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A phase Ia/Ib, open-label, dose-escalation study of the TRAILR2 agonist BI 905711 in combination with chemotherapy in patients with advanced gastrointestinal cancers
Background
Activation of the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via the extrinsic pathway. Targeting TRAILR2 is therefore an attractive therapeutic strategy in oncology, but some early TRAILR2 agonists showed limited clinical success due to low efficacy or severe hepatotoxicity. The tetravalent bispecific antibody BI 905711 represents a novel, liver-sparing, TRAILR2 agonist, which cross-links TRAILR2 with cadherin 17 (CDH17) to induce CDH17-dependent TRAILR2 oligomerisation. CDH17, a membrane protein highly expressed in gastrointestinal (GI) cancers, is not expressed in normal hepatocytes. Thus, using CDH17 as a liver-sparing anchor may avoid hepatotoxicity while increasing selectivity to cancer cells. In preclinical models of GI cancer, including colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), BI 905711 showed activity both as a single agent and in combination with chemotherapeutic agents (Garcia-Martinez et al., Mol Cancer Ther 2021;20:96–108). Preclinical studies also showed synergism of BI 905711 and SoC chemotherapy, particularly irinotecan.
Trial design
This phase Ia/Ib open-label, multicentre study (NCT05087992) aims to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE), pharmacokinetics (PK), and preliminary efficacy of BI 905711 in combination with chemotherapy (FOLFIRI; irinotecan, leucovorin, and fluorouracil) with or without bevacizumab in patients with advanced, refractory GI cancers. Up to 100 patients with histologically or cytologically confirmed, advanced, unresectable or metastatic GI cancers will be enrolled. In phase Ia, approximately 20 patients with CRC will receive intravenous BI 905711 at escalating doses (starting dose 0.6 mg/kg) on day 3 of 14-day cycles, plus FOLFIRI and bevacizumab (5 mg/kg IV infusion over 30 mins) on day 1. BI 905711 dose escalation will be guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) during the MTD evaluation period (first two 14-day cycles). BI 905711 will be administered until disease progression, unacceptable toxicities or another reason requiring treatment discontinuation. In phase Ib, patients with CRC or PDAC will be enrolled to one of two dose expansion cohorts. In the CRC cohort, patients who have progressed after prior oxaliplatin-based therapy will be randomised in a 2:1 ratio to receive FOLFIRI and bevazicumab with or without BI 905711. In the PDAC cohort, patients with CDH17-positive PDAC who have progressed after prior platin/gemcitabine-based first-line therapy will receive FOLFIRI plus BI 905711. In both cohorts, BI 905711 will be administered at the RDE determined in phase Ia. A safety run-in will be included in the PDAC cohort to confirm the RDE defined in phase Ia prior to enrolling further patients. Primary endpoints are the MTD based on the occurrence of DLTs (phase Ia), and confirmed objective response (OR) according to RECIST 1.1 (phase Ib). Secondary endpoints include PK assessments (phase Ia), progression-free survival, tumour shrinkage, duration of OR and disease control (phase Ib). Further endpoints include assessment of immunogenic response and pharmacodynamic biomarker modulation (including caspase activation and changes in circulating tumour DNA levels). Patient recruitment is active and the study is ongoing.
Clinical trial identification
NCT05087992.
Editorial acknowledgement
Medical writing assistance, supported financially by Boehringer Ingelheim Pharmaceuticals Inc., was provided by Jane Saunders of Ashfield MedComms, an Ashfield Health Company, during the preparation of this abstract. The authors received no direct payment.
Legal entity responsible for the study
Boehringer Ingelheim.
Funding
Boehringer Ingelheim.
Disclosures
S. Kopetz: Advisory / Consultancy: Roche, Redx Pharma, Jacobio, Merck, Navire Pharma, Holy Stone, Biocartis, Natera, Karyopharm Therapeutics, Repare Therapeutics, Genentech, Lilly, AstraZeneca/MedImmune, EMD Serono, Daiichi Sankyo, Amal Therapeutics, Boehringer Ingelheim, Bayer Health, Lutris, Pfizer, Amgen, Pierre Fabre, Symphogen, Novartis, Boston Biomedical, Ipsen, HalioDx, Inivata, GSK, Jazz pharmaceuticals Iylon, Xilis, Abbvie, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotechnology, Bicara Therpeutics, Endeavor BioMedicines, Numab Pharma, Johnson & Johnson/Janssen, Genomic Health, Fro; Research grant / Funding (self): Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/ Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, Daiichi Sankyo; Shareholder / Stockholder / Stock options: MolecularMatch, Frontier Medicines, Lutris, Iylon. E. Van Cutsem: Advisory / Consultancy: Abbvie, Array, Astellas, Astrazeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seattle Genetics, Servier, Sirtex, Terumo, Taiho, TRIGR, Zymeworks ; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier . Y. Kuboki: Honoraria (self): Taiho, ONO, Bayer, Sanofi, ; Advisory / Consultancy: Takeda, Boehringer Ingelheim, Taiho; Research grant / Funding (institution): Taiho, Takeda, ONO, Abbie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen,Chugai, GSK, Genmab, Astelas, Daiichi-Sankyo. T. Katakabe: Full / Part-time employment: Nippon Boehringer Ingelheim Co., Ltd.. J. Geng: Full / Part-time employment: Boehringer Ingelheim; Spouse / Financial dependant: Boehringer Ingelheim, Boehringer Ingelheim, Boehringer Ingelheim. S. Archuadze: Full / Part-time employment: Boehringer Ingelheim, Boehringer Ingelheim, Boehringer Ingelheim. L. Shen: Advisory / Consultancy: BMS/AstraZeneca/BI/MSD/Daiichi Sankyo/Roche; Research grant / Funding (institution): Yaojie Ankang (Nanjing) Technology Co., Ltd./QiLu Pharmaceutical, Baiji Shenzhou (Beijing) Biotechnology Co., Ltd/Zaiding Pharmaceutical, Beijing Xiantong Biomedical Technology Co., Ltd. The author has declared no conflicts of interest.
