(P 434) A FIRST-IN-HUMAN PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF M3554, A NOVEL ANTI-GD2 ANTIBODY-DRUG CONJUGATE, IN PATIENTS WITH ADVANCED SOLID TUMORS

Objective: 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 antibodies (e.g., dinutuximab, naxitamab) are associated with severe pain adverse events (AEs), 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 antibody drug conjugate (drug-to-antibody ratio: 8) that uses a β-glucuronide linker-payload combination to selectively deliver the Top1 inhibitor, exatecan, to GD2-overexpressing tumor cells. M3554 uses a Fc-modified anti-GD2 antibody and IgG1.4 backbone designed to reduce ADCC and CDC, potentially reducing the incidence and severity of pain AEs. In preclinical studies, M3554 showed strong antitumor activity in patient-derived xenograft models of neuroblastoma, osteosarcoma, and GBM. It had a favorable 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 multicenter, open label, dose escalation (Ph1a) and expansion (Ph1b) study to evaluate the safety, PK, and clinical activity of M3554. Eligible patients (≥18 years; ECOG PS ≤1) have histopathologically-confirmed metastatic and/or locally advanced STS or GBM (IDH-wildtype). Ph1a uses a Bayesian design, with separate dose escalations in patients with STS and GBM. The Ph1a primary endpoint is evaluating dose limiting toxicities and AEs to determine the maximum tolerated dose of M3554 (if reached), to support selection of the recommended dose for expansion. Secondary endpoints are PK, objective response, duration of response, progression-free survival, and ECG assessments. In the absence of archival tissue, fresh biopsies are collected for biomarker analysis (tertiary endpoint) in the STS dose escalation. The RDE(s) established in Ph1a will be used to evaluate the safety and preliminary antitumor activity of M3554 in Ph1b. 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) in Japan, Belgium, France, and US. Clinical trial information: NCT06641908.

Results: N/A

Conclusion: N/A