VG161 + Nivolumab for Liver Cancer

Recruiting at 2 trial locations

Overseen By Mike Teng

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Virogin Biotech Canada Ltd

Must not be taking: Antivirals, Corticosteroids, Anticoagulants

Disqualifiers: CNS malignancy, Herpes, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

97 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment, VG161 (an oncolytic virus therapy), for liver cancer, specifically assessing its safety and effectiveness. It targets two types of liver cancer: hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The study includes several groups: one uses VG161 alone, and another combines VG161 with Nivolumab, a medication that helps the immune system fight cancer. Individuals with advanced liver cancer that does not respond to standard treatments and who have a measurable tumor suitable for injection may be a good fit for this trial. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you have used antiviral agents, ganciclovir, acyclovir, or systemic corticosteroids above a certain dose within 14 days before starting the trial. It's best to discuss your current medications with the trial team.

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

In previous studies, VG161, a virus designed to kill cancer cells, was tested in patients with advanced liver cancer. These studies have shown that VG161 is generally well-tolerated. Some patients experienced mild to moderate side effects, such as fever and tiredness, but these were usually manageable.

Nivolumab, another treatment in the trial, already has FDA approval for liver cancer and other cancers. For liver cancer, research has found that it can cause serious liver-related side effects in about 17% of patients, including severe liver inflammation. However, many patients do not experience these effects, and it remains a viable option for treating certain cancers.

Together, these studies suggest both VG161 and Nivolumab have been tested for safety, though some side effects are possible. Prospective participants should discuss any concerns with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

VG161 is unique because it's an oncolytic virus therapy, which means it uses a modified virus to selectively infect and kill cancer cells. Unlike standard treatments for liver cancer, such as surgery, chemotherapy, or targeted therapies, VG161 not only directly attacks tumor cells but also stimulates the immune system to recognize and fight the cancer. Researchers are excited about VG161 because it offers a targeted approach with the potential to enhance the effects of immune checkpoint inhibitors like Nivolumab, providing a dual attack on the cancer. This innovative mechanism could lead to more effective and durable responses in patients with liver cancer.

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

Research shows that VG161, a type of virus therapy, has promising effects against liver cancer. Studies have found that VG161 can help patients live longer and is generally safe for those with advanced liver cancer. This therapy directly attacks cancer cells and boosts the immune system to fight the cancer. In this trial, some participants will receive VG161 alone, while others will receive a combination of VG161 and Nivolumab. Early results suggest that combining VG161 with Nivolumab might strengthen the immune response even more, possibly leading to better results in treating liver cancer. These findings support further research into VG161 and its combinations for liver cancer treatment. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

Adults with advanced liver cancer or bile duct cancer who've had previous treatments without success can join. They must be in good enough health to perform daily activities (ECOG 0-1) and have at least one tumor that's safe to inject with the trial drug. People with brain cancers, recent major surgeries, serious infections, HIV/syphilis, or those needing strong steroids or anticoagulants can't participate.

Inclusion Criteria

At least one measurable lesion per RECIST 1.1

I have a tumor that can be injected and is at least 15 mm big.

My liver cancer has worsened after two types of treatment, including immunotherapy.

Exclusion Criteria

I have not taken blood thinners or had an INR > 1.5 in the last 14 days.

Participation in any trial of any other investigational agent within the last 4 weeks prior to dosing. Wash out periods to be reviewed on a case by case basis with Medical Monitor, as required

My tumor is not near major organs or vessels where swelling could cause harm.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-in

10 patients will be treated with IT injection of VG161 at dose level of 1.0x10E8 PFU x 3 days

3 days

Monotherapy Treatment

Participants in Cohort 2 (HCC) and Cohort 3 (ICC) receive VG161 as a single-agent treatment

12 months

Combination Treatment

Participants in Cohort 4 receive VG161 and Nivolumab, with Nivolumab administered on days 8 and 15 of each cycle

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• VG161

Trial Overview The trial is testing VG161 alone and combined with Nivolumab for liver and bile duct cancers. It has different groups: one gets a single dose of VG161; others get it plus Nivolumab. The study will stop if not enough people show improvement after initial treatment.

How Is the Trial Designed?

Group I: Safety Run-in Cohort Experimental Treatment 1 Intervention

10 patients will be treated with IT injection of VG161 in the cohort 1 at dose level of 1.0x10E8 PFU x 3 days.

Group II: Cohort 4 (HCC and ICC) Experimental Treatment 2 Interventions

Up to 12 patients will be treated with IT injection of VG161 ar dose level of 1.0x10E8 PFU x 3 days. and Nivolumab per approved label.

Group III: Cohort 3 (ICC) Experimental Treatment 1 Intervention

20 patients will be treated with IT injection of VG161 in the cohort 1 at dose level of 1.0x10E8 PFU x 3 days.

Group IV: Cohort 2 (HCC) Experimental Treatment 1 Intervention

21 patients will be treated with IT injection of VG161 in the cohort 1 at dose level of 1.0x10E8 PFU x 3 days.

