Targeting Aurora kinase A to prevent GVHD and relapse after myeloablative allogeneic hematopoietic cell transplantation

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ABSTRACT: The success of posttransplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has driven efforts to optimize partner therapies that balance GVHD and relapse prevention. We report phase 1 dose-finding results of PTCy, sirolimus (SIR), and VIC-1911, a selective oral Aurora kinase A (AURKA) inhibitor, after myeloablative allogeneic hematopoietic cell transplantation (allo-HCT). Results from murine and in vitro studies informed the development of the novel drug combination. In the phase 1 trial, patients aged 18 to 60 years received myeloablative conditioning, followed by PTCy (50 mg/kg; days +3/+4), SIR (from day +5; target 8-12 ng/mL), and VIC-1911 (25, 50, or 75 mg twice daily; days +5 to +45). The primary end point was achieving <54% phosphorylated histone H3 serine 10 expression in CD4+ T cells by day +21. Preclinical models show that combining SIR with AURKA inhibition suppresses signaling downstream of CD28, enhancing GVHD prevention while leveraging the antileukemia activity of AURKA inhibition. In the phase 1 trial, the optimal VIC-1911 dose achieving target pathway inhibition without dose-limiting toxicities was 75 mg twice daily. Clinical outcomes included no grade 3 to 4 acute GVHD through day 180 (0%) and low rates of moderate/severe chronic GVHD (6%) and relapse (0%) through 1 year (5/16 received maintenance). The 1-year overall survival for this cohort was 94%. VIC-1911 at 75 mg twice daily, combined with PTCy and SIR, effectively suppressed AURKA activity, offering promising GVHD and relapse prevention with a favorable safety profile and promising early clinical outcomes. The trial was registered at www.clinicaltrials.gov as NCT05120570.

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