AU409 for Liver Cancer

Recruiting at 1 trial location

Overseen By Xiomara Menendez, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Southern California

Must not be taking: Warfarin, Strong P450 inducers/inhibitors

Disqualifiers: CNS metastases, Heart failure, Active infection, others

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

Compensation: Varies

Number of Visits: Unknown

36 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests AU409, a new drug, in patients with advanced liver cancers or solid tumors that have spread to the liver. AU409 aims to stop cancer cells from growing and spreading. Researchers are checking if it is safe and effective.

Do I need to stop my current medications for the trial?

The trial requires that you stop taking medications that are strong inducers or inhibitors of the cytochrome P450 enzymes at least one week before starting the treatment and during the trial. If these medications are essential and cannot be replaced, you may still be considered for enrollment after discussing with the principal investigator.

What data supports the effectiveness of the drug AU409 for liver cancer?

Research shows that a similar drug, sorafenib, significantly improved survival in patients with advanced liver cancer. Sorafenib, when combined with another drug called doxorubicin, also showed potential in improving survival outcomes. ^{1 2 3 4 5}

How does the drug AU409 differ from other liver cancer treatments?

AU409 is unique because it involves microRNA-409, which can down-regulate the Jak-Stat pathway, a process that may inhibit the progression of liver cancer. This mechanism is different from traditional treatments that often focus on directly targeting cancer cells or boosting the immune system. ^{6 7 8 9 10}

Research Team

Anthony El-Khoueiry, MD

Principal Investigator

University of Southern California

Eligibility Criteria

This trial is for adults with advanced primary liver cancers or solid tumors that have spread to the liver. Participants must have tried all standard treatments, be in good physical condition (ECOG 0-1), and not be pregnant or breastfeeding. They should also meet specific blood count and organ function criteria, agree to use contraception, and not have certain medical conditions like active infections or recent heart issues.

Inclusion Criteria

I finished any cancer treatments at least 4 weeks ago.

I have recovered from side effects of my previous cancer treatments.

Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception

Exclusion Criteria

My liver cancer is advanced with a moderate to severe impact on my health.

I haven't had cancer treatment in the last 28 days.

I am taking medication that strongly affects liver enzymes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation Treatment

Patients receive AU409 orally to determine the maximum tolerated dose and recommended phase II dose. Patients also undergo CT or MRI and collection of blood samples throughout the trial.

28 days

Multiple visits for dose escalation and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and pharmacokinetics.

Up to 30 days after treatment

Long-term Follow-up

Participants are monitored for objective radiologic response and long-term safety.

Up to 3 years

Treatment Details

Interventions

• AU-409

Trial Overview The trial tests AU409's safety, side effects, and optimal dosage on patients with advanced liver cancer or those whose solid tumors have metastasized to the liver. It aims to find out if AU409 can halt cancer growth and spread by collecting biospecimens and using imaging techniques like CT scans and MRIs.

Participant Groups

Group I: Treatment (AU409) Experimental Treatment 4 Interventions

Patients receive AU409 PO on study. Patients also undergo CT or MRI and collection of blood samples throughout the trial.

Who Is Running the Clinical Trial?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Auransa, Inc.

Collaborator

Trials

1

Recruited

40+

Findings from Research

In a study of 123 patients with primary liver cancer, those who underwent surgical resection had a median survival of 11 months, with only 12% surviving more than 5 years, indicating limited long-term efficacy of this treatment.

Adjuvant chemotherapy with doxorubicin did not improve survival compared to controls, with patients receiving chemotherapy having a median survival of 10 months versus 29 months for controls, highlighting the challenges in effectively treating primary liver cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of primary liver cancer. Hafström, L., Naredi, P., Lindnér, P., et al.[2013]

In a phase 3 clinical trial involving 356 patients with advanced hepatocellular cancer, the addition of doxorubicin to sorafenib did not improve overall survival (OS) or progression-free survival (PFS) compared to sorafenib alone, with median OS being 9.3 months for the combination therapy and 9.4 months for sorafenib alone.

The combination therapy resulted in significantly higher rates of severe adverse events, such as grade 3 or 4 neutropenia and thrombocytopenia, indicating that while doxorubicin was added to enhance treatment, it also increased the risk of serious side effects without providing additional survival benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial. Abou-Alfa, GK., Shi, Q., Knox, JJ., et al.[2023]

In a phase III trial with 602 patients, oral sorafenib (400 mg twice daily) significantly improved survival in advanced hepatocellular carcinoma, with a median survival of 10.7 months compared to 7.9 months for placebo.

Sorafenib combined with doxorubicin showed longer overall survival and progression-free survival in a phase II study of 96 patients, indicating potential benefits of combination therapy, despite not significantly delaying time to progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sorafenib: in hepatocellular carcinoma. Simpson, D., Keating, GM.[2018]

In a study of 1369 patients with hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) was the most common initial treatment, while liver transplantation was the most common second treatment, leading to the best overall survival outcomes.

Liver transplantation and hepatic resection were associated with significantly better median overall survival compared to systemic therapy, but patients who underwent three or more treatment sequences before transplantation had notably shorter survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment stage migration and treatment sequences in patients with hepatocellular carcinoma: drawbacks and opportunities. Wehling, C., Dill, MT., Olkus, A., et al.[2021]

In a study of 1158 patients with recurrent hepatocellular carcinoma (HCC), the time-to-interventional failure (TIF) was found to be a better predictor of overall survival (OS) than recurrence-free survival (RFS), with a correlation coefficient of 0.921 compared to 0.631.

Patients receiving aggressive curative treatments for recurrence, such as resection or ablation, had significantly better survival outcomes (median OS of 89.1 months) compared to those receiving non-curative treatments (median OS of 55.0 months), indicating the importance of treatment type in improving survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time-to-Interventional Failure as a New Surrogate Measure for Survival Outcomes after Resection of Hepatocellular Carcinoma. Shindoh, J., Kawamura, Y., Kobayashi, Y., et al.[2021]

MicroRNA-409 levels are significantly lower in liver cancer tissues compared to normal and paracancerous tissues, and its expression is negatively correlated with tumor stage and patient survival, suggesting it plays a critical role in liver cancer progression.

Overexpressing microRNA-409 in liver cancer cells reduces cell viability and promotes apoptosis by down-regulating the Jak-Stat signaling pathway, indicating its potential as a therapeutic target for inhibiting liver cancer growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

miR-409 down-regulates Jak-Stat pathway to inhibit progression of liver cancer. Zhang, CS., Lin, Y., Sun, FB., et al.[2020]

Transducing dendritic cells (DCs) with a CD40L-encoding adenovirus significantly enhances their ability to stimulate the immune response against hepatocellular carcinoma (HCC), leading to tumor elimination in about 70% of treated mice.

Intratumoral injection of these activated DCs not only resulted in complete tumor regression but also provided long-term immunity against future tumor challenges, indicating a robust and effective immunotherapy strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD40ligand-expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo. Gonzalez-Carmona, MA., Lukacs-Kornek, V., Timmerman, A., et al.[2022]

The study found that miR-409 is down-regulated in pancreatic carcinoma (PC) patients, and lower levels of this microRNA are associated with poorer patient prognosis, indicating its potential role as a tumor suppressor.

Experimental results showed that reduced miR-409 levels promote the proliferation, migration, and invasion of pancreatic cancer cells, highlighting its importance in cancer progression and potential as a therapeutic target.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical significance of microRNA-409 in pancreatic carcinoma and associated tumor cellular functions. Long, K., Zeng, Q., Dong, W.[2023]

Intratumoral co-stimulation with CD40L-expressing dendritic cells significantly enhances the effectiveness of a vaccine using α-fetoprotein (AFP)-transduced dendritic cells in treating hepatocellular carcinoma (HCC), leading to complete remission in 62% of treated mice.

The combination therapy not only increased the production of Th1 cytokines and improved T-cell infiltration into tumors but also induced tumor cell apoptosis, demonstrating a strong synergistic effect on tumor regression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma. Vogt, A., Sadeghlar, F., Ayub, TH., et al.[2021]

A gene therapy approach using an adenoviral vector to deliver CD40 ligand (AdCMVmCD40L) showed promising results in treating unresectable hepatocellular carcinoma (HCC) in rats, leading to complete tumor eradication in 69.5% of treated animals.

The therapy was associated with strong immune responses, including increased CD8(+) T cell activity and elevated interleukin-12 levels, while demonstrating minimal toxicity, characterized by only slight increases in liver enzyme levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenovirus-mediated CD40 ligand gene therapy in a rat model of orthotopic hepatocellular carcinoma. Schmitz, V., Barajas, M., Wang, L., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Treatment of primary liver cancer. [2013]

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

Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Sorafenib: in hepatocellular carcinoma. [2018]

4. Germany pubmed.ncbi.nlm.nih.gov

Treatment stage migration and treatment sequences in patients with hepatocellular carcinoma: drawbacks and opportunities. [2021]

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

Time-to-Interventional Failure as a New Surrogate Measure for Survival Outcomes after Resection of Hepatocellular Carcinoma. [2021]

6. Italy pubmed.ncbi.nlm.nih.gov

miR-409 down-regulates Jak-Stat pathway to inhibit progression of liver cancer. [2020]

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

CD40ligand-expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo. [2022]

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

The clinical significance of microRNA-409 in pancreatic carcinoma and associated tumor cellular functions. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Alpha-Fetoprotein- and CD40Ligand-Expressing Dendritic Cells for Immunotherapy of Hepatocellular Carcinoma. [2021]

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

Adenovirus-mediated CD40 ligand gene therapy in a rat model of orthotopic hepatocellular carcinoma. [2020]