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

Key Points: Ixazomib treatment resulted in decreases in B-cell subsets and bone marrow lymphocytes. Ixazomib treatment resulted in modest decreases in certain anti-HLA antibody specificities. Ixazomib treatment was tolerated, with modest adverse events.

Background: Ixazomib is a second-generation oral proteasome inhibitor approved for treatment of refractory multiple myeloma. We conducted an open-label phase II trial, IXAzomib for DESensitization (IXADES), testing the 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) >80%, awaiting kidney transplantation >24 months. The subjects were treated with 12 monthly cycles of ixazomib 3 mg+dexamethasone 20 mg. Efficacy was defined as a decrease of cPRA >20% or kidney transplantation. The safety end point was tolerability.

Methods: In ten 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 paradoxical in the case of anti-HLA-DR. Clinical trials combining ixazomib with other immunosuppressive agents may be more effective in addressing antibody-mediated processes in kidney transplantation.