Dose-finding designs for cell therapy cancer clinical trials evaluating drug-combinations

Abstract

Cell therapies have taken hold as a promising modality of treatment for multiple types of cancer. Despite this, their efficacy as a monotherapy has been limited, driving interest in their possible role as part of a drug combination. This paper introduces a novel dose-finding design for phase I cancer trials assessing drug combinations where one of the drugs is a cell therapy. Our design adapts the partial order continual reassessment method (POCRM) to account for late-onset dose-limiting toxicities (DLT) and feasibility concerns due to complexities related to manufacturing the cell therapy product. We illustrate our design on a proposed trial to assess the combination of a Rituximab-based bispecific antibody activated T cell product and Nivolumab for the treatment of high-grade B-cell lymphoma. We also provide simulation results that demonstrate our design's ability to accurately identify the feasible maximum tolerated dose combination (FMTDC) while managing late-onset DLTs and feasibility concerns. Our methodology aims to improve the phase I drug combination landscape for cell therapy cancer clinical trials.