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Background: Chronic myelomonocytic leukemia (CMML) is a rare, aggressive cancer for which no targeted therapy exists. Standard of care (SOC) includes azacitidine (A), with complete and partial response (CR and PR) rates ranging between 10-17%. The pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a central role in stimulating leukemic monocyte proliferation. Lenzilumab (LENZ) is a proprietary Humaneered® first-in-class monoclonal antibody with best-in-class specificity and affinity that neutralizes GM-CSF to prevent signaling through its receptor. The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M) trial assesses the efficacy of LENZ in CMML (ACTRN12621000223831p) to improve outcomes beyond those afforded by SOC. Methods: PREACH-M is a Phase 2/3 non-randomized, open-label precision medicine trial in 72 adults aged at least 18 years, newly diagnosed with WHO 2016 criteria for CMML; cytopenia (hemoglobin < 100 g/L, platelets < 100 × 109/L or absolute neutrophil count < 1.8 × 109/L): white blood cell count ≥ 13 × 109/L; as well as TET2 and/or RAS pathway mutations (NRAS, KRAS, CBL). Key exclusion criteria include prior treatment with investigational agents; radiotherapy within 28 days before treatment; treatment with G-CSF within 7 days of screening; GM-CSF within 28 days of screening; and uncontrolled medical conditions. Subjects exhibiting RAS pathway mutations, with or without TET2 mutations, receive 24 cycles (28 days) of A (SC; 75 mg/m2 for 7 days) and LENZ (IV; 552 mg; d1 & d15 of cycle 1 and d1 only for all subsequent cycles); while those with non-RAS pathway mutations receive the same A regimen and sodium ascorbate (IV; 30 g for 7 days [15 g for 1st dose only, 30 g thereafter if no evidence of tumor lysis syndrome]; PO; 1.1g on all other days). Subjects who complete 24 cycles of treatment are followed every 6 months for 24 months for survival, disease status, and CMML-related therapy. The primary endpoint is the frequency of CR or PR at any time during the first 12 cycles according to Savona Criteria. Secondary endpoints include overall survival and progression-free survival at 2 years; proportion of subjects with clinical benefit at any point during the 24 cycles; impact on physical and functional capacity; social well-being according to Multidimensional Geriatric Assessment and quality of life; as well as hematological and non-hematologic safety. Results: As of December 31, 2022, eight subjects were treated with A and LENZ (5 females, mean age of 67 years; 3 males, mean age of 69 years); among them 6 were evaluable based on at least 3 months of follow-up. CR or objective responses were observed in all evaluable patients including 2 with high risk based on molecular profiling. 10 grade 3/4 Serious Adverse Events were observed of which 2 were assessed by the investigator as possibly related to LENZ. Conclusion: The ongoing PREACH-M trial evaluates GM-CSF neutralization with LENZ in addition to SOC, in the treatment of CMML with RAS pathway mutations. Citation Format: Devendra Hiwase, David Ross, Steven Lane, Agnes Yong, Kirsty Sharplin, David Yeung, Lisa Butler, Dale Chappell, Cameron Durrant, Timothy Hughes, Daniel Thomas. A phase 2/3, multicenter trial of lenzilumab and azacitidine in chronic myelomonocytic leukemia: The PREACH-M trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT085.