Efficacy and Safety of Intraoperative Radiotherapy Combined With Serplulimab Plus Chemotherapy Versus Serplulimab Plus Chemotherapy as Neoadjuvant Therapy for Gastric or Gastroesophageal Junction Adenocarcinoma

• Patients aged 18-75 years with gastric or gastroesophageal junction adenocarcinoma, male or female;
• According to the AJCC 8th edition gastric cancer staging, patients assessed by abdominal CT as cStage III (cT3-4aN1-3M0), and diagnosed with gastric or gastroesophageal junction adenocarcinoma by gastroscopy and pathology; for gastroesophageal junction (GEJ) cancer, only Siewert type III and Siewert type II subjects who do not require combined thoracotomy are allowed to be enrolled.
• Before enrollment, after joint assessment by a attending gastrointestinal surgeon and an imaging technician, the tumor is determined to be cStage III and the patient is eligible for curative-intent R0 resection; the patient agrees to undergo radical surgery and is judged by the surgeon to have no surgical contraindications;
• No prior systemic therapy for the current disease, including surgery, anti-tumor radiotherapy/chemotherapy/immunotherapy, etc.;
• Expected survival ≥6 months;
• Measurable tumor lesions according to RECIST v1.1 criteria (see Appendix 1);
• ECOG PS score (see Appendix 2) of 0-1 within 7 days before the first dose;
• Good cardiac function and suitable for curative-intent resection. If clinically indicated, patients with underlying ischemic, valvular heart disease, or other severe heart disease should undergo preoperative evaluation by a cardiologist;

• Normal function of major organs; subjects must meet the following laboratory criteria:

  1. Absolute neutrophil count (ANC) ≥1.5×10⁹/L without the use of granulocyte colony-stimulating factor within the past 14 days;
  2. Platelet count ≥100×10⁹/L without blood transfusion within the past 14 days;
  3. Total bilirubin ≤1.5× upper limit of normal (ULN); if total bilirubin >1.5×ULN but direct bilirubin ≤ULN, enrollment is also permitted;
  4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN;
  5. Serum creatinine ≤1.5×ULN and creatinine clearance (calculated using the Cockcroft-Gault formula) ≥60 mL/min;
  6. Good coagulation function, defined as international normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN;
  7. Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within the normal range. If baseline TSH is outside the normal range, subjects with total T3 (or FT3) and FT4 within the normal range may also be enrolled;
  8. Myocardial enzyme spectrum within the normal range (if the investigator comprehensively judges it as a clinically insignificant isolated laboratory abnormality, enrollment is also permitted); Thyroid function indicators: thyroid-stimulating hormone (TSH), free thyroxine (FT3/FT4) within the normal range or with mild and clinically insignificant abnormalities; Body weight above 40 kg (including 40 kg), or BMI >18.5;

• Female patients must meet:

  1. Postmenopausal status (defined as no menstruation for at least 1 year, with no other confirmed cause other than menopause), or have undergone surgical sterilization (oophorectomy and/or hysterectomy), or patients of childbearing potential must simultaneously meet the following requirements:
  2. Pregnancy test within 7 days before the first dose must be negative;
  3. Agree to use contraceptive measures with an annual failure rate \<1% or maintain abstinence (avoid heterosexual intercourse) (from signing the informed consent form until at least 120 days after the last dose of the study drug, and at least 9 months after surgery) (contraceptive methods with an annual failure rate \<1% include bilateral tubal ligation, male sterilization, correct use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper-containing intrauterine devices.);
  4. Must not breastfeed.
• Male patients must meet:

Agree to abstinence (avoid heterosexual intercourse) or use contraceptive measures, as specified below: when the partner is a woman of childbearing potential or the partner is pregnant, male patients must maintain abstinence or correctly use condoms for at least 120 days after the last dose of the study drug and at least 9 months after surgery. The reliability of sexual abstinence should be evaluated with reference to the duration of the clinical study, patient preference, and daily lifestyle. Periodic abstinence (e.g., calendar days, ovulation period, basal...)

• Subjects read and fully understand the patient information and sign the informed consent form.

