IA Therapy for Liver Cancer

Recruiting at7 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: Koo Foundation Sun Yat-Sen Cancer Center

Must be taking: Anti-HBV therapy

Must not be taking: QT prolonging drugs

Disqualifiers: Transplantation, Recent malignancies, Cardiac disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new protein treatment for patients with inoperable liver cancer. The treatment targets and blocks the blood vessels feeding the cancer, cutting off its blood supply and causing it to die.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot have had certain treatments like small molecule drugs for HCC within the last 30 days or biological agents within the last 60 days. If you're on therapeutic anticoagulation, it must be stopped 24-72 hours before treatment and restarted no sooner than 72 hours after therapy.

What data supports the effectiveness of the IA therapy for liver cancer using CSR02-Fab-TF?

Research shows that combining certain therapeutic genes can enhance antitumor activity in liver cancer. Specifically, using a combination of genes that target cancer cells and inhibit pathways that help the cancer resist treatment has shown promising results in similar therapies. ^{1 2 3 4 5}

Is IA Therapy for Liver Cancer safe for humans?

The research articles provided do not contain specific safety data for IA Therapy for Liver Cancer or its related treatments, such as IA therapy of HCC with CSR02-Fab-TF. ^{6 7 8 9 10}

What makes the IA therapy with CSR02-Fab-TF unique for liver cancer treatment?

The IA therapy with CSR02-Fab-TF is unique because it targets the transferrin receptor, which is more commonly found on cancer cells than normal cells, allowing for a more selective attack on liver cancer cells. This approach may reduce damage to healthy cells compared to other treatments. ^{4 5 8 11 12}

Research Team

Paul Weiden, M.D.

Principal Investigator

KFSYSCC consultant

Eligibility Criteria

Adults diagnosed with intermediate-stage B or limited advanced-stage C liver cancer (HCC) who are not candidates for curative surgery, liver transplant, or ablation. They should have an ECOG performance status of ≤1, indicating they are fully active or restricted in physically strenuous activity but ambulatory and able to carry out work of a light nature. Participants must have adequate organ function as shown by specific blood tests and agree to use effective contraception.

Inclusion Criteria

I am 18 years old or older.

I have been diagnosed with liver cancer either through a biopsy or specific imaging tests.

I cannot have surgery, liver transplant, or targeted tumor removal to cure my condition.

Exclusion Criteria

I have not had any major surgery, serious injuries, or illnesses recently.

I am eligible for a transplant according to Milan criteria or could be if my condition improves.

I haven't had treatment for another cancer within the last 2 years, except for certain exceptions.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intra-arterial infusion of CSR02-Fab-TF to assess safety and tolerability

50 days

Multiple visits for infusion and monitoring

Follow-up

Participants are monitored for tumor response and adverse events

1 year

MRI on Day 50 and every 3 months

Treatment Details

Interventions

• IA therapy of HCC with CSR02-Fab-TF (Virus Therapy)

Trial Overview The trial is testing a new intra-arterial therapy called CSR02-Fab-TF specifically targeting the blood vessels feeding HCC tumors while sparing normal liver tissue. This approach aims to cut off the tumor's blood supply more selectively than current methods, potentially leading to better outcomes for patients with extensive tumors not suitable for surgical removal.

Participant Groups

Group I: Investigational Arm Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Koo Foundation Sun Yat-Sen Cancer Center

Lead Sponsor

Trials

13

Recruited

6,600+

Findings from Research

In patients with hepatocellular cancer (HCC), serum levels of sFas were significantly higher compared to those with chronic hepatitis (CH) and normal controls, suggesting a potential role of sFas in HCC development.

sFas levels were positively correlated with bilirubin levels and negatively correlated with albumin, prothrombin activity, and the ALT/AST ratio, indicating that sFas may be involved in the severity of chronic hepatitis and the resistance to apoptosis in HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparative study of serum sFas in patients with hepatocellular cancer and chronic hepatitis]. Chen, J., Zheng, XH., Tang, XP.[2017]

The TRA-8 monoclonal antibody effectively targets the DR5 receptor in pancreatic cancer cells, showing varying levels of sensitivity across different cell lines, which suggests a tailored approach may be necessary for treatment.

