods also possess several desirable properties: treating patients more safely and also neutralizing the aggressive escalation to overly toxic doses when the toxicity outcomes are late-onset. The fNOC design is exemplified with a real cancer phase I trial.
authors.affiliation: Department of Statistics and Actuarial Science, The University of Hong Kong, Pokfulam Road, Hong Kong gyin@hku.hk.
authors.forename: Ruitao
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Statistics and Actuarial Science, The University of Hong Kong, Pokfulam Road, Hong Kong gyin@hku.hk.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Yin
mesh_terms: D001499:Bayes Theorem; D017321:Clinical Trials, Phase I as Topic; D062787:Drug Overdose / Q000517:prevention & control*; D006801:Humans; D020714:Maximum Tolerated Dose; D000069436:Toxicological Phenomena
keywords: Bayesian posterior probability; Dose finding; Late-onset toxicity; Maximum tolerated dose; Overdose control