title: Dose escalation with over-dose and under-dose controls in Phase I/II clinical trials.
abstract: To save valuable time and resources in new drug development, Phase I/II clinical trials with toxicity control and drug efficacy as dual primary endpoints have become increasingly popular. Escalation with over-dose control (the EWOC) is a Bayesian adaptive Phase I clinical trial design that can accurately estimate the maximum tolerated dose (MTD) level and control the probability of overdosing patients during the dose allocation phase. In this paper, we extend EWOC to Phase I/II clinical trials by controlling for under-dosing with a Gumbel Copula model to provide patients with at least minimum drug efficacy. We propose a utility function to measure the composite effect of toxicity and efficacy and select the optimal dose. To deal with the common issue that the efficacy endpoint often cannot be quickly ascertained, we employ Bayesian data augmentation to handle delayed efficacy and allow for flexible patient accrual without a waiting period. Extensive simulations demonstrate that the proposed new design not only provides better therapeutic effect by reducing the probability of treating patients at under-dose levels while protecting patients from being overdosed, but also improves trial efficiency and increases the accuracy of dose recommendation for subsequent clinical trials. We apply the proposed design to a Phase I/II solid tumor trial.
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, United States; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States; Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, United States; Department of Radiology and Imaging Science, Emory University, Atlanta, GA 30322, United States. Electronic address: zchen38@emory.edu.
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Kutner
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, United States.
authors.forename: Taofeek
authors.initials: T
authors.lastname: Owonikoko
authors.affiliation: Department of Radiation Oncology, Emory University, Atlanta, GA 30322, United States.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, United States.
authors.forename: Fadlo
authors.initials: F
authors.lastname: Khuri
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, United States; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001499:Bayes Theorem; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D006801:Humans; D020714:Maximum Tolerated Dose; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents
keywords: Bayesian data augmentation; Escalation with over-dose control; Escalation with under-dose control; Gumbel copula model; Phase I/II clinical trial