First Clinical Results Of a Randomized Phase 2 Study Of SGI-110, a Novel Subcutaneous (SQ) Hypomethylating Agent (HMA), In Adult Patients With Acute Myeloid Leukemia (AML)

Abstract Background SGI-110 is second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume, pharmaceutically stable SQ injection allowing longer half-life and more extended decitabine exposure than DAC IV infusion. SGI-110 differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in the phase 1 trial (Kantarjian et al. 2012). Methods In a randomized Phase 2 study, relapsed/refractory AML, or elderly treatment naïve AML patients who were not suitable for induction chemotherapy (poor major organ function; poor cytogenetics; or secondary AML) were randomized to one of two SQ doses – the biologically effective dose (BED) of 60 mg/m2 QDx5 or 90 mg/m2 QDx5. The primary endpoint of the phase 2 study is the overall remission rate (CR, CRi, and CRp) based on the International Working Group Criteria 2003. Safety findings based on adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic data on Long Interspersed Nucleotide Element (LINE-1) DNA methylation (an index of global DNA methylation) activity were also assessed and reported. Results As of June 30, 2013, sixty-seven patients (50 relapsed/refractory AML, 17 treatment naïve elderly AML) were treated and had a minimum follow up of 3 months. Patients were randomized to either 60 mg/m2 dose (32 patients) or 90 mg/m2 dose (35 patients). The median age was 66 years (range, 22–84), 69% were male, and ECOG PS of 0/1/2 was reported in 11/47/9 patients respectively. Median number of prior regimens was 2 (range, 0–10). Patients’ characteristics were well balanced between the 2 dose groups. The primary endpoint of overall remissions (CR, CRp, or CRi) was observed in 17/67 patients (25% with 95% CI, 16–37%). There were 8 complete remissions (CR, CRp, or CRi) in 50 patients with relapsed/refractory AML (16% with 95% CI, 7-29%); and 9 complete remissions (CR, CRp, or CRi) in 17 treatment-naïve elderly AML patients (53% with 95% CI, 28-77%). Five patients (4 relapsed/refractory, and one treatment-naïve elderly AML) subsequently received a stem cell transplant. There was no difference in the complete remission rate between 60 and 90 mg/m2 doses (8 remissions in 32 patients at 60 mg/m2, and 9 remissions in 35 patients at 90 mg/m2). LINE-1 DNA methylation data before and after treatment was available in 50 (75%) patients enrolled. LINE-1 demethylation ≥ 10% post treatment was observed in 83% and 78% in the 60 mg/m2 and 90 mg/m2, respectively. The median maximum LINE-1 demethylation for responders is 25% as compared to 19% for non-responders. The most common adverse events (AEs) regardless of relationship to SGI-110 ≥ Grade 3 include febrile neutropenia, thrombocytopenia, anemia, leukopenia, neutropenia, and pneumonia. The 90 mg/m2 dose showed a greater frequency of Grade 3/4 related AEs ≥ 10% (anemia, febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia) compared to the 60 mg/m2 dose. Conclusions SQ SGI-110 is a new HMA which is well tolerated and clinically active in the treatment of AML. Complete remissions and potent demethylation of ≥10% were equally observed at the 2 dose groups of 60 and 90 mg/m2. These data support further phase 3 investigation of this agent in the treatment of AML. Preliminary overall remission rate of 53% in treatment-naïve elderly AML seems to compare favorably with previous results reported for HMA treatment but this needs to be confirmed in a larger number of patients and randomized studies. Disclosures: Kantarjian: Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Kropf:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Roboz:Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Savona:Astex Pharmaceuticals, Inc.: Research Funding. Ervin:Astex Pharmaceuticals, Inc.: Research Funding. Podoltsev:Astex Pharmaceuticals, Inc.: Research Funding. Pemmaraju:Astex Pharmaceuticals, Inc.: Research Funding. Daver:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Borthakur:Astex Pharmaceuticals, Inc.: Research Funding. Wierda:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Brandwein:Astex Pharmaceuticals, Inc.: Research Funding. Odenike:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Dimitrov:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Astex Pharmaceuticals, Inc.: Consultancy, Research Funding.

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