Preliminary results of a phase 1/2, first-in-human, open-label, dose escalation study of ZL-1211 (anti-Claudin 18.2 mAb) in patients with unresectable or metastatic solid tumors.
Authors: Sharma Sunil , Starodub Alexander , Xu Nong , Chaudhry Arvind , Sun Meili , Pelster Meredith , Fu Yinjia , Zhang Xinyu , Huang Zhao , Liu Wenyu , Hsu Karl 
Published: June 2023

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Background: ZL-1121 is a humanized immunoglobulin G1 monoclonal antibody targeting Claudin18.2. Site mutations (S239D and I332E) were introduced in the Fc portion of ZL-1211 to enhance antibody dependent cellular cytotoxicity. Herein, we present the preliminary results from the ongoing dose escalation part of the study. Methods: This is a first-in-human, phase 1/2, multicenter, dose escalation/cohort expansion study of ZL-1211 administered intravenously to adult patients with Claudin 18.2-positive advanced solid tumors. A Bayesian optimal interval design with 3+3 run-in was adopted to assess 5 dose levels of ZL-1211 monotherapy (1 to 40 mg/kg biweekly) for phase 1 dose escalation, followed by phase 2 cohort expansion. The primary objectives were to determine the maximum tolerated dose and/or the recommended phase 2 dose, assess the safety/tolerability, and evaluate the preliminary antitumor activities of ZL-1211. Tumor assessments were performed every 8 weeks per RECIST v1.1. Blood samples were collected for pharmacokinetic (PK) analyses. Results: As of Dec 12, 2022, 19 patients (11 pancreatic cancer, 6 gastric cancer, 1 esophageal cancer, and 1 bile duct cancer) had been enrolled in the dose escalation phase to receive ZL-1211 at 1 mg/kg (n = 3), 5 mg/kg (n = 7), 10 mg/kg (n = 4), and 20 mg/kg (n = 5). The median age was 60 years and the majority of the patients (78.9%) received ≥2 lines of prior systemic therapy. No dose limiting toxicities (DLT) had been observed as of the cut-off date. The most common treatment-related adverse events (TRAEs) were gastrointestinal disorders, including nausea (11/19, 57.9%), vomiting (6/19, 31.6%), and abdominal pain (3/19, 15.8%). Other common TRAEs (≥15%) were hypoalbuminaemia (3/19, 15.8%) and infusion-related reactions (3/19, 15.8%). Grade 3 TRAEs occurred in 3 patients, 1 with nausea and vomiting, 1 with platelet count decreased, and 1 with anaemia, leukopenia, platelet count decreased, and weight decreased. No Grade ≥ 4 TRAEs were reported. Two patients experienced serious TRAEs: 1 reporting 2 cases each of grade 3 vomiting and nausea and 1 reporting a grade 3 platelet count decreased and a grade 2 abdominal pain, all of which had recovered. TRAEs led to treatment interruption in 5 patients (26.3%) and treatment withdrawal in 1 patient (5.3%). No TRAEs leading to death were reported. Six of 9 tumor-evaluable patients achieved stable disease as the best overall response. Three patients had tumor regression: 17.1% in a pancreatic cancer patient of the 5 mg/kg cohort; 14.5% in a pancreatic cancer patient and 24.9% in a gastric cancer patient in the 10 mg/kg cohort. Preliminary PK analyses revealed linear PK of ZL-1211 over the dose range tested. Conclusions: ZL-1211 displayed an acceptable safety/tolerability profile to date and demonstrated preliminary antitumor effects. Clinical trial information: NCT05065710 .