Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project.

The Chimeric Antigen Receptor (CAR) T Cell Safety Database Project explored the use of cross-study safety data to identify risk factors associated with severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) after CAR T cell administration. Sponsors voluntarily submitted data for 1,926 subjects from 17 phases 1 and 2 studies (six acute lymphocytic leukemia [ALL], five non-Hodgkin's lymphoma [NHL], and six multiple myeloma [MM] studies). Subjects with ALL had a higher risk for developing sCRS and sNTX compared with subjects with NHL or MM. Subjects who received CAR T cells produced with gammaretrovirus vectors including CD28 sequences had higher rates of sNTX compared with subjects who received products produced with other vector designs included in the database. Use of cytokine-directed therapies and corticosteroids at lower toxicity grades were associated with lower rates of sCRS. Although this exploratory study was limited by unadjusted cross-study comparisons, it independently reproduced known risk factors for CAR T cell toxicity. Findings provide stakeholders in the CAR T cell clinical development community information on safety trends for consideration in early phase clinical trial design, as well as avenues for additional research.