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

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ClinicalTrials.gov Identifier: NCT03349255
Recruitment Status : Terminated (Will study new T-cell construct for the same indication)
First Posted : November 21, 2017
Last Update Posted : July 1, 2019
Sponsor:
Collaborators:
Renmin Hospital of Wuhan University
Eureka Therapeutics Inc.
Information provided by (Responsible Party):
Aeon Therapeutics (Shanghai) Co., Ltd.

Study Description
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Brief Summary:
Clinical study to evaluate safety and pharmacokinetics (primary objectives) and efficacy (secondary objective) of ET1402L1-CART-cells in patients with AFP+ HCC

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Liver Cancer Liver Neoplasms Metastatic Liver Cancer Biological: autologous ET1402L1-CART cells Phase 1

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 6, 2017
Actual Primary Completion Date : January 10, 2019
Actual Study Completion Date : January 10, 2019

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: intravenous (i.v.) arm
autologous ET1402L1-CART cells administered by intravenous (IV) infusion
 Biological: autologous ET1402L1-CART cells
Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1)-CAR expression construct
Experimental: intra-hepatic artery (i.a.) arm
autologous ET1402L1-CART cells administered by intra-hepatic artery (IA) infusion
 Biological: autologous ET1402L1-CART cells
Autologous T cells transduced with lentivirus encoding an anti-AFP (ET1402L1)-CAR expression construct


Outcome Measures
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Primary Outcome Measures :
  1. Number of patients with dose-limiting toxicity [ Time Frame: 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.

  2. Toxicity profile of ET1402L1-CART-cell treatment [ Time Frame: 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 Outcome Measures :
  1. Rate of disease response by RECIST in the liver [ Time Frame: 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).

  2. Rate of disease response by RECIST at non-liver sites [ Time Frame: 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).

  3. Anti-tumor responses [ Time Frame: 4 months, 1 year, 2 years ]
    Progression free survival (PFS) and Median survival (MS) at 4 months, 1 year, 2 years

  4. AFP serum levels [ Time Frame: 2 years ]
    Percent change compared to the baseline

  5. CART cell engraftment [ Time Frame: 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).

  6. AFP expression in tumors [ Time Frame: 4-8 weeks ]
    Percent of AFP-positive cells in randomly selected fields in tumor biopsies

  7. Tmax of serum cytokine levels [ Time Frame: 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.

  8. Time to baseline for serum cytokine levels [ Time Frame: 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.

  9. AUC of serum cytokine levels [ Time Frame: 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).


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03349255


Locations
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China, Hubei
Renmin Hospital of Wuhan University
Wuhan, Hubei, China, 430060
Sponsors and Collaborators
Aeon Therapeutics (Shanghai) Co., Ltd.
Renmin Hospital of Wuhan University
Eureka Therapeutics Inc.
Investigators
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Principal Investigator: Qibin Song, M.D./Ph.D. Renmin Hospital of Wuhan University
More Information
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Responsible Party: Aeon Therapeutics (Shanghai) Co., Ltd.
ClinicalTrials.gov Identifier: NCT03349255    
Other Study ID Numbers: ETCH17AFPCAR101
First Posted: November 21, 2017    Key Record Dates
Last Update Posted: July 1, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Keywords provided by Aeon Therapeutics (Shanghai) Co., Ltd.:
alpha-fetoprotein
AFP
HCC
CAR T cell therapy
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Liver Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
 Adenocarcinoma
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases