Efficacy and Safety of AK112 Combined Chemotherapy as Neoadjuvant Treatment for Signet Ring Cell-containing G/GEJ Adenocarcinoma

Inclusion criteria

• Subjects must voluntarily agree to participate in the clinical trial and sign a written informed consent form (ICF) before undergoing any trial-related procedures.
• Male or female subjects aged ≥18 and ≤75 years at the time of signing the informed consent.
• Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction with signet ring cell components. Diagnosis of locally advanced disease (based on AJCC 8th edition) must be made within 4 weeks prior to randomization.
• Tumor staging: cT3-4a or cN+ (M0) as determined by endoscopic ultrasound and/or contrast-enhanced CT/MRI. Diagnostic laparoscopy may be used as needed. The tumor must be assessed as resectable by the investigator.
• Immunohistochemical testing confirms proficient mismatch repair (pMMR) status and HER-2 negativity (IHC 0 or 1+, or IHC 2+ with negative FISH for HER-2 amplification).
• No prior systemic treatment for the current malignancy, including surgery, chemotherapy, radiotherapy, or immunotherapy.
• Eligible for radical surgery with no surgical contraindications as determined by a qualified surgeon.
• ECOG performance status of 0 or 1 within 7 days before randomization.
• Estimated life expectancy > 6 months.
• Adequate organ function, as demonstrated by the following laboratory results (without blood product transfusion or cytokine support within 2 weeks prior to first dose):

Hematologic: WBC ≥ 3.5 × 10⁹/L, ANC ≥ 1.5 × 10⁹/L, Platelets ≥ 100 × 10⁹/L, Hemoglobin ≥ 90 g/L Hepatic: Total bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 2.5 × ULN Renal: Serum creatinine ≤ 1.0 × ULN, Creatinine clearance ≥ 60 mL/min (Cockcroft-Gault formula) Coagulation: INR, APTT, PT ≤ 1.5 × ULN Thyroid: TSH within normal limits. If TSH is abnormal, subjects with normal total T3 (or FT3) and FT4 may be enrolled.

Cardiac: Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram; cardiac assessment may be required for patients with cardiac comorbidities.

Hepatitis B serology: HBsAg (-) and anti-HBc (-). If HBsAg (+) or anti-HBc (+), HBV-DNA must be <1000 copies/mL or <200 IU/mL or below the site-specific ULN.

HCV antibody (-). Subjects with positive HCV antibody but negative HCV-RNA may be considered eligible.

• For women of childbearing potential: Negative serum or urine pregnancy test within 7 days before randomization. If urine test is inconclusive, a serum test is required. Postmenopausal status is defined as ≥12 months of amenorrhea or surgical sterilization (bilateral oophorectomy/hysterectomy).

• Subjects (regardless of sex) with reproductive potential must agree to use highly effective contraception (failure rate <1%) from the start of study treatment to 120 days after last study dose (or 180 days if receiving chemotherapy).

• Breastfeeding is not permitted during the study period.

Exclusion criteria

• Histology other than adenocarcinoma with signet ring cell features, including squamous cell carcinoma, neuroendocrine carcinoma, or other subtypes.
• Tumor exhibiting deficient MMR (dMMR) or HER-2 positivity (IHC 3+, or IHC 2+ with FISH-confirmed HER-2 amplification).
• Unresectable tumors or subjects unwilling or unable to undergo surgery due to medical, anatomical, or personal reasons.
• History of other malignancies within 5 years prior to enrollment, excluding certain cured cancers (e.g., basal cell carcinoma, carcinoma in situ of cervix/breast/prostate/bladder).
• Evidence of active bleeding on endoscopy.
• Participation in another interventional clinical study or use of investigational drugs/devices within 4 weeks prior to enrollment.
• Prior immunotherapy including immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1, anti-CTLA-4, anti-TIGIT, etc.) or cellular immunotherapy.
• Use of traditional Chinese medicine with antitumor or immunomodulatory effects within 2 weeks prior to first dose.
• Active autoimmune disease requiring systemic therapy in the last 2 years. Hormonal replacement therapies are allowed.
• Use of systemic corticosteroids or immunosuppressants within 7 days before first dose (except ≤10 mg/day prednisone equivalent).
• Prior or planned organ/bone marrow transplantation (excluding corneal transplant).
• Known hypersensitivity to investigational products.
• Conditions affecting oral administration of capecitabine (e.g., dysphagia, intestinal obstruction).
• HIV infection (HIV-1/2 antibody positive).
• Active hepatitis B (HBsAg positive and HBV DNA > ULN).
• Active hepatitis C (HCV antibody positive with detectable HCV RNA).
• Receipt of live vaccines within 30 days prior to first dose. Inactivated influenza vaccines are permitted; live attenuated intranasal influenza vaccine is not.
• Pregnant or breastfeeding women.
• Serious or uncontrolled systemic illnesses, including:

Significant arrhythmias or heart block

History of myocarditis, cardiomyopathy, MI, unstable angina, CHF within 12 months

Gastrointestinal conditions (e.g., active ulcers, varices, perforation, abscess) within 6 months

Recent COPD exacerbation (within 1 month)

Grade ≥3 thromboembolic events or cerebrovascular accidents within 6 months

Poorly controlled hypertension (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg despite treatment)

Non-infectious pneumonitis or interstitial lung disease

Pulmonary tuberculosis

Active systemic infection

Decompensated liver disease

Poorly controlled diabetes (FBG >10 mmol/L or random BG >16 mmol/L)

Proteinuria ≥ ++ or 24-hour urine protein > 1.0 g

• Psychiatric illness interfering with compliance or safety.
• Major surgery or significant trauma within 30 days prior to first dose, or planned major surgery within 30 days post first dose (except minor procedures).
• Tumor necrosis on imaging, deemed high risk for bleeding by investigator.
• History of severe bleeding or coagulation disorders; active bleeding within 1 month (e.g., hematemesis, hemoptysis, significant epistaxis); long-term anticoagulation for atrial fibrillation with CHADS2 ≥ 2.
• Any condition or laboratory abnormality that, in the opinion of the investigator, may interfere with the study results or subject safety.