Clinical Study of VG161 Combined With Nivolumab Injection in Patients With Advanced Metastatic Gastric Cancer

Inclusion Criteria:

• (Subjects must meet all of the following inclusion criteria to enter the trial)

1. Subjects must give informed consent to this study before the trial and voluntarilysign a written informed consent form.
2. aged 18 to 75 years (inclusive), male or female.
3. Patients with advanced metastatic gastric or gastroesophageal junction adenocarcinomaconfirmed by histopathology or cytology.
4. According to the Guidelines for the Diagnosis and Treatment of Gastric Cancer (CSCO,version 2021), patients must have previously failed two or more systemic treatmentregimens (which must include anti-PD-1 monoclonal antibodies), or patients who cannotcontinue treatment due to severe adverse reactions as judged by the investigator.
5. Be able to provide paraffin blocks and/or tissue sections of previously archivedpathological tissues, or willing to undergo tumor tissue biopsy before administration.
6. The presence of at least one measurable CT scan according to RECIST 1.1 and meetingthe requirements for an acceptable injection dose volume (or the first injection dosevolume in Phase IIa) in the current dose group, tumor metastases that can be injectedunder ultrasound guidance (injected lesions are best major tumor burden lesions), andthe baseline longest diameter of the injected lesion (lymph node lesions are shortdiameters) > 1.5 cm.
7. Positive test result for herpes simplex virus I antibodies (HSV-1 IgG or HSV-1 IgM).
8. ECOG performance status score 0-1.
9. Expected survival time of more than 3 months.
10. adequate organ function: 1) blood routine (no blood transfusion or colony-stimulatingfactor treatment within 14 days): ANC ≥ 1.5 × 10^9/L, PLT ≥ 100 × 10^9/L, Hb ≥ 85 g/L,lymphocyte count ≥ 1.5 × 10^9/L (for lymphocyte count 0.8 × 10^9/L to 1.5 × 10^9/L,the investigator judged whether to enroll); 2) liver function: TBIL ≤ 1.5 × ULN, ALT ≤ 3 × ULN, AST ≤ 3 × ULN; 3) renal function: Cr ≤ 1.5 × ULN, and creatinine clearance ≥ 45ml/min (calculated according to Cockcroft-Gault formula); 4) coagulation function:activated partial thromboplastin time (APTT) ≤ 1.5 × ULN, international normalizedratio (INR) ≤ 1.5 × ULN.
11. eligible subjects of childbearing potential (men and women) must agree to use areliable method of contraception (hormonal or barrier method or abstinence) during thetrial and for at least 90 days after the last dose (VG161 or nivolumab, calculated atthe later of the day).
12. Female patients of childbearing age must have a negative blood pregnancy test within 1day prior to enrollment.

Exclusion Criteria:

• (Any of the following criteria must be excluded)

1. received chemotherapy, radiotherapy, biological therapy, endocrine therapy, targetedtherapy, immunotherapy and other anti-tumor drugs within 4 weeks before the first useof the study drug, of which oral fluorouracil and small molecule targeted drugs werewithin 2 weeks before the first use of the study drug or within 5 half-lives of thedrug (whichever was longer).
2. received other unmarketed clinical trial treatment within 4 weeks before the firstdose of study drug.
3. Major organ surgery (excluding needle biopsy) or significant trauma within 4 weeksbefore the first dose of study drug.
4. Patients who have received systemic corticosteroids (prednisone > 10 mg/day orequivalent doses of the same class of drugs) or other immunosuppressive agents within 14 days before the first dose of study drug; except for the following: topical,ocular, intra-articular, intranasal, and inhaled corticosteroids; short-termcorticosteroids (≤ 10 mg prednisone equivalent) for prophylaxis (e.g., prevention ofcontrast agent allergy).
5. Vaccination within 4 weeks prior to the first dose of study drug.
6. Adverse reactions of previous anti-tumor treatment have not recovered to CTCAE 5.0grade evaluation ≤ 1 (except alopecia and other toxicities judged by the investigatoras having no safety risk).
7. Patients with central nervous system metastasis, spinal cord metastasis and/or spinalcord compression.
8. patients with active diverticulitis or symptomatic gastrointestinal ulcers;
9. in the herpes simplex virus recurrence infection period, and there are correspondingclinical manifestations, such as oral herpes labialis, herpes keratitis herpeticum,genital herpes, etc., or there are herpes infection-related complications (herpeskeratitis, encephalitis, nerve injury, etc.), and intermittent or long-term use ofanti-herpes drugs (e.g., acyclovir) treatment, except intermittent local use.
10. other active uncontrolled infections.
11. History of immunodeficiency, including positive HIV antibody test and positiveTreponema pallidum antibody test.
12. Patients with active chronic hepatitis B or active hepatitis C (except hepatitis Bvirus carriers, stable hepatitis B after drug treatment [HBV-DNA test negative or < 50IU/ml] and cured hepatitis C patients [HCV RNA test negative]);
13. history of serious cardiovascular disease: 1) ventricular arrhythmia requiringclinical intervention; 2) QTc interval > 480 ms; 3) Acute coronary syndrome,congestive heart failure, stroke or other Grade III or higher cardiovascular eventswithin 6 months; 4) New York Heart Association (NYHA) functional classification ≥ IIor left ventricular ejection fraction (LVEF) < 40%; 5) uncontrolled hypertension aftertreatment (as judged by the investigator).
14. Patients with active, or have had and have had autoimmune diseases that may recur (such as interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis,nephritis, hyperthyroidism, hypothyroidism, including but not limited to thesediseases or syndromes, etc.); but excluding patients with clinically stable autoimmunethyroiditis, autoimmune-mediated hypothyroidism treated with stable doses of thyroidreplacement hormone; type I diabetes using stable doses of insulin; vitiligo orrecovered childhood asthma/allergy, and patients who do not require any interventionin adulthood.
15. Having received immunotherapy and have experienced immune-related adverse events (irAEs) such as immune-related pneumonia and myocarditis, which may affect the safetyof the investigational drug as judged by the investigator.
16. Patients who have received immune checkpoint inhibitors and develop serious adversereactions after treatment and need to be permanently disabled.
17. Known alcohol or drug dependence.
18. Mental disorders or poor compliance.
19. Pregnant or lactating women.
20. subjects with pleural effusion or pericardial effusion or ascites requiring clinicalintervention.
21. The investigator believes that the subject has other serious systemic diseases orother reasons and is not suitable for this clinical study.