ECT204 T-Cell Therapy for Liver Cancer

(ARYA-3 Trial)

Recruiting at 7 trial locations

Overseen By Teresa Klask, MBA

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Eureka Therapeutics Inc.

Must not be taking: Investigational agents

Disqualifiers: Congestive heart failure, Uncontrolled infection, 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: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called ECT204 T-cell therapy for liver cancer, specifically targeting GPC3-positive HCC. Researchers aim to assess the safety of this treatment and its potential to combat cancer when other treatments have failed. The trial consists of two parts: determining the optimal dose and then testing its effectiveness. Suitable candidates are adults with inoperable liver cancer, specific tumor markers, and a history of unsuccessful treatment with at least two other cancer therapies. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications for the ECT204 T-Cell Therapy trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on other investigational agents or liver tumor-directed therapies while participating.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ECT204 T-cell therapy is still under investigation, but some findings about its safety have emerged. T-cell therapy uses a person's own modified immune cells to combat cancer, and this treatment has shown promise in targeting liver cancer cells.

In earlier studies, some patients experienced partial remissions, where their cancer reduced in size, while others maintained stable disease for over three years, meaning their cancer did not progress. This suggests the treatment can be effective without severe side effects for some individuals.

However, this remains an investigational treatment in the middle stages of testing, requiring further research to fully understand its safety. Participants in the study are closely monitored for any side effects, and researchers adjust doses to determine the safest amount.

For those considering joining this trial, it is important to remember that the treatment is experimental, but there is growing evidence that it can be well-tolerated by some patients. Always discuss any concerns or questions with a doctor to understand the possible risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ECT204 T-cell therapy for liver cancer because it harnesses the power of modified T cells to specifically target and attack cancer cells. Unlike traditional treatments like surgery, chemotherapy, and targeted therapies such as sorafenib, which can affect both healthy and cancerous tissues, ECT204 offers a precision approach with the potential for fewer side effects. Additionally, in one treatment arm, regorafenib is used as a pre-treatment to potentially enhance the T-cell therapy's effectiveness, offering a novel combination strategy that could improve outcomes for patients.

What evidence suggests that this trial's treatments could be effective for liver cancer?

Studies have shown that ECT204 T-cell therapy targets a protein called GPC3, often found in large amounts on liver cancer cells, particularly in hepatocellular carcinoma (HCC). Research indicates that these specially designed T-cells can effectively identify and attack these cancer cells. In early studies, ECT204 demonstrated strong activity against tumors with GPC3. Initial findings suggest that this therapy could help shrink tumors or slow their growth in patients with advanced liver cancer.

In this trial, participants will join different treatment arms. One arm will receive ECT204 T-cell therapy as monotherapy, while another will receive ECT204 T-cell therapy following pre-treatment with regorafenib. This approach represents a promising new way to treat liver cancer by harnessing the body's immune system. ^{1 2 3 4 6}

Who Is on the Research Team?

Pei Wang, PhD

Principal Investigator

Eureka Therapeutics Inc.

Are You a Good Fit for This Trial?

Adults with advanced liver cancer (HCC) who have tried at least two treatments without success can join this trial. They should have a life expectancy of 4+ months, good organ function, and their cancer must show GPC3-positive expression. A score indicating mild liver disease (Child-Pugh A6 or better) and a performance status showing they're mostly independent are also required.

Inclusion Criteria

Life expectancy of at least 4 months per Principal Investigator's opinion

My liver cancer cells test positive for GPC3.

I am able to care for myself but may not be able to do active work.

Exclusion Criteria

My liver cancer affects more than half of my liver.

I have a serious health condition like heart failure.

I am currently undergoing or have recently finished (within 14 days) a treatment specifically targeting liver tumors.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 (Dose Escalation)

Completed; RP2D of ECT204 was determined

21 months

Phase 2 (Expansion)

Subjects receive ECT204 as monotherapy or with pre-treatment regorafenib

2 years

Long Term Follow-Up

Subjects are followed for assessment of treatment safety and overall survival

13 years

What Are the Treatments Tested in This Trial?

