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 thrombocytopenia: (throm-buh-sie-tuh-PEE-nee-uh) A condition in which there is a shortage of platelets in the bloodstream. This results in a low platelet count. Bleeding and bruising often occur with thrombocytopenia. (n=13), anemia anemia: (uh-NEE-mee-uh) A condition in which there is a shortage of red blood cells in the bloodstream. This causes a low red blood cell count. Symptoms of anemia are fatigue and tiredness. (n=12), neutropenia neutropenia: (noo-truh-PEE-nee-uh) A condition in which there is a shortage of neutrophils in the bloodstream. Neutrophils are a type of white blood cell. This results in a low white blood cell count. (n=9), febrile neutropenia (n=9), pneumonia (n=6), and hypoxia (n=5). Thrombocytopenia requiring a platelet transfusion platelet transfusion: A procedure in which platelets are given to a person through an intravenous (IV) line into the bloodstream. Platelets are more likely than red blood cells to cause an immune response, such as chills and fever. The use of platelets from one donor (apheresis) reduces the chance of reaction to… 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 platelet: The smallest type of blood cell. Platelets help the blood to clot and stop bleeding. Also called a thrombocyte. 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 mutation: Any change or alteration in a gene. A mutation may cause disease or may be a normal variation. Paroxysmal nocturnal hemoglobinuria (PNH) occurs because of a mutation in the PIG-A gene of a single stem cell in the bone marrow. 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.