VG161 is already approved in United States, China for the following indications:

Approved in United States as VG161 for:

• Hepatocellular Carcinoma (HCC)
• Intrahepatic Cholangiocarcinoma (ICC)

Approved in China as VG161 for:

• Hepatocellular Carcinoma (HCC)
• Intrahepatic Cholangiocarcinoma (ICC)

Who Is Running the Clinical Trial?

Virogin Biotech Canada Ltd

Lead Sponsor

Trials

2

Recruited

110+

Published Research Related to This Trial

Nivolumab, a targeted cancer therapy, can lead to rare cutaneous side effects such as plaque morphea, as demonstrated in a case study of a 48-year-old female patient with metastatic melanoma.

The plaque morphea lesion responded well to treatment with topical corticosteroids and calcipotriol, highlighting the importance of monitoring for less common skin reactions in patients receiving PD-1 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-induced plaque morphea in a malign melanoma patient. Acar, A., Oraloglu, G., Yaman, B., et al.[2021]

The novel oncolytic herpes simplex virus type 1 (VG161) effectively destroys tumor cells while also enhancing immune activation through the delivery of IL-12, IL-15, and a PD-1/PD-L1 blocking peptide, leading to superior anti-tumor responses in animal models.

VG161 not only shows strong anti-tumor effects and immune cell infiltration but also has an excellent safety profile, as demonstrated in toxicity studies with cynomolgus monkeys, indicating its potential as a safe cancer treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes. Chouljenko, DV., Ding, J., Lee, IF., et al.[2020]

VG161, a recombinant oncolytic herpes simplex virus, shows strong antitumor potential in pancreatic cancer by enhancing both acquired and innate immunity, as evidenced by increased CD8+ T and natural killer cells after treatment.

The combination of VG161 with immune checkpoint inhibitors has demonstrated a long-term antitumor effect by remodeling the tumor microenvironment, suggesting that further clinical trials are warranted to explore its efficacy as a monotherapy or in combination with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VG161 activates systemic antitumor immunity in pancreatic cancer models as a novel oncolytic herpesvirus expressing multiple immunomodulatory transgenes. Shen, Y., Song, W., Lin, D., et al.[2023]

The novel oncolytic herpes simplex virus VG161 significantly inhibits breast cancer growth and enhances the immune response when combined with the chemotherapy drug paclitaxel (PTX) in a mouse model.

This combination therapy not only reduces primary breast cancer growth but also significantly decreases lung metastasis, likely due to increased infiltration of immune cells like CD4+ and CD8+ T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of novel oncolytic herpesvirus with paclitaxel as an efficient strategy for breast cancer therapy. Deng, X., Shen, Y., Yi, M., et al.[2023]

Nivolumab is an effective immune checkpoint inhibitor for treating various cancers, including melanoma and non-small-cell lung cancer, and its efficacy may be linked to the expression of PD-L1 in tumors.

In comparing two antibodies for detecting PD-L1, the 28-8 antibody showed superior detection capabilities over E1L3N, highlighting the importance of antibody choice and detection methods in assessing PD-L1 expression for predicting treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Analytical Comparison of Dako 28-8 PharmDx Assay and an E1L3N Laboratory-Developed Test in the Immunohistochemical Detection of Programmed Death-Ligand 1. Cogswell, J., Inzunza, HD., Wu, Q., et al.[2021]

Nivolumab, a PD-1 inhibitor, was found to be safe and well-tolerated in virally suppressed patients with chronic hepatitis B, with no serious adverse events reported during the study.

The treatment led to significant declines in hepatitis B surface antigen (HBsAg) levels in most patients, with one patient achieving undetectable HBsAg, indicating potential for durable control of the virus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study. Gane, E., Verdon, DJ., Brooks, AE., et al.[2020]

The engineered HSV-1-based oncolytic virus, when combined with the PD-1 antibody Keytruda, significantly improved immune cell infiltration and activity in tumors, leading to better overall survival in hPD-1 knock-in mice with non-immunogenic melanoma.

This study suggests that oncolytic viruses can enhance the effectiveness of immune checkpoint therapies, particularly for tumors that typically do not respond well to such treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The oncolytic virus VT09X optimizes immune checkpoint therapy in low immunogenic melanoma. Zhu, W., Lv, J., Xie, X., et al.[2022]

The study evaluated two oncolytic herpes simplex viruses (HSV), NV1023 and NV1042, in treating colon cancer, showing that both can effectively kill cancer cells in vitro with 100% cytotoxicity.

NV1042, which produces the cytokine IL-12, allowed for effective tumor reduction and cures at lower viral doses compared to NV1023, suggesting that combining oncolytic therapy with immunomodulation could enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin 12 secretion enhances antitumor efficacy of oncolytic herpes simplex viral therapy for colorectal cancer. Bennett, JJ., Malhotra, S., Wong, RJ., et al.[2019]

Nivolumab is a monoclonal antibody that effectively blocks the PD-1 receptor, enhancing T-cell responses and potentially improving antitumor immunity in cancer patients.

