A Clinical Study of Sintilimab Combined With Chemothrapy Versus Chemotherapy as Adjuvant Therapy for Gastric/Gastroesophageal Junction Adenocarcinoma

Sintilimab Combined With SOX Versus SOX as Adjuvant Therapy for Patients With Stage pIIIC or dMMR/MSI-H Stage pIIIA/IIIB Gastric or Gastroesophageal Junction Adenocarcinoma: A Single-center, Randomized Controlled Phase II Clinical Trial

This study aims to explore the efficacy and safety of sintilimab combined with SOX versus SOX alone as adjuvant therapy for patients with pIIIC stage or dMMR/MSI-H pIIIA/IIIB stage gastric/gastroesophageal junction adenocarcinoma. A total of 276 subjects are planned to be enrolled in this study. Patients will be randomly assigned in a 1:1 ratio to receive up to 8 cycles of sintilimab combined with SOX or SOX alone as adjuvant therapy.

This is a single-center, randomized controlled phase II clinical study.The primary endpoint was 3-year disease-free survival (3yr-DFS). The secondary endpoints were disease-free survival (DFS), overall survival (OS), and safety. The study used RECIST v1.1 for imaging assessment. Tumor imaging evaluations were conducted every 12 weeks (±7 days) until disease recurrence, death, or up to 24 months, and then every 24 weeks (±7 days) thereafter. The same imaging technique should be used for the same subject throughout the study period. Safety follow-up was from the first treatment to 30 days after the last treatment.

Inclusion Criteria:

1. Signed written informed consent.

2. Male or female, age ≥18 years.

3. Histopathologically confirmed adenocarcinoma of the stomach or gastroesophageal junction (GEJ).

4. Diagnosed with pTNM stage IIIC or pTNM stage IIIA/IIIB.

5. Diagnosed with mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) of biopsy tissue or microsatellite instability-high (MSI-H) by genetic sequencing.

6. Underwent D2 or more extensive radical resection and achieved R0 resection.

7. Able to swallow tablets normally.

8. ECOG performance status 0-1.

9. Life expectancy >6 months.

10. Adequate organ function, subjects must meet the following laboratory criteria:

    1. Absolute neutrophil count (ANC) ≥1.5×10^9/L without granulocyte colony-stimulating factor within the past 14 days.
    2. Platelets ≥100×10^9/L without transfusion within the past 14 days.
    3. Hemoglobin >9 g/dL without transfusion or erythropoietin use within the past 14 days.
    4. Total bilirubin ≤1.5×ULN; if total bilirubin >1.5×ULN but direct bilirubin ≤ULN, enrollment is also permitted.
    5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN.
    6. Serum creatinine ≤1.5×ULN and creatinine clearance (calculated by Cockcroft-Gault formula) ≥60 ml/min.
    7. Good coagulation function, defined as international normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN.
    8. Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within 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.
    9. Cardiac enzyme panel within normal range (isolated laboratory abnormalities deemed clinically insignificant by the investigator are also permitted for enrollment).

11. For female subjects of childbearing potential, a urine or serum pregnancy test must be negative within 3 days prior to the first dose of study drug (Cycle 1 Day 1). If the urine pregnancy test cannot be confirmed as negative, a serum pregnancy test is required. Non-childbearing potential is defined as postmenopausal for at least 1 year, or surgically sterile or hysterectomy.

12. If at risk of conception, all subjects (male or female) must use contraceptive measures with a failure rate of <1% per year throughout the treatment period and for 120 days after the last dose of study drug (or 180 days after the last dose of chemotherapy).

Exclusion Criteria:

1. Cancers involving the EGJ with the tumor center located in the proximal stomach ≤2 cm from the EGJ.

2. Diagnosis of any other malignant disease other than gastric cancer within 5 years prior to first dose (excluding curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or curatively resected carcinoma in situ).

3. Currently participating in interventional clinical study treatment, or has received other investigational drugs or used investigational devices within 4 weeks prior to first dose.

4. Prior receipt of the following therapies: anti-PD-1, anti-PD-L1, or drugs targeting another stimulatory or co-inhibitory T-cell receptor (including but not limited to CTLA-4, OX-40, CD137, etc.).

5. Received systemic therapy with Chinese patent medicines with anti-tumor indications or immunomodulatory drugs (including thymosin, interferons, interleukins, except for local use to control pleural effusion) within 2 weeks prior to first dose.

6. Active autoimmune disease requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within 2 years prior to first dose. Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) is not considered systemic treatment.

7. Receiving systemic corticosteroid therapy (excluding nasal spray, inhaled, or other topical corticosteroids) or any other form of immunosuppressive therapy within 7 days prior to first dose.

8. Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation.

9. Known allergy to any drug used in this study.

10. Has not adequately recovered from toxicities and/or complications caused by any prior intervention prior to starting treatment (i.e., ≤ grade 1 or returned to baseline, excluding fatigue or alopecia).

11. Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1/2 antibody positive).

12. Untreated active hepatitis B (defined as HBsAg positive and HBV-DNA copy number above the upper limit of normal of the testing laboratory at the study site). Subjects meeting the following criteria may also be enrolled:

    1. HBV viral load <1000 copies/ml (200 IU/ml) prior to first dose, subjects should receive anti-HBV therapy during the entire study chemotherapy treatment to prevent reactivation.
    2. For subjects with anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load (-), prophylactic anti-HBV therapy is not required, but close monitoring for viral reactivation is needed.

13. Subjects with active HCV infection (HCV antibody positive and HCV-RNA level above the lower limit of detection).

14. Received a live vaccine within 30 days prior to first dose (Cycle 1, Day 1).

15. Pregnant or breastfeeding women.

16. Presence of any severe or uncontrolled systemic disease, such as:

    1. Abnormalities in resting ECG in rhythm, conduction, or morphology that are significant and severely symptomatic and difficult to control, such as complete left bundle branch block, second-degree or higher heart block, ventricular arrhythmias, or atrial fibrillation.
    2. Unstable angina, congestive heart failure, chronic heart failure with New York Heart Association (NYHA) class ≥2.
    3. Any arterial thrombotic, embolic, or ischemic event within 6 months prior to enrollment, such as myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.
    4. Uncontrolled hypertension (systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg).
    5. History of non-infectious pneumonitis requiring corticosteroid treatment within 1 year prior to first dose, or current clinically active interstitial lung disease.
    6. Active pulmonary tuberculosis.
    7. Active or uncontrolled infection requiring systemic therapy.
    8. Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction.
    9. Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis.
    10. Poorly controlled diabetes (fasting blood glucose (FBG) >10 mmol/L).
    11. Urinalysis indicates proteinuria ≥++ and confirmed 24-hour urine protein quantification >1.0 g.
    12. Patients with mental disorders who are unable to comply with treatment.

17. History or evidence of disease, treatment, or laboratory abnormalities that may interfere with the study results, hinder the subject's full participation in the study, or other conditions that the investigator deems unsuitable for enrollment, or the investigator believes there are other potential risks that make participation inappropriate.