Abstract
Background: Phase I cancer trials increasingly incorporate dose-expansion cohorts (DECs), reflecting a growing demand to acquire more information about investigational drugs. Protocols commonly fail to provide a sample-size justification or analysis plan for the DEC. In this study, we develop a statistical framework for the design of DECs. Methods: We assume the maximum tolerated dose (MTD) for the investigational drug has been identified in the dose-escalation stage of the trial. We use the 80% lower confidence bound and the 90% upper confidence bound for the response and toxicity rates, respectively, as decision thresholds for the dose-expansion stage. We calculate the operating characteristics with reference to prespecified minimum effective response rates and maximum safe DLT rates. Results: We apply our framework to specify a system of DEC plans. The design comprises three components: 1) the number of subjects enrolled at the MTD, 2) the minimum number of responses necessary to indicate provisional drug efficacy, and 3) the maximum number of dose-limiting toxicities (DLTs) permitted to indicate drug safety. We demonstrate our method in an application to a cancer immunotherapy trial. Conclusions: Our simple and practical tool enables creation of DEC designs that appropriately address the safety and efficacy objectives of the trial.
Original language | English (US) |
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Pages (from-to) | 3339-3345 |
Number of pages | 7 |
Journal | Cancer |
Volume | 124 |
Issue number | 16 |
DOIs | |
State | Published - Aug 2018 |
Keywords
- design
- dose expansion
- dose-finding
- efficacy
- safety
ASJC Scopus subject areas
- Oncology
- Cancer Research