ET140203 T Cells for Pediatric Liver Cancer

(ARYA-2 Trial)

Recruiting at 2 trial locations

Overseen By Teresa Klask, MBA

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Eureka Therapeutics Inc.

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Heart failure, Uncontrolled infections, Active malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

15 Participants Needed

Trial Summary

What is the purpose of this trial?

Open-label, dose escalation, multi-center, Phase I/II clinical trial to assess the safety/tolerability and determine the recommended Phase II Dose (RP2D) of ET140203 T-cells in pediatric subjects who are AFP-positive/HLA-A2-positive and have relapsed/refractory HB, HCN-NOS, or HCC.

Will I have to stop taking my current medications?

The trial requires that participants stop taking certain medications, such as cytotoxic chemotherapy, radiation, other anti-cancer therapies, immunosuppressive therapy, or systemic corticosteroids above a certain dose, at least two weeks before certain procedures. However, topical and inhaled corticosteroids and physiological replacement doses for adrenal insufficiency are allowed.

What data supports the effectiveness of the treatment ET140203 T Cells for Pediatric Liver Cancer?

Research on similar T-cell therapies for liver cancer shows promising results, such as a study where patients treated with their own modified immune cells had a high survival rate and low recurrence of cancer. Additionally, T-cell therapies have been effective in treating other conditions, like viral infections in children, suggesting potential benefits for pediatric liver cancer. ^{1 2 3 4 5}

What safety data exists for ET140203 T Cells or similar treatments?

The safety of similar T cell therapies has been evaluated in clinical trials for liver cancer, showing that these treatments are generally safe and well-tolerated. For example, in one study, patients experienced only mild flu-like symptoms, and no severe adverse events were reported. ^{1 6 7 8 9}

How is the ET140203 T Cells treatment different from other treatments for pediatric liver cancer?

ET140203 T Cells treatment is unique because it uses a patient's own T cells that are engineered to specifically target cancer cells, offering a personalized immunotherapy approach. This is different from traditional treatments like chemotherapy, which do not specifically target cancer cells and can affect healthy cells as well. ^{1 2 7 10 11}

Research Team

Pei Wang, PhD

Principal Investigator

Eureka Therapeutics Inc.

Eligibility Criteria

This trial is for pediatric patients aged 1-21 with relapsed/refractory liver cancers (HB, HCN-NOS, or HCC) who are AFP-positive/HLA-A2-positive. They should have a life expectancy over 4 months and good performance status. Patients must not have had recent cancer treatments or other investigational therapies and should not be on systemic immunosuppressants.

Inclusion Criteria

For enrollment to the dose-finding cohort, subjects must have at least one (1) lesion ≥ 5 mm in diameter or two (2) or more lesions ≥ 3 mm in diameter. For the dose-expansion cohort, subjects must have measurable disease by RECIST v1.1.

My disease came back after initial treatment or didn't respond to it.

My organs are working well.

Exclusion Criteria

I am on medication to suppress my immune system due to an autoimmune disease.

I cannot take certain chemotherapy drugs like Fludarabine and Cyclophosphamide.

I haven't had certain cancer treatments or steroids in the last 2 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

A traditional dose escalation model (3+3) design will be used to determine the recommended phase II dose (RP2D)

Up to 2 years

Expansion

Subjects will be treated at the RP2D in the expansion phase of the trial

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, with tumor response assessments at Months 1, 3, 6, 9, 12, 18, and 24

2 years

7 visits (in-person) for tumor response assessments

Long-term Follow-up

Subjects will be followed for 15 years post-treatment for assessment of treatment safety and overall survival

15 years

Treatment Details

Interventions

• ET140203 T Cells

Trial Overview The trial tests ET140203 T-cells in children with specific liver cancers to find the safest dose that works best (Phase I/II). It's an open-label study where all participants receive the treatment, starting at lower doses which increase gradually to determine the optimal dose.

Participant Groups

Group I: ET140203 T Cells Experimental Treatment 1 Intervention

ET140203 Autologous T Cells

ET140203 T Cells is already approved in United States for the following indications:

Approved in United States as ET140203 for:

• Hepatoblastoma (HB)

Who Is Running the Clinical Trial?

Eureka Therapeutics Inc.

Lead Sponsor

Trials

12

Recruited

160+

Findings from Research

In a Phase I clinical trial involving 15 patients with primary hepatocellular carcinoma (HCC), adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) demonstrated low toxicity, with only mild flu-like symptoms reported after treatment.

After a median follow-up of 14 months, all patients were alive, and 80% showed no evidence of disease, suggesting that this immunotherapy could be an effective new treatment option for HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma. Jiang, SS., Tang, Y., Zhang, YJ., et al.[2018]

In a randomized clinical trial involving 101 patients with hepatocellular carcinoma, the infusion of activated and expanded autologous peripheral blood lymphocytes showed a lower recurrence rate of cancer (13 cases) compared to the control group (22 cases).

Minor adverse reactions were reported in 57% of the treated patients, indicating that while the treatment may have some side effects, it is generally well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prevention of cancer recurrence by infusion of activated autologous lymphocytes]. Sekine, T., Takayama, T., Konomi, Y., et al.[2017]

The study successfully developed bispecific CAR T cells (CoG133-CAR T cells) targeting both CD133 and glypican-3 (GPC3) antigens in hepatocellular carcinoma (HCC), demonstrating enhanced tumor-suppression efficacy in both in vitro and in vivo models.

