An Open-Label, Multiple-Center, Phase IIa/IIb Clinical Trial to Evaluate the Efficacy, Safety and Tolerability of VG161 as Monotherapy and in Combination With Nivolumab for Treatment of Patients With Hepatocellular Carcinoma or Intrahepatic Cholangiocarcinoma

Inclusion Criteria:

1. Signed written informed consent.
2. Males or females aged 18 years and older.
3. Performance status: Eastern Cooperative Oncology Group (ECOG) 0 or 1.
4. For subject in Cohort 2: cytologically confirmed advanced/metastatic or surgically unresectable HCC, with documented disease progression after at least two lines of FDA approved systemic therapy, including immunotherapy or anti-angiogenesis therapy as the first line treatment and at least one regimen of the following agents as the second line: anti-angiogenesis agents, tyrosine kinase inhibitors or immunotherapy.
5. For subject in Cohort 3: Histologically or cytologically confirmed advanced/metastatic or surgically unresectable ICC, with documented disease progression after chemotherapy as the first line systemic therapy. For patients with known IDH1 mutation, they must receive the appropriate targeted therapy with a IDH1 inhibitor and for patients with MSI-H tumors, they must receive immunotherapy with PD-1 inhibitors.
6. For subjects in Cohort 1 and Cohort 4: should fulfill either inclusion criteria 4) or 5).
7. Liver function: Child-Pugh A-B for cohort 1 and 2.
8. At least one measurable lesion per RECIST 1.1
9. At least 1 injectable lesion; ≥15 mm in longest diameter and deemed injectable as per Investigator's discretion. Subjects with deep or visceral lesions (such as hepatic or intraperitoneal lymph nodes) that can be safely injected under guided imaging can be considered for intratumoral injection of VG161..

Exclusion Criteria:

1. Participation in any trial of any other investigational agent within the last 4 weeks prior to dosing. Wash out periods to be reviewed on a case by case basis with Medical Monitor, as required.
2. Tumors to be injected lying in mucosal regions or close to an airway, major blood vessel or spinal cord that, in the opinion of the Investigators, could cause occlusion or compression in the case of tumor swelling or erosion into a major vessel in the case of necrosis.
3. Subjects with any primary Central Nervous System (CNS) malignancy including glioma and current, active, progressing CNS malignancy, including carcinomatosis meningitis are excluded. Subjects with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging \[MRI\] or computed tomography \[CT\] scan) during the screening period and off steroids (for at least 2 weeks prior to first dose of IP).
4. Major surgery within 14 days prior to dosing.
5. Intercurrent serious infections within 28 days prior to Screening or treated systematically with antibiotics within 14 days prior to signing ICF.
6. Life-threatening illness unrelated to cancer.
7. Active Herpes infection.
8. Treatment with antiviral agents within 14 days prior to dosing.
9. Uncontrolled congestive heart failure.
10. Known to test positive for human immunodeficiency virus (HIV) or syphilis.
11. Active infection including hepatitis B (HBV) or hepatitis C (HCV) that currently under anti-virus treatment which can affect study drug treatment as per investigator's decision.
12. Use of ganciclovir or acyclovir within 14 days prior to dosing.
13. Subjects with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to dosing. Inhaled or topical steroids, and adrenal replacement steroid doses ≤10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
14. Subjects who have been on systemic anticoagulants within 14 days prior to dosing and/or with International Normalized Ratio (INR) \> 1.5 x the upper limit of the reference range are excluded from this study.
15. Subjects with prior radiation therapy to the tumor lesion to be injected are excluded from the study, unless there is evidence of tumor progression in the most recent imaging, following completion of radiotherapy.