6509 Background: There is an unmet need for new treatment (tx) options in lower-risk MDS (LR-MDS) to address cytopenias and prevent progression to higher-risk MDS and acute myeloid leukemia. Here, we report safety and preliminary efficacy data from phase 2 of the ASTREON study, which evaluated 14-day Oral-AZA regimens in pts with Low-/Int-risk MDS. Methods: ASTREON is a phase 2/3, multicenter study evaluating safety and efficacy of Oral-AZA plus best supportive care (BSC) in pts with Low-/Int-risk MDS (NCT05469737). Phase 2 is an open-label, dose optimization study to determine the recommended phase 3 Oral-AZA dose. Eligible pts (≥ 18 years of age with Revised International Prognostic Scoring System [IPSS-R] Low-/Int-risk MDS and ≥ 1 cytopenia) were randomized 1:1 to receive Oral-AZA 200 mg or 300 mg QD for 14 d per 28-d cycle plus BSC. Primary endpoints are rates of adverse events (AEs) and complete remission (CR) within 6 cycles per International Working Group (IWG) 2006 criteria. Secondary endpoints include achievement of overall response (OR) (including CR, partial remission, marrow CR, hematologic improvement-erythroid response [HI-E], HI-platelet response, and HI-neutrophil response per IWG 2006 criteria); best OR; and OR duration. HI rates within 6 cycles were calculated by investigator assessment per IWG 2006 criteria for pts who received ≥ 75% of the cycle 1 dose and had ≥ 1 post-baseline (BL) efficacy assessment (modified intent-to-treat [mITT] population). Results: As of December 4, 2023, 47 pts were randomized and received ≥ 1 Oral-AZA dose (200 mg, n = 24; 300 mg, n = 23); 6 and 5 pts discontinued tx in the 200 mg and 300 mg arms. The median (range) tx durations were 24.1 (12.1–34.1) and 24.7 (7.7–39.1) wk for the 200 mg and 300 mg arms, respectively. IPSS-R scores and RBC transfusion burden at BL were balanced between tx arms. Most pts (42/47 [89.4%]) had prior MDS tx, including but not limited to erythropoiesis-stimulating agents, lenalidomide, luspatercept, and imetelstat. AE rates were similar between arms: 11/24 (45.8%) vs 12/23 (52.2%) pts in the 200 mg vs 300 mg arms reported ≥ 1 tx-related grade 3 or 4 tx-emergent AE. The most common tx-related AEs in both arms were hematologic and gastrointestinal. Tx-related serious AEs occurred in 1/24 and 3/23 pts in the 200 mg and 300 mg arms, respectively. One death occurred in the 300 mg arm and was considered tx-related. In the mITT population, 8/22 and 7/21 pts achieved any HI in the 200 mg and 300 mg arms, respectively. Six pts in each dose group achieved HI-E. Among mITT pts with anemia at BL, 6/19 (31.6%) pts in the 200 mg and 5/18 (27.8%) pts in the 300 mg arm achieved HI-E. Updated results will be presented. Conclusions: The safety of Oral-AZA 200 mg and 300 mg was consistent with the known Oral-AZA safety profile. Preliminary efficacy data support continued evaluation of Oral-AZA in LR-MDS. Clinical trial information: NCT05469737 .