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TL10: Efficacy-Driven Dose-Finding with Toxicity Control in Phase I Oncology Studies with Moderate Treatment Effect (302340)

Qiqi Deng, Boehringer Ingelheim Pharmaceuticals, Inc. 
Frank Fleischer, Boehringer Ingelheim Pharma GmbH & Co. KG 
*Junxian Geng, Boehringer Ingelheim Pharmaceuticals, Inc. 
Qingyang Liu, University of Connecticut  

Keywords: dose-finding; double-sided isotonic regression; warm-up phase; local investigation; adaptive randomization

Traditionally, dose-finding process for oncology compound is carried out in phase I dose escalation study and is driven by safety in order to find maximum tolerated dose (MTD). However, with the recent paradigm shift from cytotoxic drugs to new generation of targeted therapies and immuno-oncology therapies, it may be difficult or unnecessary to identify the MTD because of the possible non-monotonic dose-response curves, and efficacy data should be incorporated into the dose-finding process. In this article, we have proposed efficacy driven dose finding designs with a safety driven warm-up phase. Both local investigation and adaptive randomization using the framework of double-sided isotonic regression are investigated. Simulation studies are used to compare the proposed design to the original double-sided isotonic design. The results show that a safety driven warm-up phase at the beginning can significantly improve the performance of double-sided isotonic regression, and both local investigation and adaptive randomization have good operating characteristics for finding the best dose/dose range under different tested scenarios.