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A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6.

Abstract

TPS3175
Background: B7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumors, but with little to no expression detected in normal tissues[Brandt et al. J Exp Med 2009;206.1495–503; Boehringer Ingelheim. Data on file]. BI 765049 is a novel IgG-like bispecific T-cell engager (TcE) designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent antitumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, treatment with BI 765049 led to profound infiltration of T cells into the tumor tissue, which correlated with apoptosis and tumor shrinkage. The inflammatory tumor microenvironment created by treatment with the B7-H6/CD3 TcE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells [Hipp et al. AACR Annual Meeting 2021]. This upregulation of PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor. Methods: NCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have progressed on, or be ineligible for, standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD, and preliminary efficacy of BI 765049 ± ezabenlimab. The trial will assess up to four intravenous dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in dosing); C (BI 765049 + ezabenlimab q3w). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ̃120 patients enrolled. As of January 2022, eight patients have been recruited in early dose-escalation cohorts. Clinical trial information: NCT04752215.

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Journal of Clinical Oncology
Pages: TPS3175

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Published in print: June 01, 2022
Published online: June 02, 2022

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Gerald Steven Falchook
Sarah Cannon Research Institute at HealthONE, Denver, CO;
Manish R. Patel
Florida Cancer Specialists and Research Institute, Sarasota, FL;
Susanna Varkey Ulahannan
The University of Oklahoma Health Sciences Center/Sarah Cannon Research Institute, Oklahoma City, OK;
Daniela Maier
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany;
Susanne Hipp
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT;
Hisaya Azuma
Boehringer Ingelheim International GmbH, Ingelheim Am Rhein, Germany;
David R. Spigel
Sarah Cannon Research Institute/Tennessee Oncology Nashville, PLLC, Nashville, TN;
Sarah Cannon Research Institute at HealthONE, Denver, CO; Florida Cancer Specialists and Research Institute, Sarasota, FL; The University of Oklahoma Health Sciences Center/Sarah Cannon Research Institute, Oklahoma City, OK; Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT; Boehringer Ingelheim International GmbH, Ingelheim Am Rhein, Germany; Sarah Cannon Research Institute/Tennessee Oncology Nashville, PLLC, Nashville, TN

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Boehringer Ingelheim.

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Gerald Steven Falchook, Manish R. Patel, Susanna Varkey Ulahannan, Daniela Maier, Susanne Hipp, Hisaya Azuma, David R. Spigel
Journal of Clinical Oncology 2022 40:16_suppl, TPS3175-TPS3175

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