Early Phase Dose‐Finding Designs for‐T Cell Therapies

Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine

ABSTRACT Chimeric Antigen Receptor (CAR)‐T cell is an immunotherapy which revolutionised the treatment of relapsed/refractory lymphoma and leukaemia. It is shown to have a higher response rate, higher mid‐to‐long term overall survival, and lower toxicity than standard treatments. However, due to a lack of dose‐limiting toxicity (DLT) and unclear dose‐effect relationship, traditional phase I designs of clinical trials cannot lead to accurate selections of the optimal dose (OD). Beside clinical outcomes, the CAR‐T cell expansion from serial blood samples is measured at various time points. We propose a novel early phase dose‐finding design for CAR‐T cells, using both toxicity and activity endpoints to locate the OD. The number of CAR‐T cells measured in the peripheral blood is used to indicate activity, which is more sensitive than the short‐term clinical responses traditionally used. A Bi‐Exponential model is used for the repeated measures of the number of cells for each patient, and is estimated under a Bayesian framework. The model is motivated by biological concerns and is flexible enough to accommodate different shapes of the cell‐expansion curve. Three criteria for activity are considered: (1) the number of cells at specific time points, (2) the duration before all cells are eliminated, (3) the area under the cell‐expansion curve. Simulation studies show that the OD can be selected with high accuracy even under small sample sizes.