A phase 1/2, first-in-human study of an ADC targeting CDH17 (DB-1324) in participants with advanced/metastatic gastrointestinal tumor

Background: Cadherin-17 (CDH17), belonging to a subclass of the 7D-cadherin superfamily, is a biomarker for gastrointestinal (GI) cancers characterized by its overexpression in multiple GI cancers but controlled expression in normal tissues from healthy adults. CDH17 is therefore considered a possible therapeutic target for GI cancers. DB-1324 is an anti-CDH17 antibody-drug conjugate (ADC) in which a humanized antibody is linked to a proprietary topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker, with a drug-antibody ratio of approximately 8. Preclinical studies of DB-1324 showed that DB-1324 specifically binds to the CDH17 extracellular domains, with no binding to other cadherin family proteins. It demonstrated antitumor activity in human CDH17-positive murine cancer models and an acceptable safety profile, warranting further clinical development. Methods: This is a global, first-in-human, Phase 1/2 study to assess the safety, tolerability, pharmacokinetics, and antitumor activity of DB-1324 in participants with advanced/unresectable, or metastatic GI tumors (NCT07263594). Eligible participants must have a GI tumor (regardless of CDH17 or other biomarker expression levels) that has relapsed or progressed on or after standard systemic treatments, or is intolerable with standard treatment, or for which no standard treatment is available; have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1; and evidence adequate organ function. Multiple dose levels of DB-1324 will be evaluated to identify the maximum tolerated dose in Phase 1, which includes Dose Escalation, Backfill, and Dose Expansion. Phase 2 will consist of one or more cohorts intended to confirm early signals of efficacy identified in Phase 1. DB-1324 will be administered intravenously as monotherapy until disease progression, loss of clinical benefit, unacceptable toxicity, withdrawal of consent, or loss to follow up. The study plans to enroll approximately 127 participants in Phase 1 Dose Escalation and Backfill parts from locations including but not limited to Australia, United States and China. The study is currently open in multiple centers and is currently recruiting.