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

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)

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

Study Overview

• Status: Terminated
• Conditions: Liver Neoplasms; Hepatocellular Carcinoma; Liver Cancer; Metastatic Liver Cancer
• Intervention / Treatment: Biological: autologous ET1402L1-CART cells

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 Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430060
      • Renmin Hospital of Wuhan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	28 days up to 2 years
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.	28 days up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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), complete remission (CR), partial response (PR), stable disease (SD), no response (NR), overall survival (OS).	2 years
Anti-tumor responses	Progression free survival (PFS) and Median survival (MS) at 4 months, 1 year, 2 years	4 months, 1 year, 2 years
AFP serum levels	Percent change compared to the baseline	2 years
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).	2 years
AFP expression in tumors	Percent of AFP-positive cells in randomly selected fields in tumor biopsies	4-8 weeks
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.	24 weeks
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.	24 weeks
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).	24 weeks

Collaborators and Investigators

• Sponsor: Aeon Therapeutics (Shanghai) Co., Ltd.
• Collaborators: Renmin Hospital of Wuhan University; Eureka Therapeutics Inc.
• Investigators: Principal Investigator: Qibin Song, M.D./Ph.D., Renmin Hospital of Wuhan University

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2017
• Primary Completion (Actual): January 10, 2019
• Study Completion (Actual): January 10, 2019

Study Registration Dates

• First Submitted: October 24, 2017
• First Submitted That Met QC Criteria: November 16, 2017
• First Posted (Actual): November 21, 2017

Study Record Updates

• Last Update Posted (Actual): July 1, 2019
• Last Update Submitted That Met QC Criteria: June 27, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: HCC; alpha-fetoprotein; AFP; CAR T cell therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms
• Other Study ID Numbers: ETCH17AFPCAR101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• 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