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- Title
A phase I-II design based on periodic and continuous monitoring of disease status and the times to toxicity and death.
- Authors
Lee, Juhee; F. Thall, Peter; Msaouel, Pavlos; F Thall, Peter
- Abstract
A Bayesian phase I-II dose-finding design is presented for a clinical trial with four coprimary outcomes that reflect the actual clinical observation process. During a prespecified fixed follow-up period, the times to disease progression, toxicity, and death are monitored continuously, and an ordinal disease status variable, including progressive disease (PD) as one level, is evaluated repeatedly by scheduled imaging. We assume a proportional hazards model with piecewise constant baseline hazard for each continuous variable and a longitudinal multinomial probit model for the ordinal disease status process and include multivariate patient frailties to induce association among the outcomes. A finite partition of the nonfatal outcome combinations during the follow-up period is constructed, and the utility of each set in the partition is elicited. Posterior mean utility is used to optimize each patient's dose, subject to a safety rule excluding doses with an unacceptably high rate of PD, severe toxicity, or death. A simulation study shows that, compared with the proposed design, a simpler design based on commonly used efficacy and toxicity outcomes obtained by combining the four variables described above performs poorly and has substantially smaller probabilities of correctly choosing truly optimal doses and excluding truly unsafe doses.
- Subjects
PROPORTIONAL hazards models; EXPERIMENTAL design; COMPUTER simulation; RESEARCH; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; RESEARCH funding; PROBABILITY theory
- Publication
Statistics in Medicine, 2020, Vol 39, Issue 15, p2035
- ISSN
0277-6715
- Publication type
journal article
- DOI
10.1002/sim.8528