P-169 A first-in-human phase Ia/b, open-label, multicentre, dose-escalation study of BI 905711 in patients with advanced gastrointestinal cancers

Activation of the tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via caspase activation. Hence, targeting TRAILR2 is an attractive therapeutic strategy; however, early trials of TRAILR2 agonists resulted, in some cases, in severe hepatotoxicity that may have been due to TRAILR2 activation on hepatocytes. Cadherin 17 (CDH17), a membrane protein highly expressed in gastrointestinal (GI) cancers, is not expressed in normal hepatic cells. Thus, the hepatotoxicity of prior TRAILR2 agonists may be avoided through crosslinking with CDH17. BI 905711 is a tetravalent bispecific antibody targeting both TRAILR2 and CDH17 that demonstrated a potency shift of ∼1000 fold compared with previously described TRAILR2-binding agents. In pre-clinical assays, BI 905711 induced apoptosis in CDH17-positive tumour cells in vitro, impaired tumour growth in patient-derived colorectal cancer (CRC) xenografts, and was not associated with hepatic toxicity (Garcia-Martinez J-M. AACR 2019, ENA 2018). This is an international, phase Ia/Ib, first-in-human trial of BI 905711 in patients with treatment-refractory GI cancers (NCT04137289). Eligibility includes histologically-confirmed unresectable/metastatic CRC, gastric, oesophageal, pancreatic adenocarcinoma or cholangiocarcinoma progressing on standard of care therapies; adequate hepatic, renal and bone marrow functions; age ≥18 years, ECOG PS ≤1; and for phase Ib only, CRC with ≥1 lesion site evaluable per RECIST v1.1. The starting dose of BI 905711 is 0.02 mg/kg every 14 days intravenously. Treatment will continue until disease progression or unacceptable toxicities. CRC patients will be recruited as mandatory cohorts in phase Ia that will include 1 patient at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 patients at each subsequent dose level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). Dose escalation will proceed sequentially assuming no dose-limiting toxicities (DLTs) in the first 28 days of treatment. In parallel to the dose escalation in CRC patients, up to 4 patients with non-CRC GI cancers may be included at the dose level below that of the CRC cohort. In phase Ia, a Bayesian logistic regression model will be applied to determine the next dose levels in the CRC and non-CRC cohorts, and evaluate the maximum tolerated dose (MTD). In addition, a dose range will be selected based on efficacy signals. In phase Ib, patients with CRC will be randomised into up to four dose cohorts of up to 20 patients each in a 2-stage design (10 patients at stage 1) to define the recommended phase II dose. If an objective response (OR) is observed in a particular tumour type in phase Ia, the dose cohort will be increased to up to 10 patients with the same tumour type. In phase Ia, the MTD (primary endpoint) will be determined based on the proportion of patients with DLTs as assessed by CTCAE v.5.0. Secondary endpoints include pharmacokinetic parameters and OR in patients with measurable disease. For phase Ib, the primary endpoint is OR, and secondary endpoints include tumour shrinkage, duration of response, and progression-free survival. CDH17 expression (immunohistochemistry) and other biomarkers will also be evaluated. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Jim Sinclair of GeoMed, an Ashfield Company, part of UDG Healthcare plc. The authors. Boehringer Ingelheim.