PROJECT SUMMARY Relapse prevention post-allogeneic hematopoietic cell transplantation (alloHCT) remains a paramount challenge. This project aims to test a novel graft-versus-host disease (GVHD) prophylaxis regimen that could also prevent malignant relapse. Our novel regimen accomplishes this goal by eliminating mycophenolate mofetil (MMF) from a post-transplant cyclophosphamide (PTCy) and sirolimus (SIR)-based regimen, and instead adding a novel, oral Aurora kinase A inhibitor that not only constrains GVHD through CD28 signal transduction blockade but also provide direct anti-tumor effects. Elimination of both MMF and tacrolimus (TAC) from our proposed regimen enhances graft-versus-leukemia (GVL) effects, further contributing to relapse mitigation. We propose to compare our GVHD prophylaxis regimen of PTCy/SIR/VIC-1911 to the widely used PTCy/SIR/mycophenolate mofetil (MMF) regimen in a randomized, phase II clinical trial in adults with hematologic malignancies undergoing myeloablative alloHCT. We hypothesize that substitution of VIC-1911 for MMF will result in a significantly better 1-year graft-versus-host disease-free, relapse-free survival (GRFS), setting a new standard in the field. Preclinical and phase I human data from the University of Minnesota show significant promise in the combined PTCy/SIR/VIC regimen, with low rates of acute/chronic GVHD and relapse, while not adding significant patient burden or side effects to the GVHD prophylaxis regimen. Partnering with the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) will provide a robust platform for trial implementation, capitalizing on their expertise, multicenter collaborative infrastructure, and access to a large and diverse patient population, ensuring rigorous evaluation of our innovative regimen and its transformative potential in the field of alloHCT. The University of Minnesota unequivocally affirms its commitment to the BMT CTN, bringing its expertise and institutional resources to further enhance its mission and objectives through clinical trials such as the one we propose herein.