Clinical Study of VG161 in Subjects With Advanced Primary Liver Cancer

Study Overview
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Brief Summary
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VG161 is a recombinant human-IL12/15/PDL1B oncolytic HSV-1 Injectable. This phase I study will be conducted in HSV-seropositive subjects with advanced primary liver cancer that are refractory to conventional therapies. This is an open label study and it's divided into two parts. Part 1: This part is ascending dose design to determine the safety and tolerability of VG161 and find recommended dose of VG161. Part 2: This part is extended dose design to determine the effectiveness of VG161.

Detailed Description
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Part 1: This part will be conducted in 5 dose ascending cohorts, including 1 single dose accelerated titration design pilots and 4 multiple dose escalation groups. Descriptive statistics will be used to summarize data. Part 2: This part will only include the part 1 recommended dose. Hypothesis test and descriptive statistics will be used to summarize data.

Official Title
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A Dose Ascending, Open Phase I Clinical Study to Evaluate the Safety, Tolerability , Pharmacokinetics Characteristics and Preliminary Effectiveness of VG161 in Subjects With Advanced Primary Liver Cancer

Conditions
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Primary Liver Cancer

Intervention / Treatment
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* Drug: Recombinant Human IL12/15-PDL1B Oncolytic HSV-1 Injection (Vero Cell))


