Phase 2 Expansion Study Of Oral Rigosertib Combined With Azacitidine (Aza) In Patients (Pts) With Higher-Risk (Hr) Myelodysplastic Syndromes (Mds): Efficacy And Safety Results In Hma Treatment Naive & Relapsed (Rel)/Refractory (Ref) Patients

Background: AZA is first line therapy for pts with HR-MDS with an overall response rate (ORR) between 35 and 60% in various publications; with CR/PR rates ranging between 23 and 29% in 3 randomized phase II/III studies (Silverman et al., JCO 2002; Fenaux et al., Lancet Oncol 2009; Sekeres, JCO 2017). AZA also has demonstrated efficacy in older pts with AML (Dombret et al., Blood 2015; Fenaux et al., JCO 2010). Rigosertib interferes with the RAS-binding domains of RAF kinases and inhibits the RAS-RAF-MEK and the PI3Ks pathways (Athuluri-Divakar, Cell 2016). RAS and other genes in this pathway are frequently mutated in HR MDS and putatively drive the malignant clone (Sperling et al., Nat Rev CA 2017). In vitro, the combination of rigosertib with AZA synergistically inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (Skidan et al; AACR 2006 Abstract 1310).