Improvements to the Escalation with Overdose Control Design and a Comparison with the Restricted Continual Reassessment Method

• Activity Number: 315 - SPEED: Biopharmaceutical Applications: Trials, Biomarkers, and Enpoint Validation
• Type: Contributed
• Date/Time: Tuesday, July 31, 2018 : 9:25 AM to 10:10 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Lingyun Ji* and Richard Sposto and Juan Pablo Lewinger and Mark Krailo and David Conti and Susan Groshen and Shahab Asgharzadeh
• Companies: University of Southern California and University of Southern California and University of Southern California and University of Southern California and University of Southern California and University of Southern California and University of Southern California
• Keywords: Dose Finding; Continual Reassessment Method; CRM; EWOC; Phase I; Bayesian

Abstract

The Escalation with Overdose Control (EWOC) design for cancer dose finding clinical trials is a variation of the Continual Reassessment Method (CRM) that was proposed to overcome the limitation of the original CRM of exposing patients to high toxic doses. In this paper we assess the properties of the EWOC design and of the restricted CRM and some variations of these designs. We show that EWOC has several weaknesses that CRM does not have that make it impractical to use in its original formulation. We propose modified EWOC designs that address some of the weaknesses and that have some desirable statistical properties compared to the original EWOC design, the restricted CRM design, and the 3+3 design. However, their statistical properties are sensitive to correct specification of the prior distribution of their parameters, and hence nevertheless will need to be used with some caution. The restricted CRM design is shown to have more stable performance across a wider family of dose-toxicity curves than EWOC and therefore may be a preferable general choice in cancer clinical research.