CRUK: Phase II trial of ginisortamab with (1) 1st-line gemcitabine + nab-paclitaxel (AG) or (2) MEK inhibitor as maintenance therapy in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).

TPS793 Background: mPDAC has a poor prognosis with a median overall survival < 1 year with chemotherapy. Gremlin-1, secreted by cancer-associated fibroblasts and tumor cells, represses bone morphogenetic protein (BMP) signalling, thereby promoting proliferation and invasiveness. GREM1 mRNA is detected in the stroma of approximately 70% of PDAC cases. Gremlin-1 protein expression correlates with poor prognosis in PDAC. In pre-clinical models, Ab7326 (murine version of ginisortamab), blocks gremlin-1 BMP binding, restores BMP-2, 4, & 7 signalling and downstream SMAD pathway activation, and increases survival in the gremlin-1 expressing KPC murine model of PDAC in combination with either gemcitabine or MEK inhibition. Ginisortamab, a fully humanised IgG monoclonal antibody, was well tolerated when administered as monotherapy by intravenous (IV) infusion on days 1 & 15 of a 28-day cycle in pts with advanced refractory cancers in a first-in-human ONCO01 study (https://clinicaltrials.gov/study/NCT04393298). Methods: Phase II multi-centre study (UK, Norway, Spain, Germany) with safety run-in and dose expansion (proof of concept) in 2 modules in pts with mPDAC, ECOG ≤ 1, adequate organ function, RECIST1.1 measurable disease. Module 1 (no prior chemotherapy for mPDAC): non-randomised exploratory efficacy study (n = 60) with primary outcomes of progression-free survival (PFS) and disease control rate (DCR) at 16 weeks. Pts receive ginisortamab 2000mg IV infusion on days 1 & 15 with AG (standard doses) IV on days 1, 8, 15 (28-day cycle). Radiological assessment (RECIST1.1), QoL, CA19-9 every 8 weeks. PK collected days 1, 2, 4, 8, 15, 16, 18, 22 (cycle 1), days 1, 8, 15 (cycle 2) and pre-infusion days 1, 15 other cycles (safety run-in pts). Mandatory pre- and on-treatment (cycle 2 day 8 +/- 5 days) tumor biopsy to include SMAD4 and gremlin-1 expression (all pts). Module 1 commenced recruitment Q2 2024. Module 2: mPDAC (n = 60) with ongoing stable disease or response after ≥ 16 weeks of standard of care 1 st -line chemotherapy, randomised 2:1 to ginisortamab (IV days 1, 15) + MEK inhibitor vs observation with primary outcome of PFS. Module 2 is planned to commence in Q3 / Q4 2025. This study is funded and sponsored by Cancer Research UK in collaboration with UCB. The EU CT Number is 2024-514129-43, and the IRAS Identifier is 1007925. Clinical trial information: NCT04393298 .