Abstract
Summary: Dose finding methods aiming at identifying an optimal dose of a treatment with a given schedule may be at a risk of misidentifying the best treatment for patients. We propose a phase I-II clinical trial design to find the optimal dose-schedule combination. We define schedule as the method and timing of administration of a given total dose in a treatment cycle. We propose a Bayesian dynamic model for the joint effects of dose and schedule. The model proposed allows us to borrow strength across dose-schedule combinations without making overly restrictive assumptions on the ordering pattern of the schedule effects. We develop a dose-schedule finding algorithm to allocate patients sequentially to a desirable dose-schedule combination, and to select an optimal combination at the end of the trial. We apply the proposed design to a phase I-II clinical trial of a γ-secretase inhibitor in patients with refractory metastatic or locally advanced solid tumours, and we examine the operating characteristics of the design through simulations.
Original language | English (US) |
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Pages (from-to) | 259-272 |
Number of pages | 14 |
Journal | Journal of the Royal Statistical Society. Series C: Applied Statistics |
Volume | 65 |
Issue number | 2 |
DOIs | |
State | Published - Feb 1 2016 |
Keywords
- Bayesian dynamic model
- Dose-schedule combination
- Efficacy
- Probit model
- Schedule-response relationship
- Toxicity
ASJC Scopus subject areas
- Statistics and Probability
- Statistics, Probability and Uncertainty