Abstract CT121: A phase 1/2a, multicenter, open-label, first in human study of a bispecific ADC targeting B7H3 and PDL1 (DB-1419) in advanced or metastatic solid tumors

Abstract Background: Both B7H3 and PD-(L)1 are highly expressed in various solid tumors, including lung cancer, hepatocellular cancer, breast cancer, melanoma, and many others. Dual blockade of B7H3 and PD-(L)1 improved antitumor activity compared to either agent alone. However, no bispecific antibodies targeting both PD-(L)1 and B7H3 are in clinical development. DB-1419 is a bispecific antibody-drug conjugate (ADC) comprised of a humanized anti-B7H3/PD-L1 IgG1 antibody covalently linked to a proprietary DNA topoisomerase I inhibitor (P1003) via a cleavable linker containing maleimide tetrapeptide, with a drug-to-antibody ratio of approximately 8. Preclinical studies demonstrated that DB-1419 exhibited both direct cancer cell killing and immune-modulating functions. These studies warrant further clinical development of DB-1419. Methods: This is a multicenter, open-label, multiple-dose, first-in-human Phase 1/2a study (NCT06554795) to assess the safety, tolerability, and anti-tumor activities of the study drug DB-1419 in participants with pretreated advanced/metastatic solid tumors unselected for B7H3/PD-L1 expression. The trial is planned to enroll 360 participants from the United States, Australia, and China (90 in Phase 1a and 270 in Phase 1b/2a). In phase 1a (the dose escalation part), participants who have previously treated, histologically confirmed, unresectable advanced/metastatic solid tumors will be enrolled to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D). Approximately six ascending dose levels of DB-1419 (accelerated titration design for the first dose level and “3+3” design for other dose levels) will be administrated by intravenous infusion. When a dose level is confirmed to be safe by the Safety Monitoring Committee (SMC), backfill participants may be enrolled to further evaluate the safety, tolerability, preliminary efficacy, and PK characteristics. Phase 1b/2a (the dose expansion part) will initiate with selected indications (e.g., small cell lung cancer [SCLC], hepatocellular cancer, and non-small cell lung cancer) randomized to one of two different dose levels for dose optimization. Five other cohorts will enroll participants with melanoma, esophageal squamous cell carcinoma, triple-negative breast cancer, extensive-stage SCLC who have received 4 cycles of first-line induction therapy without disease progression, and other solid tumors to further assess the safety and tolerability, antitumor activity, and other exploratory endpoints of DB-1419. The study is currently open in multiple centers and is on recruiting. As of Dec 05, 2024, four participants have been enrolled in Australia and the United States. Enrollment in China is scheduled to commence in March 2025. Citation Format: Shun Lu, Charlotte Lemech, Afaf Abed, John Powderly, Stephen V. Liu, Ziming Li, Li Jiang, Wei Gu, Qiqi Liu, Lianghua Fang, Yang Qiu, Rong Shi, Yujie Liu. A phase 1/2a, multicenter, open-label, first in human study of a bispecific ADC targeting B7H3 and PDL1 (DB-1419) in advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT121.