Sequential Tite-CRM: Designing a Two-Dimensional Dose-Finding Trial

• Activity Number: 622
• Type: Contributed
• Date/Time: Thursday, August 5, 2010 : 8:30 AM to 10:20 AM
• Sponsor: Biometrics Section
• Author(s): Matthew Schipper*+ and Edgar Ben-Josef
• Companies: University of Michigan and University of Michigan
• Keywords: trial design ; CRM ; dose finding ; toxicity

Abstract

Many new phase I oncology trials seek to identify the MTD of a new agent (NA) when given in combination with chemo or radiation (RT). We discuss a 2-dimensional dose finding trial for RT (3 levels) and NA (6 levels). The goal is to identify 3 dose combinations that result in similar levels of toxicity. The design is similar to the recently proposed sequential CRM design, such that the trial is split into 3 subtrials, each escalating NA dose at a fixed dose of RT. We discuss important design issues such as how the prior toxicity curve for one subtrial may be obtained from the posterior toxicity curve of another and how the starting dose level can be updated after completion of the first subtrial. We also discuss what simulations are necessary to ensure patient safety and what to do when the model selects a dose which is an escalation in both dimensions from the previous subtrial MTD.