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

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Novel Therapeutics I
Hematology Disease Topics & Pathways:
Diseases, Adult, Therapies, Non-Biological, MDS, chemotherapy, Study Population, Clinically relevant, Myeloid Malignancies
Saturday, December 1, 2018: 4:45 PM
Grand Hall A (Manchester Grand Hyatt San Diego)

Guillermo Garcia-Manero, MD1, Koji Sasaki, MD2, Guillermo Montalban-Bravo, MD1*, Kristy R. Bodden1*, Prithviraj Bose, MD3, Yesid Alvarado, MD1, Naval G. Daver, MD3, Gautam Borthakur, MD2, Farhad Ravandi, MBBS4, Koichi Takahashi, MD5, Jorge E. Cortes, MD2, Elias J. Jabbour, MD 6, Kiran Naqvi, MD, MPH2, Courtney D. DiNardo, MD, MSc7, Christopher B. Benton, MD3, Naveen Pemmaraju, MD8, Tapan M. Kadia, MD9, Maro N. Ohanian, DO2, Sherry A. Pierce, BSN, BA2* and Hagop M. Kantarjian, MD1

1Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
6Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
7Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX
8Department of Leukemia, The University of Texas MD Anderson Cancer Center, Bellaire, TX
9Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX

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 score showed tendency of lower rates of response (p=0.063; hazard ratio [HR], 1.383; 95% confidence interval [CI], 0.982-1946). However, MVA did not show any prognostic factors for response. By MVA characteristics associated with survival were: complex karyotype (p=0.036; HR, 2.345; 95% CI, 1.055-5.210), and response to therapy (p=0.003; HR, 0.272; 95% CI, 0.114-0.648).

In conclusion: SGI-110 is well tolerated in previously untreated MDS. ORR appears to be better than expected compared to azacitidine or decitabine. Longer follow-up and randomized trials will be needed to understand effect on survival.

Disclosures: Sasaki: Otsuka Pharmaceutical: Honoraria. Bose: Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Pfizer, Inc.: Research Funding. Daver: Kiromic: Research Funding; ImmunoGen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Sunesis: Consultancy; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Alexion: Consultancy; Pfizer: Consultancy, Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Karyopharm: Consultancy, Research Funding; Novartis: Research Funding; Otsuka: Consultancy; Novartis: Consultancy, Research Funding. Ravandi: Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding. Takahashi: Symbio Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Agios: Consultancy. Cortes: Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Jabbour: Spectrum: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy. DiNardo: Syros: Honoraria; Abbvie: Consultancy; Medimmune: Honoraria; Bayer: Honoraria; Agios: Consultancy; Celgene: Consultancy; Karyopharm: Honoraria; Jazz: Honoraria. Pemmaraju: SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Kadia: Novartis: Consultancy; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Takeda: Consultancy. Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria.

*signifies non-member of ASH