Interventions

• ECT204 T cells

Trial Overview

The ECT204 T-cell therapy is being tested in adults with HCC that's not removable by surgery or has spread. This Phase I/II trial will determine the safest dose to use while checking how well it works against liver cancer.

How Is the Trial Designed?

Group I: Dose Escalation, RP2D Confirmatory, and Expansion (Phase 1/2 Single Arm) Experimental Treatment 1 Intervention

Dose Escalation Cohort: Patients receive a single infusion of ECT204 T cells at one of four predefined dose levels on Day 0 after conditioning. Conditioning consists of fludarabine (Flu) and cyclophosphamide (Cy). RP2D Confirmatory Cohort: Patients receive ECT204 T cells at the RP2D on Day 0 and may receive a second infusion approximately one month later. This cohort uses the same Flu/Cy conditioning as the dose-escalation cohort; no conditioning is given before the second ECT204 infusion. Expansion Cohort: Patients receive multiple ECT204 infusions at the RP2D (initial on Day 0, planned second on Day 31, and optional third or later doses). The third infusion may be administered no earlier than Day 60, and each subsequent infusion must be separated by at least 30 days. Patients receive Flu/Cy/regorafenib before the first infusion and regorafenib alone before the second and subsequent infusions.

ECT204 T cells is already approved in United States for the following indications:

Approved in United States as ECT204 for:

• Hepatocellular carcinoma (HCC) - Orphan drug designation

Who Is Running the Clinical Trial?

Eureka Therapeutics Inc.

Lead Sponsor

Trials

12

Recruited

160+

Published Research Related to This Trial

The CT017 CAR T cell therapy, targeting the GPC3 antigen in patients with advanced hepatocellular carcinoma (HCC), demonstrated a manageable safety profile, with all patients experiencing cytokine release syndrome (CRS) that resolved after treatment, but no cases of neurotoxicity were observed.

Among the six heavily pretreated patients, there was a 16.7% objective response rate and a 50% disease control rate, indicating promising antitumor activity, with a median overall survival of 7.9 months, suggesting potential efficacy that warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RUNX-3-expressing CAR T cells targeting glypican-3 in patients with heavily pretreated advanced hepatocellular carcinoma: a phase I trial. Fu, Q., Zheng, Y., Fang, W., et al.[2023]

The fourth-generation GPC3-targeted CAR-T cells (GPC3-BBZ-7×19) demonstrated enhanced proliferation and chemotactic abilities compared to second-generation CAR-T cells, indicating a potentially more effective treatment for hepatocellular carcinoma (HCC).

In vivo studies showed that GPC3-BBZ-7×19 CAR-T cells significantly eliminated GPC3-positive HCC tumors in immunodeficient mice, suggesting they could provide a durable and effective therapeutic option for HCC in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Construction and function of Glypican-3-targeted fourth-generation chimeric antigen receptor T cells (secreting IL-7 and CCL19)]. Huang, W., Liu, Y., Hu, Y., et al.[2020]

In two phase I studies involving 13 patients with advanced GPC3+ hepatocellular carcinoma, CAR-GPC3 T-cell therapy showed an initial safety profile, with manageable side effects like fever and cytokine release syndrome, and no severe neurotoxicity reported.

The therapy demonstrated early signs of antitumor activity, with overall survival rates of 50.3% at 6 months and 42.0% at 1 year, along with two partial responses observed, suggesting potential efficacy in treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials. Shi, D., Shi, Y., Kaseb, AO., et al.[2021]

Dual-targeting CAR-T cells that express both GPC3 and EGFR showed effective anti-tumor activity against hepatocellular carcinoma (HCC) in vitro and in vivo, suggesting a promising therapeutic approach.

This dual-targeting strategy may help reduce on-target, off-tumor toxicity, which is a common issue with therapies targeting specific antigens, as demonstrated by improved tumor suppression compared to single-target CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of GPC3 and EGFR-dual-targeting chimeric antigen receptor-T cells for adoptive T cell therapy. Li, K., Qian, S., Huang, M., et al.[2021]

A phase I clinical trial demonstrated that a vaccine based on glypican-3 (GPC3) was safe and successfully induced immune responses in patients with hepatocellular carcinoma (HCC).

