A Phase 2 interventional study of Zolbetuximab and Durvalumab in CLDN18.2-Positive Gastric Cancer and CLDN18.2-Positive Gastroesophageal Junction Adenocarcinoma, sponsored by National Cancer Center, Japan. Recruiting at 4 sites in Japan. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-20.
Sponsored by National Cancer Center, Japan · Phase 2, Interventional, and Treatment
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).
\<Background and Rationale> Locally advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma are commonly treated with perioperative chemotherapy. In Japan, FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus durvalumab is expected to be established as a standard perioperative treatment for cT2-4 and/or cN+ gastric/GEJ cancer in 2026, with a reported pathological complete response (Grade 3, per the Japanese Classification of Gastric Carcinoma) rate of 19.2%. Zolbetuximab, a chimeric monoclonal antibody against Claudin 18.2 (CLDN18.2), has demonstrated clinically meaningful benefit in combination with chemotherapy for CLDN18.2-positive unresectable advanced or recurrent gastric/GEJ adenocarcinoma, both as first-line therapy in combination with oxaliplatin/fluoropyrimidine-based chemotherapy and, with monotherapy, in later lines. Identified risks of zolbetuximab include nausea, vomiting, and hypersensitivity reactions (including infusion-related reactions); potential risks include neutropenia and anemia. Based on this efficacy and safety profile, this trial investigates whether adding zolbetuximab to FLOT plus durvalumab further improves the pathological response of neoadjuvant chemotherapy for CLDN18.2-positive, locally advanced, resectable gastric or GEJ adenocarcinoma, anticipating an improvement in the Grade 3 histological response rate, a reduction in recurrence, and prolonged survival.
\<Study Objectives> The primary objective is to evaluate the efficacy of neoadjuvant chemotherapy with FLOT plus durvalumab plus zolbetuximab, using the histological complete response rate (Grade 3, per central pathological review) as the primary endpoint. The secondary objective is to evaluate the safety, tolerability, and efficacy of this combination therapy.
\<Study Design> This is a single-arm, open-label, multicenter, investigator-initiated phase II trial conducted at 4 sites in Japan (National Cancer Center Hospital [coordinating site], The Cancer Institute Hospital of JFCR, Saitama Cancer Center, and Kanagawa Cancer Center). The tolerability and safety of zolbetuximab combined with FLOT plus durvalumab are evaluated during a dose-limiting toxicity (DLT) evaluation period covering the first 2 weeks after the first dose of zolbetuximab (Cycle 1). If the 800 mg/m\^2 loading dose of zolbetuximab is not tolerated based on this DLT evaluation, a reduced loading dose of 600 mg/m\^2 is evaluated in an additional cohort of 3-6 participants before proceeding to the efficacy evaluation cohort.
\<Study Treatment>
Participants receive 4 cycles (2-week cycles) of neoadjuvant chemotherapy:
Zolbetuximab and FLOT plus durvalumab may be administered on the same day (zolbetuximab first) or, per investigator judgment, split across 2 consecutive days. After completion of the 4 cycles of neoadjuvant chemotherapy, surgery is performed within 4-8 weeks.
\<Efficacy Assessments> The primary efficacy endpoint, histological response, is evaluated on the surgical specimen by a central pathological review committee according to the Japanese Classification of Gastric Carcinoma, 15th edition (Grade 3 for the primary endpoint; Grade 2 or higher for a key secondary endpoint).
\<Endpoints> Primary Endpoint: Histological complete response rate (Grade 3), per central pathological review.
Secondary Endpoints: Incidence of adverse events; treatment completion rate through surgery; dose intensity of neoadjuvant chemotherapy; R0 resection rate; histological response rate (Grade 2 or higher), per central pathological review.
\<Statistical Considerations> The historical Grade 3 histological response rate with FLOT plus durvalumab alone is reported as 19.2%; this trial sets a threshold response rate of 19% and an expected response rate of 37% for the combination with zolbetuximab. With a one-sided alpha of 5% and 80% power, simulation-based sample size calculation (evaluated using the two-sided 90% Wilson score confidence interval for the response rate) indicates that 29 evaluable participants are required; the planned enrollment is approximately 30 participants (target annual enrollment: 15 participants; planned enrollment period: 2 years).
\<Study Oversight and Funding> National Cancer Center Hospital, Japan, is the coordinating site, responsible for overall trial coordination (Coordinating Investigator: Hirokazu Shoji). Astellas Pharma Inc. supplies zolbetuximab and provides funding for the trial under a contract with National Cancer Center Hospital.
2,914 studies on the registry are indexed under Stomach Neoplasms; 881 are open to participants now.
This study's planned enrollment of 29 is below the median of 66 across 2,143 interventional studies indexed under Stomach Neoplasms.
Browse Stomach Neoplasms studies →National Cancer Center, Japan is the lead sponsor of 18 studies on the registry; 13 are open to participants now.
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Female patients are not pregnant and meet all of the following:
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:
(ア) Judged by the investigator to be unresectable with curative intent. (イ) Meets the following criterion for local disease by clinical TNM staging: cT1N0.
Participants receive neoadjuvant zolbetuximab, durvalumab, and FLOT (5-fluorouracil, oxaliplatin, leucovorin, and docetaxel) for 4 cycles (2-week cycles), followed by surgery within 4-8 weeks after completion of chemotherapy.
Drug: Zolbetuximab · Drug: Durvalumab · Drug: FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel)
Zolbetuximab 800 mg/m\^2 (loading dose; reduced to 600 mg/m\^2 if not tolerated) is administered intravenously on Cycle 1 Day 1, followed by 400 mg/m\^2 on Day 1 of Cycles 2-4 (2-week cycles).
Durvalumab 1,500 mg (or 20 mg/kg for participants weighing 30 kg or less) is administered intravenously on Cycle 1 Day 2 and Cycle 3 Day 1 or 2 only (2 administrations in total).
FLOT (5-fluorouracil 2,600 mg/m\^2, leucovorin 100 mg/m\^2, oxaliplatin 85 mg/m\^2, and docetaxel 50 mg/m\^2) is administered intravenously every 2 weeks for 4 cycles, in combination with zolbetuximab and durvalumab, as neoadjuvant treatment prior to surgery.
Histological complete response rate (Grade 3), per central pathological review
Proportion of participants achieving a histological complete response (Grade 3), evaluated on the surgical specimen as assessed by a central pathological review committee.
Time frame: At the time of surgery, expected within approximately 12-20 weeks after enrollment
Incidence of adverse events
Incidence of adverse events and serious adverse events, coded using MedDRA and graded using CTCAE version 6.0, summarized by system organ class and preferred term.
Time frame: From the start of protocol treatment (Cycle 1; 14-day cycles) until 30 days after the last dose of study treatment (up to approximately 20 weeks)
Dose intensity of neoadjuvant chemotherapy
Dose intensity of zolbetuximab, durvalumab, and FLOT during the neoadjuvant treatment period
Time frame: From enrollment through completion of neoadjuvant chemotherapy, up to approximately 8 weeks
R0 resection rate
Proportion of participants achieving R0 resection at surgery
Time frame: At the time of surgery, up to approximately 20 weeks after enrollment
Histological response rate (Grade 2 or higher)
Proportion of participants achieving a histological response of Grade 2 or higher as assessed by a central pathological review committee
Time frame: At the time of surgery, up to approximately 20 weeks after enrollment
Plan to share: No
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From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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Studies of the drugs tested here: Zolbetuximab · Durvalumab
National Cancer Center, Japan