IA Therapy for Liver Cancer

Recruiting at 9 trial locations

Overseen By Gabriela Sanchez

Age: 18+

Sex: Any

Trial Phase: Phase < 1

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

Compensation: Varies

Number of Visits: 50

Duration: 50 days

43 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for liver cancer, targeting tumors that can't be surgically removed. The goal is to test a new drug, IA therapy of HCC with CSR02-Fab-TF, which aims to cut off the blood supply to liver tumors, shrinking or killing them while preserving the rest of the liver's blood supply. The trial seeks individuals with liver cancer who haven't found success with other treatments and are ineligible for surgery or a liver transplant. Participants should have a liver cancer diagnosis and have experienced issues with previous liver-focused treatments or medications. As an Early Phase 1 trial, this research focuses on understanding how the new treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

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 prior data suggests that this IA therapy is safe for liver cancer treatment?

Research shows that CSR02-Fab-TF, used in a type of treatment for liver cancer, generally causes side effects that are not severe. Although detailed safety information specific to CSR02-Fab-TF is not yet available, the researchers aim to find a dose that is both safe and effective for patients.

Since this treatment is in the early stages of testing, more information about its safety in people is needed. Early trials focus on understanding how well people tolerate the treatment and identifying any side effects.

Prospective participants should remember that early trials help ensure the treatment is safe enough for further research. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for liver cancer, which often include options like surgery, chemotherapy, or targeted therapies, IA therapy with CSR02-Fab-TF offers a novel approach by directly delivering treatment to the tumor via the bloodstream. This method allows for more precise targeting of cancer cells while potentially minimizing damage to surrounding healthy tissue. Researchers are particularly excited about CSR02-Fab-TF because it employs a unique mechanism of action, utilizing a specific fragment (Fab) that binds to tumor markers, which might improve efficacy and reduce side effects compared to traditional therapies.

What evidence suggests that IA therapy of HCC with CSR02-Fab-TF could be effective for liver cancer?

Research has shown that intra-arterial (IA) therapy can be crucial for treating liver cancer, particularly when the tumor is too large for surgical removal. IA therapy blocks the tumor's blood supply, causing it to die. In this trial, participants will receive the investigational treatment CSR02-Fab-TF, designed to target only the blood vessels feeding the liver tumor, sparing healthy liver tissue. This focused approach may result in fewer side effects and more effective treatment. Early indications suggest that this method could improve outcomes for patients with challenging liver tumors. ^{1 6 7 8 9}

Who Is on the Research Team?

Paul Weiden, M.D.

Principal Investigator

KFSYSCC consultant

Are You a Good Fit for This Trial?

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

My liver functions well despite my illness, and I don't have serious fluid buildup in my abdomen.

Adequate laboratory parameters including specific values for bilirubin, liver enzymes, creatinine, prothrombin time, neutrophil count, platelet count, and hemoglobin

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• IA therapy of HCC with CSR02-Fab-TF

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04601428

NCT04601428 | Hepatic IA Therapy in Stage B or Limited ... Intra-arterial (IA) therapy is generally used to treat HCC tumors that are too extensive to excise or treat with potentially curative local therapy.

2. ichgcp.net ichgcp.net/clinical-trials-registry/NCT04601428

IA therapy of HCC with CSR02-Fab-TF in Hepatocellular ... Intra-arterial (IA) therapy is generally used to treat HCC tumors that are too extensive to excise or treat with potentially curative local ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9322128/

Intraarterial Therapies for the Management of Hepatocellular ... Transarterial therapies consist of a group of catheter-based treatments where embolic agents are delivered directly into the tumor via their supplying arteries.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27983883/

Intra-arterial therapies for liver cancer: assessing tumor ... Intra-arterial therapies (IATs) play an integral role in the management of unresectable hepatocellular carcinoma and liver metastases.

5. hbsn.amegroups.org hbsn.amegroups.org/article/view/141256/html

Efficacy of hepatic arterial infusion chemotherapy in advanced ... Results: HAIC significantly improved OS [hazard ratio (HR) =0.51] and PFS (HR =0.55) compared to TACE in advanced HCC. Subgroup analyses ...

6. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04601428/

Clinical Trial: NCT04601428 Intra-arterial (IA) therapy is generally used to treat HCC tumors that are too extensive to excise or treat with potentially curative local ...

7. withpower.com withpower.com/trial/early-phase-1-carcinoma-2021-ad6db

IA Therapy for Liver Cancer 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 ...

8. aging.networkofcare.org aging.networkofcare.org/sanmateo/CommunityResources/ClinicalTrials/Detail/NCT04601428?keyword=%22Hepatoma%22

San Mateo Clinical Trial Hepatic IA Therapy in Stage B or ... The current study is designed first, to identify a safe and optimal dose of CSR02-Fab-TF in patients , and then second, to determine the response rate of HCC ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11543349/

Therapeutic advances in hepatocellular carcinoma The treatment exhibited a manageable safety profile, with an ORR of 50% and a median PFS of 4.27 months.