LAUSR

The growing interest in new classes of anti‐cancer agents, such as molecularly‐targeted therapies and immunotherapies with modes of action different from those of cytotoxic chemotherapies, has changed the dose‐finding paradigm. In this setting, the observation of late‐onset toxicity endpoints may be precluded by treatment and trial discontinuation due to disease progression, defining a competing event to toxicity. Trial designs where dose‐finding is modeled in the framework of a survival competing risks model appear particularly well‐suited. We aim to provide a phase I/II dose‐finding design that allows dose‐limiting toxicity (DLT) outcomes to be delayed or unobserved due to competing progression within the possibly long observation window. The proposed design named the Survival‐continual reassessment method‐12, uses survival models for right‐censored DLT and progression endpoints. In this competing risks framework, cause‐specific hazards for DLT and progression‐free of DLT were considered, with model parameters estimated using Bayesian inference. It aims to identify the optimal dose (OD), by minimizing the cumulative incidence of disease progression, given an acceptable toxicity threshold. In a simulation study, design operating characteristics were evaluated and compared to the TITE‐BOIN‐ET design and a nonparametric benchmark approach. The performance of the proposed method was consistent with the complexity of scenarios as assessed by the nonparametric benchmark. We found that the proposed design presents satisfying operating characteristics in selecting the OD and safety.