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

Primary Purpose

Hepatocellular Carcinoma, Liver Cancer, Liver Neoplasms

Status
Terminated
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
autologous ET1402L1-CART cells
Sponsored by
Aeon Therapeutics (Shanghai) Co., Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring alpha-fetoprotein, AFP, HCC, CAR T cell therapy

Eligibility Criteria

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

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

Sites / Locations

  • Renmin Hospital of Wuhan University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

intravenous (i.v.) arm

intra-hepatic artery (i.a.) arm

Arm Description

autologous ET1402L1-CART cells administered by intravenous (IV) infusion

autologous ET1402L1-CART cells administered by intra-hepatic artery (IA) 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-CART-cells, which is irreversible, or life threatening or CTCAE Grade 3-5. Assessed at all visits.
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.

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), complete remission (CR), partial response (PR), stable disease (SD), no response (NR), overall survival (OS).
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).
Anti-tumor responses
Progression free survival (PFS) and Median survival (MS) at 4 months, 1 year, 2 years
AFP serum levels
Percent change compared to the baseline
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).
AFP expression in tumors
Percent of AFP-positive cells in randomly selected fields in tumor biopsies
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.
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.
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).

Full Information

First Posted
October 24, 2017
Last Updated
June 27, 2019
Sponsor
Aeon Therapeutics (Shanghai) Co., Ltd.
Collaborators
Renmin Hospital of Wuhan University, Eureka Therapeutics Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT03349255
Brief Title
Clinical Study of ET1402L1-CAR T Cells in AFP Expressing Hepatocellular Carcinoma
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2019
Overall Recruitment Status
Terminated
Why Stopped
Will study new T-cell construct for the same indication
Study Start Date
October 6, 2017 (Actual)
Primary Completion Date
January 10, 2019 (Actual)
Study Completion Date
January 10, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Aeon Therapeutics (Shanghai) Co., Ltd.
Collaborators
Renmin Hospital of Wuhan University, Eureka Therapeutics Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

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.

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
Keywords
alpha-fetoprotein, AFP, HCC, CAR T cell therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
intravenous (i.v.) arm
Arm Type
Experimental
Arm Description
autologous ET1402L1-CART cells administered by intravenous (IV) infusion
Arm Title
intra-hepatic artery (i.a.) arm
Arm Type
Experimental
Arm Description
autologous ET1402L1-CART cells administered by intra-hepatic artery (IA) infusion
Intervention Type
Biological
Intervention Name(s)
autologous ET1402L1-CART cells
Intervention Description
Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1)-CAR expression construct
Primary Outcome Measure Information:
Title
Number of patients with dose-limiting toxicity
Description
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.
Time Frame
28 days up to 2 years
Title
Toxicity profile of ET1402L1-CART-cell treatment
Description
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.
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), complete remission (CR), partial response (PR), stable disease (SD), no response (NR), overall survival (OS).
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), complete remission (CR), partial response (PR), stable disease (SD), no response (NR), overall survival (OS).
Time Frame
2 years
Title
Anti-tumor responses
Description
Progression free survival (PFS) and Median survival (MS) at 4 months, 1 year, 2 years
Time Frame
4 months, 1 year, 2 years
Title
AFP serum levels
Description
Percent change compared to the baseline
Time Frame
2 years
Title
CART cell engraftment
Description
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).
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 cytokine levels
Description
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 Frame
24 weeks
Title
Time to baseline for serum cytokine levels
Description
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.
Time Frame
24 weeks
Title
AUC of serum cytokine levels
Description
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).
Time Frame
24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Qibin Song, M.D./Ph.D.
Organizational Affiliation
Renmin Hospital of Wuhan University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Renmin Hospital of Wuhan University
City
Wuhan
State/Province
Hubei
ZIP/Postal Code
430060
Country
China

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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