Challenges of Phase I Trials with Dose Expansion Cohorts

• Activity Number: 147
• Type: Invited
• Date/Time: Monday, August 5, 2013 : 10:30 AM to 12:20 PM
• Sponsor: ENAR
• Author(s): Alexia Iasonos*+ and John O'Quigley
• Companies: Memorial Sloan-Kettering Cancer Center and Universsity Paris 6
• Keywords: Phase I ; expansion cohorts ; efficacy ; sequential monitoring rule

Abstract

The primary objective of all Phase I trials is to establish the maximum tolerated dose (MTD) for an investigational agent.Recent reports show that Phase I trials are increasingly including dose expansion cohorts, after the MTD has been reached, in order to better characterize the toxicity profile.In addition, expansion cohorts are frequently used to seek early signs of efficacy within a specific disease population or to evaluate other exploratory endpoints.We will discuss the aims of Phase I trials with expansion cohorts or Phase I/II trials and provide a link between the aims, designs, and methods of analysis.We will illustrate how to implement a sequential monitoring rule for safety or/and efficacy and how to carry out a complete analysis using information from all patients.The proposed analysis and monitoring rule can incorporate auxiliary information provided by toxicity, efficacy, pharmacokinetics or other endpoints.The methods are evaluated through simulated trials.We show that there is 50% chance of recommending a higher Phase II dose than the pre-expansion MTD, when toxicity outcomes from the expansion cohort are taken into account.