Work

Aurora Kinase a Inhibition for Gvhd and Relapse Prevention after Allogeneic HCT: Phase I Trial in Combination with Ptcy/Sirolimus

Year: 2024

Type: article

Abstract: The rising use of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has sparked interest in finding better drug partners to achieve efficient GVHD control while enhancing graft-versus-tumor effects. Sirolimus (SIR) has been used with PTCy. However, it incompletely blocks CD28 co-stimulation in alloreactive T cells. In this context, Aurora kinase A (AURKA) provides an alloreactivity escape route. Combining SIR with AURKA inhibition fully suppresses CD28 signals, thus providing synergistic GVHD prevention in preclinical models. Additionally, AURKA inhibitors possess anti-leukemia properties. Here, we report dose finding results of our first-in-human phase 1 trial using PTCy, SIR, and VIC-1911, a specific oral AURKA inhibitor, for GVHD and relapse prevention post-myeloablative allogeneic hematopoietic cell transplantation (alloHCT). The phase I trial (NCT05120570) evaluates the efficacy of AURKA pathway suppression and the safety of the PTCy/SIR/VIC combination. The goal is to determine the lowest biologically effective VIC-1911 dose based on a <54% pH3ser10 expression target in CD4+ T cells at day +21. Patients aged 18-60 years receive myeloablative conditioning of TBI alone at a dose of 1320 cGy. PTCy is given as 50 mg/kg on days +3 and +4, SIR on day +5 with levels targeting 8-12 ng/ml and tapered after day +100, and VIC-1911 is given on days +5 to +45 at doses of 25, 50, or 75 mg BID. Patients receiving PTCy/SIR/mycophenolate mofetil (MMF) in a separate clinical trial serve as controls for studies of CD4+ immunophenotyping. Prior experiments combining PTCy/SIR with another AURKA inhibitor, alisertib, showed significant protection against GVHD and tumor recurrence in mice (Figure 1A-C). Unlike previous AURKA inhibitors, VIC-1911 shows minimal myelosuppression, justifying this trial. In vitro, VIC-1911 effectively suppresses pH3ser10+ expression in CD4+ T cells (Figure 2A) and kills leukemia cells (Figure 2B). The optimal VIC-1911 dose is 75 mg BID, suppressing AURKA activity below the set target (Figure 2C). Engraftment data and patient outcomes appear favorable, with no observed dose-limiting toxicities during escalation (Figure 3). VIC-1911 (75 mg BID) effectively suppresses AURKA activity when combined with SIR, showing no dose-limiting side effects. The ongoing phase I expansion study will further assess VIC-1911′s potential in preventing GVHD and relapse in PTCy-based alloHCT.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2023.12.364