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

Early Phase 1

Completed

• Conditions: Hepatocellular Carcinoma; Liver Neoplasms; Metastatic Liver Cancer; Liver Cancer
• Interventions: Biological: ET1402L1-ARTEMIS™ T cells -Intratumoral Injections; Biological: ET1402L1-ARTEMIS™ T cells -intra-hepatic artery; Biological: ET1402L1-ARTEMIS™ T cells -IV

• Registration Number: NCT03888859
• Lead Sponsor: First Affiliated Hospital Xi'an Jiaotong University

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.

Study Timeline

• Study Start: 2017-12-06
• Study First Submitted: 2019-02-01
• Study First Submitted QC: 2019-03-22
• Study First Posted: 2019-03-25
• Primary Completion: 2019-04-13
• Study Completion: 2020-12-08
• Status Verified: 2021-03
• Last Update Submitted: 2021-03-26
• Last Update Posted: 2021-03-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Intratumoral Injections (i.t.) arm	ET1402L1-ARTEMIS™ T cells -Intratumoral Injections	autologous ET1402L1-ARTEMIS™2 T cells administered by intratumoral injections (i.t.) infusion
Intra-hepatic artery (i.a.) arm	ET1402L1-ARTEMIS™ T cells -intra-hepatic artery	autologous ET1402L1-ARTEMIS™2 T cells administered by intra-hepatic artery (IA) infusion
Intravenous (i.v.) arm	ET1402L1-ARTEMIS™ T cells -IV	autologous ET1402L1-ARTEMIS™2 T cells administered by intravenous (IV) infusion

Primary Outcome Measures

Name	Time	Method
Number of patients with dose-limiting toxicity	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-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	Time Frame: 28 days up to 2 years	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

Name	Time	Method
AFP serum levels	2 years	Percent change compared to the baseline
Rate of disease response by RECIST at non-liver sites	2 years	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 in the liver	2 years	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)	at 4 months, 1 year, 2 years	Progression free survival (PFS) at 4 months, 1 year and 2 years
% of ET1402L1-ARTEMIS™2 T cells in peripheral blood	2 years	%of ET1402L1-ARTEMIS™2 T cells in peripheral blood will be presented as Time to peak, Time to baseline level
Median Survival（MS）	at 4 months, 1 year, 2 years	Median Survival（MS）at 4 months, 1 year and 2 years
Overall survival（OS）	at 2 years	overall survival（OS）at 2 years
Number of ET1402L1-ARTEMIS™2 T cells in peripheral blood	2 years	Number of ET1402L1-ARTEMIS™2 T cells in peripheral blood will be presented as Time to peak, Time to baseline level
AUC of serum IL-2, IL-4, IL-6, IL-10, TNF-α and INFγ	24 weeks	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	24 weeks	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.
AFP expression in tumors	4-8 weeks	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)	24 weeks	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.

Trial Locations

Locations (1)

The First Affiliated Hospital of Xi'an Jiaotong University; 🇨🇳 Xi'an, China