Background: Activation of the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via the extrinsic pathway. Targeting TRAILR2 presents an attractive therapeutic strategy, but some early TRAILR2 agonists showed low efficacy or severe hepatotoxicity. BI 905711 (TRAILR2 agonist) is a novel, liver-sparing, tetravalent bispecific antibody that cross-links TRAILR2 with the membrane protein cadherin 17 (CDH17; highly expressed in GI cancers), inducing CDH17-dependent TRAILR2 oligomerization. CDH17 is not expressed in normal hepatocytes, thus increasing BI 905711 selectivity to GI cancer cells while sparing hepatocytes. Preclinical models and studies in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) showed BI 905711 activity ± CT, and synergy with standard of card CT irinotecan, respectively. Methods: This Phase Ia/Ib, open-label, multicenter study (NCT05087992) aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), and efficacy of BI 905711 with CT (FOLFIRI; irinotecan, leucovorin, and fluorouracil) ± bevacizumab (BEV) in pts with advanced GI cancers. Up to 100 pts with histologically/cytologically confirmed, advanced, unresectable, or metastatic GI cancers will be enrolled. In Phase Ia, ~20 pts with CRC will receive BI 905711 intravenously every two weeks at escalating doses (starting dose 0.6 mg/kg) on Day 3 of 14-day cycles, + FOLFIRI and BEV (5 mg/kg intravenous infusion for 30 minutes) on Day 1. A Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) during the MTD evaluation period (first 2 cycles) will guide BI 905711 dose escalation. BI 905711 will be administered until disease progression, unacceptable toxicity, or other reasons requiring treatment discontinuation. In Phase Ib, pts with CRC or PDAC will be enrolled to one of two dose expansion cohorts. In the CRC cohort, pts with prior progression on oxaliplatin-based therapy will be randomized 2:1 to receive FOLFIRI and BEV ± BI 905711. In the PDAC cohort, pts with CDH17+ PDAC with prior progression on gemcitabine-based first-line therapy will receive FOLFIRI + BI 905711. Both cohorts will receive BI 905711 at the RDE defined in Phase Ia. A safety run-in period will confirm the Phase Ia RDE result before enrolling pts to the PDAC cohort. Primary endpoints: MTD based on incidence of DLTs (Phase Ia) and confirmed objective response (OR; RECIST 1.1; Phase Ib). Secondary endpoints include PK assessments (Phase Ia), progression-free survival, tumor shrinkage, duration of OR, and disease control (Phase Ib). Further endpoints include immunogenic response assessment and pharmacodynamic biomarker modulation. As of September 2022, eight pts have been enrolled; one additional pt is in screening. The study is ongoing. Clinical trial information: NCT05087992.