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A product of independent beta probabilities dose escalation design for dual‐agent phase I trials
Author(s) -
Mander Adrian P.,
Sweeting Michael J.
Publication year - 2015
Publication title -
statistics in medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.996
H-Index - 183
eISSN - 1097-0258
pISSN - 0277-6715
DOI - 10.1002/sim.6434
Subject(s) - maximum tolerated dose , computer science , bayesian probability , bayesian inference , isotonic regression , monotonic function , dual (grammatical number) , inference , nonparametric statistics , clinical trial , statistics , artificial intelligence , medicine , mathematics , art , mathematical analysis , literature , pathology , estimator
Dual‐agent trials are now increasingly common in oncology research, and many proposed dose‐escalation designs are available in the statistical literature. Despite this, the translation from statistical design to practical application is slow, as has been highlighted in single‐agent phase I trials, where a 3 + 3 rule‐based design is often still used. To expedite this process, new dose‐escalation designs need to be not only scientifically beneficial but also easy to understand and implement by clinicians. In this paper, we propose a curve‐free (nonparametric) design for a dual‐agent trial in which the model parameters are the probabilities of toxicity at each of the dose combinations. We show that it is relatively trivial for a clinician's prior beliefs or historical information to be incorporated in the model and updating is fast and computationally simple through the use of conjugate Bayesian inference. Monotonicity is ensured by considering only a set of monotonic contours for the distribution of the maximum tolerated contour, which defines the dose‐escalation decision process. Varied experimentation around the contour is achievable, and multiple dose combinations can be recommended to take forward to phase II. Code for R , Stata and Excel are available for implementation. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.