title: Escalation with overdose control using all toxicities and time to event toxicity data in cancer Phase I clinical trials.
abstract: The primary purposes of Phase I cancer clinical trials are to determine the maximum tolerated dose (MTD) and the treatment schedule of a new drug. Phase I trials usually involve a small number of patients so that fully utilizing all toxicity information including time to event toxicity data is key to improving the trial efficiency and the accuracy of MTD estimation. Chen et al. proposed a novel normalized equivalent toxicity score (NETS) system to fully utilize multiple toxicities per patient instead of a binary indicator of dose limiting toxicity (DLT). Cheung and Chappell developed the time to toxicity event (TITE) approach to incorporate time to toxicity event data. Escalation with overdose control (EWOC) is an adaptive Bayesian Phase I design which can allow rapid dose escalation while controlling the probability of overdosing patients. In this manuscript, we use EWOC as a framework and integrate it with the NETS system and the TITE approach to develop an advanced Phase I design entitled EWOC-NETS-TITE. We have conducted simulation studies to compare its operating characteristics using selected derived versions of EWOC because EWOC itself has already been extensively compared with common Phase I designs [3]. Simulation results demonstrate that EWOC-NETS-TITE can substantially improve the trial efficiency and accuracy of MTD determination as well as allow patients to be entered in a staggered fashion to significantly shorten trial duration. Moreover, user-friendly software for EWOC-NETS-TITE is under development.
authors: 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. Electronic address: zchen38@emory.edu.
authors: Zhengjia
authors: Z
authors: Chen
authors: ICF International, 3 Corporate Square, NE, Suite 370, Atlanta, GA 30329, United States.
authors: Ye
authors: Y
authors: Cui
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, United States.
authors: Taofeek K
authors: TK
authors: Owonikoko
authors: Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute, Emory University, Atlanta, GA 30322, United States.
authors: Zhibo
authors: Z
authors: Wang
authors: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, United States.
authors: Zheng
authors: Z
authors: Li
authors: School of Public Health, Georgia State University, Atlanta, GA 30303, United States.
authors: Ruiyan
authors: R
authors: Luo
authors: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, United States.
authors: Michael
authors: M
authors: Kutner
authors: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, United States.
authors: Fadlo R
authors: FR
authors: Khuri
authors: 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: Jeanne
authors: J
authors: Kowalski
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001499:Bayes Theorem; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020714:Maximum Tolerated Dose; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy*; D012107:Research Design; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents
keywords: Escalation with overdose control; Multiple toxicities; Normalized equivalent toxicity score; Phase I clinical trial; Quasi-continuous; Time to toxicity event