Escalation with Overdose Control Using Time to Toxicity for Cancer Phase I Clinical Trials

• Type of Material: Article
• Authors: Mourad Tighiouart, Samuel Oschin Comprehensive Cancer Institute; Yuan Liu, Emory University; Andre Rogatko, Samuel Oschin Comprehensive Cancer Institute
• Language: English
• Date: 2014-03-24
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Tighiouart et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0093070
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 3
• Start Page: e93070
• End Page: e93070
• Grant/Funding Information: This work was supported in part by the National Center for Research Resources, Grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000124 (M.T and A.R), Grant 5P01CA098912-05 (A.R.), P01DK046763 (A.R.), and 2R01CA108646-07A1 (A.R.).
• Keywords: Multidisciplinary Sciences; Science & Technology; DESIGNS; DOSE-ESCALATION; CONTINUAL REASSESSMENT METHOD; LATE-ONSET TOXICITIES; Science & Technology - Other Topics
• Research Categories: Biology, Biostatistics; Health Sciences, Oncology

Abstract

Escalation with overdose control (EWOC) is a Bayesian adaptive phase I clinical trial design that produces consistent sequences of doses while controlling the probability that patients are overdosed. However, this design does not take explicitly into account the time it takes for a patient to exhibit dose limiting toxicity (DLT) since the occurrence of DLT is ascertained within a predetermined window of time. Models to estimate the Maximum Tolerated Dose (MTD) that use the exact time when the DLT occurs are expected to be more precise than those where the variable of interest is categorized as presence or absence of DLT, given that information is lost in the process of categorization of the variable. We develop a class of parametric models for time to toxicity data in order to estimate the MTD efficiently, and present extensive simulations showing that the method has good design operating characteristics relative to the original EWOC and a version of time to event EWOC (TITE-EWOC) which allocates weights to account for the time it takes for a patient to exhibit DLT. The methodology is exemplified by a cancer phase I clinical trial we designed in order to estimate the MTD of Veliparib (ABT-888) in combination with fixed doses of gemcitabine and intensity modulated radiation therapy in patients with locally advanced, un-resectable pancreatic cancer.