Exclusion Criteria:

• Patients with a prior (within 5 years) or concurrent other malignancy. Cured localized tumors, such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the prostate, carcinoma in situ of the cervix, carcinoma in situ of the breast, stage I lung cancer, stage I colorectal cancer, etc., may be enrolled;
• Patients preparing to undergo or having previously received organ or bone marrow transplantation;
• Any bleeding event of severity grade 3 or above according to CTCAE 5.0 occurring within 4 weeks before screening;
• Abnormal coagulation function with a bleeding tendency (INR >1.5 of the normal value without the use of anticoagulants); patients treated with anticoagulants or vitamin K antagonists such as warfarin, heparin, or their analogues; on the premise that the prothrombin time international normalized ratio (INR) ≤1.5, low-dose warfarin (1 mg orally, once daily) or low-dose aspirin (daily dose not exceeding 100 mg) for prophylactic purposes is permitted;
• Occurrence of arterial/venous thrombotic events within 6 months before screening, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis (except those caused by venous catheterization due to prior chemotherapy and judged by the investigator to have healed), and pulmonary embolism, etc.;
• Occurrence of myocardial infarction or poorly controlled arrhythmia (including QTc interval ≥450 ms in males and ≥470 ms in females) within 6 months before the first dose (QTc interval calculated using the Fridericia formula);
• Presence of NYHA class III-IV cardiac insufficiency or echocardiography: LVEF (left ventricular ejection fraction) \<50%;
• Urinalysis indicating urine protein ≥++ and confirmed 24-hour urine protein quantification >1.0 g;
• Presence of multiple factors affecting oral medication (such as inability to swallow, chronic diarrhea, and intestinal obstruction, etc.);
• Symptomatic pleural effusion or ascites requiring clinical intervention;
• Human immunodeficiency virus (HIV) infection;
• Active pulmonary tuberculosis;
• Long-term non-healing wounds or incompletely healed fractures;
• Prior and current interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, severe impairment of pulmonary function, etc., which may interfere with the detection and management of suspected drug-related pulmonary toxicity;
• Presence of known active or suspected autoimmune disease, except those in a stable state of the disease at enrollment (not requiring systemic immunosuppressive therapy);
• History of severe chronic autoimmune disease, such as systemic lupus erythematosus, etc.; history of inflammatory bowel disease such as ulcerative colitis and Crohn's disease; history of chronic diarrheal diseases such as irritable bowel syndrome; history of sarcoidosis or tuberculosis; history of active hepatitis B, hepatitis C, and HIV infection; well-controlled non-severe immune diseases such as dermatitis, arthritis, psoriasis, etc., may be enrolled. Hepatitis B virus titer \<500 copies/mL may be enrolled;
• Patients requiring systemic corticosteroids (>10 mg/day prednisone-equivalent dose) or other immunosuppressive therapy within 14 days before the first dose or during the study period. However, the following conditions are permitted for enrollment: in the absence of active autoimmune disease, patients are permitted to use topical or inhaled steroids, or adrenal hormone replacement therapy at a dose ≤10 mg/day prednisone-equivalent dose;
• Any active infection requiring systemic anti-infective treatment within 14 days before the first dose; except for receiving prophylactic antibiotic treatment (such as prevention of urinary tract infection or chronic obstructive pulmonary disease);
• Treatment with live vaccines within 28 days before the first dose; except for inactivated viral vaccine treatment for seasonal influenza;
• Prior treatment with antibody/drug therapy targeting immune checkpoints, such as PD-1, PD-L1, CTLA-4 inhibitors, etc.;
• Treatment with immune-related drugs or medical technologies within 6 months before the first dose (including but not limited to the following: thymopentin, thymalfasin, interferon, CAR-T therapy, etc.);
• Currently receiving other drug-related clinical study treatment, or the planned start time of this study treatment is less than 1 month from the end of the previous drug-related clinical study treatment;
• Known history of allergy or intolerance to any study drug or its components;
• Patients with a history of alcoholism, drug use, and drug abuse. Patients who have stopped drinking alcohol may be enrolled;
• Patients with non-compliance with medical advice, non-compliance with prescribed medication, or incomplete data, etc., which may affect the assessment of efficacy or safety;
• Pregnant or lactating female patients;
• Patients with conditions that may increase the risk of participating in the study and study drug use, or other severe, acute, and chronic diseases, who, as judged by the investigator, are not suitable for participation in clinical research.
• Other circumstances judged by the investigator as unsuitable for this clinical trial.