Reprioritizing Risk and Benefit: The Future of Study Design in Early‐Phase Cancer Research

Bryan Anthony Sisk

Clinical fellow in pediatric hematology/oncology in the Department of Pediatrics at Washington University School of Medicine

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James Dubois

Professor in the Department of Medicine at Washington University School of Medicine

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Brian P. Hobbs

Associate staff member in the Department of Quantitative Health Sciences in the Lerner Research Institute at the Cleveland Clinic

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Eric Kodish

Professor of pediatrics, oncology, and bioethics at Case Western Reserve and Cleveland Clinic Lerner College of Medicine

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First published: 19 November 2019

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The scientific purpose of phase I trials is to determine the maximum tolerated dose and/or optimal biological dose of experimental agents. Yet most participants in phase I oncology trials enroll hoping for direct medical benefit. The most common phase I trial designs use low starting doses and escalate cautiously in a “risk‐escalation” model focused on minimizing risk for each participant. This approach ensures that a proportion of subjects will likely not receive any benefit, even if the intervention proves to be successful at appropriate doses. In this article, we propose that trial designs should employ dosing strategies that increase chances of providing benefit if the investigational agent should prove to be successful while limiting risk to reasonable levels. We then describe how adaptive trial designs can facilitate refined dose optimization based on both therapeutic benefit and toxicity, which can simultaneously decrease the risk of harm while increasing the chances of benefit.

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