Journal article
Statistical justification of expansion cohorts in phase 1 cancer trials
Cancer, Vol.124(16), pp.3339-3345
08/15/2018
DOI: 10.1002/cncr.31577
PMCID: PMC6108930
PMID: 29975406
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. Phase 1 cancer trials increasingly incorporate dose‐expansion cohorts that are not subject to the same high level of statistical scrutiny as other trial components. A statistical framework for the design of a dose‐expansion cohort is described that involves prospectively specifying the efficacy and toxicity criteria that define trial success. See related editorial on pages 3290‐2, this issue.
Details
- Title: Subtitle
- Statistical justification of expansion cohorts in phase 1 cancer trials
- Creators
- Ali A Mokdad - Southern Methodist UniversityXian‐Jin Xie - University of IowaHong Zhu - University of Texas Southwestern Medical CenterDavid E Gerber - University of Texas Southwestern Medical CenterDaniel F Heitjan - University of Texas Southwestern Medical Center
- Resource Type
- Journal article
- Publication Details
- Cancer, Vol.124(16), pp.3339-3345
- DOI
- 10.1002/cncr.31577
- PMID
- 29975406
- PMCID
- PMC6108930
- ISSN
- 0008-543X
- eISSN
- 1097-0142
- Number of pages
- 8
- Grant note
- National Institute of Health (K24 CA201543; 1P30 CA142543; TL1 TR001104; UL1 RR024982)
- Language
- English
- Date published
- 08/15/2018
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917777502771
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