Efficacy-Driven Dose Finding with Toxicity Control in Phase I Oncology Studies

Qingyang Liu, Junxian Geng (), Frank Fleischer and Qiqi Deng
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Qingyang Liu: University of Connecticut
Junxian Geng: Boehringer-Ingelheim Pharmaceutical Inc.
Frank Fleischer: Boehringer Ingelheim Pharma GmbH & Co. KG
Qiqi Deng: Boehringer-Ingelheim Pharmaceutical Inc.

Statistics in Biosciences, 2022, vol. 14, issue 3, No 3, 413-431

Abstract: Abstract 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.

Keywords: Dose-finding; Double-sided isotonic regression; Warm-up phase; Local investigation; Adaptive randomization (search for similar items in EconPapers)
Date: 2022
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DOI: 10.1007/s12561-021-09327-1

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