A Time-to-Event Generalized Continual Reassessment Method for Two-Agent Phase I Trials

• Activity Number: 342
• Type: Contributed
• Date/Time: Tuesday, July 31, 2012 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Nan Jia*+ and Thomas M Braun
• Companies: University of Michigan and University of Michigan
• Keywords: Phase I Clinical Trials ; Continual Reassessment Method ; Bayesian Statistics ; Time-to-Event

Abstract

We propose a generalized version of the Continual Reassessment Method (CRM), denoted gCRM, for identifying the maximum tolerated combination (MTC) in Phase I trials of two agents. For each dose of one agent, we apply the traditional CRM to study doses of the other agent; each of these CRM designs assumes the same dose-toxicity model, as well as the value of the parameter used in the model. However, each model includes a second parameter that varies among the models in an effort to allow flexibility when modeling the probability of dose-limiting toxicity of all combinations, yet borrow strength among neighboring combinations as well. We incorporate an adaptive Bayesian algorithm to sequentially assign each patient to the most appropriate dose combination. We test the performance and sensitivity of our method via extensive simulations in various scenarios. We compare the operating characteristics of our approach to several other recently-published approaches. We also develop a Time-to-Event version of the proposed method so that a new patient can be assigned with a dose combination right upon his arrival regardless of the completeness of the previously enrolled patients.