Using a non-viral minicircle DNA (mcDNA) vector for gene delivery resulted in high transfection efficiency and safety, with no significant 'off-target' effects observed in major organs, indicating a promising approach for CAR T therapy in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonviral mcDNA-mediated bispecific CAR T cells kill tumor cells in an experimental mouse model of hepatocellular carcinoma. Wang, H., Wang, X., Ye, X., et al.[2022]

A new T cell receptor (TCR) targeting the alpha-fetoprotein (AFP) peptide has been identified as a promising candidate for immunotherapy against hepatocellular carcinoma (HCC), showing effective anti-tumor activity while minimizing cross-reactivity with normal tissues.

The selected AFP TCR has undergone rigorous testing for safety and efficacy, leading to the initiation of an early phase clinical trial (NCT03971747) to evaluate its effectiveness in treating HCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selection of a Clinical Lead TCR Targeting Alpha-Fetoprotein-Positive Liver Cancer Based on a Balance of Risk and Benefit. Luo, X., Cui, H., Cai, L., et al.[2021]

Adoptive T-cell transfer has shown clear clinical benefits in treating viral infections and posttransplant lymphoproliferative disease in pediatric patients, particularly after allogeneic transplants.

Recent advances in T-cell therapies for childhood malignancies focus on enhancing T-cell functions through strategies like gene modification and improving the host environment, although challenges remain in developing these therapies for various cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell-based therapies for malignancy and infection in childhood. Ahmed, N., Heslop, HE., Mackall, CL.[2021]

The administration of autologous invariant natural killer T (iNKT) cells in 10 patients with advanced hepatocellular carcinoma was found to be safe and well-tolerated, with no severe adverse events reported, even at high doses (up to 1×10^10 cells).

Expanded iNKT cells showed a strong T-helper 1-like immune response, producing significant amounts of cytokines associated with antitumor activity, suggesting potential effectiveness in treating hepatocellular carcinoma, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial. Gao, Y., Guo, J., Bao, X., et al.[2021]

Adoptive transfer of T cells with engineered T cell receptors (TCRs) shows potential as a treatment for hepatocellular carcinoma (HCC), especially since current treatment options are limited.

The study explores the possibility of targeting hepatitis B viral antigens as specific markers for HCC, suggesting that HBV-specific TCR redirected T cells could effectively attack cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell receptor-therapy in HBV-related hepatocellularcarcinoma. Bertoletti, A., Brunetto, M., Maini, MK., et al.[2022]

Adoptive T cell transfer, particularly using engineered T cells like CAR T cells, has shown significant promise in cancer treatment by enhancing the immune system's ability to target and eliminate tumor cells, with reduced off-target toxicity.

The FDA granted 'breakthrough therapy' designation to anti-CD19 CAR T cell therapy in 2014, highlighting its potential effectiveness, which has been supported by numerous preclinical and clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cell Therapy in Hematology. Ataca, P., Arslan, Ö.[2018]

Using electroporation to introduce mRNA encoding anti-HBV T-cell receptors (TCR) into T cells resulted in about 80% of CD8(+) T cells expressing functional HBV TCR, which is significantly higher than the 18% achieved with traditional retroviral methods.

Although the functionality of these TCR-electroporated T cells was transient, they effectively prevented tumor growth and suppressed established tumors in a model of hepatocellular carcinoma (HCC), indicating a promising and safer approach for cell therapy in HCC and potentially other HBV-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus. Koh, S., Shimasaki, N., Suwanarusk, R., et al.[2022]

The study involved 83 patients with hepatocellular carcinoma (HCC) and 15 healthy donors, revealing that γδ T cells can be effectively expanded using zoledronate and IL-2, which may enhance their potential for immunotherapy.

Despite the amplification of γδ T cells, their tumor-killing capacity and the levels of immunosuppressive factors like regulatory T cells (Tregs) and IL-17A remained unchanged, suggesting that these cells could be safely used in HCC treatment without increasing immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

γδ T cell-mediated individualized immunotherapy for hepatocellular carcinoma considering clinicopathological characteristics and immunosuppressive factors. Tian, W., Ma, J., Shi, R., et al.[2020]

TCR gene transfer can effectively generate AFP-specific cytotoxic T lymphocytes (CTLs), which are crucial for targeting hepatocellular carcinoma (HCC), as demonstrated by increased specific cytotoxicity and IFN-γ secretion in engineered T cells.

The study showed that transgenic CTLs had a significantly higher ability to recognize and kill AFP+ HCC cells both in vitro and in vivo compared to traditional methods using peptide-pulsed dendritic cells, indicating a more effective approach for immunotherapy against HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered cytotoxic T lymphocytes with AFP-specific TCR gene for adoptive immunotherapy in hepatocellular carcinoma. Sun, L., Guo, H., Jiang, R., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma. [2018]

2. Japan pubmed.ncbi.nlm.nih.gov

[Prevention of cancer recurrence by infusion of activated autologous lymphocytes]. [2017]

3. England pubmed.ncbi.nlm.nih.gov

Nonviral mcDNA-mediated bispecific CAR T cells kill tumor cells in an experimental mouse model of hepatocellular carcinoma. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Selection of a Clinical Lead TCR Targeting Alpha-Fetoprotein-Positive Liver Cancer Based on a Balance of Risk and Benefit. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

T-cell-based therapies for malignancy and infection in childhood. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

T cell receptor-therapy in HBV-related hepatocellularcarcinoma. [2022]

8. Turkey pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cell Therapy in Hematology. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

A practical approach to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis B virus. [2022]

10. Greece pubmed.ncbi.nlm.nih.gov

γδ T cell-mediated individualized immunotherapy for hepatocellular carcinoma considering clinicopathological characteristics and immunosuppressive factors. [2020]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Engineered cytotoxic T lymphocytes with AFP-specific TCR gene for adoptive immunotherapy in hepatocellular carcinoma. [2022]