Abstract CT156: Phase 1 dose-optimization study evaluating the safety of ginisortamab (UCB6114), an anti-gremlin-1 monoclonal antibody (mAb) with first-in-class potential, as monotherapy in advanced solid tumors

Abstract Background: Gremlin-1, secreted by cancer-associated fibroblasts and tumor cells, represses bone morphogenetic protein (BMP) expression, enhancing tumor stemness, proliferation, and invasiveness. Ginisortamab blocks gremlin-1-BMP binding, restoring BMP 2, 4, and 7 signaling, and downstream SMAD pathway activation. Blocking gremlin-1 shows antitumor activity in preclinical models, including colorectal and pancreatic cancer. ONC001 (NCT04393298) is a first-in-human, nonrandomized, open-label, Phase 1/2 study assessing ginisortamab ± standard of care (SoC) in advanced solid tumors; results from Part A (monotherapy dose-escalation) have been reported previously.1 Methods: We present primary (safety), secondary (pharmacokinetics), and exploratory (biomarker, efficacy) endpoints from Part A1 (monotherapy dose-optimization); patients (pts) were aged ≥18 years with advanced disease resistant or refractory to SoC; ginisortamab was administered as 1 of 4 intravenous dose schedules (2000 mg Q2W 30- or 60-min infusion, 4000 mg Q4W 120-min, 28-day cycle; 3000 mg Q3W 90-min 21-day cycle). Results: In total, 32 pts received ≥1 ginisortamab dose (n=8 for each dose schedule); median age 63 (39-82) years, 59% male, median prior anti-cancer therapies 3.5 (1-8); most common tumor type colorectal adenocarcinoma (81%). There were no DLTs. At 4000 mg Q4W, one pt had two serious treatment-related adverse events (grade 3 hypoxia, grade 2 thromboembolic event) and two pts discontinued the study due to treatment-emergent adverse events (TEAEs) unrelated to ginisortamab (large intestine perforation, biliary obstruction). At 2000 mg Q2W (30-min infusion), three pts had TEAEs leading to temporary interruption to infusion and/or delay in next dose (anemia, vascular device infection, back pain, dysuria). There were no unexpected safety signals in dose schedules tested. Ginisortamab and associated gremlin-1 concentrations aligned with expectations based on Part A.1 Immunohistochemistry analysis of baseline biopsies suggested high tissue gremlin-1 expression. Baseline pSMAD1/5/8 staining showed high intra-/inter-patient variability with no consistent increase in staining observed in paired post-treatment biopsies. RNA-Seq analysis of paired biopsies found transcriptional changes consistent with increases in BMP-driven inhibitor of DNA binding genes (ID1, ID3) expression. A best objective response of stable disease occurred in 5/32 pts; all had high baseline tissue gremlin-1 expression. Conclusions Safety, PK, biomarker, and efficacy data presented here support the flexibility to utilize different ginisortamab schedules with combination SoC partner regimens and current ongoing studies. 1. Sarker D, et al. Cancer Res 2023;83(8_Supplement) Citation Format: Debashis Sarker, Toros A. Dincman, Ruth Plummer, Udai Banerji, Natalie Cook, Heinz-Josef Lenz, Mark White, Elodie Garric, Paul Jones, Joanne Mann, Ivan Matthews, Abdul (Moe) Muhith, Sarah P. Blagden, on behalf of ONC001 Study Group. Phase 1 dose-optimization study evaluating the safety of ginisortamab (UCB6114), an anti-gremlin-1 monoclonal antibody (mAb) with first-in-class potential, as monotherapy in 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 CT156.