Fractional accumulative calibration‐free odds (f‐aCFO) design for delayed toxicity in phase I clinical trials

Abstract

The calibration‐free odds (CFO) design has been demonstrated to be robust, model‐free, and practically useful but faces challenges when dealing with late‐onset toxicity. The emergence of the time‐to‐event (TITE) method and fractional method leads to the development of TITE‐CFO and fractional CFO (fCFO) designs to accumulate delayed toxicity. Nevertheless, existing CFO‐type designs have untapped potential because they primarily consider dose information from the current position and its two neighboring positions. To incorporate information from all doses, we propose the accumulative CFO (aCFO) design by utilizing data at all dose levels similar to a tug‐of‐war game where players distant from the center also contribute their strength. This approach enhances full information utilization while still preserving the model‐free and calibration‐free characteristics. Extensive simulation studies demonstrate performance improvement over the original CFO design, emphasizing the advantages of incorporating information from a broader range of dose levels. Furthermore, we propose to incorporate late‐onset outcomes into the TITE‐aCFO and f‐aCFO designs, with f‐aCFO displaying superior performance over existing methods in both fixed and random simulation scenarios. In conclusion, the aCFO and f‐aCFO designs can be considered robust, efficient, and user‐friendly approaches for conducting phase I trials without or with late‐onsite toxicity.