Modified isotonic regression based phase I/II clinical trial design identifying optimal biological dose

Abstract

Conventional phase I/II clinical trial designs often use complicated parametric models to characterize the dose-response relationships and conduct the trials. However, the parametric models are hard to justify in practice, and the misspecification of parametric models can lead to substantially undesirable performances in phase I/II trials. Moreover, it is difficult for the physicians conducting phase I/II trials to clinically interpret the parameters of these complicated models, and such significant learning costs impede the translation of novel statistical designs into practical trial implementation. To solve these issues, we propose a transparent and efficient phase I/II clinical trial design, referred to as the modified isotonic regression-based design (mISO), to identify the optimal biological doses for molecularly targeted agents and immunotherapy. The mISO design makes no parametric model assumptions on the dose-response relationship and yields desirable performances under any clinically meaningful dose-response curves. The concise, clinically interpretable dose-response models and dose-finding algorithm make the proposed designs highly translational from the statistical community to the clinical community. We further extend the mISO design and develop the mISO-B design to handle the delayed outcomes. Our comprehensive simulation studies show that the mISO and mISO-B designs are highly efficient in optimal biological dose selection and patients allocation and outperform many existing phase I/II clinical trial designs. We also provide a trial example to illustrate the practical implementation of the proposed designs. The software for simulation and trial implementation are available for free download.