Background: In this open label phase 1 dose escalation study, safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of AMG 330 were evaluated in patients (pts) with R/R AML (NCT#02520427). Methods: AMG 330 was evaluated as a continuous IV (cIV) infusion using a 3+3 design. Response was assessed per revised IWG criteria. Each cycle (2–4 weeks duration) was followed by an infusion-free interval. Eligible pts were ≥18 y/o with > 5% blasts in bone marrow and ≥1 line/s of prior therapy. Results: As of December 10, 2019, 55 pts (median age, 58.0 [18.0–80.0] years) were enrolled in 16 cohorts. AMG 330 was administered on 4 schedules (0–3 dose steps) prior to the target dose (TD, 0.5–720 µg/day). Dose steps were implemented in the dose schedule design based on the adverse event (AE) profile. Across all schedules, 55 (100%) pts reported treatment-emergent AEs (any grade). AMG 330–related AEs reported in 49/55 (89%) pts included cytokine release syndrome (CRS; 67%; ≥ grade 3 in 13%), (60%) and nausea (20%) as the most frequent AEs. CRS was reversible and occurred in a dose/schedule-dependent manner mostly within the first 24 hours of administration of triggering AMG 330 dose. The frequency and severity of CRS correlated with the dose level and leukemic burden at baseline. AMG 330 exhibited dose-dependent increase in steady state exposures over the studied dose range with clinical PK profile consistent with cIV administration. Eight of 42 evaluable pts responded: 3 complete remissions (CR; including 1 CR with negative measurable residual disease reported after data snapshot), 4 CR with incomplete hematologic recovery, and 1 morphologic leukemia free state. Seven responders who achieved CR/CRi received a TD equal or above the minimal efficacious dose of 120 μg/day. Among analyzed CR/CRi responders, 4/6 (67%) had adverse cytogenetic risk profile, 3/6 (50%) had ≥4 lines of prior therapy and all had relapsed disease. Responders had higher AMG 330 exposures and 3 responders treated with ≥600 μg/day TD remain in CR/CRi: 1 patient for > 5 months after cycle 1, 1 patient bridged to hematopoietic stem cell transplant after cycle 4 and 1 patient is in cycle 3. Preliminary response assessment showed a correlation with lower tumor burden at baseline with a trend towards higher CD8+ lymphocyte count and E:T ratio. Conclusions: AMG 330 dosed up to 720 μg/day provided early evidence of acceptable safety profile, drug tolerability and anti-leukemic activity, and supports further dose escalation. Clinical trial information: NCT02520427.