Time‐to‐event calibration‐free odds design: A robust efficient design for phase I trials with late‐onset outcomes

Abstract

AbstractCompared with most of the existing phase I designs, the recently proposed calibration‐free odds (CFO) design has been demonstrated to be robust, model‐free, and easy to use in practice. However, the original CFO design cannot handle late‐onset toxicities, which have been commonly encountered in phase I oncology dose‐finding trials with targeted agents or immunotherapies. To account for late‐onset outcomes, we extend the CFO design to its time‐to‐event (TITE) version, which inherits the calibration‐free and model‐free properties. One salient feature of CFO‐type designs is to adopt game theory by competing three doses at a time, including the current dose and the two neighboring doses, while interval‐based designs only use the data at the current dose and is thus less efficient. We conduct comprehensive numerical studies for the TITE‐CFO design under both fixed and randomly generated scenarios. TITE‐CFO shows robust and efficient performances compared with interval‐based and model‐based counterparts. As a conclusion, the TITE‐CFO design provides robust, efficient, and easy‐to‐use alternatives for phase I trials when the toxicity outcome is late‐onset.