gBOIN: A Unified Model-Assisted Phase I Trial Design Accounting for Toxicity Grades, and Binary or Continuous End Points

Summary The landscape of oncology drug development has recently changed with the emergence of molecularly targeted agents and immunotherapies. These new therapeutic agents appear more likely to induce multiple low or moderate grade toxicities rather than dose limiting toxicities. Various model-based dose finding designs and toxicity severity scoring systems have been proposed to account for toxicity grades, but they are difficult to implement because of the use of complicated dose–toxicity models and the requirement to refit the model at each decision of dose escalation and de-escalation. We propose a generalized Bayesian optimal interval design, gBOIN, that accommodates various existing toxicity grade scoring systems under a unified framework. As a model-assisted design, gBOIN derives its optimal decision rule on the basis of the exponential family of distributions but is carried out in a simple way as the algorithm-based design: its decision of dose escalation and de-escalation involves only a simple comparison of the sample mean of the end point with two prespecified dose escalation and de-escalation boundaries. No model fitting is needed. We show that gBOIN has the desirable finite property of coherence and a large sample property of consistency. Numerical studies show that gBOIN yields good performance that is comparable with or superior to that of some existing, more complicated model-based designs. A Web application for implementing gBOIN is freely available from http://www.trialdesign.org.