HIPEC Priming Followed by Serplulimab Plus SOX/XELOX in Locally Advanced Gastric Cancer

A Prospective Exploratory Study of a HIPEC Priming Strategy Followed by Serplulimab Combined With SOX/XELOX as Neoadjuvant Therapy for Locally Advanced Gastric Cancer

Patients with locally advanced gastric cancer (LAGC), particularly those with serosal invasion, remain at high risk of peritoneal recurrence despite standard perioperative treatment. Hyperthermic intraperitoneal chemotherapy (HIPEC) may eradicate free intraperitoneal tumor cells and microscopic peritoneal disease while potentially enhancing systemic anti-tumor immune activation.

This is a prospective, single-center, single-arm exploratory study evaluating a HIPEC priming strategy followed by serplulimab-based neoadjuvant therapy in patients with locally advanced gastric cancer (cT3-4aN+M0). Eligible patients will undergo diagnostic laparoscopy confirming no visible peritoneal metastasis (P0) and negative peritoneal cytology (CY0), followed by docetaxel-based HIPEC.

After recovery from HIPEC, patients will initially receive one cycle of serplulimab combined with fluoropyrimidine monotherapy (S-1 or capecitabine), followed by subsequent cycles of serplulimab combined with SOX/XELOX chemotherapy prior to radical gastrectomy.

The primary endpoints are pathological complete response (pCR) rate and major pathological response (MPR) rate. Secondary endpoints include R0 resection rate, objective response rate (ORR), peritoneal recurrence-free survival (PRFS), overall survival (OS), and safety.

Locally advanced gastric cancer (LAGC) remains associated with a high risk of recurrence after curative-intent treatment, particularly peritoneal recurrence in patients with serosal invasion. Although perioperative chemotherapy improves survival outcomes, current systemic treatment strategies remain insufficient for controlling microscopic peritoneal dissemination.

Hyperthermic intraperitoneal chemotherapy (HIPEC) delivers heated chemotherapeutic agents directly into the peritoneal cavity, resulting in enhanced regional drug exposure and hyperthermia-mediated cytotoxicity. In addition to direct anti-tumor effects, accumulating evidence suggests that HIPEC may induce immunogenic cell death, enhance tumor antigen release, and activate systemic anti-tumor immune responses.

Serplulimab is a humanized anti-programmed cell death protein 1 (PD-1) monoclonal antibody that restores T-cell-mediated anti-tumor immunity through blockade of the PD-1/PD-L1 signaling pathway. The sequential administration of HIPEC followed by PD-1 blockade-based neoadjuvant therapy may therefore provide synergistic anti-tumor activity in locally advanced gastric cancer.

This prospective, single-center, single-arm exploratory study is designed to evaluate the efficacy and safety of HIPEC followed by serplulimab-based neoadjuvant therapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma.

Approximately 48 patients with clinically staged cT3-4aN+M0 disease will be enrolled. After screening and informed consent, all eligible patients will undergo diagnostic laparoscopy with peritoneal lavage cytology. Patients confirmed to have no visible peritoneal metastasis (P0) and negative cytology (CY0) will receive docetaxel-based HIPEC.

Following postoperative recovery, patients will receive one induction cycle of serplulimab combined with fluoropyrimidine monotherapy (S-1 or capecitabine). Subsequent neoadjuvant treatment will consist of serplulimab combined with SOX or XELOX administered every 3 weeks for a total of 3-4 treatment cycles. Patients considered resectable after radiologic reassessment will undergo standard radical gastrectomy with D2 lymphadenectomy.

The primary endpoints are pathological complete response (pCR) and major pathological response (MPR). Secondary endpoints include R0 resection rate, objective response rate (ORR), peritoneal recurrence-free survival (PRFS), overall survival (OS), and treatment-related safety assessed according to NCI-CTCAE criteria.

Inclusion Criteria:

• Aged 18 to 75 years (inclusive); gender unrestricted.
• Histologically confirmed gastric or gastroesophageal junction adenocarcinoma via endoscopic biopsy.
• Clinical stage cT3-4a (imaging evidence of tumor invasion into or penetration through the serosa), N+ (lymph node positive), M0 (no distant organ metastasis), based on the 8th Edition of the AJCC Staging Manual.
• HER2-negative disease, defined as HER2 IHC 0 or 1+, or IHC 2+ with negative ISH.
• Diagnostic laparoscopy confirms the absence of macroscopic peritoneal metastasis (P0) and negative peritoneal lavage cytology (CY0).
• Adequate cardiac function, rendering the patient eligible for curative-intent resection. If clinically indicated, patients with underlying ischemic heart disease, valvular heart disease, or other severe cardiac conditions must undergo a preoperative cardiac evaluation by a cardiologist.
• ECOG Performance Status (PS) score of 0 or 1 within 7 days prior to enrollment.
• Anticipated survival time of ≥ 6 months.
• Hepatitis B surface antigen (HBsAg) negative (-) and Hepatitis B core antibody (HBcAb) negative (-). If HBsAg is positive (+) or HBcAb is positive (+), the Hepatitis B virus DNA (HBV-DNA) level must be < 1000 copies/mL, < 200 IU/mL, or below the upper limit of normal (ULN) at the study center to be eligible for enrollment.
• HCV antibody negative (-).
• Major organ function is normal, defined as meeting the following criteria (having not received transfusions of blood products, albumin, recombinant human thrombopoietin, or colony-stimulating factors [CSF] within 14 days prior to randomization):

