TILT-123 + Avelumab for Melanoma

(AVENTIL Trial)

Not currently recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: TILT Biotherapeutics Ltd.

Must be taking: PD-1/PDL-1 blockers

Must not be taking: Immunosuppressants, Proton pump inhibitors

Disqualifiers: Organ transplant, Cardiovascular disease, Lung disease, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination treatment for people with advanced melanoma, a type of skin cancer that hasn't responded to other treatments. It uses a virus-based therapy called TILT-123 (an oncolytic adenovirus coding for TNFa and IL2) alongside a drug named avelumab (also known as MSB0010718C or Bavencio) to determine their safe combined use. Suitable participants have melanoma that has not improved with previous treatments and at least one tumor accessible for injections. The trial aims to assess the safety of this new treatment combination and observe patient responses. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this novel therapy.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use systemic immunosuppressive medications or have had anti-cancer therapy within 30 days before the trial starts. It's best to discuss your specific medications with the trial team.

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

Research shows that TILT-123, a virus designed to target cancer cells, is under study for safety. This virus delivers proteins called TNFa and IL2, which might help the body's immune system fight cancer. Earlier studies have primarily focused on its safety, especially in combination with other treatments, and found that side effects can usually be managed.

Avelumab, a type of immune therapy, has been tested in people with advanced cancers. Research has found it to be generally safe, meaning most people can use it without serious problems. It has also demonstrated lasting effects, working well for a long time in some patients.

Both treatments are being studied together to ensure they are safe and effective. The goal is to enhance the body's ability to fight cancer while keeping side effects under control. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about TILT-123 combined with avelumab for melanoma because this combo introduces a novel approach to immunotherapy. While standard treatments like BRAF inhibitors and checkpoint inhibitors focus on blocking cancer growth or unleashing the immune system, TILT-123 is designed to enhance the immune response by altering the tumor's environment, making it more susceptible to attack. This unique mechanism could potentially increase the effectiveness of avelumab, an existing checkpoint inhibitor, by enabling it to work more efficiently against melanoma cells. This synergy could lead to better outcomes for patients battling this aggressive skin cancer.

What evidence suggests that TILT-123 and avelumab could be effective for melanoma?

In this trial, participants will receive a combination of TILT-123 and Avelumab. Research has shown that TILT-123 is a promising treatment for melanoma. It uses a virus to target cancer cells and carries two proteins, TNFa and IL2, which enhance the immune system's ability to attack cancer. Some studies have found that TILT-123 can shrink tumors and even lead to complete remission in certain patients.

Avelumab has also shown effectiveness against cancers like melanoma. Previous studies indicate that patients treated with Avelumab experienced long-lasting responses and improved survival rates. It works by blocking a protein that cancer cells use to evade the immune system, allowing the body to fight the cancer more effectively. Together, TILT-123 and Avelumab may provide a strong combination to enhance the immune response against melanoma. ^{2 3 5 6 7}

Who Is on the Research Team?

Tuomo Alanko

Principal Investigator

Docrates Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with certain advanced solid tumors (like melanoma or head and neck cancers) that have stopped responding to standard treatments, including anti-PD(L)1 immunotherapy. Participants need a tumor large enough for biopsy and injection, good liver function, no curative treatment options available, and must have completed prior PD-1/PDL-1 therapy.

Inclusion Criteria

My liver and kidney functions are normal.

I can carry out all my daily activities without help.

Subject must have life expectancy longer than 3 months according to investigator assessment

Exclusion Criteria

I have a history of lung tissue disease.

Subject has a LDH value > 3 x ULN (melanoma)

Subject is pregnant, breastfeeding, or intends to become pregnant

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive multiple administrations of TILT-123 and avelumab in a dose-escalation format

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• TILT-123

Trial Overview The study tests TILT-123 (an oncolytic adenovirus) combined with Avelumab in patients whose tumors are not responding to previous therapies. It's an early-phase trial designed to find out the safest dose of TILT-123 when used with Avelumab.

How Is the Trial Designed?

Group I: TILT-123 and avelumab Experimental Treatment 2 Interventions

Patients will receive multiple administrations of TILT-123 and avelumab. Escalation to the next dose of TILT-123 level will occur when the safety data has been evaluated for all patients in the preceding dose level.

Avelumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

TILT Biotherapeutics Ltd.

Lead Sponsor

Trials

5

Recruited

100+

Published Research Related to This Trial

Intratumoral injection of ONCOS-102, a chimeric oncolytic adenovirus, combined with pembrolizumab, was found to be a safe and effective treatment for melanoma that is resistant to anti-PD-1 therapy.

The treatment led to increased lymphocyte infiltration and enhanced expression of genes related to cytotoxicity and costimulation, suggesting a mechanism of action that boosts the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ONCOS-102: A Step Forward or Sideways? Levi, ST., Boland, GM.[2023]

In a pilot study involving 21 patients with advanced melanoma resistant to anti-PD-1 therapy, the combination of ONCOS-102 (an oncolytic adenovirus) and pembrolizumab was well tolerated, with most side effects being mild to moderate, such as fever and chills.

The treatment resulted in an objective response rate of 35%, with 53% of patients showing a reduction in size of non-injected tumors, indicating a systemic immune response and suggesting that ONCOS-102 effectively enhances T-cell infiltration and activity against melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot Study of ONCOS-102 and Pembrolizumab: Remodeling of the Tumor Microenvironment and Clinical Outcomes in Anti-PD-1-Resistant Advanced Melanoma. Shoushtari, AN., Olszanski, AJ., Nyakas, M., et al.[2023]

TILT-123, an oncolytic adenovirus designed to enhance T-cell therapies and immune checkpoint inhibitors, has been shown to be safe in animal studies, both as a standalone treatment and in combination with the anti-PD-1 immune checkpoint inhibitor.

The treatment effectively stimulates the immune response by expressing cytokines like tumor necrosis factor alpha and interleukin-2, and it is rapidly cleared from healthy tissues without causing damage to vital organs, supporting its progression to a phase 1 clinical trial in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine-Coding Oncolytic Adenovirus TILT-123 Is Safe, Selective, and Effective as a Single Agent and in Combination with Immune Checkpoint Inhibitor Anti-PD-1. Havunen, R., Kalliokoski, R., Siurala, M., et al.[2021]

In a phase Ib study involving 44 patients with advanced melanoma resistant to PD-1 therapy, the combination of the TLR9 agonist vidutolimod and pembrolizumab showed a manageable safety profile and resulted in durable responses in 25% of patients.

The treatment led to tumor regression in both injected and non-injected lesions, and responders exhibited an increase in an IFNγ gene signature and systemic expression of the chemokine CXCL10, indicating a strong immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma. Ribas, A., Medina, T., Kirkwood, JM., et al.[2022]

Immune checkpoint inhibitors, particularly anti-PD-1 antibodies like pembrolizumab and nivolumab, have transformed the treatment of metastatic melanoma, achieving long-term survival rates over 50% in some patients, especially when combined with ipilimumab.

These treatments are generally well tolerated, although the combination of nivolumab and ipilimumab can lead to higher toxicity, prompting ongoing research into new immunotherapy combinations and strategies for patients with poor prognoses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 and Novel Combinations in the Treatment of Melanoma-An Update. Gellrich, FF., Schmitz, M., Beissert, S., et al.[2020]

The oncolytic adenovirus CAdVEC demonstrated strong antitumor activity in humanized mouse models and was safe for use in humans, with no significant toxicities reported after a single low-dose injection in four patients.

CAdVEC not only repolarized the tumor microenvironment by increasing CD8 T cell infiltration but also showed promising results in controlling tumors, leading to one complete and two partial responses, especially when combined with immune checkpoint antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultralow-dose binary oncolytic/helper-dependent adenovirus promotes antitumor activity in preclinical and clinical studies. Wang, D., Porter, CE., Lim, B., et al.[2023]

Ipilimumab (Yervoy) is the first new therapy approved for melanoma in over a decade, functioning as an antibody that blocks CTLA-4, which enhances the immune response against tumors, leading to durable tumor regression and improved overall survival in patients with advanced melanoma.

