Phase 1, Open-label, Three Routes IV, Intratumoral Injections and Intra-hepatic Artery Dose-escalation Clinical Study to Evaluate the Safety and Efficacy of ET1402L1-ARTEMIS™2™ T- Cells in AFP Expressing Hepatocellular Carcinoma (HCC)
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Number of patients with dose-limiting toxicity
研究概览
简要总结
Clinical study to evaluate safety (primary objectives) and efficacy (secondary objective) of ET1402L1-ARTEMIS™2 T cells in patients with alpha fetoprotein positive (AFP+ ) hepatocellular carcinoma (HCC).
详细描述
The molecular target for ET1402L1-ARTEMIS™2 is human leukocyte antigen (HLA) -A02 complexed with a HLA-A02-restricted peptide of alpha fetoprotein (AFP), which is expressed on 60-80 percent of hepatocellular carcinoma (HCC). ARTEMIS™2 is a second generation ARTEMIS™ receptor engineered with a human antibody domain against the anti-HLA-A02/AFP complex. This clinical study evaluates the safety and pharmacokinetics of ET1402L1-ARTEMIS™2 T-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 intra-hepatic artery (IA) arm or Intratumoral Injections arm, with the ET1402L1-ARTEMIS™2 T-cells administered via intrahepatic artery catheter. Patients with extrahepatic metastasis will be enrolled in the intravenous (IV) arm, with the ET1402L1-ARTEMIS™2 T-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 75 Years（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.
- •Abandon or failure in first or second line treatment
- •Molecular HLA class I typing confirms participant carries at least one HLA-A02 allele
- •Child-Pugh score of A or B, Barcelona Clinic Liver Cancer stage of C or D
- •Life expectancy > 4 months
- •Karnofsky score ≥70%
- •Adequate organ function as defined below:
- •Patients must have a serum Total bilirubin ≤2 x Upper Limit of Normal (ULN), Alanine transaminase (ALT) and Aspartate transaminase (AST) ≤5 times the institutional ULN.
- •A pretreatment measured creatinine clearance (absolute value) of ≥ 50 ml/minute
- •Ejection fraction measured by echocardiogram or Multiple gated acquisition scanning (MUGA) >45% (evaluation done with 6 weeks of screening does not need to be repeated)
- •Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) or Forced Expiratory Volume in the first second (FEV1)>45% predicted
- •Absolute neutrophil count (ANC) ≥ 1500/mm3 (10^9/L)
- •Platelet count ≥ 50,000/mm3 (10^9/L)
- •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 tumor infiltration in the portal vein, hepatic veins or inferior vena cava that completely blocks circulation in liver.
- •Patients with an organ transplantation history
- •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)
- •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.
- •Women who are pregnant or breast-feed
- •HIV-infection
结局指标
主要结局
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-ARTEMIS™2 T-cells, which is irreversible, or life threatening or CTCAE Grade 3-5. Assessed at all visits.
Frequency of ARTEMIS T cell treatment-related adverse events
时间窗: Time Frame: 28 days up to 2 years
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.
次要结局
- AFP serum levels(2 years)
- Rate of disease response by RECIST at non-liver sites(2 years)
- Rate of disease response by RECIST in the liver(2 years)
- Progression free survival (PFS)(at 4 months, 1 year, 2 years)
- % of ET1402L1-ARTEMIS™2 T cells in peripheral blood(2 years)
- Median Survival（MS）(at 4 months, 1 year, 2 years)
- Overall survival（OS）(at 2 years)
- Number of ET1402L1-ARTEMIS™2 T cells in peripheral blood(2 years)
- AUC of serum IL-2, IL-4, IL-6, IL-10, TNF-α and INFγ(24 weeks)
- Time to baseline for serum IL-2, IL-4, IL-6, IL-10, TNF-α and INFγ(24 weeks)
- AFP expression in tumors(4-8 weeks)
- Tmax of serum Interleukin (IL)-2, IL-4, IL-6, IL-10, Tumor necrosis factor(TNF)-α and Interferon gamma (INFγ)(24 weeks)