Final Report of a Phase II Study of Guadecitabine (SGI-110) in Patients (pts) with Previously Untreated Myelodysplastic Syndrome (MDS)

Introduction: The hypomethylating agents (HMA) are the standard of care for a majority of patients with higher-risk MDS. SGI-110 is a second generation HMA that molecularly is a dinucleotide derivative of decitabine and therefore a more potent inhibitor of DNA methyltransferase activity. SGI-110 is currently being studied in front-line AML and second-line MDS multicenter studies. Here we present results of a single arm phase II trial of SGI-110 for patients with previously untreated MDS. Methods: Patients, age 18 or older, with adequate renal and hepatic functions, with int-2 or high risk MDS by IPSS or more than 10% blasts in bone marrow were eligible. One prior cycle of azacitidine or decitabine was allowed. No prior other therapies were allowed. SGI-110 was administered at a dose of 60 mg/m2 SC daily x 5 days every 4 weeks. The study was designed with stopping rules for response, toxicity, and mortality (first 3 months). A maximum of 100 patients could be treated. Results: From 11/14/2014 to 7/31/2018, 94 patients have been treated. Median age was 69 years (22.7-91.9), 72 patients (77%) had INT-2, 13 patients (14%) high risk. Median % of marrow blasts was 10 (range, 0-20). Median white blood cell count and platelet count were 2.5 (×106/L), and 52 (×106/L) respectively. Twenty two patients (23%) were diploid, 36 (38%) complex, and 33 (35%) others. Mutation distribution was as follows: TP53, 29 (31%); ASXL1, 26 (28%); TET2, 20 (21%); RUNX1, 19 (20%); RAS, 12 (13%); DNMT3A, 10 (11%); EZH2, 9 (10%); SRSF2, 6 (7%); PHF6, 4 (4%); BCOR, 3 (3%); CEBPA, 3 (3%); SF3B1, 3 (3%); IDH2, 3 (3%); BRAF, 2 (2%); CBL 2 (2%); MPL, 2 (2%); NPM1, 2 (2%); U2AF1, 2 (2%); WT1, 2 (2%); CREBBP, 1 (1%); ETV6, 1 (1%); FLT3-ITD, 1 (1%); GATA2, 1 (1%); IDH1, 1 (1%); SETBP1, 1 (1%); ZRSR2, 1 (1%). The median number of cycles received was 5 (range 1 - 32). Ninety four (100 %) patients are evaluable for toxicity. Early mortality was 0%. Common toxicities were fatigue (61%), infection (46%), nausea (27%), pain (19%), and constipation (16%), mucositis (16%), dyspnea (15%), local injection toxicity (15%), and diarrhea (12%). Eighty seven (93%) patients were evaluable for response. The median number of cycles to response was 3 (range 1 - 11). Overall response rate was 53 (61%); CR 19 (22%), CRp 3 (3%), HI 31 (36%), SD 5 (6%), NR 27 (31%), and died 2 (2%). With a median follow-up of 15 months, the median OS was 15 months and the median EFS was 14 months (Figure 1). By UVA, higher ACE-27 scor