Clinical Study of VG161 Combined With Camrelizumab in Patients With Advanced Primary Hepatocellular Carcinoma

Inclusion Criteria:

• Subjects must give informed consent to this study before the trial and voluntarilysign a written informed consent form.
• Age 18 to 75 (inclusive), gender is not limited.
• Patients with advanced primary hepatocellular carcinoma confirmed by histopathology orcytology.
• According to the CSCO Guidelines for the Diagnosis and Treatment of Primary LiverCancer (2022 Edition), patients who have received at least previous first-linetreatment regimens that have failed treatment (disease progression or inability totolerate treatment) must have been treated.
• According to RECIST 1.1, it is determined that at least one CT examination shows thatit is measurable and meets the requirements of the volume of injection administration (or the volume of first injection administration in phase IIa) that can be injectedunder ultrasound guidance (preferably the main tumor burden lesion) under ultrasoundguidance, and the longest baseline diameter of the injection lesion (short diameter oflymph node lesions) is >1.5 cm (of which the portal vein lymph node is short, thediameter needs to be > 20 mm).
• Those with positive herpes simplex virus antibody test results (HSV-1 IgG or HSV-1IgM).
• ECOG physical status score 0-1.
• Estimated survival time of more than 3 months.
• Have adequate organ function:

1. Routine blood (no blood transfusion or colony-stimulating factor therapy within 14 days): ANC≥ 1.5×109/L, PLT≥75×109/L, Hb≥85g/L, lymphocyte count ≥1.5×109/L (for lymphocyte count 0.8×109/L to 1.5×109/L is determined by the investigatorwhether to enroll);
2. Liver function: TBIL≤1.5×ULN, ALT≤5×ULN, AST≤5×ULN;
3. Child-Pugh A or better B (≤ 7);
4. Renal function: Cr≤1.5×ULN, and creatinine clearance ≥ 45ml/min (calculatedaccording to Cockcroft-Gault formula);
5. Coagulation function: activated partial thromboplastin time (APTT) ≤ 1.5×ULN,international normalized ratio (INR) ≤1.5×ULN.

• Eligible subjects of childbearing potential (male and female) must agree to use areliable method of contraception (hormonal or barrier or abstinence) during the trialand at least 90 days after the last dose (VG161 or carrelizumab, whichever occurslater); Female patients of childbearing age must have a negative blood pregnancy testwithin 7 days prior to enrollment.

Exclusion Criteria:

• Known fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma,cholangiocarcinoma or mixed hepatocellular carcinoma.
• Have received chemotherapy, radiotherapy, biological therapy, endocrine therapy,targeted therapy, immunotherapy and other anti-tumor drugs within 4 weeks before thefirst use of study drugs, among which oral fluorouracils and small molecule targeteddrugs are the first use of study drugs. Within the first 2 weeks or the 5 half-livesof the drug (whichever is longer).
• Have received other unmarketed clinical trial treatments within 4 weeks before usingthe study drug for the first time.
• Have undergone major organ surgery (excluding puncture biopsy) or experiencedsignificant trauma within 4 weeks before taking the study drug for the first time.
• Patients who have received systemic corticosteroids (prednisone >10 mg/day orequivalent doses of similar drugs) or other immunosuppressants within 14 days beforethe first use of study drugs;Exceptions are the following: treatment with topical,ocular, intraarticular, intranasal, and inhaled corticosteroids; short-term use ofcorticosteroids (≤10 mg prednisone equivalent) for prophylactic treatment (e.g.,prevention of contrast media allergy).
• Have received vaccination within 4 weeks before the first use of study drugs.
• Known severe allergic reaction to any monoclonal antibody.
• The adverse reactions of previous anti-tumor treatments have not returned to CTCAE 5.0grade ≤1 (except for toxicities such as hair loss that the researcher has judged tohave no safety risks).
• Liver tumor burden is greater than 50% of the total liver volume, or those who havereceived liver transplantation in the past.
• Patients with central nervous system metastasis, spinal cord metastasis and/or spinalcord compression are not suitable for inclusion according to the investigator'sjudgment.
• In the period of recurrent infection of herpes simplex virus, with correspondingclinical manifestations, such as cold sores, herpetic keratitis, herpetic dermatitis,genital herpes, etc.
• Other uncontrolled active infections.
• Have a history of immunodeficiency, including positive HIV antibody test and positiveTreponema pallidum antibody test.
• Patients with active chronic hepatitis B or active hepatitis C (except hepatitis Bvirus carriers, stable hepatitis B after drug treatment [negative HBV-DNA test or <50IU/ml] and cured hepatitis C patients [HCV RNA Tested negative]).
• Have a history of serious cardiovascular and cerebrovascular diseases:

1. Ventricular arrhythmias requiring clinical intervention;
2. QTc interval>480ms;
3. Acute coronary syndrome, congestive heart failure, stroke or other grade III orabove cardiovascular events within 6 months;
4. New York Heart Association (NYHA) cardiac function class ≥ class II or leftventricular ejection fraction (LVEF) <40%;
5. Uncontrolled hypertension (systolic blood pressure ≥140mmHg, or diastolic bloodpressure ≥90mmHg after treatment).

• Patients with active or past autoimmune diseases that may relapse (such asinterstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis,hyperthyroidism, hypothyroidism (including but not limited to these diseases orsyndromes, etc.); but does not include patients with clinically stable autoimmunethyroiditis, autoimmune-mediated hypothyroidism treated with a stable dose of thyroidreplacement hormone; Type I diabetes on insulin; patients with vitiligo or childhoodasthma/allergies that have resolved and do not require any intervention in adulthood.
• Have received immunotherapy and experienced immune-related adverse events (irAEs) suchas immune-related pneumonia, myocarditis, etc., which may affect the safety of thetrial medication as judged by the researcher.
• Known alcohol or drug dependence.
• People with mental disorders or poor compliance.
• Pregnant or lactating women.
• Patients with obvious symptoms and unstable pleural effusion, peritoneal effusion orpericardial effusion (those with stable clinical symptoms after treatment of pleuraleffusion, ascites or pericardial effusion can be included).
• The researcher believes that the subject has other serious systemic diseases or otherreasons and is not suitable to participate in this clinical study.