A phase 1b/2, multicenter, open-label study to evaluate the efficacy and safety of GSK5764227 (GSK’227), alone and in combination in patients with previously treated advanced unresectable or metastatic gastrointestinal solid tumors.

TPS264 Background: B7-homolog 3 protein (B7-H3), an immune checkpoint protein, is overexpressed in many types of solid tumors but has limited expression in normal tissues. B7-H3 expression is correlated with tumor progression, metastasis, and poor clinical outcomes across various malignancies. GSK’227 (HS-20093) is a novel antibody-drug conjugate composed of a fully human anti–B7-H3 monoclonal antibody linked to a topoisomerase I inhibitor via a protease-cleavable linker. GSK’227 has shown acceptable safety and promising antitumor activity in an Asian patient (pt) population with advanced solid tumors (NCT05276609; NCT05830123). This study (NCT06885034) will first assess GSK’227 as monotherapy for efficacy, safety, tolerability, PK, and immunogenicity and subsequently in combination therapy, in pts with previously treated advanced, unresectable, gastrointestinal (GI) solid tumors, in a global population. Methods: This Phase 1b/2, open-label, multicenter study will assess early efficacy and safety signals of GSK’227 in pts with advanced, unresectable GI solid tumors. The study will include Cohort A, evaluating two doses (1:1 randomization) of GSK’227 administered 3-weekly (Q3W) in pts with advanced, unresectable colorectal cancer (CRC, sub-cohort CRC-A). The study will also assess two additional doses (1:1 randomization) administered 2-weekly (Q2W) (sub-cohort CRC-B). In parallel, Cohort B will assess a single Q3W dose of GSK’227 in pts with advanced, unresectable pancreatic ductal adenocarcinoma (PDAC). The study has two parts per cohort. Part 1 involves signal seeking (and dose optimization for CRC only) and an optional extension, in which GSK’227 is evaluated as monotherapy. Subsequently, Part 2 (expansion) may evaluate combination treatments with GSK’227. The optional extension component and the expansion part will be guided by the totality of emerging data . Eligible adults must have histologically confirmed advanced, unresectable CRC or PDAC, 1–2 lines of prior treatment (only 1 for PDAC), and ECOG PS of 0–1. Part 1’s primary endpoint is confirmed ORR. Secondary endpoints include unconfirmed ORR, DoR, PFS, safety/tolerability, PK, immunogenicity, and pt-reported AEs/tolerability. Efficacy will be assessed per RECIST v1.1, with imaging every 6 weeks (±7 days) from date of randomization (sub-cohorts CRC-A and CRC-B) or first dose (cohort B) for the first 48 weeks, and then every 12 weeks (±7 days) thereafter. Safety follow-up will be assessed at 30 (±3), 60 (±7), and 90 (±7) days after the last dose. Safety, tolerability, and efficacy analyses will be summarized descriptively; efficacy analyses will also include point estimates with 2-sided 95% CIs. Clinical trial information: NCT06885034 .