Design of a first-in-human multicenter open-label study of ZW171, a mesothelin x CD3 targeting bispecific T-cell engager, in participants with advanced solid tumors: ZWI-ZW171-101.
Background: Mesothelin (MSLN) is a membrane glycoprotein overexpressed in several solid tumors, making it a promising target for cancer treatments, including T cell engagers (TCEs). ZW171 is a humanized trivalent bispecific TCE antibody that targets a threshold level of MSLN expression with 2 binding sites and CD3e receptor on T cells with 1 binding site. Preclinical studies of ZW171 demonstrated favorable pharmacology, pharmacokinetics (PK), and toxicology, showing it preferentially kills MSLN-overexpressing cells, activates T cells without significant toxicity, inhibits tumor growth, and is well tolerated in cynomolgus monkeys, suggesting its potential for treating MSLN-expressing tumors1 while sparing healthy tissues with low levels of expression. This first-in-human, phase 1, ongoing study (ZWI-ZW171-101) evaluates safety, tolerability, PK, and anti-tumor activity of ZW171 in participants with advanced solid tumors. Methods: This 2-part study enrolls eligible adult participants with unresectable MSLN-expressing ovarian cancer (OC), non-small cell lung cancer (NSCLC), or other MSLN-expressing cancers, with measurable disease per RECIST v1.1, ECOG PS score of 0 to 1, adequate organ function, and a minimum life expectancy of 12 weeks. Participants with additional progressing malignancies, recent transplants, clinically significant ongoing toxicity, uncontrolled renal, pancreatic or liver disease, or active autoimmune diseases requiring high-dose corticosteroids or immunosuppressive drugs are excluded. Part 1 evaluates the safety and tolerability of ZW171 and Part 2 evaluates the anti-tumor activity while continuing to evaluate safety and tolerability. Part 1 is dose escalation to identify maximum tolerated dose (using modified toxicity probability interval [mTPI-2] design, n=40) among participants with OC or NSCLC receiving subcutaneous ZW171 monotherapy on days 1, 8, and 15 of 3-week (21-day) cycles. Approximately 6 dose levels will be explored based on safety and tolerability. Step-up dosing will be used for cycle 1. Dose level 1, determined by QSP-based MABEL approach2, is administered at 4.2 µg (day 1), 12.6 µg (day 8), and 38.0 µg (day 15). Part 2 is dose expansion in participants with OC, NSCLC, and other MSLN-expressing cancers (MSLN expression evaluated retrospectively). Primary objectives are to evaluate safety and tolerability of ZW171 and determine the maximum tolerated dose. Key secondary objectives are to assess PK, anti-drug antibodies, and anti-tumor activity. This is a global study with sites in North America, Europe, and Asia; and actively enrolling participants into Part 1. Clinical trial information: NCT06523803. References: 1. Afacan N, et al. Presented at AACR Annual Meeting 2023; abstract 2942. 2. Afacan N, et al. Presented at SITC Annual Meeting 2024; abstract 1062.
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Author Details
Melissa Johnson
Sarah Cannon Research Institute, Nashville, TN
Abstract Details
Meeting
2025 ASCO Annual Meeting
Session Type
Poster Session
Session Title
Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
Track
Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
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