A Phase Ib/II study of ceralasertib, a selective inhibitor of ATR, in patients with relapsed or refractory MDS and CMML

Pre-mRNA splicing gene mutations are common in MDS and CMML and induce R-loops which trigger ATR activation. We studied ceralasertib, an orally bioavailable ATR inhibitor, in adult patients with R/R MDS or CMML in a phase Ib/II study including a safety run-in and expansion of 160mg BID during a 28-day cycle on two schedules: days 1-14 (14on/14off) or days 1-7 and 15- 21 (7on/7off). Response rates and survival were estimated. Forty-four evaluable patients were treated. Grade 3 or higher all-cause adverse events in 10% or more patients included thrombocytopenia (n=13), anemia (n=12), neutropenia (n=9), febrile neutropenia (n=9), pneumonia (n=6), and hypoxia (n=5). Thrombocytopenia requiring a platelet transfusion during the first cycle was reduced to 1 of 10 patients on 7on/7off compared to 8 of 16 patients on 14on/14off among patients with a baseline platelet count >50k (p=0.087). ORR was 29.5% (13 of 44 patients) and included one CR, 5 marrow CR (2 with HI-N), and 7 with HI (HI-E=4, HI-N=2, HI-P=1). Median PFS was 4.8mo and OS was 12 months (95%CI 11, 24). ORR (p=0.72), PFS (p=0.9) and OS (p=0.65) did not differ between schedules. While splicing factor mutation VAFs were stable, RUNX1 mutation VAFs typically increased at progression. Serum inflammatory cytokine levels including TNFRSF8 (CD30) and other TNF family members decreased during ceralasertib exposure; this effect was blunted in RUNX1 mutant samples. In conclusion, ceralasertib 160mg BID d1-7 and 15-21 was established as monotherapy dosing with a response rate of 30% in patients with R/R MDS and CMML. NCT03770429.