CALIBRATE: A Phase 2 Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis.

Objectives To assess safety and mechanism of action, and generate preliminary efficacy data on rituximabfollowed by belimumab for refractory lupus nephritis. Methods Forty three participants with recurrent or refractory lupus nephritis were treated with rituximab, cyclophosphamide, and glucocorticoids, followed by randomization to belimumab infusions (RCB) until Week 48, or no infusion (RC) in a multicenter, randomized, open label clinical trial. Patients were followed until Week 96. Total and autoreactive B cell subsets were analyzed by flow cytometry. Results Addition of belimumab did not increase the incidence of adverse events. At Week 48, complete or partial renal response occurred in 11/21 (52%) in those receiving belimumab, versus 9/22 (41%) in those that did not (p=0.452). LN was the major reason for treatment failure. B cell depletion occurred in both groups, but B cells remained lower in those receiving belimumab (Week 60: Geom. Mean=53 cells/μL vs. 11, p=0.0012). The percentage of total and autoreactive transitional B cells increased from baseline to Week 48 in both groups, however the percentage of total and autoreactive naive B cells (p=0.0349) decreased in the belimumab group, consistent with impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. Conclusion The addition of belimumab to rituximab and cyclophosphamide was safe. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution and enhanced negative selection of autoreactive B cells. The combination did not improve clinical efficacy compared to B cell depletion alone.