A0648
Title: DEMO: Dose exploration, monitoring, and optimization using a biological mediator for clinical outcomes
Authors: Ruitao Lin - The University of Texas MD Anderson Cancer Center (United States) [presenting]
Abstract: Phase 1-2 designs provide a methodological advance over phase 1 designs for dose finding by using both clinical response and toxicity. A phase 1-2 trial still may fail to select a truly optimal dose. Early response is not a perfect surrogate for long-term therapeutic success. To address this problem, a generalized phase 1-2 design first uses a phase 1-2 design component to identify a set of candidate doses, adaptively randomizes patients among the candidates, and, after a longer follow-up, selects a dose to maximize long-term success rate. This paradigm is extended by proposing a design that exploits an early treatment-related, real-valued biological outcome, such as pharmacodynamic activity or an immunological effect, that may act as a mediator between dose and clinical outcomes, including tumor response, toxicity, and survival time. Multivariate dose-outcome models are assumed to include effects appearing in causal pathways from dose to the clinical outcomes. Bayesian model selection is used to identify and eliminate biologically inactive doses. At the end of the trial, a therapeutically optimal dose is chosen from the set of doses that are acceptably safe, clinically effective, and biologically active to maximize restricted mean survival time. Results of a simulation study show that the proposed design may provide substantial improvements over designs that ignore the biological variable.
