Background: Despite treatment advances, pts with AML or higher-risk MDS who are ineligible for standard intensive treatments still have poor survival, highlighting the need for novel therapies. Overexpression of CD47 is common in leukemic stem cells and AML blasts and correlates with poor clinical outcomes. Lemzo is an anti-CD47 antibody with red blood cell–sparing properties. Treatment with ven plus aza has shown favorable safety and efficacy in older/unfit pts with AML and higher-risk MDS. Blocking CD47 is hypothesized to hypersensitize AML cells to the antitumor activity of ven and aza. This study will evaluate the safety and dose-limiting toxicities (DLTs) of lemzo with ven + aza for pts with treatment-naïve AML, as well as lemzo with aza ± ven for treatment-naïve higher-risk MDS. Methods: This phase 1b, open-label, dose-escalation study (NCT04912063) is enrolling adults with: (1) treatment-naïve AML with adverse cytogenetic/molecular risk not suitable for induction therapy, with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 0–2 (aged ≥75 years) or 0–3 (aged ≥18–74 years) excluding acute promyelocytic leukemia; or (2) treatment-naïve higher-risk MDS (Revised International Prognostic Scoring Score > 3) with < 20% bone marrow blasts, ECOG-PS 0–2, and no immediately planned stem cell transplant. For each 28-day cycle, aza is administered subcutaneously or intravenously (IV) daily for 7 days within the first 9 days (7-0-0 or 5-2-2 schedule); ven is administered orally daily on days 1–28 (AML, following dose ramp-up) or days 1–14 (ven-containing MDS cohorts). Lemzo is administered IV at a schedule that is to be determined in this study. Dose escalation has Bayesian optimal interval design and may be expanded to investigate alternate dosing for lemzo. Dose expansion will initiate at recommended phase 2 dose. Treatment discontinuation criteria are unacceptable toxicity, progressive disease, lack of partial/complete remission or clinical benefit within 6 cycles, or at physician’s discretion. Pts who discontinue study treatment without progression will continue with posttreatment follow-up; pts who progress will enter survival follow-up. The primary endpoints are DLTs of lemzo. Secondary endpoints for both cohorts include best overall responses of complete remission, duration of response, event-free survival, and overall survival. Exploratory biomarker endpoints are included. Safety assessments include adverse event (AE, graded per National Cancer Institute Common Terminology Criteria for AEs v5.0) monitoring, physical examinations, vital signs, electrocardiograms, and laboratory tests. Response rates will be analyzed with estimates and 95% confidence intervals based on exact binomial distribution. Time-to-event endpoints will be analyzed using Kaplan–Meier methodology. Clinical trial information: NCT04912063.