PROJECT SUMMARY / ABSTRACT The Transplant and Cellular Therapy Program at Washington University has been affiliated with the BMT CTN since its inception, initially as a part of the Case Western Consortium, and as a Core Clinical Center since 2011. During that time, our institution has made significant contributions to the BMT CTN through clinical trials accrual and trial design input. The specific purpose of applying for this Notice of Funding Opportunity (NOFO) is to continue participation as a BMT CTN Core Clinical Center. The long term goal of the proposed clinical trial is to apply novel concepts in immunology and cellular therapies to improve outcomes and further expand clinical application of adoptive transgenic chimeric antigen receptor (CAR) T-cell therapies. While the use of CAR T-cells have emerged as a groundbreaking advancement in the treatment of many malignant diseases, and has shown a remarkable promise in a variety of non-malignant disorders, cytokine-release syndrome (CRS) remains a major cause of morbidity and a significant barrier to a successful outcome. CRS is a hyper-immune reaction driven by excessive inflammatory cytokine activation and proliferation, with interleukin-6 (IL-6) thought to be one of the most functionally important cytokines during CRS. Although there are agents used for the treatment of established CRS, including IL-6 antagonist tocilizumab, there are no FDA-approved agents for CRS prophylaxis. Duvelisib is an oral, dual PI3K-δ,γ inhibitor that is FDA- approved for the treatment of adults with several hematologic malignancies, with acceptable safety profile. Using a protein kinase inhibitor library researchers have identified PI3K-δ,γ inhibitors, including duvelisib, as most potent inhibitors of IL-6 secretion, without attenuating CAR T-cell function. We and others have performed extensive in vitro and in vivo experiments investigating the effect of duvelisib on CRS cytokines, leading to a phase I dose escalation and dose expansion study of duvelisib for CRS prophylaxis in patients with non-Hodgkin lymphomas undergoing CAR T-cell treatments, open for enrollment at Washington University. Preliminary results from that study show that duvelisib is safe and tolerable, and delays the onset and reduces the severity of CRS. Based on these data, we propose a phase III, multi-site, randomized, placebo-controlled study with the primary objective to assess the efficacy of duvelisib in preventing grade ≥2 CRS in patients with large B-cell lymphoma and mantle cell lymphoma undergoing therapies with axicabtagene ciloleucel, lisocabtagene maraleucel or brexucabtagene autoleucel (Aim 1). The expected outcome of this trial is to provide definitive data on the effectiveness of duvelisib for CRS prophylaxis within the study population, without negatively affecting the efficacy of CAR T-cells. In addition, variety of correlative studies will provide further insight into the biologic impact of PI3K inhibition, paving the way to ...