Utility-Based Optimization of Schedule-Dose Regimes Based on the Times to Response and Toxicity

• Activity Number: 277
• Type: Topic Contributed
• Date/Time: Tuesday, August 5, 2014 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Peter Thall*+ and Hoang Q. Nguyen and Tom Braun and Muzaffar Qazilbash
• Companies: MD Anderson Cancer Center and MD Anderson Cancer Center and University of Michigan and MD Anderson Cancer Center
• Keywords: Adaptive Design ; Bayesian Design ; Cancer therapy ; Phase I-II Clinical Trial ; Utility

Abstract

A Bayesian two-stage phase I-II design for jointly optimizing administration schedule and dose of an experimental agent based on the times to response and toxicity will be described. Sequentially adaptive decisions are based on the joint utility of the two event times. A utility surface is constructed by partitioning the two-dimensional positive quadrant of possible event time pairs into rectangles, eliciting a numerical utility for each rectangle, and fitting a smooth parametric function to the elicited values. Event times are modeled using a gamma distribution with shape and scale parameters both functions of schedule and dose. Adaptive safety and efficacy acceptability conditions are imposed on the schedule-dose regimes. In stage 1, patients are randomized fairly among schedules, and a dose is chosen within each schedule using an algorithm that hybridizes greedy optimization and randomization among nearly optimal doses. In stage 2, fair randomization among schedules is replaced by the hybrid algorithm. An extension to accommodate death or discontinuation of follow up is described. The method is illustrated by an autologous stem cell transplantation trial in multiple myeloma.