A randomized phase II clinical trial evaluating the safety and efficacy of initial dose adjustment of zolbetuximab plus chemotherapy in patients with HER2-negative and CLDN18.2-positive unresectable advanced or recurrent gastric, gastroesophageal junction cancer or esophageal adenocarcinoma (GENTLE-Z).

Abstract

TPS504 Background: Zolbetuximab, a monoclonal antibody targeting CLDN18.2, was recently approved in Japan for patients with HER2-negative/CLDN18.2-positive metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). On-target GI toxicities such as nausea and vomiting are commonly observed during first infusion, occasionally leading to early treatment discontinuation. Effective management of these toxicities is essential for the successful use of zolbetuximab in clinical practice. This study aims to assess whether omitting the loading dose in the first cycle can reduce zolbetuximab-related GI toxicities without compromise efficacy . Methods: GENTLE-Z is a prospective, open-label, multi-intuitional, randomized phase II trial designed to compare the safety and efficacy of fixed-dose of zolbetuximab without loading dose vs. the standard zolbetuximab dose in combination with first-line mFOLFOX6 or CAPOX for patients with HER2-negative/CLDN18.2-positive mGC/GEJC. Patients are randomly assigned (1:1) to receive either a fixed dose of zolbetuximab (400 mg/m 2 q2w or 600 mg/m 2 q3w) or standard zolbetuximab regimen (800 mg/m 2 loading dose followed by 400 mg/m 2 q2w or 600 mg/m 2 q3w) with chemotherapy. The primary endpoint is the vomit-free rate during cycle 1, and secondary endpoints include efficacy outcomes such as objective response rate, progression-free survival and overall survival. The sample size is set based on the hypothesis that omitting loading dose will improve the vomit-free rate from 50% to 75%. The planned sample size is 86 patients, with a one-sided alpha error of 5% and power of 75%, over an estimated enrollment period of 1.5 years. Enrollment has been ongoing since September 2024 across 55 sites in Japan. This trial is registered in Japan Registry of Clinical Trials (jRCTs031240347). Clinical trial information: jRCTs031240347.