A combined phase I/II study of a novel bicycle tumor-targeted immune cell agonist BT7480 in patients with nectin-4 associated advanced malignancies.

TPS2689 Background: BT7480 is a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist ( Bicycle TICA) that co-ligates cluster of differentiation (CD)137 (on immune cells) and Nectin-4 (on tumor cells). BT7480 comprises 3 bicyclic peptides ( Bicycles), 1 that binds to Nectin-4 and 2 that bind to CD137. The Bicycles are conjugated via a branched trimeric polyethylene glycol linker. Co-ligation of Nectin-4 and CD137 by BT7480 is hypothesized to induce oligomerization and activation of CD137 resulting in a tumor-localized costimulatory signal that leads to an antitumor response in preclinical studies. Nectin-4 is reported to be highly expressed in numerous tumors with unmet medical need including bladder, pancreas, breast, ovary, esophagus, head and neck, stomach, and lung cancers. Many of these tumor types also contain CD137 expressing cells. BT7480 exhibited a favorable preclinical profile supporting initiation of a first-in-human study to investigate safety and efficacy in indications with evidence of Nectin-4 expression. Methods: BT7480-100 (NCT05163041) is a PhI/II study to evaluate safety and tolerability of BT7480 administered as an intravenous infusion QW in a 28-day cycle, and to determine a recommended Phase 2 dose to further explore efficacy and safety. Patients will be recruited with advanced solid tumors associated with Nectin-4 expression including urothelial; head and neck squamous cell; non-small cell lung; ovarian, breast, gastric or esophageal carcinoma after exhausting standard of care options. Patients must have available tumor tissue, acceptable hematologic and other critical organ function. Exclusion criteria include uncontrolled brain metastases, uncontrolled hypertension, significant history of autoimmune disease and prior CD137 targeted therapy. Pharmacokinetic and pharmacodynamic analyses will be performed to support dose escalation decisions and increase the understanding of safety and clinical activity signals observed during the study. Tumor response will be assessed per RECIST every 8 weeks. Cohorts 1 and 2 have been completed without DLT. Enrollment in cohort 3 began in January 2022. Clinical trial information: NCT05163041.