In an orthotopic pancreatic cancer model, combining TRA-8 with gemcitabine resulted in enhanced tumor growth inhibition and improved survival rates compared to gemcitabine alone, particularly after two cycles of therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth. Derosier, LC., Vickers, SM., Zinn, KR., et al.[2022]

Death receptor 5 (DR5) is highly expressed in human hepatocellular carcinoma (HCC) cell lines, making it a promising target for cancer treatment, while it is rarely expressed in normal liver cells.

The agonistic monoclonal antibody (DR5mAb) effectively induced apoptosis in HCC cells (52.45% apoptosis rate) compared to TRAIL (14.74% apoptosis rate), and importantly, DR5mAb showed minimal effects on normal liver cells, suggesting a selective and safe therapeutic approach for HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Relationship between death receptor 5 and apoptosis in hepatocellular carcinoma]. Zhu, RX., Lin, JS., Song, YH., et al.[2006]

A novel oncolytic adenovirus vector targeting alpha-fetoprotein (AFP)-positive hepatocellular carcinoma (HCC) was developed, showing strong antitumor effects in both lab and animal studies, particularly when combining the therapeutic genes SOCS3 and TRAIL.

The treatment demonstrated safety due to specific replication in AFP-positive HCC cells and the ability of SOCS3 to inhibit the JAK/STAT3 pathway, leading to reduced cancer cell survival and enhanced effectiveness against HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmenting the antitumor effect of TRAIL by SOCS3 with double-regulated replicating oncolytic adenovirus in hepatocellular carcinoma. Wei, RC., Cao, X., Gui, JH., et al.[2012]

The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated in patients with pancreatic ductal adenocarcinoma (PDAC), showing no dose-limiting toxicities and an 80% disease control rate in the refractory cohort.

Preliminary efficacy results were promising, with median progression-free survival of 3.6 months and overall survival of 7.8 months in the refractory cohort, suggesting that this treatment strategy may enhance tumor immunity and could be improved with stronger chemotherapy in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study. Wang-Gillam, A., Lim, KH., McWilliams, R., et al.[2023]

Intratumoral administration of TWEAK, either through an adenoviral vector or as an Fc-fusion protein, significantly inhibits tumor growth in a breast cancer xenograft model, highlighting its potential as a therapeutic agent.

The anti-Fn14 agonistic antibody, BIIB036, specifically binds to the Fn14 receptor and promotes tumor cell death in various xenograft models, demonstrating its efficacy in inhibiting tumor growth across different cancer types, independent of TNF signaling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of an Fn14 agonistic antibody as an anti-tumor agent. Michaelson, JS., Amatucci, A., Kelly, R., et al.[2021]

FAP-4-1BBL is a bispecific antibody that activates T-cells specifically in the presence of cancer-associated fibroblasts, potentially enhancing tumor-targeted therapy.

Mathematical modeling combined with in vitro data suggests that optimal dosing for FAP-4-1BBL to achieve maximum T-cell activation could range from 2 to 145 mg, but variability in patient responses may complicate establishing a clear dose-response relationship.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A model-based approach leveraging in vitro data to support dose selection from the outset: A framework for bispecific antibodies in immuno-oncology. Sánchez, J., Claus, C., Albrecht, R., et al.[2023]

The chimeric antibody D2C, targeting the transferrin receptor (TfR), shows strong tumor-specific localization and effectively inhibits tumor cell proliferation, demonstrating its potential as a selective cancer therapy.

In vivo studies in mice with human liver cancer xenografts revealed a significant tumor-to-normal tissue radioactivity distribution ratio for D2C, while in vitro studies showed it can induce apoptosis and activate immune responses against tumor cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The in vitro antitumor effect and in vivo tumor-specificity distribution of human-mouse chimeric antibody against transferrin receptor. Qing, Y., Shuo, W., Zhihua, W., et al.[2011]

In a meta-analysis of five studies involving 425 patients with hepatocellular carcinoma (HCC), the combination of TACE plus tyrosine kinase inhibitors and immune checkpoint inhibitors (TACE + T + I) significantly improved the objective response rate, progression-free survival, and overall survival compared to TACE plus tyrosine kinase inhibitors alone (TACE + T).

While TACE + T + I was associated with a higher incidence of hypertension, no significant differences in other adverse events were found, suggesting that the combination treatment is effective without a major increase in safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TACE plus tyrosine kinase inhibitors and immune checkpoint inhibitors versus TACE plus tyrosine kinase inhibitors for the treatment of patients with hepatocellular carcinoma: a meta-analysis and trial sequential analysis. Liu, J., Wang, P., Shang, L., et al.[2023]

The newly developed bispecific T-cell engager antibody (TfR-BiTE) effectively targets and kills TfR-positive cancer cells by activating T cells and promoting their proliferation, while leaving TfR-negative cells unharmed.

In a subcutaneous HepG2 xenograft model, low concentrations of TfR-BiTE were able to significantly inhibit tumor growth, suggesting its potential as a targeted immunotherapy for hepatocellular carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Bispecific T-Cell Engager Antibody Targeting the Transferrin Receptor. Fu, M., He, Q., Guo, Z., et al.[2020]

TRAIL effectively induces apoptosis in cancer cells like SW480 and H460, but it also poses a risk of toxicity to normal human liver cells, raising safety concerns for systemic use in cancer treatment.

Using a caspase 9 inhibitor (Z-LEHD-FMK) can protect normal liver cells from TRAIL-induced death while still allowing for the killing of certain cancer cells, suggesting a potential strategy to enhance the safety and efficacy of TRAIL in clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. Ozoren, N., Kim, K., Burns, TF., et al.[2012]

Inhibition of the c-Src protooncogene in hepatoma cell lines significantly sensitizes these cancer cells to TRAIL-induced apoptosis, allowing effective doses of TRAIL to be reduced to as low as 1 ng/ml.

Importantly, this sensitization does not affect primary human hepatocytes, suggesting a targeted approach that minimizes toxicity to normal liver cells while enhancing the efficacy of TRAIL therapy in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

P60-c-src suppresses apoptosis through inhibition of caspase 8 activation in hepatoma cells, but not in primary hepatocytes. De Toni, EN., Kuntzen, C., Gerbes, AL., et al.[2017]

References

1. China pubmed.ncbi.nlm.nih.gov

[A comparative study of serum sFas in patients with hepatocellular cancer and chronic hepatitis]. [2017]

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

TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth. [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Relationship between death receptor 5 and apoptosis in hepatocellular carcinoma]. [2006]

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

Augmenting the antitumor effect of TRAIL by SOCS3 with double-regulated replicating oncolytic adenovirus in hepatocellular carcinoma. [2012]

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

Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study. [2023]

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

Development of an Fn14 agonistic antibody as an anti-tumor agent. [2021]

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

A model-based approach leveraging in vitro data to support dose selection from the outset: A framework for bispecific antibodies in immuno-oncology. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

The in vitro antitumor effect and in vivo tumor-specificity distribution of human-mouse chimeric antibody against transferrin receptor. [2011]

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

TACE plus tyrosine kinase inhibitors and immune checkpoint inhibitors versus TACE plus tyrosine kinase inhibitors for the treatment of patients with hepatocellular carcinoma: a meta-analysis and trial sequential analysis. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic Bispecific T-Cell Engager Antibody Targeting the Transferrin Receptor. [2020]

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

The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. [2012]

12. Netherlands pubmed.ncbi.nlm.nih.gov

P60-c-src suppresses apoptosis through inhibition of caspase 8 activation in hepatoma cells, but not in primary hepatocytes. [2017]