Clinical Study of ET1402L1-CAR T Cells in AFP Expressing Hepatocellular Carcinoma

Study Overview
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Brief Summary
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Clinical study to evaluate safety and pharmacokinetics (primary objectives) and efficacy (secondary objective) of ET1402L1-CART-cells in patients with AFP+ HCC

Detailed Description
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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.

Official Title
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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)

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

Intervention / Treatment
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* Biological: autologous ET1402L1-CART cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. KPS ≥70% 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. Exclusion criteria: 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

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intravenous (i.v.) arm<br>autologous ET1402L1-CART cells administered by intravenous (IV) infusion | Biological: autologous ET1402L1-CART cells<br>* Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1)-CAR expression construct<br>|
| Experimental: intra-hepatic artery (i.a.) arm<br>autologous ET1402L1-CART cells administered by intra-hepatic artery (IA) infusion | Biological: autologous ET1402L1-CART cells<br>* Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1)-CAR expression construct<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with dose-limiting toxicity | 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. | 28 days up to 2 years | 
| Toxicity profile of ET1402L1-CART-cell treatment | 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. | 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), complete remission (CR), partial response (PR), stable disease (SD), no response (NR), overall survival (OS). | 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 | 
| Anti-tumor responses | Progression free survival (PFS) and Median survival (MS) at 4 months, 1 year, 2 years | 4 months, 1 year, 2 years | 
| AFP serum levels | Percent change compared to the baseline | 2 years | 
| CART cell engraftment | Number and % of ET1402L1-CART cells in peripheral blood will be presented as Time to peak, Time to baseline level and the overall exposure will be presented as area under curve (AUC). | 2 years | 
| AFP expression in tumors | Percent of AFP-positive cells in randomly selected fields in tumor biopsies | 4-8 weeks | 
| Tmax of serum cytokine levels | Increases or decreases in the amount of cytokine produced compared to baseline at time points measured up to 24 weeks since dosing. Cytokines as measured by Bio-Plex Multiplex Immuoassays will be presented as time to peak level. | 24 weeks | 
| Time to baseline for serum cytokine levels | Increases or decreases in the amount of cytokine produced compared to baseline at time points measured up to 24 weeks since dosing. Cytokines as measured by Bio-Plex Multiplex Immuoassays will be presented as Time to baseline. | 24 weeks | 
| AUC of serum cytokine levels | Increases or decreases in the amount of cytokine produced compared to baseline at time points measured up to 24 weeks since dosing. Cytokines as measured by Bio-Plex Multiplex Immuoassays will be presented as area under curve (AUC). | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alpha-fetoprotein, AFP, HCC, CAR T cell therapy