Statistical Evaluation of Dose Expansion Cohorts in Phase I Trials

• Activity Number: 144
• Type: Contributed
• Date/Time: Monday, August 10, 2015 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Matthew Schipper*
• Keywords: Phase I ; 3+3 ; CRM ; Dose Expansion Cohort ; Trial Design

Abstract

An increasingly common feature of phase I trials is the inclusion of a dose expansion cohort (DEC), in which additional patients are treated at the estimated maximum tolerated dose (MTD) after completing a dose-escalation phase. We aimed to evaluate this design feature with respect to standard phase I metrics and in terms of how many subjects were treated at the estimated MTD. Methods We conduct a simulation study of two phase I designs: the "3+3" and the Continual Reassessment Method (CRM). We quantify how many patients are assigned the true and estimated MTD using a 10-20 patient DEC and how a sensible re-analysis using the DEC changes the probability of selecting the true MTD. We compare these results with those from an equivalently sized larger CRM that does not include a DEC. With either the 3+3 or CRM, re-analysis with the DEC increases the probability of identifying the true MTD. However, a large CRM without a DEC is more likely to identify the true MTD while still treating 10 or 15 patients at this dose level. Where feasible, a CRM design with no explicit DEC is preferred to designs that fix a dose for all patients in a DEC.