A phase Ia/Ib, open-label, dose escalation study of the TRAILR2 agonist BI 905711 in combination with chemotherapy (CT) in patients (pts) with advanced GI cancers.

作者：Scott Kopetz, Eric Van Cutsem, Yasutoshi Kuboki, Benny Johnson, Tetsuya Katakabe, Min He, Shorena Archuadze, Lin Shen · 发表于：Journal of Clinical Oncology · 年份：2023 · DOI：10.1200/jco.2023.41.4_suppl.tps820 · 被引用次数：2 · 研究领域：Cancer Research and Treatments、Cell death mechanisms and regulation

TPS820 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 ...