Preclinical studies showed that nivolumab did not cause adverse immune-related events in cynomolgus macaques, indicating a favorable safety profile, which has been supported by human clinical trials demonstrating its efficacy in treating various solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Wang, C., Thudium, KB., Han, M., et al.[2022]

Pre-existing immunity to herpes simplex virus type-1 (HSV-1) significantly enhances the anticancer efficacy of the oncolytic virus VG161, as shown in mouse models where immunized mice exhibited reduced tumor growth compared to naïve mice.

Multicycle treatment with VG161 in humanized intrahepatic cholangiocarcinoma models also improved anticancer effects, suggesting that repeated administration could be beneficial for long-term treatment in patients, particularly those with pre-existing HSV-1 immunity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-Existing HSV-1 Immunity Enhances Anticancer Efficacy of a Novel Immune-Stimulating Oncolytic Virus. Ding, J., Murad, YM., Sun, Y., et al.[2023]

The recombinant herpes simplex virus type 1 (HSV-1) engineered to express anti-PD-1 antibodies (HSV-aPD-1) significantly enhances anti-tumor immune responses and T-cell infiltration in mouse models, indicating its potential as an effective cancer treatment.

HSV-aPD-1 shows similar efficacy in controlling tumor growth compared to traditional anti-PD-1 therapies, suggesting it could be a promising option for tumors that are resistant to existing immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced anti-tumor response elicited by a novel oncolytic HSV-1 engineered with an anti-PD-1 antibody. Tian, C., Liu, J., Zhou, H., et al.[2022]

In a multicenter retrospective study, anti-PD-1 therapy was found to be more effective in treating non-liver cancer patients infected with hepatitis B virus (HBV) compared to those without HBV, indicating a potential benefit of this therapy in this specific patient group.

Single-cell RNA sequencing revealed that HBV+ patients had increased cytotoxic T cell activity and a specific subset of CD8+ T cells associated with better outcomes, suggesting that the immune response in HBV+ patients may enhance the efficacy of anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 therapy achieves favorable outcomes in HBV-positive non-liver cancer. Zhou, J., Chen, G., Wang, J., et al.[2023]

In a phase I trial involving 41 patients with recurrent glioblastoma (rGBM), the oncolytic herpes virus CAN-3110 was safely administered without dose-limiting toxicities, showing potential for preferential tumor replication due to its unique genetic modifications.

Patients with pre-existing HSV1 antibodies experienced improved survival and tumor response, suggesting that CAN-3110 can enhance immune responses against tumors even in challenging microenvironments, providing a promising avenue for treating cancers resistant to traditional immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trial links oncolytic immunoactivation to survival in glioblastoma. Ling, AL., Solomon, IH., Landivar, AM., et al.[2023]

Citations

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Clinical Study of VG161 in Subjects with Advanced Primary ... This phase I study will be conducted in HSV-seropositive subjects with advanced primary liver cancer that are refractory to conventional therapies.

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5. researchgate.net researchgate.net/publication/395982306_Hypothesis-generating_evaluation_of_multi-armoured_oncolytic_HSV-1_VG161_in_intrahepatic_cholangiocarcinoma_pooled_insights_from_multicentre_studies

pooled insights from multicentre studies Results The oncolytic virus therapy VG161 was well tolerated and showed encouraging antitumour activity, including improved overall survival ...

6. opdivohcp.com opdivohcp.com/safety/hcc/opdivo-yervoy

Safety Profile in Hepatocellular Carcinoma (HCC) - Opdivo Liver-related serious adverse reactions occurred in 17% of patients receiving OPDIVO with YERVOY, including Grade 3-4 events in 16% of patients. The most ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10165088/

The safety concerns regarding immune checkpoint ... Methods: The study enrolled 106 patients with primary liver cancer, including 81 with hepatocellular carcinoma and 25 with intrahepatic cholangiocarcinoma.

8. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2765293

A Phase 2 Study of Nivolumab for Patients With Advanced ... This multicenter phase 2 study evaluates the anticancer activity of nivolumab in patients with advanced refractory biliary tract cancer.

9. journals.lww.com journals.lww.com/ajg/Fulltext/2016/10001/Single_Center_Study_of_Safety_and_Anti_tumor.2474.aspx

Single-Center Study of Safety and Anti-tumor Activity of... 8 out of 11 patients have HCC, ages ranged from 45-65 with PS 0 or 1. They are contributed by 4 hepatitis B, 2 hepatitis C, 1 cryptogenic and 1 hemochromatosis.

10. ascopubs.org ascopubs.org/doi/10.1200/GO-25-00128

Effectiveness and Safety of Immunotherapy for ... Immunotherapy-based combinations have shown promising survival benefits in patients with hepatocellular carcinoma (HCC) included in clinical ...