Estimands for single arm dose optimization trials in oncology (2501.18930v1)

Abstract: Phase I dose escalation trials in oncology generally aim to find the maximum tolerated dose (MTD). However, with the advent of molecular targeted therapies and antibody drug conjugates, dose limiting toxicities are less frequently observed, giving rise to the concept of optimal biological dose (OBD), which considers both efficacy and toxicity. The Estimand framework presented in the addendum of the ICH E9(R1) guidelines strengthens the dialogue between different stakeholders by bringing in greater clarity in the clinical trial objectives and by providing alignment between the targeted estimand under consideration and the statistical analysis methods. However, there lacks clarity in implementing this framework in early phase dose optimization studies. This manuscript aims at discussing the Estimand framework for dose optimization trials in oncology considering efficacy and toxicity through utility functions. Such trials should include Pharmacokinetics (PK) data, toxicity data, and efficacy data. Based on these data, the analysis methods used to identify the optimized dose/s are also described. Focusing on optimizing the utility function to estimate the OBD, the population-level summary measure should reflect only the properties used for the estimating this utility function. A detailed strategy recommendation for intercurrent events has been provided using a real-life oncology case study. Key recommendations regarding the estimand attributes include that in a seamless Phase I/II dose optimization trial, the treatment attribute should start when the subject receives the first dose. We argue that such a framework brings in additional clarity to dose optimization trial objectives and strengthens the understanding of the drug under consideration that would enable the correct dose to move to Phase II of clinical development.