A first-in-human phase Ia/b, open-label, multicenter study of the TRAILR2 agonist BI 905711 in patients (pts) with advanced gastrointestinal (GI) cancers.
Authors: Harding James J. , Hofheinz Ralf-Dieter , Elez Elena , Kuboki Yasutoshi , Rasco Drew W. , Cecchini Michael , Shen Lin , Dowling Elizabeth , Archuadze Shorena , de Pereira Bruna Andrade , Pant Shubham 
Published: January 2022

TPS222 Background: Activation of the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via caspase activation. Targeting TRAILR2 is an attractive therapeutic strategy, but some early TRAILR2 agonists were associated with severe hepatotoxicity. Cadherin 17 (CDH17), a membrane protein highly expressed in GI cancers, is not expressed in normal hepatocytes so using CDH17 as a liver-sparing anchor may avoid hepatotoxicity. BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17 to induce CDH17-dependent TRAILR2 oligomerisation. In preclinical assays, BI 905711 demonstrated a potency shift of ̃1000 fold versus the 1st-generation TRAILR2 agonist lexatumumab. BI 905711 induced apoptosis in CDH17-positive tumor cells in vitro, impaired tumor growth in pt-derived colorectal cancer (CRC) xenografts, and no hepatotoxicity was observed. Methods: This phase Ia/Ib study (NCT04137289) aims to determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 905711 in pts with advanced, refractory GI cancers. Up to 140 adult pts with histologically confirmed, advanced unresectable/metastatic colorectal, gastric, esophageal or pancreatic adenocarcinoma, cholangiocarcinoma, or gallbladder or small intestine carcinoma, who have progressed on standard-of-care therapies, will be enrolled. In phase Ia, pts will receive intravenous BI 905711 at escalating doses (range 0.02–4.8 mg/kg) every 14 days, until disease progression or unacceptable toxicities. Dose escalation will be guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) in the first 28 days. In phase Ia, a minimum number of CRC pts will be enrolled to each cohort: ≥1 CRC pt at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts at each subsequent dose level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). In parallel to dose escalation in CRC pts, up to 4 pts with non-CRC GI cancers will be included at the dose level below that of the CRC cohort. If an objective response (OR) per RECIST v1.1 is observed in CRC or non-CRC GI pts at a safe dose level, up to 10 additional pts with the same tumor type will be recruited at that dose level. In phase Ib, CRC pts will be randomized into up to 4 dose cohorts (as determined in phase Ia; n=20 each) to define the recommended phase II dose. The primary endpoints are determination of the MTD based on the proportion of pts with DLTs (phase Ia) and OR rate based on RECIST v1.1 (phase Ib). Secondary endpoints include PK parameters and OR in pts with measurable disease (phase Ia), and disease control, tumor shrinkage, duration of response, and progression-free survival (phase Ib). Trial enrollment is ongoing, with 33 pts enrolled to date. Clinical trial information: NCT04137289.