Ixazomib for Desensitization (IXADES) in Highly Sensitized Kidney Transplant Candidates: A Phase II Clinical Trial

BACKGROUND: Ixazomib is a second-generation oral proteasome inhibitor approved for treatment of refractory multiple myeloma. We conducted an open label phase II trial, IXADES (IXAzomib for DESensitization) testing safety of Ixazomib treatment as an approach to decreasing the level and diversity of specificities of anti-HLA antibodies in subjects awaiting kidney transplantation. The trial (NCT03213158) enrolled highly sensitized kidney transplant candidates, defined as subjects with calculated panel reactive antibodies (cPRA) \u3e80%, awaiting kidney transplantation \u3e24 months. The subjects were treated with 12 monthly cycles of ixazomib 3 mg + dexamethasone 20 mg. Efficacy was defined as a decrease of cPRA \u3e20% or kidney transplantation. The safety endpoint was tolerability. METHODS: In 10 enrolled subjects, no grade IV, five grade III, 11 grade II, and 43 grade I adverse events were noted. The adverse events included infection, transient paresthesia, nausea, vomiting, and diarrhea. The IXADES regimen was not associated with significant change in levels or diversity of anti-HLA antibodies (cPRA). RESULTS: Although the IXADES regimen did not exhibit a clear impact on levels and diversity of anti-HLA antibodies in this small cohort, the prolonged half-life of IgG could necessitate a longer duration of treatment for accurate evaluation of efficacy. CONCLUSIONS: In conclusion, treatment with ixazomib/dexamethasone engendered mild to moderate toxicity. The impact on anti-HLA was modest and in the case of anti-HLA-DR paradoxical. Clinical trials combining ixazomib with other immunosuppressive agents may be more effective in addressing antibody-mediated processes in kidney transplantation