ET 140202 -T Cell Combined With TAE or Sorafenib in the Treatment of Liver Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of ET 140202 -T cell combined With TAE or Sorafenib in the treatment of liver cancer

Detailed Description
-----------------
The molecular target for ET140202-T cells is HLA-A02 complexed with a HLA-A02-restricted peptide of alpha fetoprotein (AFP), which is expressed on 60-80 percent of hepatocellular carcinoma (HCC). This clinical study evaluates the safety and pharmacokinetics of ET140202-T cells with TAE or Sorafenib in patients with HCC who have no available curative therapeutic options and a poor overall prognosis.

Official Title
-----------------
Clinical Study of ET 140202 -T Cell Combined With TAE or Sorafenib in the Treatment of Advanced Liver Cancer

Conditions
-----------------
Hepatocellular Carcinoma, Liver Cancer, Liver Neoplasms, Metastatic Liver Cancer

Intervention / Treatment
-----------------
* Combination Product: Sorafenib combined with ET140202-T cell
* Combination Product: TAE combined with ET140202-T cell
* Biological: ET140202-T cell


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: AFP-expressing HCC and serum AFP >10 x ULN 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, ECOG 0-2, Life expectancy > 6 months Measurable disease as defined by: at least 1 liver lesion that can be accurately and serially measured. Negative serum pregnancy test for women with childbearing potential Adequate organ function as defined below: A pretreatment measured creatinine clearance (absolute value) of ≥50 ml/minute. Patients must have a serum direct bilirubin ≤3 x ULN, ALT and AST ≤5 x ULN. Ejection Fraction measured by echocardiogram or MUGA >50% (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) INR ≤1.5 x ULN Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent. Exclusion Criteria: 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ET140202-T cell combine with Sorafenib<br>Sorafenib treatment everyday and autologous ET140202-T cell administered by intravenous (IV) infusion | Combination Product: Sorafenib combined with ET140202-T cell<br>* Sorafenib starting dose of 400mg b.i.d. a.c. Autologous T cells transduced with lentivirus encoding an anti-AFP (ET140202) expression construct by intravenous (IV) infusion<br>|
| Experimental: ET140202-T cell combine with TAE<br>TAE treatment ahead every two times of autologous ET140202-T cell administered by intravenous (IV) infusion | Combination Product: TAE combined with ET140202-T cell<br>* Transarterial embolization(TAE) treatment Autologous T cells transduced with lentivirus encoding an anti-AFP (ET140202) expression construct -intravenous (i.v.)<br>|
| Experimental: solo ET140202-T cell<br>autologous ET140202-T cell administered by intravenous (IV) infusion | Biological: ET140202-T cell<br>* Autologous T cells transduced with lentivirus encoding an anti-AFP (ET140202) - expression construct -intravenous (i.v.)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of ARTEMIS T cell treatment-related adverse events | 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. | 28 days up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of disease response by RECIST in the liver | Response rates will be estimated as the percent of patients with objective response (OR)，which was defined as any of complete remission (CR), partial response (PR) at 2 years. | 2 years | 
| Rate of disease response by RECIST at non-liver sites | Response rates will be estimated as the percent of patients with objective response (OR), complete remission (CR), partial response (PR), stable disease (SD), no response (NR), overall survival (OS). | 2 years | 
| Progression free survival (PFS) | Progression free survival (PFS) at 4 months, 1 year and 2 years | at 4 months, 1 year, 2 years | 
| Median Survival（MS） | Median Survival（MS）at 4 months, 1 year and 2 years | at 4 months, 1 year, 2 years | 
| Overall survival（OS） | overall survival（OS）at 2 years | at 2 years | 
| AFP serum levels | Percent change compared to the baseline | 2 years | 
| Number of ET140202-T cells in peripheral blood | Number of ET140202-T cells in peripheral blood will be presented as Time to peak, Time to baseline level | 2 years | 
| Alpha-fetoprotein (AFP) expression in tumors | Percent of AFP-positive cells in randomly selected fields in tumor biopsies. | 4-8 weeks | 
| IL-6 serum levels | Amount change compared to the baseline | 4-8 weeks | 
| IL-2 serum levels | Amount change compared to the baseline | 4-8 weeks | 
| IL-10 serum levels | Amount change compared to the baseline | 4-8 weeks | 
| TNF-α serum levels | Amount change compared to the baseline | 4-8 weeks | 
| IFN-γ serum levels | Amount change compared to the baseline | 4-8 weeks |