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
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 44
- 试验地点
- 1
- 主要终点
- Part1: Occurence of DLT
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Life expectancy is at least 3 months.
- •Required organ function:
- •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.
排除标准
- •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:
- •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.
- •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.
- •known to have alcohol or drug dependence.
- •Persons with mental disorders or poor compliance.
- •Pregnant or lactating women.
- •Subjects with any significant unrelated systemic illness that to the investigator's opinion would compromise the subject's eligibility to participate the study.
研究组 & 干预措施
VG161
Part1:
- 1.0*10^8 PFU on Day 1(1.0×10^8PFU)
- 1.0*10^8 PFU on Days 1 to 2(2.0×10^8PFU)
- 1.0*10^8 PFU on Days 1 to 3(3.0×10^8PFU)
- 1.3*10^8 PFU on Days 1 to 3(4.0×10^8PFU)
- 1.7*10^8 PFU on Days 1 to 3(5.0×10^8PFU)
Part2:
Depends on the recommended dose in Part1
干预措施: Recombinant Human IL12/15-PDL1B Oncolytic HSV-1 Injection (Vero Cell)) (Drug)
结局指标
主要结局
Part1: Occurence of DLT
时间窗: 1month
Occurence of DLT (Dose Limiting Toxicity)
Part1: MTD/Recommended dose
时间窗: 7 month
MTD (Maximum tolerable dose) /Recommended dose
Part1: Numbers of DLT
时间窗: 1 month
Numbers of DLT (Dose Limiting Toxicity)
Part1: Occurence of AE and SAE（NCI CTCAE 5.0）
时间窗: 7 months
Occurence of Adverse Event (AE) and Serious Adverse Event (SAE) （NCI CTCAE 5.0）
Part1: Frequency of AE and SAE（NCI CTCAE 5.0）
时间窗: 7 months
Frequency of Adverse Event (AE) and Serious Adverse Event (SAE) （NCI CTCAE 5.0）
Part2:ORR
时间窗: 7 months
Evaluate Objective Response Rate by RECIST 1.1
次要结局
- Part 1:CD3+, CD4+, CD8+(7 months)
- Part 1:IL15(7 months)
- Part 1:PD-L1, PD-1(7 months)
- Part 2:PFS(7 months)
- Part 2:OS rate(17 months)
- Part 2: OS(17 months)
- Part 2:DOR(7 months)
- Part 2:IL15(7 months)
- Part 2:Safety indicators：AEs(7 months)
- Part 2:Safety indicators：ECOG(7 months)
- Part 2:Safety indicators：12-lead electrocardiograms(7 months)
- Part 2:Safety indicators：laboratory tests results(7 months)
- Part1:Tmax(h)(At the end of Cycle 1 (each cycle is 28 days))
- Part1:Cmax(copies/ugDNA)(At the end of Cycle 1 (each cycle is 28 days))
- Part1:ORR(7 months)
- Part1:DOR(7 months)
- Part1:PFS(7 months)
- Part1:OS rate(17 months)
- Part 2:CD3+, CD4+, CD8+(7 months)
- Part 2:PD-L1, PD-1(7 months)