Study protocol of the C-SOLVE (JACCRO GC-12) trial; a randomized, non-comparative phase II trial of CapeOX or SOX plus zolbetuximab in HER2-negative, CLDN18.2-positive unresectable advanced gastric or esophagogastric junction cancer

Background: Capecitabine + oxaliplatin (CapeOX) + zolbetuximab and 5-FU + oxaliplatin (mFOLFOX6) + zolbetuximab are recommended as first-line treatments for chemotherapy-naïve patients with HER2-negative, CLDN18.2-positive advanced gastric or esophagogastric junction cancer. However, no prospective trials have evaluated the efficacy and safety of S-1 + oxaliplatin (SOX) + zolbetuximab. This study is planned as a non-comparative, prospective, randomized phase II clinical trial to evaluate the efficacy and safety of SOX + zolbetuximab in chemotherapy-naïve patients with HER2-negative, CLDN18.2-positive advanced gastric or esophagogastric junction cancer. Methods/design: This randomized study will enroll patients ≥ 18 years old with histologically confirmed HER2-negative, CLDN18.2-positive (IHC defined as ≥ 75% of tumour cells showing moderate-to-strong membranous CLDN18 staining) advanced gastric or esophagogastric junction cancer. Participants (n = 140) will be randomly assigned (1:1) to receive either SOX + zolbetuximab or CapeOX + zolbetuximab. The primary endpoint is the 12-month progression-free survival (PFS) rate, with a threshold of 17% and an expected rate of 33% for SOX + zolbetuximab. To account for a 10% deviation risk, the target enrollment for each arm is 70 patients. CapeOX + zolbetuximab will serve as a prospective observational arm without hypothesis testing. Secondary endpoints will include PFS, overall survival, objective response rate, disease control rate, duration of response, time to response, and safety. The enrollment period is 2 years, followed by a 2-year observation period. Discussion: Since replacing capecitabine with S-1 should provide the same level of therapeutic efficacy, SOX + zolbetuximab may be increasingly used to treat advanced gastric or esophagogastric junction cancer in Asian countries. Verifying the efficacy and safety of SOX + zolbetuximab is thus an important task. Trial registration: The protocol has been registered at the website of the Japan Registry of Clinical Trials (JRCT), Japan (protocol ID jRCTs031240510, protocol version: 1.11) on November 26, 2024. The details are available at https://jrct.mhlw.go.jp/.