The clinical development of ipilimumab revealed its unique side effects profile and the long-lasting nature of its therapeutic responses, paving the way for future combination therapies with other checkpoint inhibitors currently being tested.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory therapy for melanoma: ipilimumab and beyond. Callahan, MK., Postow, MA., Wolchok, JD.[2021]

Immunotherapy for melanoma has shown promise, particularly through the use of dendritic cell (DC) vaccines and adenovirus (Ad) vectors, which have been found to be safe and capable of inducing immune responses in some patients.

Recent advancements in understanding DC biology and the interactions between AdVs and DCs, along with improvements in cytokine delivery and AdV design, are paving the way for more effective DC-based therapies in melanoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New approaches to the development of adenoviral dendritic cell vaccines in melanoma. Butterfield, LH., Vujanovic, L.[2021]

In a study of 37 patients with stage IV metastatic melanoma, high levels of soluble CD73 (sCD73) enzyme activity in the serum were linked to significantly poorer overall survival and progression-free survival when treated with nivolumab.

Patients with high sCD73 activity had a median progression-free survival of only 2.6 months compared to 14.2 months for those with lower activity, suggesting that measuring sCD73 could help predict how well patients will respond to nivolumab therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. Morello, S., Capone, M., Sorrentino, C., et al.[2018]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

Oncolytic adenoviral therapy with TILT-123 shows promise as a single-agent treatment for ovarian cancer and enhances the effectiveness of immune checkpoint inhibitors (ICIs) like anti-PD-1 and anti-PD-L1, leading to reduced tumor viability and improved T cell activation.

In mouse models, combining TILT-123 with ICIs significantly hindered tumor growth, suggesting that this combination therapy could be a viable approach for treating ovarian cancer in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective Combination Immunotherapy with Oncolytic Adenovirus and Anti-PD-1 for Treatment of Human and Murine Ovarian Cancers. Heiniö, C., Clubb, J., Kudling, T., et al.[2022]

Ipilimumab showed a best overall response rate (BORR) of 5.8% and a disease control rate (DCR) of 27% in patients with advanced melanoma, indicating some level of efficacy in this challenging population.

The treatment resulted in promising long-term survival rates, with 1- and 2-year survival rates of 47.2% and 32.8%, respectively, and a median overall survival of 10.2 months, while adverse events were primarily immune-related but manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. O'Day, SJ., Maio, M., Chiarion-Sileni, V., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9394192/

Real-world clinical outcomes with avelumab in patients with ... Patients with avelumab treatment had an rwORR of 73% (95% CI: 64 to 83), median rwPFS of 24.4 months (95% CI: 8.31 to not estimable (NE)), and median OS of 30.7 ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2018.36.5_suppl.191

Avelumab in patients with previously treated metastatic ... Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in pts with previously treated metastatic melanoma.

3. bavencio.com bavencio.com/en_US/patients-and-caregivers/mcc-home/clinical-study-results.html

Clinical Study Results | BAVENCIO® (avelumab) Efficacy Efficacy of BAVENCIO® (avelumab) in clinical studies. See how effective BAVENCIO® (avelumab) is for patients with Merkel cell carcinoma.

4. merkelcell.org merkelcell.org/news-and-publications/2025/real-world-safety-and-effectiveness-of-avelumab-in-immune-compromised-ic-and-non-ic-patients-with-merkel-cell-carcinoma-mcc-results-from-a-prospective-german-registry-mcc-trim/

Real-world safety and effectiveness of avelumab in immune ... In non-IC and IC subgroups, median (95% CI) overall survival from start of first-line avelumab was 38.2 (15.7-not estimable) and 9.9 (4.8-29.8) ...

5. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2675910

Efficacy and Safety of First-line Avelumab Treatment in ... First-line avelumab monotherapy in patients with metastatic Merkel cell carcinoma was associated with early responses, high response rates, and a manageable ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30651126/

phase 1b results from the JAVELIN Solid Tumor trial Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in patients with previously treated metastatic melanoma.

7. pfizer.com pfizer.com/news/press-release/press-release-detail/european_commission_approves_bavencio_avelumab_for_metastatic_merkel_cell_carcinoma

European Commission Approves Bavencio (avelumab) for ... The objective response rate was 62%, with 14% of patients experiencing a complete response (CR) and 48% of patients experiencing a partial ...