Carfilzomib for treatment of refractory chronic graft vs. host disease: A Chronic GVHD Consortium pilot phase II trial

Abstract Prior experimental and clinical data suggest proteasome inhibition may have immunomodulatory activity relevant to graft vs. host disease (GVHD). To explore the safety and activity of carfilzomib in advanced chronic GVHD, we conducted a multi-center pilot phase II trial through the Chronic GVHD Consortium. Carfilzomib was administered at 20 mg/m2 on day 1, and then 36mg/m2 on days 8 and 15 of a 28-day treatment cycle (cycle 1), and then 36 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle (cycles 2-6). The primary endpoint was 6 month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic immune suppressive (IS) therapy. A total of 20 subjects were enrolled at 4 institutions. Median time from chronic GVHD onset to enrollment was 1.5 years (IQR 0.5-3.7). Chronic GVHD was NIH moderate (30%) or severe (70%), predominantly classic (90% vs. overlap 10%), and involved multiple diverse organ sites. Prior lines of systemic therapy for chronic GVHD were ≤ 2 (n=6, 30%) or ≥ 3 (n=14, 70%). Doses were held primarily for infection (50% of total held doses); only 3 patients (15%) completed all planned doses of the 6 cycles of carfilzomib. SAEs occurred in 40% of subjects, and 7 deaths occurred among study participants occurring between 0.3-9 months after last carfilzomib dose, but none were attributed to carfilzomib. The 6 month treatment failure rate was not significantly improved vs. the historical benchmark (40% vs. 44%, p=0.36). Overall survival at 6 and 12 months was 80% and 65%. Failure-free survival at 12 months was 32%. These pilot phase II data suggest that carfilzomib therapy in this advanced chronic GVHD population did not improve expected 6 month treatment failure rates achieved under conventional practices and is not recommended for further study for this indication.