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: According to 'The Diagnostic and Therapeutic Criteria for Primary Liver Cancer' (NMPA, 2019 Edition), subject with advanced primary hepatocellular carcinoma, intrahepatic cholangiocarcinoma, combined hepatocellular which is refractory/relapsed after and/or intolerant of standard therapies or for which no standard therapy exists. There are tumor lesions intrahepatic and / or extrahepatic metastases that can be injected under B ultrasound and meet the volume requirements of the current dose group, and the longest diameter of injectable tumor lesion >1.5cm（or the shortest diameter of lymph node lesions） Eastern Cooperative Oncology Group (ECOG) scores 0 or 1. Life expectancy is at least 3 months. Required organ function: 1) Hematology blood (no blood transfusion or colony stimulating factor treatment within 14 days): absolute neutrophil count (ANC)≥1.5×10^9L, platelets (PLT)≥75×10^9L, hemoglobin (Hb)≥85g/L, lymphocyte (LYM)≥0.8×10^9L; 2) Liver function: Total Serum bilirubin (TBIL)≤1.5×ULN (the upper limit of the reference range), Alanine aminotransferase (ALT)≤5×ULN, aspartate aminotransferase (AST)≤5×ULN; 3)Child-Pugh A-B level; 4) Renal function: Serum creatinine≤1.5×ULN, and creatinine clearance≥45 ml/min (calculated per Cockcroft-Gault formula); 5) Coagulation function: activated partial thromboplastin time (APTT)≤1.5×ULN, prothrombin time(PT) ≤1.5×ULN, international standardized ratio (INR)≤1.5×ULN. 6.If HBsAg is positive or HBcAb is positive ,must meet HBV-DNA<10^3 IU/ml. Subject with positive HBsAg must follow 'Guidelines for the prevention and treatment of chronic hepatitis B' (2019 Edition) for antiviral treatment. 7.Subjects of childbearing potential (male and female) must agree to use a reliable contraceptive method (hormone or barrier method or abstinence) during the study and for at least 90 days following the last dose; females of childbearing potential must have a negative blood pregnancy test within 7 days of study enrollment. 8.Signed written informed consent. Exclusion Criteria: Subject in prior anti-tumor therapies such as chemotherapy, radiotherapy, biotherapy, endocrinotherapy, targeted therapy, immunotherapy within 4 weeks of study treatment initiation. Transcatheter arterial chemoembolization(TACE) within 4 weeks of study treatment initiation Participation in clinical trials of any other investigational agents within 4 weeks of study treatment initiation. Major organ surgery (excluding puncture biopsy) or significant trauma within 4 weeks of study treatment initiation. Patients who received systemic treatment with either corticosteroids ( >10 mg/ daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study treatment initiation. Subjects with any ≥Grade 1 toxicity (as per NCI CTC AE Version 5.0) related to prior anti-cancer therapy (except for toxicity that the investigator assessed to be no safety risk, such as alopecia.). Subjects with Central Nervous System (CNS) metastasis or meningeal metastasis . Seronegative for Herpes Simplex Virus (HSV) (HSV-1IgG and HSV-1IgM). Subjects with the relapse of HSV infection and relevant clinical manifestations, such as lip herpes, herpes keratitis, herpes dermatitis, and genital herpes. Subjects with other uncontrolled active infections. Known history of immunodeficiency and test positive of human immunodeficiency virus (HIV). History of severe cardiovascular disease: 1)Ventricular arrhythmias requiring clinical intervention; 2)QTc interval >480 ms; 3)Acute coronary syndrome, congestive heart failure, stroke or other cardiovascular events of III grade or above within 6 months; 4)The cardiac function grade≥II or left ventricular ejection fraction (LVEF) <50% per the New York Heart Association (NYA); 5)Uncontrolled hypertension. 13. Subjects with active or past autoimmune diseases that are likely to recur (e.g. systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.); acceptable for patients with clinically stable autoimmune thyroiditis. 14. known to have alcohol or drug dependence. 15. Persons with mental disorders or poor compliance. 16. Pregnant or lactating women. 17. Subjects with any significant unrelated systemic illness that to the investigator's opinion would compromise the subject's eligibility to participate the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Part1: 1.0*10^8 PFU on Day 1 1.0*10^8 PFU on Days 1 to 2 1.0*10^8 PFU on Days 1 to 3 1.0*10^8 PFU on Days 1 to 4 1.0*10^8 PFU on Days 1 to 5 Part2: Depends on the recommended dose in Part1 | Drug: Recombinant Human IL12/15-PDL1B Oncolytic HSV-1 Injection (Vero Cell))<br>* Intratumoral injection only. The dosing date can be the Day 1 only or Days 1 through 5.<br>* Other names: VG161;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part1: MTD/Recommended dose | MTD (Maximum tolerable dose) /Recommended dose | 7 month | 
| Part1: Occurence of DLT | Occurence of DLT (Dose Limiting Toxicity) | 1month | 
| Part1: Numbers of DLT | Numbers of DLT (Dose Limiting Toxicity) | 1 month | 
| Part1: Occurence of AE and SAE（NCI CTCAE 5.0） | Occurence of Adverse Event (AE) and Serious Adverse Event (SAE) （NCI CTCAE 5.0） | 7 months | 
| Part1: Frequency of AE and SAE（NCI CTCAE 5.0） | Frequency of Adverse Event (AE) and Serious Adverse Event (SAE) （NCI CTCAE 5.0） | 7 months | 
| Part2:ORR | Evaluate Objective Response Rate by RECIST 1.1 | 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part1:Tmax(h) | Time to peak | At the end of Cycle 1 (each cycle is 28 days) | 
| Part1:Cmax(copies/ugDNA) | Maximum concentration | At the end of Cycle 1 (each cycle is 28 days) | 
| Part1:ORR | Evaluate Objective Response Rate by iRECIST | 7 months | 
| Part1:DOR | Evaluate Disease Control Rate by iRECIST | 7 months | 
| Part1:PFS | Evaluate medium Progression Free Survival by iRECIST | 7 months | 
| Part1:OS rate | Evaluate Overall Survival rate | 17 months | 
| Part 1:CD3+, CD4+, CD8+ | Concentration of CD3+, CD4+, CD8+ | 7 months | 
| Part 1:IL15 | Concentration of IL15 | 7 months | 
| Part 1:PD-L1, PD-1 | Concentration of PD-L1, PD-1 | 7 months | 
| Part 2:PFS | Evaluate medium Progression Free Survival by iRECIST | 7 months | 
| Part 2:OS rate | Evaluate Overall Survival rate | 17 months | 
| Part 2: OS | Overall Survival | 17 months | 
| Part 2:DOR | Evaluate Disease Control Rate by iRECIST | 7 months | 
| Part 2:Safety indicators：AEs | Incidence of adverse events (NCI CTCAE 5.0) | 7 months | 
| Part 2:Safety indicators：ECOG | Incidence of abnormal ECOG scores | 7 months | 
| Part 2:Safety indicators：12-lead electrocardiograms | Incidence of abnormal 12-lead electrocardiograms | 7 months | 
| Part 2:Safety indicators：laboratory tests results | Incidence of abnormal laboratory tests results | 7 months | 
| Part 2:CD3+, CD4+, CD8+ | Concentration of CD3+, CD4+, CD8+ | 7 months | 
| Part 2:IL15 | Concentration of IL15 | 7 months | 
| Part 2:PD-L1, PD-1 | Concentration of PD-L1, PD-1 | 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Cancer