Abstract CT248: First in human trial of DB1305 in patients with advanced malignant solid tumors
Authors: Ueno Naoto T. , Gao Jie , Liu Liming , Shi Rong , Liu Shengxue , Tang Lili , Miao Peizhen , Qiu Yang , Gu Wei , Ying Cheng 
Published: April 2023

Abstract
Background: Trophoblast cell-surface antigen 2 (Trop-2) is known as tumor-associated calcium signal transducer 2 (TACSTD2) and plays a role in tumor progression, given its active interplay with several key molecular pathways associated with cancer development and progression. DB-1305 is a Trop-2 antibody-drug conjugate (ADC) composed of a humanized anti-Trop-2 immunoglobulin G1 (IgG1) monoclonal antibody, covalently linked to a proprietary DNA topoisomerase I inhibitor P1021 via a cleavable linker containing maleimide tetrapeptide, with a drug-to-antibody ratio (DAR) of approximately 4. Preclinical in vivo models show that DB-1305 demonstrates robust anti-tumor activity in Trop-2-high triple-negative breast cancer (TNBC), Trop-2-low small cell lung cancer (SCLC) and Trop-2-medium colon cancer but not Trop-2-negative SCLC, demonstrating the dependence of Trop-2 expression for the tumor-suppression activity of DB-1305 and appropriate safety profile supports the intended clinical use. This study aims to evaluate DB-1305 in terms of tolerability and preliminary anti-tumor activity in patients with advanced solid tumors.
Methods: This is an open-label, multicenter, multiple-dose, Phase 1/2a study (NCT05438329), including dose escalation Phase 1 and dose-expansion Phase 2a in patients with pretreated advanced solid tumors. Patients should have histologically documented progressed/refractory disease on or after standard systemic anticancer treatments with proven benefits for their disease or without available standard treatments; adequate performance score (ECOG 0-1); adequate organ function and measurable disease as per RECIST v1.1 while without uncontrolled metastatic central nervous system (CNS) involvement and history of interstitial lung diseases. The dose escalation part will evaluate approximately five ascending dose levels of DB-1305 with accelerated titration for the first dose level followed by a “3+3” design for subsequent dose levels to identify the optimal dose, which will enroll up to 70 patients from the United States and China. Upon determining the optimal dose, seven tumor cohorts of 10-40 patients will be included in the dose expansion part, including non-small cell lung cancer, SCLC, hormone receptor-positive breast cancer, and TNBC. DB-1305 will be dosed in both parts until disease progression, clinical deterioration, withdrawal of consent, or unacceptable toxicity. The primary objectives are evaluating safety tolerability and identifying the optimal dose from Phase 1; assessing safety, tolerability, and objective response rate per RECIST v1.1 from Phase 2a. Secondary objectives include the assessment of the pharmacokinetics and immunogenicity of DB-1305. Exploratory objectives include the assessment of pharmacodynamic biomarkers and Exposure-Response correlation. As of 19 Dec 2022, 20 patients have been enrolled in the dose escalation part.
Citation Format: Naoto T. Ueno, Jie Gao, Liming Liu, Rong Shi, Shengxue Liu, Lili Tang, Peizhen Miao, Yang Qiu, Wei Gu, Cheng Ying. First in human trial of DB1305 in patients with advanced malignant solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT248.