Hepatocellular Carcinoma, Liver Cancer, Liver Neoplasms, Metastatic Liver Cancer
Conditions
Keywords
alpha-fetoprotein, AFP, HCC, CAR T cell therapy
Brief summary
Clinical study to evaluate safety and pharmacokinetics (primary objectives) and efficacy (secondary objective) of ET1402L1-CART-cells in patients with AFP+ HCC
Detailed description
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.
Interventions
BIOLOGICALautologous ET1402L1-CART cells
Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1)-CAR expression construct
Sponsors
Renmin Hospital of Wuhan University
Eureka Therapeutics Inc.
Aeon Therapeutics (Shanghai) Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with dose-limiting toxicity | 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. |
| Toxicity profile of ET1402L1-CART-cell treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anti-tumor responses | 4 months, 1 year, 2 years | Progression free survival (PFS) and Median survival (MS) at 4 months, 1 year, 2 years |
| AFP serum levels | 2 years | Percent change compared to the baseline |
| CART cell engraftment | 2 years | 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). |
| Rate of disease response by RECIST in the liver | 2 years | 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). |
| Tmax of serum cytokine levels | 24 weeks | 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. |
| Time to baseline for serum cytokine levels | 24 weeks | 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. |
| AUC of serum cytokine levels | 24 weeks | 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). |
| AFP expression in tumors | 4-8 weeks | Percent of AFP-positive cells in randomly selected fields in tumor biopsies |
| Rate of disease response by RECIST at non-liver sites | 2 years | 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). |
Countries
China
Outcome results
None listed