Rituximab Plus Cyclophosphamide followed by Belimumab (CALIBRATE)

The objective of the CALIBRATE study is to determine if treating lupus nephritis with a combination of rituximab (Rituxan®) and cyclophosphamide (Cytoxan®), or a combination of rituximab and cyclophosphamide followed by treatment with belimumab (Benlysta®) is safe and if this drug combination can block the immune system attacks on the kidney.

Rituximab (anti-CD20) depletes B cells which are known to be key mediators in autoimmune diseases like lupus nephritis. Belimumab is a monoclonal antibody that inhibits B cell activating factor (BAFF), a potent cytokine important for B cell maturation. The rationale for the CALIBRATE trial is based on the observation that BAFF levels are known to be elevated following B cell depletion, and high BAFF levels have been associated with an increased risk of recurrent disease flare. It is likely that the circulating high BAFF levels that exist following B cell depletion permit the maturation of autoreactive B cells, by allowing them to bypass tolerance checkpoints and enter the immune repertoire. B cell reconstitution in the absence of high levels of BAFF might result in a tolerized B cell repertoire without autoreactivity and a sustained clinical response.

This study is a prospective, randomized, open label multicenter study that will enroll 40 adults with active lupus nephritis who are refractory to standard-of-care treatment. Participants will be randomized to two treatment groups: One will receive rituximab and cyclophosphamide followed by belimumab and corticosteroids, and the other will receive rituximab and cyclophosphamide followed by corticosteroids alone. The primary objective is to assess the safety of this regimen, and secondarily will assess clinical responses at weeks 24, 48, and 96, and tolerance (a sustained clinical response) at week 96. In addition, the number of the autoreactive B cells will be assessed at 48 weeks as a unique and important mechanistic correlate of tolerance.   

This trial reflects the ITN’s strategy that tolerance induction in autoimmune diseases will likely require a combination of agents that target multiple components of the immune system. The regimen in the CALIBRATE study combines immune cell depletion (rituximab) followed by cytokine blockade (belimumab), with the goal of durably altering the B cell compartment such that autoreactivity is diminished.