Abstract CT113: A first-in-human phase 1, multicenter, open-label study of M3554, a novel anti-GD2 antibody-drug conjugate (ADC), in patients with advanced solid tumors

Abstract Background: GD2 is a glycosphingolipid with limited expression in normal tissues and overexpression in various cancers, particularly neuroblastoma, glioblastoma (GBM), and several sarcoma subtypes. GD2 is a clinically validated target in pediatric neuroblastoma; however, currently approved anti-GD2 antibody treatments, such as dinutuximab and naxitamab, have been associated with severe adverse events (AEs) of pain, likely due to Fcγ receptor-mediated immune activation via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). M3554 is a first-in-class, anti GD2 ADC (drug-to-antibody ratio: 8) that uses a unique linker-payload combination, utilizing a β-glucuronide linker to selectively deliver the topoisomerase 1 inhibitor, exatecan, to GD2 overexpressing tumor cells. M3554 uses a Fc-modified anti-GD2 antibody and IgG1.4 backbone designed to reduce ADCC and abolish CDC effector functions, potentially reducing the incidence and severity of pain AEs associated with anti-GD2 antibodies without cytotoxic payloads. In preclinical studies, M3554 showed strong antitumor activity in patient-derived xenograft models of neuroblastoma, osteosarcoma, and GBM. Moreover, it had a favorable pharmacokinetic (PK) and safety profile in animal studies. We present the design of the currently active, first-in-human study of M3554 accruing patients with soft tissue sarcomas (STS) and targeting a future cohort of IDH wildtype GBM. Methods: This is a Phase 1, multicenter, open label, dose escalation (Phase 1a) and expansion (Phase 1b) study to evaluate the safety, PK, and clinical activity of M3554. Patients aged ≥18 years with histopathologically-confirmed metastatic and/or locally advanced STS or GBM (IDH-wildtype), with ECOG PS ≤1 are eligible. Phase 1a employs a Bayesian design, with separate dose escalations in patients with STS and GBM based on recommendations of a Safety Monitoring Committee. The primary endpoint in Phase 1a is the assessment of dose-limiting toxicities and AEs to determine the maximum tolerated dose(s) of M3554 (if reached), to support the selection of the recommended dose(s) for expansion (RDEs). Secondary endpoints include PK assessments, objective response, duration of response, progression-free survival, and ECG assessments. In the absence of archival tissue, fresh biopsies are being collected for biomarker analysis (tertiary endpoint) in the STS dose escalation. The RDE(s) established in Phase 1a will be used to further evaluate the safety and preliminary antitumor activity of M3554 in Phase 1b. The study is currently recruiting and aims to enroll 52 patients in the dose escalation phase and 110 patients in the dose expansion phase (STS, n=80; GBM, n=30), across different global sites including, Japan, Belgium, France, and the US. Clinical trial information: NCT06641908. Citation Format: Antoine Italiano, Kan Yonemori, Candace L. Haddox, Jordi R. Ahnert, Nicolas Penel, Patrick Schöffski, Christina Habermehl, Vanesa P. Sanz, George Demetri. A first-in-human phase 1, multicenter, open-label study of M3554, a novel anti-GD2 antibody-drug conjugate (ADC), in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT113.