The study identified GPC3-derived long peptides that can stimulate CD4+ T cells, and their presence was linked to improved overall survival in HCC patients, suggesting their potential as effective tools for cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of glypican-3-derived long peptides activating both CD8+ and CD4+ T cells; prolonged overall survival in cancer patients with Th cell response. Sayem, MA., Tomita, Y., Yuno, A., et al.[2021]

Dual-targeted CAR-T cells that target both GPC3 and ASGR1 showed no cytotoxicity to tumor cells lacking GPC3, suggesting a reduced risk of on-target, off-tumor toxicity while effectively targeting hepatocellular carcinoma (HCC).

These dual-targeted CAR-T cells demonstrated enhanced anti-tumor activity, including higher cytokine secretion and proliferation, and effectively suppressed the growth of GPC3+ASGR1+ HCC tumors in xenograft models, outperforming single-targeted CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of T cells carrying two complementary chimeric antigen receptors against glypican-3 and asialoglycoprotein receptor 1 for the treatment of hepatocellular carcinoma. Chen, C., Li, K., Jiang, H., et al.[2017]

The study developed a novel bispecific T cell engager CAR-T therapy (GPC3-BiTE CAR) that targets both GPC3 and B7H3, showing enhanced antitumor activity against hepatocellular carcinoma (HCC) cells with varying antigen expression.

GPC3-BiTE CAR-T cells demonstrated superior cytotoxicity against both GPC3 positive and negative HCC cell lines compared to traditional single-target CAR-T cells, indicating a promising approach to overcome challenges posed by tumor antigen heterogeneity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GPC3-targeted CAR-T cells secreting B7H3-targeted BiTE exhibit potent cytotoxicity activity against hepatocellular carcinoma cell in the in vitro assay. Cao, G., Zhang, G., Liu, M., et al.[2022]

Researchers developed T cells with a specific receptor for the GPC3 antigen, which is found in 75% of hepatocellular carcinoma (HCC) cases, allowing these T cells to effectively target and kill GPC3-expressing tumor cells.

The study demonstrated that these engineered T cells not only recognized GPC3-positive cells in laboratory settings but also slowed the growth of HCC tumors in mice, suggesting a promising approach for adoptive T-cell therapy in treating liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T Cells Engineered to Express a T-Cell Receptor Specific for Glypican-3 to Recognize and Kill Hepatoma Cells In Vitro and in Mice. Dargel, C., Bassani-Sternberg, M., Hasreiter, J., et al.[2022]

Transgenic expression of IL15 and IL21 in GPC3-CAR T cells significantly enhances their ability to proliferate and persist, leading to improved antitumor activity against hepatocellular carcinoma (HCC) in preclinical models.

The combination of IL15 and IL21 with a second-generation GPC3-CAR (GBBz) resulted in superior T cell expansion and a higher percentage of memory T cell populations, suggesting a promising approach for future clinical trials in HCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glypican-3-Specific CAR T Cells Coexpressing IL15 and IL21 Have Superior Expansion and Antitumor Activity against Hepatocellular Carcinoma. Batra, SA., Rathi, P., Guo, L., et al.[2020]

T cells engineered with GPC3-specific CARs demonstrated strong cytotoxic effects against various solid tumors, including hepatocellular carcinoma and malignant rhabdoid tumors, indicating their potential as an effective treatment option.

Among the different CAR constructs tested, the GBBz CAR showed superior T cell expansion and a Th1-biased cytokine profile, suggesting it may be the most promising candidate for further clinical development in treating GPC3-positive solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity. Li, W., Guo, L., Rathi, P., et al.[2022]

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ECT204 T-Cell Therapy for Liver Cancer (ARYA-3 Trial)

This trial is testing a new treatment where a patient's immune cells are modified to better fight liver cancer. It is for adults with a specific type of ...

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