ET1402L1-ARTEMIS™2 T Cells in Alpha Fetoprotein (AFP) Expressing Hepatocellular Carcinoma

Hepatocellular Carcinoma Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03888859
• Other study ID #: XJTU1AF2017LSL-C002
• Status: Completed
• Phase: Early Phase 1
• Start date: December 6, 2017
• Est. completion date: December 8, 2020

Study information

• Verified date: March 2021
• Source: First Affiliated Hospital Xi'an Jiaotong University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: December 8, 2020
• Est. primary completion date: April 13, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma
• Liver Cancer
• Liver Neoplasms
• Metastatic Liver Cancer

Intervention

Biological:
• ET1402L1-ARTEMIS™ T cells -IV
Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1) -ARTEMIS™2 expression construct -intravenous (i.v.) arm
• ET1402L1-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
• ET1402L1-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

Locations

Country	Name	City	State
China	The First Affiliated Hospital of Xi'an Jiaotong University	Xi'an

Sponsors (3)

Lead Sponsor	Collaborator
First Affiliated Hospital Xi'an Jiaotong University	Aeon Therapeutics (Shanghai) Co., Ltd., Eureka Therapeutics Inc.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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-ARTEMIS™2 T-cells, which is irreversible, or life threatening or CTCAE Grade 3-5. Assessed at all visits.	28 days up to 2 years
Primary	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.	Time Frame: 28 days up to 2 years
Secondary	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
Secondary	Rate of disease response by RECIST at non-liver sites	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
Secondary	Progression free survival (PFS)	Progression free survival (PFS) at 4 months, 1 year and 2 years	at 4 months, 1 year, 2 years
Secondary	Median Survival(MS)	Median Survival(MS)at 4 months, 1 year and 2 years	at 4 months, 1 year, 2 years
Secondary	Overall survival(OS)	overall survival(OS)at 2 years	at 2 years
Secondary	AFP serum levels	Percent change compared to the baseline	2 years
Secondary	Number of ET1402L1-ARTEMIS™2 T cells in peripheral blood	Number of ET1402L1-ARTEMIS™2 T cells in peripheral blood will be presented as Time to peak, Time to baseline level	2 years
Secondary	% of ET1402L1-ARTEMIS™2 T cells in peripheral blood	%of ET1402L1-ARTEMIS™2 T cells in peripheral blood will be presented as Time to peak, Time to baseline level	2 years
Secondary	AFP expression in tumors	Percent of AFP-positive cells in randomly selected fields in tumor biopsies.	4-8 weeks
Secondary	Tmax of serum Interleukin (IL)-2, IL-4, IL-6, IL-10, Tumor necrosis factor(TNF)-a and Interferon gamma (INF?)	Increase or decreases in the amount of serum IL-2, IL-4, IL-6, IL-10, TNF-a and INF-? 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.	24 weeks
Secondary	AUC of serum IL-2, IL-4, IL-6, IL-10, TNF-a and INF?	Increase or decreases in the amount of serum IL-2, IL-4, IL-6, IL-10, TNF-a and INF? 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).	24 weeks
Secondary	Time to baseline for serum IL-2, IL-4, IL-6, IL-10, TNF-a and INF?	Increase or decreases in the amount of IL-2, IL-4, IL-6, IL-10, TNF-a and INF? produced compared to baseline at time points measured up to 24 weeks since dosing.	24 weeks