Project Summary: The goal of the Blood and Marrow Transplant Clinical Trial Network (BMT CTN) is to generate efficacy and safety data from multicenter Phase II and III trials, and advance the science and technology of immune and hematopoietic cellular therapies for the cure of blood disorders. The Moffitt Consortium brings scientific leadership, expertise in research conduct, and robust clinical volumes to support the mission of the BMT CTN. We also submit a project to specifically address major knowledge gaps in the domain of CAR-T therapy, namely the optimal lymphodepleting chemotherapy approach. We propose a national randomized phase II trial to identify an alternative lymphodepleting chemotherapy (LD-chemo) approach that optimizes efficacy and safety in the setting of CD19 CAR-T therapy for large B cell lymphoma (utilizing two approved, commercially available products, axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel). The study arms include 1) fludarabine/cyclophosphamide (Flu/Cy) with fludarabine dosing optimized using mathematical modeling of fludarabine exposure, 2) Bendamustine (Benda), and 3) Cladribine/Cy (Clad/Cy). Each of these approaches has been studied in single center series and have evidence in support of improved outcomes. Our proposed trial will for the first time prospectively test these regimens to determine which outperforms traditional Flu/Cy for efficacy (12 month progression-free survival) and toxicity (composite severe toxicity endpoint inclusive of grade 3 or higher cytokine release syndrome (CRS) and immune cell therapy associated neurologic toxicity (ICANS), day 30 severe cytopenias, and severe infection). In parallel, we will interrogate the biologic differences in immune cells and homeostatic cytokines in each study arm and correlate these findings with clinical outcomes. This highly innovative trial has major potential to determine which of these LD-chemo approaches optimizes outcomes, and will inform selection of an approach to be tested in a subsequent randomized phase III trial against conventional standard of care Flu/Cy. The findings will have major impact on clinical practice, the current state of the science, and potential to directly improve patient outcomes.