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

Primary Purpose

Hepatocellular Carcinoma, Liver Cancer, Liver Neoplasms

Status

Completed

Phase

Early Phase 1

Locations

China

Study Type

Interventional

Intervention

ET1402L1-ARTEMIS™ T cells -IV

ET1402L1-ARTEMIS™ T cells -intra-hepatic artery

ET1402L1-ARTEMIS™ T cells -Intratumoral Injections

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

The First Affiliated Hospital of Xi'an Jiaotong University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Intravenous (i.v.) arm

Intra-hepatic artery (i.a.) arm

Intratumoral Injections (i.t.) arm

Arm Description

autologous ET1402L1-ARTEMIS™2 T cells administered by intravenous (IV) infusion

autologous ET1402L1-ARTEMIS™2 T cells administered by intra-hepatic artery (IA) infusion

autologous ET1402L1-ARTEMIS™2 T cells administered by intratumoral injections (i.t.) infusion

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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.

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.

Progression free survival (PFS)

Progression free survival (PFS) at 4 months, 1 year and 2 years

Median Survival（MS）

Median Survival（MS）at 4 months, 1 year and 2 years

Overall survival（OS）

overall survival（OS）at 2 years

AFP serum levels

Percent change compared to the baseline

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

% 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

AFP expression in tumors

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)

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

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

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.

Full Information

NCT ID

NCT03888859

First Posted

February 1, 2019

Last Updated

March 26, 2021

Sponsor

First Affiliated Hospital Xi'an Jiaotong University

Collaborators

Eureka Therapeutics Inc., Aeon Therapeutics (Shanghai) Co., Ltd.

1. Study Identification

Unique Protocol Identification Number

NCT03888859

Brief Title

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

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)

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Completed

Study Start Date

December 6, 2017 (Actual)

Primary Completion Date

April 13, 2019 (Actual)

Study Completion Date

December 8, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

First Affiliated Hospital Xi'an Jiaotong University

Collaborators

Eureka Therapeutics Inc., Aeon Therapeutics (Shanghai) Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Early Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

12 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Intravenous (i.v.) arm

Arm Type

Experimental

Arm Description

autologous ET1402L1-ARTEMIS™2 T cells administered by intravenous (IV) infusion

Arm Title

Intra-hepatic artery (i.a.) arm

Arm Type

Experimental

Arm Description

autologous ET1402L1-ARTEMIS™2 T cells administered by intra-hepatic artery (IA) infusion

Arm Title

Intratumoral Injections (i.t.) arm

Arm Type

Experimental

Arm Description

autologous ET1402L1-ARTEMIS™2 T cells administered by intratumoral injections (i.t.) infusion

Intervention Type

Biological

Intervention Name(s)

ET1402L1-ARTEMIS™ T cells -IV

Intervention Description

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

Intervention Type

Biological

Intervention Name(s)

ET1402L1-ARTEMIS™ T cells -intra-hepatic artery

Intervention Description

Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1) -ARTEMIS™2 expression construct: intra-hepatic artery (i.a.) arm

Intervention Type

Biological

Intervention Name(s)

ET1402L1-ARTEMIS™ T cells -Intratumoral Injections

Intervention Description

Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1) -ARTEMIS™2 expression construct: Intratumoral Injections (i.t.) arm

Primary Outcome Measure Information:

Title

Number of patients with dose-limiting toxicity

Description

Time Frame

28 days up to 2 years

Title

Frequency of ARTEMIS T cell treatment-related adverse events

Description

Time Frame

Time Frame: 28 days up to 2 years

Secondary Outcome Measure Information:

Title

Rate of disease response by RECIST in the liver

Description

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.

Time Frame

2 years

Title

Rate of disease response by RECIST at non-liver sites

Description

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.

Time Frame

2 years

Title

Progression free survival (PFS)

Description

Progression free survival (PFS) at 4 months, 1 year and 2 years

Time Frame

at 4 months, 1 year, 2 years

Title

Median Survival（MS）

Description

Median Survival（MS）at 4 months, 1 year and 2 years

Time Frame

at 4 months, 1 year, 2 years

Title

Overall survival（OS）

Description

overall survival（OS）at 2 years

Time Frame

at 2 years

Title

AFP serum levels

Description

Percent change compared to the baseline

Time Frame

2 years

Title

Number of ET1402L1-ARTEMIS™2 T cells in peripheral blood

Description

Number of ET1402L1-ARTEMIS™2 T cells in peripheral blood will be presented as Time to peak, Time to baseline level

Time Frame

2 years

Title

% of ET1402L1-ARTEMIS™2 T cells in peripheral blood

Description

%of ET1402L1-ARTEMIS™2 T cells in peripheral blood will be presented as Time to peak, Time to baseline level

Time Frame

2 years

Title

AFP expression in tumors

Description

Percent of AFP-positive cells in randomly selected fields in tumor biopsies.

Time Frame

4-8 weeks

Title

Tmax of serum Interleukin (IL)-2, IL-4, IL-6, IL-10, Tumor necrosis factor(TNF)-α and Interferon gamma (INFγ)

Description

Time Frame

24 weeks

Title

AUC of serum IL-2, IL-4, IL-6, IL-10, TNF-α and INFγ

Description

Time Frame

24 weeks

Title

Time to baseline for serum IL-2, IL-4, IL-6, IL-10, TNF-α and INFγ

Description

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.

Time Frame

24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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: 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. A pretreatment measured creatinine clearance (absolute value) of ≥ 50 ml/minute 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) Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) or Forced Expiratory Volume in the first second (FEV1)>45% predicted Absolute neutrophil count (ANC) ≥ 1500/mm3 (10^9/L) 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Chang Liu, PhD

Organizational Affiliation

First Affiliated Hospital Xi'an Jiaotong University

Official's Role

Principal Investigator

Facility Information:

Facility Name

The First Affiliated Hospital of Xi'an Jiaotong University

City

Xi'an

ZIP/Postal Code

710061

Country

China

12. IPD Sharing Statement

Learn more about this trial

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

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