Neoadjuvant Tislelizumab with LM-302 plus S-1 or with SOX for CLDN18.2-positive gastric and gastroesophageal junction adenocarcinoma.

Tislelizumab Combined With LM-302 and S-1 Versus Tislelizumab Combined With SOX for Neoadjuvant Treatment of Claudin 18.2-positive Locally Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a Prospective, Randomized, Exploratory Study

This trial tests whether giving Tislelizumab together with a CLDN18.2-targeting agent (LM-302) plus S-1 or giving Tislelizumab with oxaliplatin and S-1 before surgery helps people with CLDN18.2-positive, locally advanced gastric or GEJ adenocarcinoma.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 88 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Ruijin Hospital (Academic / other)
• Drugs / interventions: Tislelizumab
• Locations: 1 site (Shanghai, Huangpu District)
• Trial ID: NCT07569068 on ClinicalTrials.gov

What this trial studies

This is a phase 2, neoadjuvant interventional trial comparing two preoperative combination regimens in patients with CLDN18.2-positive, HER2-negative, resectable (T3-4 N+ M0) gastric or gastroesophageal junction adenocarcinoma. One arm receives Tislelizumab plus LM-302 and S-1, and the other receives Tislelizumab with oxaliplatin and S-1 (SOX), applied prior to planned radical surgery. Key eligibility includes CLDN18.2 expression in ≥25% of tumor cells, ECOG 0-1, and adequate organ function, with exclusion of patients with distant metastases or prior CLDN18.2-targeted therapy. The trial will monitor tumor response, surgical outcomes, and safety to determine whether the experimental combination increases preoperative tumor control compared with the comparator regimen.

Who should consider this trial

Good fit: Adults (≥18) with histologically confirmed, HER2-negative, CLDN18.2-positive (≥25% membrane staining) gastric or GEJ adenocarcinoma that is locally advanced but surgically resectable (T3-4 N+ M0), ECOG 0-1, and with adequate organ function are the intended participants.

Not a fit: Patients with HER2-positive disease, peritoneal or other distant metastases, positive peritoneal cytology, tumors centered ≤2 cm from the EGJ involving the proximal stomach, poor performance status, or prior CLDN18.2-targeted therapy are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the regimen could increase tumor shrinkage before surgery and improve the chance of a complete resection and longer-term disease control.

How similar studies have performed: Combinations of PD-1 inhibitors with chemotherapy have shown benefit in gastric cancer and CLDN18.2-targeting agents have shown promising activity in metastatic settings, but using LM-302 in the neoadjuvant setting is novel.

Eligibility criteria

Inclusion Criteria:

* Patients voluntarily participate in this study and sign the informed consent form;
* Age ≥ 18 years;
* Histopathologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma;
* HER2 negative;
* Determined by contrast-enhanced CT and laparoscopy to have radically resectable disease with clinical stage T3-4 N+ M0 (according to the AJCC 8th edition);
* Claudin 18.2 positive (≥25% of tumor cells showing moderate-to-strong membrane staining);
* No prior receipt of other targeted therapies against claudin 18.2;
* ECOG performance status 0-1;
* Life expectancy ≥ 12 months;
* Adequate major organ function.

Exclusion Criteria:

* Known HER2-positive gastric cancer；
* Gastroesophageal junction (EGJ) cancer involving the proximal stomach with the tumor center located ≤2 cm from the EGJ；
* Peritoneal metastasis, positive peritoneal cytology (CY1P0), or retroperitoneal lymph node metastasis (No. 16a2/b1) or other distant metastases;
* Presence of unresectable factors, including unresectability due to tumor characteristics, surgical contraindications, or patient refusal of surgery;
* Prior or concurrent other malignancy, except for cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, and carcinoma in situ of the breast;
* Presence of any of the following cardiac clinical symptoms or diseases:

  * New York Heart Association (NYHA) class ≥2 heart failure or left ventricular ejection fraction (LVEF) \<50% on color Doppler echocardiography;
  * Unstable angina;
  * Resting electrocardiogram (ECG) showing QTc \>450 ms (male) or QTc \>470 ms (female);
  * Resting ECG showing clinically significant abnormalities (e.g., abnormalities in heart rate, conduction, morphology), complete left bundle branch block, third-degree atrioventricular block, second-degree atrioventricular block, or PR interval \>250 ms.
* History of gastrointestinal perforation, intra-abdominal abscess, or intestinal obstruction within the past 3 months, or evidence of intestinal obstruction by imaging or clinical symptoms;
* Arterial/venous thrombotic events within 6 months before randomization, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, or pulmonary embolism;
* Known hereditary or acquired bleeding or thrombotic predisposition (e.g., hemophilia, coagulation disorders, thrombocytopenia);
* Active peptic ulcer, unhealed wound, or bone fracture;
* Active infection requiring antimicrobial therapy (e.g., antibacterial, antiviral, or antifungal treatment);
* Active hepatitis \[hepatitis B: HBsAg positive and HBV DNA ≥500 IU/mL; hepatitis C: HCV antibody positive and HCV viral load \> upper limit of normal\]; 13. Congenital or acquired immunodeficiency (e.g., HIV-infected patients);
* Planned or prior organ or allogeneic bone marrow transplantation;
* Current interstitial pneumonia or interstitial lung disease, or a history of interstitial pneumonia/ lung disease requiring steroid therapy, or other pulmonary conditions that may interfere with the assessment and management of immune-related lung toxicity, including pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), pneumoconiosis, drug-induced pneumonitis, idiopathic pneumonitis, or active pneumonia or severe pulmonary dysfunction on screening CT scan;
* Active pulmonary tuberculosis;
* Any active autoimmune disease or history of autoimmune disease with potential for relapse \[including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (patients controlled with hormone replacement therapy alone are eligible)\];
* Known hypersensitivity to any study drug or excipient;
* Lactating women;
* Any other condition that, in the investigator's judgment, may affect the study results or necessitate premature termination of the study, such as alcohol or drug abuse, other serious diseases (including psychiatric disorders) requiring concomitant treatment, significant laboratory abnormalities, or family/social factors that could compromise patient safety.

Where this trial is running

Shanghai, Huangpu District

• Ruijin Hospital Shanghai Jiao Tong University School of Medicine — Shanghai, Huangpu District, China (Recruiting)

Study contacts

• Study coordinator: Zhongyin Yang

Conditions Gastric or Esophagogastric Junction Adenocarcinoma; Claudin 18.2; LM-302; Tislelizumab; SOX