The success of post-transplant 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 I dose-finding results of PTCy, sirolimus (SIR), and VIC-1911, a selective oral Aurora kinase A (AURKA) inhibitor, following myeloablative allogeneic hematopoietic cell transplantation (alloHCT). Results from murine and in vitro studies informed the development of the novel drug combination. In the phase I trial (NCT05120570), patients aged 18-60 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 BID, days +5 to +45). The primary endpoint was achieving <54% pH3ser10 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 anti-leukemia activity of AURKA inhibition. In the phase I trial, the optimal VIC-1911 dose achieving target pathway inhibition without dose-limiting toxicities was 75 mg BID. Clinical outcomes included no grade III-IV 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 BID, combined with PTCy and SIR, effectively suppresses AURKA activity, offering promising GVHD and relapse prevention with a favorable safety profile and promising early clinical outcomes.
Holtan et al. (Tue,) studied this question.