Drug Exposure and Dose-Limiting Toxicities in Early-Phase Oncology Trials

• Activity Number: 435
• Type: Contributed
• Date/Time: Tuesday, August 11, 2015 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Yihua Zhao* and Shu Zhang
• Companies: Boehringer Ingelheim and Boehringer Ingelheim
• Keywords: Dose limiting toxicity ; Drug exposure ; Maximum tolerated dose ; Oncology

Abstract

In early phase oncology trials, dose limiting toxicities (DLTs) occurred during the first treatment cycle are used for the purpose of dose escalation and assessment of maximum tolerated dose (MTD). However, the time of DLT occurrence and related drug exposure are usually not considered, and this may result in underestimating the MTD, which may in turn lead to a higher than expected adverse event rate or toxicities in later trials. In this presentation, we explore the impact of drug exposure and the time of DLT occurrence on the assessment of MTD, and propose a new method to determine the MTD taking into account of drug exposure. We show that the new method can reduce bias in estimating MTD as compared with the conventional method. In addition, we conducted simulations to assess the relationship between drug exposure, DLT and MTD.