Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias and potentially transform to acute myeloid leukemia (AML). Treatment (tx) with hypomethylating agents (HMAs) is the standard of care for patients (pts) with tx-naïve higher-risk (HR) MDS who are not candidates for intensive chemotherapy/allogeneic stem cell transplant. Currently, azacitidine (AZA) is the only drug shown to prolong survival in tx-naïve HR MDS. However, ~50% of pts treated with HMA alone do not derive clinical benefit. Venetoclax (VEN) is a potent, orally bioavailable BCL-2-specific inhibitor, VEN plus AZA has demonstrated a tolerable safety profile and promising efficacy in elderly pts with tx-naïve AML (incl. secondary AML) ineligible for intensive chemotherapy. Preclinical data indicate activity of VEN in HR MDS (Jilg, 2016). Thus, the unmet medical need in HR MDS as well as relevant clinical data with VEN in AML provide a rationale for assessing VEN plus AZA in pts with tx-naïve HR MDS. Methods: This open-label, Phase 1b dose-escalation study evaluates VEN in combination with AZA for tx-naive HR MDS (NCT02942290) and consists of 2 portions, an initial dose-escalation (∼24 pts) and a safety expansion (∼20 pts) at the recommended Phase 2 dose (RPTD). Key eligibility criteria are no prior therapy for MDS, an overall International Prognostic Scoring System score of ≥1.5 (Int-2 and HR), bone marrow blasts ≥5% and < 20%, and ECOG score of ≤2. VEN will be administered at starting dose level of 100 mg daily for 14 days/cycle (28 days) and may be escalated up to 400 mg for subsequent dose-level cohorts. AZA will be administered at the standard dose (75 mg/m²) for 7 days/cycle. Primary study objectives are to assess safety and pharmacokinetics, and to determine the RPTD and dosing schedule of VEN plus AZA. Secondary objectives incl. rates of overall response, hematologic improvement, transfusion independence, and cytogenetic response, as well as duration of response, progression-free survival, overall survival, and time to transformation to AML. Exploratory objectives include patient-reported outcomes and translational biomarkers of response and resistance. Clinical trial information: NCT02942290