Hematologic System Absolute Neutrophil Count (ANC) ≥ 1.5×10⁹/L Platelets (PLT) ≥ 100×10⁹/L Hemoglobin (Hb) ≥ 90 g/L Liver Function Total Bilirubin (TBIL) ≤ 1.5×Upper Limit of Normal (ULN) Alanine Aminotransferase (ALT) ≤ 2.5×ULN; ≤ 5.0×ULN for patients with liver metastases Aspartate Aminotransferase (AST) ≤ 2.5×ULN; ≤ 5.0×ULN for patients with liver metastases Alkaline Phosphatase (ALP) ≤ 2.5×ULN; ≤ 5.0×ULN for patients with liver and/or bone metastases Albumin ≥ 25 g/L Renal Function Creatinine Clearance (CrCl) ≥ 50 mL/min (calculated using the Cockcroft-Gault formula) Coagulation Function Activated Partial Thromboplastin Time (APTT) ≤ 1.5×ULN Prothrombin Time (PT) ≤ 1.5×ULN International Normalized Ratio (INR) ≤ 1.5×ULN -Female patients must meet the following criteria:

Be in a postmenopausal state (defined as having had no menstruation for at least 1 year, with no other confirmed cause for amenorrhea other than menopause), or have undergone surgical sterilization (removal of ovaries and/or uterus); alternatively, patients with reproductive potential must simultaneously meet the following requirements:

• A serum pregnancy test result must be negative within 7 days prior to randomization;
• Agree to use a contraceptive method with an annual failure rate of < 1% or practice abstinence (avoidance of heterosexual intercourse) (from the time of signing the informed consent form until at least 120 days after the last dose of the investigational drug, and at least 6 [months] after the last dose of the chemotherapy drug ...months (contraceptive methods with an annual failure rate of < 1% include bilateral tubal ligation, vasectomy, correct use of ovulation-suppressing hormonal contraceptives, hormone-releasing intrauterine devices [IUDs], and copper-containing IUDs);
• Must not be breastfeeding. -Male patients must meet the following criteria: Agree to practice abstinence (avoid heterosexual intercourse) or use contraception, as specified below: If the partner is a female of childbearing potential or is pregnant, the male patient must practice abstinence or correctly use condoms for contraception-to prevent drug exposure to the embryo-during the chemotherapy treatment period and for at least 6 months after the last dose of chemotherapy medication, and for at least 120 days after the last dose of the investigational drug. The reliability of sexual abstinence should be evaluated with reference to the duration of the clinical study, patient preference, and lifestyle. Periodic abstinence (e.g., calendar-based, ovulation-based, basal body temperature, or post-ovulation methods) and withdrawal (coitus interruptus) are not considered acceptable methods of contraception.

Exclusion Criteria:

• History of other active malignancies within the past 5 years, or the presence of other active malignancies at the time of enrollment. Patients with 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, or carcinoma in situ of the breast-are eligible for enrollment.
• Presence of documented distant metastases (e.g., liver, lung, or bone metastases) or laparoscopically confirmed peritoneal seeding (P1).
• Patients scheduled to undergo, or with a history of having undergone, organ or bone marrow transplantation.
• Occurrence of myocardial infarction or poorly controlled arrhythmias (including a QTc interval ≥ 450 ms for males or ≥ 470 ms for females; QTc interval calculated using the Fridericia formula) within 6 months prior to enrollment.
• Presence of NYHA Class III or IV heart failure, or a cardiac ultrasound result showing a Left Ventricular Ejection Fraction (LVEF) < 50%.
• Human Immunodeficiency Virus (HIV) infection.
• Presence of active pulmonary tuberculosis.
• History of, or current presence of, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-induced pneumonitis, or severe impairment of pulmonary function that could interfere with the detection or management of suspected drug-related pulmonary toxicity.
• Presence of a known active or suspected autoimmune disease. Exceptions are made for patients whose disease is in a stable state at the time of enrollment (defined as requiring no systemic immunosuppressive therapy).
• Receipt of a live vaccine within 28 days prior to enrollment; inactivated viral vaccines for seasonal influenza are permitted.
• Patients requiring systemic corticosteroid therapy (at a prednisone-equivalent dose > 10 mg/day) or other immunosuppressive medications within 14 days prior to enrollment or during the study period. However, the following exceptions are permitted: in the absence of active autoimmune disease, patients may use topical or inhaled corticosteroids, or receive adrenal replacement therapy at a prednisone-equivalent dose ≤ 10 mg/day.
• Presence of any active infection requiring systemic anti-infective treatment within 14 days prior to enrollment; prophylactic antibiotic treatment (e.g., for the prevention of urinary tract infections or chronic obstructive pulmonary disease) is an exception.
• Prior receipt of any anti-tumor therapy for the current gastric cancer, including chemotherapy, radiotherapy, targeted therapy, or immunotherapy.
• Currently receiving treatment in another clinical study, or the planned start date of the treatment in this study is less than 14 days after the completion of treatment in a previous clinical study.
• Known history of severe allergy to any monoclonal antibody or excipients of the investigational drug.
• Known history of substance abuse (including drug abuse); patients who have ceased alcohol consumption are eligible for enrollment.
• Presence of any condition that may increase the risks associated with study participation or the investigational drug, or presence of other severe, acute, or chronic diseases that, in the investigator's judgment, render the patient unsuitable for participation in the clinical study.