A phase 1b/2 study of ceralasertib, a selective inhibitor of ATR, in patients with relapsed or refractory MDS and...

Pre-mRNA splicing gene mutations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) induce R-loops, which trigger ataxia telangiectasis and Rad3-related kinase (ATR). We studied ceralasertib, an orally bioavailable ATR inhibitor, in adults with relapsed or refractory (R/R) MDS or CMML in a phase 1b/2 study 160mg twice daily during 28-day cycles on 2 dosing schedules: days 1 to 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 adverse events 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 with 8/16 patients on 14on/14off among patients with a baseline platelet count >50 × 109/L (P = .087). Overall response rate (ORR) was 29.5% (13/44 patients) and included 1 complete response (CR), 5 marrow CR (2 with hematologic improvement [HI] in neutrophils [HI-N]), and 7 with HI (HI in erythroid/red cells, n = 4; HI-N, n = 2; HI in platelets, n = 1). Median progression-free survival (PFS) was 4.8 months, and overall survival (OS) was 12 months. ORR (P = .72), PFS (P = .9), and OS (P = .65) did not differ between schedules. Splicing factor mutation variant allele frequencies (VAFs) remained stable while RUNX1 mutation VAFs typically increased at progression. Serum inflammatory cytokine levels (TNFRSF8 [CD30], TNF family members) decreased during ceralasertib exposure; this effect was blunted in RUNX1-mutant samples. Ceralasertib 160 mg twice daily on days 1-7 and 15-21 was established as monotherapy dosing. This trial was registered at www.clinicaltrials.gov as NCT03770429.