Specifications of a continual reassessment method design for phase I trials of combined drugs
In studies of combinations of agents in Phase I oncology trials, the dose-toxicity relationship may not be monotone for all combinations, in which case the toxicity probabilities follow a partial order. The continual reassessment method for partial orders (PO-CRM)  is a design for Phase I trials of combinations that leans upon identifying possible complete orders associated with the partial order. This article addresses some practical design considerations not previously undertaken when describing the PO-CRM. We describe an approach to choosing a proper subset of possible orderings, formulated according to the known toxicity relationships within a matrix of combination therapies. Other design issues, such as working model selection and stopping rules, are also discussed. We demonstrate the practical ability of PO-CRM as a Phase I design for combinations through its use in a recent trial designed at the University of Virginia Cancer Center.
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