Safety, tolerability and efficacy of mesutoclax to treat patients with myeloid malignancies

Abstract Background :Venetoclax has been approved for the treatment of newly diagnosed acute myeloid leukemia (AML) in elderly or unfit patients. Although venetoclax has demonstrated clinical benefits, its application has also encountered challenges related to safety concerns, short treatment duration and overall survival as reported in real world settings. Mesutoclax is a novel, potent, highly selective BCL-2 inhibitor. It exhibits favourable pharmacokinetic profile without any major metabolites. Mesutoclax have deomontrated good safety profile and encouraging efficacy in patients with B-cell malignancies. Methods:ICP-CL-01205 (NCT06656494) is an ongoing, global, phase I study evaluating mesutoclax in combination with azacitidine (AZA) in patients with AML or myelodysplastic syndromes (MDS). Patients with unfit TN AML, or with relapsed or refractory (R/R) AML were included. In the AML dose escalation cohort, 3 dose regimens (100 mg, 125 mg, and 150 mg administered on 28-day treatment schedules) are being evaluated. Dose-limiting toxicities (DLTs) are assessed during Cycle 1. Recommeded dose for expansion are being evaluated in AML patients. Antitumor activity in AML is assessed based on the European Leukemia Net 2017 response criteria. Herein, we report safety, tolerability and efficacy for mesutoclax + AZA in pts with AML in this phase 1 study. Results: As of 21 July, 2025, a total of 24 subjects with AML were enrolled including 5 relapsed/refractory and 19 newly diagnosed (ND) patients. 18 remain on treatment. The median age of patients was 61.5 years (range, 35-81). 83.3% of patients experienced Grade ≥3 cytopenia at baseline. 50% patients were at adverse risk per 2017 ELN. Among the 10 ND subjects, 7 achieved composite CR (CR+CRi, cCR%: 70%) and 57% patients with remission were MRD negative after the first cycle of treatment. 60% cCR% was achieved in adverse risk per 2017 ELN classification. The 6-month OS rate is 100%. There is no DLT or TLS events, and no deaths occurred during the whole study. The most common (≥20%) grade ≥3 TEAEs were white blood cell decreased, neutropenia , thrombocytopenia (45.4%) and anemia; Patients experienced fast recovery of neutropenia and thrombocytopenia following remission. No TEAEs lead to dose discontinuation. Only 2 SAEs were reported. Summary/Conclusion:In the phase 1 study ICP-CL-01205, the combination of mesutoclax and AZA demonstrated well tolerated safety profile and encouraging antitumor activity, which supports the future development to address the unmet medical needs for myeloid malignancies patients.