Hepatocellular Carcinoma, Liver Cancer, Liver Neoplasms, Metastatic Liver Cancer
Conditions
Brief summary
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).
Detailed description
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.
Interventions
BIOLOGICALET1402L1-ARTEMIS™ T cells -intra-hepatic artery
Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1) -ARTEMIS™2 expression construct: intra-hepatic artery (i.a.) arm
BIOLOGICALET1402L1-ARTEMIS™ T cells -Intratumoral Injections
Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1) -ARTEMIS™2 expression construct: Intratumoral Injections (i.t.) arm
BIOLOGICALET1402L1-ARTEMIS™ T cells -IV
Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1) -ARTEMIS™2 expression construct -intravenous (i.v.) arm
Sponsors
Eureka Therapeutics Inc.
Aeon Therapeutics (Shanghai) Co., Ltd.
First Affiliated Hospital Xi'an Jiaotong University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* 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: 1. 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. 2. A pretreatment measured creatinine clearance (absolute value) of ≥ 50 ml/minute 3. 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) 4. Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) or Forced Expiratory Volume in the first second (FEV1)\>45% predicted 5. Absolute neutrophil count (ANC) ≥ 1500/mm3 (10\^9/L) 6. 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.
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
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-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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival (PFS) | at 4 months, 1 year, 2 years | Progression free survival (PFS) at 4 months, 1 year and 2 years |
| Median Survival（MS） | at 4 months, 1 year, 2 years | Median Survival（MS）at 4 months, 1 year and 2 years |
| Overall survival（OS） | at 2 years | overall survival（OS）at 2 years |
| AFP serum levels | 2 years | Percent change compared to the baseline |
| Number of ET1402L1-ARTEMIS™2 T cells in peripheral blood | 2 years | Number of ET1402L1-ARTEMIS™2 T cells in peripheral blood will be presented as Time to peak, Time to baseline level |
| 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)，which was defined as any of complete remission (CR), partial response (PR) at 2 years. |
| AFP expression in tumors | 4-8 weeks | Percent of AFP-positive cells in randomly selected fields in tumor biopsies. |
| Tmax of serum Interleukin (IL)-2, IL-4, IL-6, IL-10, Tumor necrosis factor(TNF)-α and Interferon gamma (INFγ) | 24 weeks | Increase or decreases in the amount of serum IL-2, IL-4, IL-6, IL-10, TNF-α and INF-γ produced compared to baseline at time points measured up to 24 weeks since dosing. Data will be presented as time to peak level for Tmax. |
| AUC of serum IL-2, IL-4, IL-6, IL-10, TNF-α and INFγ | 24 weeks | Increase or decreases in the amount of serum IL-2, IL-4, IL-6, IL-10, TNF-α and INFγ produced compared to baseline at time points measured up to 24 weeks since dosing. Data will be presented as time to peak level for area under curve (AUC). |
| Time to baseline for serum IL-2, IL-4, IL-6, IL-10, TNF-α and INFγ | 24 weeks | Increase or decreases in the amount of IL-2, IL-4, IL-6, IL-10, TNF-α and INFγ produced compared to baseline at time points measured up to 24 weeks since dosing. |
| % of ET1402L1-ARTEMIS™2 T cells in peripheral blood | 2 years | %of ET1402L1-ARTEMIS™2 T cells in peripheral blood will be presented as Time to peak, Time to baseline level |
| 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)，which was defined as any of complete remission (CR), partial response (PR) at 2 years. |
Countries
China
Outcome results
None listed