Statistical justification of expansion cohorts in phase 1 cancer trials.
Cancer
; 124(16): 3339-3345, 2018 08.
Article
en En
| MEDLINE
| ID: mdl-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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proyectos de Investigación
/
Ensayos Clínicos Fase I como Asunto
/
Neoplasias
Tipo de estudio:
Guideline
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Cancer
Año:
2018
Tipo del documento:
Article