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

• Activity Number: 70
• Type: Contributed
• Date/Time: Sunday, July 31, 2011 : 4:00 PM to 5:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Yuan Liu*+ and Mourad Tighiouart and André Rogatko
• Companies: Emory University and Emory University and Samuel Oschin Comprehensive Cancer Institute
• Keywords: EWOC ; Time to Toxicity ; Bayesian Adaptive Design ; Phase I Clinical Trials

Abstract

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 these 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) proposed by Mauguen et al. (1).