Clinical trial NCT03349255: 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
Overall status: TERMINATED
Phase: PHASE1
Conditions: Hepatocellular Carcinoma
Liver Cancer
Liver Neoplasms
Metastatic Liver Cancer
Keywords: alpha-fetoprotein
AFP
HCC
CAR T cell therapy
Lead sponsor: Aeon Therapeutics (Shanghai) Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Renmin Hospital of Wuhan University
name: Eureka Therapeutics Inc.
First posted: 2017-11-21
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of patients with dose-limiting toxicity
timeFrame: 28 days up to 2 years
measure: Toxicity profile of ET1402L1-CART-cell treatment
timeFrame: 28 days up to 2 years
Secondary outcomes:
measure: Rate of disease response by RECIST in the liver
timeFrame: 2 years
measure: Rate of disease response by RECIST at non-liver sites
timeFrame: 2 years
measure: Anti-tumor responses
timeFrame: 4 months, 1 year, 2 years
measure: AFP serum levels
timeFrame: 2 years
measure: CART cell engraftment
timeFrame: 2 years
measure: AFP expression in tumors
timeFrame: 4-8 weeks
measure: Tmax of serum cytokine levels
timeFrame: 24 weeks
measure: Time to baseline for serum cytokine levels
timeFrame: 24 weeks
measure: AUC of serum cytokine levels
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Wuhan
country: China
facility: Renmin Hospital of Wuhan University
state: Hubei
Study officials:
affiliation: Renmin Hospital of Wuhan University
name: Qibin Song, M.D./Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: