Abstract Background: ZL-1310, a novel antibody-drug conjugate (ADC) targeting delta-like protein 3 (DLL3) with a camptothecin derivative as its payload via a protease-cleavable linker, employs TMALIN® (Tumor Microenvironment Activable LINker-payload) ADC technology platform. DLL3, an inhibitory Notch pathway ligand and a validated target for directed therapy, is highly expressed in more than 80% of patients with small cell lung cancer (SCLC) and also has variable expression in other neuroendocrine (NE) tumors. There remains an unmet medical need for 2nd-line SCLC, as the standard of care chemotherapy has a modest response rate of ~25%. ZL-1310 is designed to minimize payload toxicity and improve anti-tumor effectiveness. Methods: This is an open-label, multiple-dose, phase 1 study of ZL-1310 administered to subjects with relapsed/refractory (r/r) metastatic SCLC who have progressed after at least one platinum-based chemotherapy regimen. The study consists of two parts: Part 1 (dose escalation) and Part 2 (dose expansion). In Part 1, the Bayesian optimal interval (BOIN) design is employed for dose escalation, while in Part 2, patients will be randomized into two cohorts with different doses of ZL-1310 to further define safety and preliminary antitumor activity. The major inclusion criteria are as follows: (1) Subjects must have histologically or cytologically confirmed metastatic or extensive-stage SCLC with no more than 3 prior regimens in the r/r setting. (2) Subjects must have at least one measurable target lesion as defined by RECIST v1. 1. (3) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The major exclusion criteria include: (1) Prior exposure to DLL3-targeted therapy. (2) Subjects with symptomatic or uncontrolled brain metastasis requiring concurrent treatment, impaired major organ functions, active autoimmune disease, or active infections. Part 1 Dose Escalation is recruiting subjects in the US and China. Citation Format: Afshin Dowlati, Alexander Spira, Xiaodong Shen, Yinjia Fu, Yiyuan Pan, Linda Liu, Renke Zhou, Yi-Long Wu. Trial in progress: A phase Ia/Ib, an open-label, multicenter study of ZL-1310 to evaluate the safety, tolerability, and pharmacokinetics in subjects with small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT155.
Dowlati et al. (2024) studied this question.