▪5-azacitidine (5-AZA) is standard of care in the first-line setting for higher-risk patients with Myelodysplastic Syndrome (MDS). However, 40-50% of patients are refractory to 5-AZA and most responders ultimately demonstrate disease progression within 2 years, often progressing to AML. For patients refractory to 5-AZA, 2-year survival probability is low (15%). Thus, there is a need for more effective initial and second-line therapies for patients with higher-risk MDS. The Inhibitors of Apoptosis (IAP) Proteins are a family of molecules that suppress apoptotic cell death. Expression of IAPs is dysregulated in MDS, suggesting a potential path for therapeutic intervention. SMAC (second mitochondrial activator of caspases) is an IAP antagonist, resulting in caspase activation, inhibition of NF-kB and increased apoptosis. Birinapant is a potent bivalent SMAC mimetic with improved tolerability and therapeutic index compared to other SMAC mimetics. This Phase Ib/2a study was designed primarily to determine the MTD and recommended Phase 2 dose and schedule of birinapant in combination with 5-AZA in patients with higher-risk MDS who are naïve or have relapsed or are refractory to 5-AZA.To date, 11 patients have been enrolled in the Phase 1b portion of the study, including 7 with IPSS classification high-risk MDS (5 male, 2 female; median age 75, range 64-82) and 4 with intermediate-risk MDS (2 male, 2 female; median age 72.5, range 65-84). All patients received standard 5-AZA, administered via either intravenous (IV) or subcutaneous (SC) routes, at 75 mg/m2 for 7 days of a 28-day cycle in combination with birinapant. Birinapant was administered IV twice weekly (Days 1 and 4) for either 3 of 4 weeks or 4 of 4 weeks per 28-day cycle at a dose of 13 mg/m2.No cycle 1 dose-limiting toxicities have been observed. Adverse events ≥ Grade 2 observed in two or more patients and judged to be related to treatment were rash/pruritis (Grade 2, 2 patients), thrombocytopenia (Grade 4, 2 patients) and neutropenia (Grade 4, 1 patient; Grade 3, 1 patient). Two SAEs, Grade 3 abdominal soft tissue necrosis with abdominal pain in the area of subcutaneous injections of 5-AZA, and Grade 3 cellulitis were judged to be related to treatment. These local injection site reactions/cellulitis were more severe than usually expected with SC 5-AZA, suggesting an on target pharmacodynamic (TNF mediated) localized synergistic effect in skin, but were not observed with IV administration. Both occurred after cycle 1 and were not considered DLTs. Data showing inhibition of NF-kB, a downstream pro-survival molecule activated by IAPs, in circulating blast cells from patients treated with birinapant at a dose of 13 mg/m2 twice weekly for 3 weeks out of 4, suggests that birinapant is pharmacologically active at this dosing schedule. Based on these and other pharmacodynamic data, despite not determining the formal MTD, the Phase 2 dosing regimen has been established as birinapant administered at 13 mg/m2 IV twice weekly for 3 weeks of a 28-day cycle in combination with 5-AZA at 75 mg/m2 by IV infusion for 7 days of a 28-day cycle.Although not a primary endpoint, evidence of clinical activity in 5-AZA resistant/refractory patients was observed in 2 of 11 patients to date, with an additional good clinical response in a 5-AZA naive high-risk MDS/CMML patient. One patient with prior 5-AZA-refractory MDS (cytogenetics: hypodiploid and +11q) showed bone marrow (BM) blast count reduction from 25% to 2% after 1 cycle of 5-AZA/birinapant treatment. Another patient with MDS (cytogenetics: +X; +19; +21) refractory to single-agent 5-AZA showed BM blast count reduction from 21% to 7% after 2 cycles. A third patient with treatment-naïve MDS/CMML-2 (cytogenetics: 46, XY, inv(6)(p11.2q15), t(6;21)(q21;q22) ) who had received prior hydroxyurea demonstrated BM blast count reduction from 17% to 2% after 3 cycles and underwent hematopoietic stem cell transplant. Several patients remain on study and are in active follow-up.This Phase 1b trial provide data for an acceptable safety profile of the first combination of a SMAC mimetic (birinapant) administered with IV 5-AZA. Early signs of clinical activity including in 5-AZA naïve and refractory patients were observed. These results provide rationale for a randomized Phase 2 study comparing birinapant in combination with 5-AZA against 5-AZA alone in the first-line setting for patients with higher-risk MDS. DisclosuresBorthakur:Tetralogic Pharmaceuticals: Research Funding. Foran:TetraLogic Pharmaceuticals: Research Funding. Wang:Tetralogic Pharmaceuticals: Research Funding. Rakkar:Tetralogic Pharmaceuticals: Research Funding. Hager:Tetralogic Pharmaceuticals: Research Funding. Frey:Tetralogic Pharmaceuticals: Research Funding. Andreeff:TetraLogic Pharmaceuticals: Research Funding. Carter:Tetralogic Pharmaceuticals: Research Funding. Minderman:Tetralogic Pharmaceuticals: Research Funding. Russell:Tetralogic Pharmaceuticals: Employment. Tibes:Tetralogic Pharmaceuticals: Research Funding.