Abstract
Due to the limited sample size and large dose exploration space, obtaining a desirable dose combination is a challenging task in the early development of combination treatments for cancer patients. Most existing designs for optimizing the dose combination are model-based, requiring significant efforts to elicit parameters or prior distributions. Model-based designs also rely on intensive model calibration and may yield unstable performance in the case of model misspecification or sparse data. We propose to employ local, underparameterized models for dose exploration to reduce the hurdle of model calibration and enhance the design robustness. Building upon the framework of the partial ordering continual reassessment method, we develop local data-based continual reassessment method designs for identifying the maximum tolerated dose combination, using toxicity only, and the optimal biological dose combination, using both toxicity and efficacy, respectively. The local data-based continual reassessment method designs only model the local data from neighboring dose combinations. Therefore, they are flexible in estimating the local space and circumventing unstable characterization of the entire dose-exploration surface. Our simulation studies show that our approach has competitive performance compared to widely used methods for finding maximum tolerated dose combination, and it has advantages over existing model-based methods for optimizing optimal biological dose combination.
Original language | English (US) |
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Pages (from-to) | 2049-2063 |
Number of pages | 15 |
Journal | Statistical Methods in Medical Research |
Volume | 32 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2023 |
Keywords
- Bayesian adaptive design
- dose optimization
- drug combination
- early-phase clinical trials
- local model
ASJC Scopus subject areas
- Epidemiology
- Statistics and Probability
- Health Information Management
MD Anderson CCSG core facilities
- Biostatistics Resource Group