48: Statistical considerations of monitoring early clinical activity in dose-finding trials

Music City Center 

Phase I study aims to determine the safety and tolerability of compounds in selected indications. In targeted therapy and immunotherapy, the objective of dose finding is often to identify the optimal biologically effective dose, rather than the maximum tolerated dose (MTD). To optimize the treatment benefit, it is important to consider toxicity and efficacy simultaneously and their risk-benefit trade-off during dose finding. With the rapid development of genomics and big-data technology in the past two decades, numerous gene signatures have been developed to guide clinical care and improve stratification of patients for tumor therapy. Gene signatures with high sensitivity and specificity can be used to stratify patients into different risk groups to predict treatment response. Differentially expressed gene analysis is commonly used to select related genes, but it is not optimal in small one-arm dose finding studies. Bayesian dose-response models were used to capture early immune response and anti-tumor activity across different doses. A fit-for-purpose strategy for the pharmacodynamic gene signature is more appropriate in early phase trials.

Dose finding

gene expression signature

prognostic biomarker 

Biopharmaceutical Section