A Phase 1 Clinical Trial of Siltuximab for the Treatment of Antibody-Mediated Rejection After Lung Transplantation

Long-term outcomes after lung transplantation remain disappointing, and the median survival is 6.7 years. Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. Antibody-mediated rejection (AMR), which is increasingly recognized after lung transplantation, is caused by donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) and frequently results in CLAD and death. Recent multicenter studies using intensive monitoring for AMR report an incidence over 25%. Treatment for AMR has generally focused on antibody depletion and prevention of additional antibody development. Various combinations have been used including high-dose corticosteroids, intravenous immune globulin (IVIG), Rituximab, Carfilzomib, anti-thymocyte globulin (ATG), and plasma exchange (PLEX). However, there have been no randomized controlled trials to guide management, and outcomes after AMR are dismal. One-year allograft survival after AMR is approximately 50%, and 2-year survival is only 20%. IL-6, initially identified as B-cell stimulating factor 2 (BSF-2), is a pleiotropic cytokine that drives deleterious inflammatory, alloimmune, and fibrogenic responses. In conjunction with other cytokines, IL-6 is responsible for normal antibody production and is critical for the induction of follicular helper T cells as well as the production of IL-21 which regulates immunoglobulin synthesis. IL-6 is also crucial for B-cell differentiation into plasmablasts and for enhancing plasmablast survival. These characteristics make IL-6 an especially attractive cytokine to target in the management of AMR. Human studies examining the role of IL-6 signaling blockade in the management of AMR after kidney transplantation have shown promising results, even in refractory cases. Preliminary experience with use of IL-6 signaling blockade in a very small number of lung transplant recipients with AMR has been encouraging. The principal hypothesis for this study is that IL-6 signaling blockade added to routine immunosuppressive treatment for AMR will improve clinical outcomes. However, evaluating the safety of this approach is necessary before examining efficacy in larger clinical trials because infections are the most common serious adverse events associated with IL-6 signaling blockade and a common cause of death at all timepoints after lung transplantation. This study is a Phase 1 clinical trial using Siltuximab, a monoclonal antibody to IL-6, in addition to routine immunosuppressive therapy for AMR to examine safety and define the optimal dose for the treatment of AMR. The primary endpoint is safety and tolerability, and secondary endpoints include pharmacodynamics and functional biological measures relevant to AMR (e.g., DSA, cell-free DNA). Data from this trial will inform the design of a future Phase 2 clinical trial that assesses efficacy. Carefully designed and implemented clinical trials are necessary to improve outcomes after lung transplantation.

• incidence of CTCAE ≥ grade 3 [Срок оценки: during a period of 180 days after randomization]
• serum high-sensitivity CRP [Срок оценки: Up to 90 and 180 days after randomization]
• Blood Sultiximab levels [Срок оценки: Up to 90 days after randomization]
• Clearance of donor specific antibodies [Срок оценки: From randomization to day 180]
• Infections [Срок оценки: Between randomization and day 180]
• Change in Forced Vital Capacity (FVC) [Срок оценки: between randomization and day 180]
• Change in Forced Expiratory Volume in One Second (FEV1) [Срок оценки: between randomization and day 180]
• Development of Chronic Lung Allograft Dysfunction [Срок оценки: between randomization and day 180]
• Allograft survival [Срок оценки: between randomization and day 180]
• Hyperuricemia [Срок оценки: between randomization and day 180]
• Hyperlipidemia [Срок оценки: between randomization and day 180]