A flexible dose-response modeling framework based on continuous toxicity outcomes in phase I cancer clinical trials

Abstract

Abstract Background The past few decades have seen remarkable developments in dose-finding designs for phase I cancer clinical trials. While many of these designs rely on a binary toxicity response, there is an increasing focus on leveraging continuous toxicity responses. A continuous toxicity response pertains to a quantitative measure represented by real numbers. A higher value corresponds not only to an elevated likelihood of side effects for patients but also to an increased probability of treatment efficacy. This relationship between toxicity and dose is often nonlinear, necessitating flexibility in the quest to find an optimal dose. Methods A flexible, fully Bayesian dose-finding design is proposed to capitalize on continuous toxicity information, operating under the assumption that the true shape of the dose-toxicity curve is nonlinear. Results We conduct simulations of clinical trials across varying scenarios of non-linearity to evaluate the operational characteristics of the proposed design. Additionally, we apply the proposed design to a real-world problem to determine an optimal dose for a molecularly targeted agent. Conclusions Phase I cancer clinical trials, designed within a fully Bayesian framework with the utilization of continuous toxicity outcomes, offer an alternative approach to finding an optimal dose, providing unique benefits compared to trials designed based on binary toxicity outcomes.