Phase 1, Open-label, Two Routes IV and Intra-hepatic Artery Dose-escalation Clinical Study to Evaluate the Safety and Efficacy of ET1402L1-CAR T- Cells in AFP Expressing Hepatocellular Carcinoma (HCC)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Toxicity profile of ET1402L1-CART-cell treatment
研究概览
简要总结
Clinical study to evaluate safety and pharmacokinetics (primary objectives) and efficacy (secondary objective) of ET1402L1-CART-cells in patients with AFP+ HCC
详细描述
The molecular target for ET1402L1-CART is alpha fetoprotein (AFP), which is expressed on 60-80 percent of hepatocellular carcinoma (HCC). ET1402L1-CART is a second generation (CD28/CD3ζ) chimeric antigen receptor (CAR) engineered with a human single-chain variable antibody fragments (scFv) against the anti-HLA-A02/AFP complex. This clinical study evaluates the safety and pharmacokinetics of ET1402L1-CART-cells in patients with HCC who have no available curative therapeutic options and a poor overall prognosis.
Patients with lesion(s) localized in liver will be enrolled in the IA arm, with the ET1402L1-CART-cells administered via intrahepatic artery catheter. Patients with extrahepatic metastasis will be enrolled in the IV arm, with the ET1402L1-CART-cells administered through intravenous infusion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •AFP-expressing HCC and serum AFP >100 ng/mL.
- •Measurable disease as defined by: at least 1 liver lesion that can be accurately and serially measured in at least 1 dimension and for which the longest diameter is ≥ 20 mm.
- •Molecular HLA class I typing confirms participant carries at least one HLA-A02 allele
- •Child-Pugh score of A or B
- •Life expectancy > 4 months
- •Age at time of enrollment is ≥18 years of age.
- •Adequate organ function as defined below:
- •A pretreatment measured creatinine clearance (absolute value) of ≥50 ml/minute.
- •Patients must have a serum direct bilirubin ≤2 x ULN, ALT and AST ≤5 times the institutional upper limits of normal.
- •Ejection Fraction measured by echocardiogram or MUGA >45% (evaluation done within 6 weeks of screening does not need to be repeated)
- •DLCO or FEV1 >45% predicted
- •Absolute neutrophil count (ANC) ≥ 1500/mm3 (10^9/L)
- •Platelet count ≥ 50,000/mm3 (10^9/L)
- •Negative serum pregnancy test for women with childbearing potential
- •Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent.
排除标准
- •Patients with decompensated cirrhosis: Child-Pugh Score C
- •Patients with an organ transplantation history
- •Patients with tumor infiltration in the portal vein, hepatic veins or inferior vena cava that completely blocks circulation in liver.
- •Patients with dependence on corticosteroids
- •Patients with active autoimmune diseases requiring systemic immunosuppressive therapy
- •Patients who are currently receiving or received within past 30 days anti-cancer therapy, local treatments for liver tumors (radiotherapy, embolism, ablation) or liver surgery
- •Patients currently receiving other investigational treatments (biotherapy, chemotherapy, or radiotherapy)
- •Patients undergoing current treatment known to interfere with lymphodepleting chemotherapy (cyclophosphamide, etc.).
- •Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within two years. Patients with a history of successfully-treated tumors with no sign of recurrence in the last two years may be enrolled.
- •Patients with other uncontrolled diseases, such as active infections:
- •Acute or chronic active hepatitis B or hepatitis C.
- •HIV-infection
- •Women who are pregnant
研究组 & 干预措施
intravenous (i.v.) arm
autologous ET1402L1-CART cells administered by intravenous (IV) infusion
干预措施: autologous ET1402L1-CART cells (Biological)
intra-hepatic artery (i.a.) arm
autologous ET1402L1-CART cells administered by intra-hepatic artery (IA) infusion
干预措施: autologous ET1402L1-CART cells (Biological)
结局指标
主要结局
Toxicity profile of ET1402L1-CART-cell treatment
时间窗: 28 days up to 2 years
Frequency of treatment-related adverse events that occurred at any time from the first day of infusion that are "possibly", "likely", or "definitely" related to the study, including infusion related toxicity and ET1402L1-CART T cells related toxicity. Include but not limited to: Fever, chills, nausea, vomiting, jaundice and other gastrointestinal symptoms; Fatigue, hypotension, respiratory distress; Tumor lysis syndrome; Cytokine release syndrome; Neutropenia, thrombocytopenia; Liver and kidney dysfunction. Assessed at all visits.
Number of patients with dose-limiting toxicity
时间窗: 28 days up to 2 years
A dose limiting toxicity is defined as any toxicity that is considered to be primarily related to the ET1402L1-CART-cells, which is irreversible, or life threatening or CTCAE Grade 3-5. Assessed at all visits.
次要结局
- AFP expression in tumors(4-8 weeks)
- Time to baseline for serum cytokine levels(24 weeks)
- Rate of disease response by RECIST in the liver(2 years)
- AFP serum levels(2 years)
- Anti-tumor responses(4 months, 1 year, 2 years)
- CART cell engraftment(2 years)
- Rate of disease response by RECIST at non-liver sites(2 years)
- Tmax of serum cytokine levels(24 weeks)
- AUC of serum cytokine levels(24 weeks)