A phase 1, first-in-human, multicenter study of ZW251, a novel glypican-3 (GPC3)–targeted antibody-drug conjugate (ADC), in participants with hepatocellular carcinoma (HCC).

TPS608 Background: GPC3 is highly expressed in HCC and in select solid tumors, with limited expression in normal tissues, making it an attractive therapeutic target. ZW251 is a novel GPC3-targeted ADC composed of a humanized IgG1 antibody covalently linked to ZD06519, a camptothecin derivative topoisomerase-I inhibitor. Preclinical studies demonstrated potent in vivo antitumor activity against a broad panel of HCC xenograft models, with a wide range of GPC3 expressions. ZW251 exhibits a favorable pharmacokinetic (PK) profile, and is well tolerated in non-human primates, suggesting a favorable hepatic safety profile in the setting of concurrent underlying liver dysfunction. Methods: This global, open-label, two-part phase 1 study, (dose escalation [Part 1] and dose optimization [Part 2]) will enroll approximately 100 participants. The study is enrolling adult participants (≥18 years) and adolescents (≥12 to <18 years, Part 1 backfill only) with locally advanced (unresectable, and ineligible for transplant), histologically or radiographically confirmed metastatic HCC (Part 1 backfill only), who have progressed on at least 1 treatment regimen which includes an approved and available PD-L1 inhibitor, and have measurable disease per RECIST 1.1, ECOG PS 0–1 or Karnofsky score ≥50% (for participants ≥16 years), or Lansky score ≥50% (for those ≥12 to <16 years), Child-Pugh Class A liver function (HCC only), adequate organ function, and a minimum life expectancy of 12 weeks. GPC3-expression will be evaluated retrospectively using archival FFPE tumor tissue or a new/fresh biopsy collected prior to enrollment. Primary objectives in Part 1 are to evaluate safety, tolerability, and to determine the maximum tolerated dose (MTD) and recommended dose(s) (RD) of ZW251. Part 2 primary objective is to identify the optimized dose and further assess safety and preliminary antitumor activity in participants with advanced HCC. Secondary endpoints in both parts include pharmacokinetics, immunogenicity, and efficacy outcomes per RECIST v1.1, including objective response rate, duration of response, and progression-free survival. In Part 1, approximately 60 participants will receive ZW251 intravenously once every 3 weeks across ~6 dose levels, starting at 3.2 mg/kg, to determine MTD and RD using Bayesian optimal interval (BOIN) design. Adolescent participants may be enrolled in backfill cohorts at dose levels determined to be safe and clinically active in adults. In Part 2, approximately 40 adults with advanced HCC will be randomized 1:1 to two dose levels selected from Part 1. The study is actively enrolling. EudraCT number: 2025-523088-39. Clinical trial information: NCT07164313 .