Overview

Claudin 18.2 (CLDN18.2) is a molecular target expressed in a subset of gastric and gastroesophageal junction (GEJ) adenocarcinomas. Zolbetuximab, a chimeric monoclonal antibody targeting CLDN18.2, has shown clinical benefit in combination with chemotherapy for CLDN18.2-positive unresectable advanced or recurrent gastric cancer, and in Japan, FLOT plus durvalumab is expected to become a standard perioperative treatment for locally advanced gastric/GEJ adenocarcinoma. This trial evaluates whether adding zolbetuximab to FLOT plus durvalumab further improves the pathological response of neoadjuvant chemotherapy in CLDN18.2-positive, locally advanced, resectable gastric or GEJ adenocarcinoma.

This is a single-arm, open-label, multicenter, investigator-initiated phase II trial conducted at four sites in Japan. Eligible participants are adults (18 years or older) with previously untreated (no prior chemotherapy, radiotherapy, or immunotherapy), histologically confirmed gastric or GEJ adenocarcinoma classified as cT2-4 and/or cN+, M0 by the UICC/TNM Classification (8th edition), confirmed to be CLDN18.2-positive (moderate or greater membranous staining in 75% or more of tumor cells) by immunohistochemistry, with an ECOG performance status of 0 or 1.

The primary endpoint is the histological complete response rate (Grade 3) on the surgical specimen, assessed by a central pathological review committee. Key secondary endpoints include the incidence of adverse events, the treatment completion rate through surgery, the dose intensity of neoadjuvant chemotherapy, the R0 resection rate, and the histological response rate (Grade 2 or higher).

Eligibility

Inclusion Criteria:

1. Histologically confirmed gastric cancer (either a general histological type or a lymphoid stroma-type carcinoma) on endoscopic biopsy from the primary lesion in the stomach or gastroesophageal junction.
2. No prior chemotherapy, radiotherapy, or immunotherapy, including treatment for other cancers, and classified as cT2-4 and/or cN+ M0 according to the UICC TNM Classification, 8th edition.
3. Moderate or greater membranous staining in \>-75% of tumor cells confirmed by CLDN18.2 immunohistochemistry.
4. No distant metastasis on contrast-enhanced CT of the chest, upper abdomen, and pelvis.
5. No prior treatment with an immune checkpoint inhibitor.
6. Age \>=18 years at the time of enrollment.
7. ECOG Performance Status (PS) of 0 or 1.
8. No history of any surgical treatment for gastric cancer other than endoscopic resection (ESD or EMR).
9. No marked bleeding or severe stenosis from the gastric cancer lesion.
10. Laboratory test values obtained within 14 days before enrollment meet a given criteria.
11. Written consent to participate in the study has been obtained from the patient.
12. Female patients are not pregnant and meet all of the following:
    • Not a woman of childbearing potential (WOCBP), or agrees to follow the contraception guidance throughout the treatment period, for at least 9 months after the last dose of oxaliplatin, and for at least 6 months after the last dose of all other study drugs.
    • Agrees not to breastfeed during the screening period, the study period, and for 6 months after the last dose of study drug.
    • Agrees not to donate ova during the screening period, the study period, for 9 months after the last dose of oxaliplatin, and for 6 months after the last dose of all other study drugs.

Male patients with a female partner of childbearing potential agree to use contraception during the study period and for at least 6 months after the last dose of study drug. Male patients with a pregnant or breastfeeding partner agree to remain abstinent or use a condom during that period. Male patients agree not to donate sperm from the start of screening through 6 months after the last dose of study drug.

Exclusion Criteria:

1. Patients with a history of severe allergic reaction or intolerance to zolbetuximab or to known components of humanized or chimeric monoclonal antibodies.
2. Patients known to have immediate or delayed hypersensitivity to any component of the study drugs, or for whom any component of the study drugs is contraindicated.
3. Patients who have used another investigational drug or device within 28 days before the first dose of study drug.
4. Patients with a history of systemic immunosuppressive therapy, such as systemic corticosteroids, within 14 days before the first dose of study drug.
5. Patients with complete gastric outlet obstruction, or partial obstruction with persistent recurrent vomiting.
6. Patients with significant gastric bleeding and/or untreated gastric ulcer judged by the investigator to be inappropriate for participation in this study.
7. Patients with central nervous system metastasis and/or carcinomatous meningitis from gastric/GEJ cancer.
8. Patients known to be positive for human immunodeficiency virus infection, or known to have active hepatitis B (positive for hepatitis B surface antigen) or hepatitis C infection.
9. Patients who have experienced unstable angina, myocardial infarction, or intervention/hospitalization for heart failure due to ventricular arrhythmia within 6 months before the first dose of study drug.
10. Patients with active infection requiring systemic treatment who have not fully recovered within 7 days before the first dose of study drug.
11. Patients with active autoimmune disease requiring systemic immunosuppressive therapy within 3 months before the first dose of study drug.
12. Patients with a clinically significant disease or comorbidity that, in the investigator's judgment, would adversely affect the safe conduct of treatment in this study or make the patient inappropriate for participation.
13. Patients with a psychiatric disorder or social situation that, in the investigator's judgment, could interfere with compliance with the study.
14. Patients who have undergone major surgery within 28 days before the first dose of study drug.
15. Patients who have not fully recovered from major surgery by 14 days before the first dose of study drug.
16. Patients judged by the investigator to have another malignancy requiring treatment.
17. Patients who are ineligible for FLOT therapy or durvalumab administration due to a history of prior conditions or comorbidities.
18. Patients meeting any of the following (surgical-related):

(ア) Judged by the investigator to be unresectable with curative intent. (イ) Meets the following criterion for local disease by clinical TNM staging: cT1N0.