Avelumab + Valproic Acid for Viral Associated Cancer

(LATENT Trial)

Overseen By John Walker, MD PhD FRCPC

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Must not be taking: Immunosuppressants

Disqualifiers: Cardiovascular disease, Brain metastases, Autoimmune, 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

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for certain cancers linked to viral infections, such as some types of cervical or oral cancers. The treatment combines Valproic acid, which may expose hidden viruses to the immune system, with Avelumab (also known as Bavencio), an immune therapy that helps maintain the body's defenses against cancer. The goal is to determine if this combination can enhance the body's ability to fight cancer. Suitable candidates for this trial have specific types of cancer, such as certain squamous cell carcinomas or lymphomas, associated with viral infections. As a Phase 2 trial, the 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 does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive medication, you may need to stop, except for certain types like low-dose steroids or specific premedications. 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?

Research has shown that combining Avelumab with Valproic Acid may help treat cancers linked to viruses. Avelumab is already used for various cancers and is generally well-tolerated. One study found that Avelumab alone helped shrink or eliminate cancer in 15% of patients with Merkel cell carcinoma, a rare skin cancer.

Early findings suggest that using Avelumab with Valproic Acid is safe and effective. Valproic Acid may help the immune system better recognize and attack virus-related cancers. This combination aims to strengthen the body's natural defenses against cancer by keeping immune cells active longer.

So far, the treatment appears well-tolerated, with studies indicating it is safe for most patients. Most people can undergo the treatment without experiencing severe side effects. While monitoring individual reactions is important, current data provides a positive view of the treatment's safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Avelumab and Valproic Acid (VPA) for viral-associated cancers because it offers a novel approach that differs from traditional treatments like chemotherapy and radiation. Avelumab is an immunotherapy drug that enhances the body's immune response to cancer cells by targeting a protein called PD-L1, which often helps cancer cells evade the immune system. Valproic Acid, typically used as a seizure medication, is being repurposed here to potentially enhance the effectiveness of Avelumab by modifying gene expression in cancer cells. This innovative combination could provide a more effective and targeted treatment option with potentially fewer side effects than conventional therapies.

What evidence suggests that Avelumab combined with Valproic Acid could be effective for viral associated cancer?

Studies have shown that Avelumab can help treat several types of cancer by boosting the immune system. It keeps immune cells active, aiding the body in fighting cancer. In this trial, participants will receive a combination of Avelumab and Valproic Acid. This combination aims to enhance Avelumab's effect, particularly for cancers linked to viruses like HPV. Valproic Acid may help reveal hidden viral infections, making them easier for the immune system to target. Although researchers are still investigating the effectiveness of this combination in virus-related cancers, the approach appears promising based on the individual effects of these drugs. ^{1 2 4 6 7}

Who Is on the Research Team?

John Walker, MD PhD FRCPC

Principal Investigator

Alberta Health services

Are You a Good Fit for This Trial?

Adults with certain virus-associated cancers (like HPV-related cervical or oral cavity cancer) can join this trial. They must have specific types of squamous cell carcinoma or lymphoma, be able to consent, and meet blood count and organ function criteria. Women who can get pregnant need a negative pregnancy test and must use effective birth control.

Inclusion Criteria

Patients of childbearing/reproductive potential should use highly effective birth control methods during the study treatment period and for 60 days after the last dose of study drug

Absence of any condition hampering compliance with the study protocol and follow-up schedule

I have a specific type of cancer that is p16 or EBER positive.

Exclusion Criteria

I have a history of lung scarring or fibrosis.

I have been diagnosed with an immune system disorder.

I do not have any severe health or mental conditions that could affect my participation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Valproic Acid once per day and Avelumab every 2 weeks for up to 2 years

up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• Valproic Acid

Trial Overview The trial is testing Valproic Acid combined with Avelumab, an immune therapy drug. Valproic Acid may expose chronic viral infections to the immune system while Avelumab activates immune cells to potentially enhance the body's defense against cancer.

How Is the Trial Designed?

Group I: Avelumab with VPA Experimental Treatment 2 Interventions

Valproic Acid (VPA, 12.5 mg/kg) once per day and Avelumab (10 mg/kg IV) every 2 weeks for up to 2 years.

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?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

EMD Serono

Industry Sponsor

Trials

147

Recruited

27,800+

Dr. Shepard

EMD Serono

Chief Medical Officer since 2021

MD from University of Cincinnati Medical School, Fellowships in Hematology and Oncology at University of Chicago Hospitals and Clinics

Miguel Fernández Alcalde

EMD Serono

Chief Executive Officer

Bachelor's Degree in Pharmacy from the University Complutense in Madrid, MBA from the University of Alcalá de Henares, Master's Degree in Management from IESE Business School

Published Research Related to This Trial

In the JAVELIN Lung 100 trial involving 1214 patients with advanced NSCLC, avelumab showed longer median progression-free survival (PFS) compared to platinum-based chemotherapy (8.4 months vs. 5.6 months), indicating its potential efficacy as a first-line treatment.

Although avelumab demonstrated longer median overall survival (OS) compared to chemotherapy (20.1 months vs. 14.9 months), the differences were not statistically significant, suggesting that while avelumab may be beneficial, it did not meet the primary objective of the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial. Reck, M., Barlesi, F., Yang, JC., et al.[2023]

Avelumab, a PD-L1 inhibitor, has shown overall response rates for advanced Merkel cell carcinoma (MCC) ranging from 29.1% to 72.1% in real-world studies, with median progression-free survival between 8.1 to 24.1 months, indicating its efficacy across diverse populations.

The treatment is generally safe, with common side effects including fatigue and infusion-related reactions, and it appears to be particularly effective in immunosuppressed patients, although further research is needed to evaluate long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab for Advanced Merkel Cell Carcinoma: Global Real-World Data on Patient Response and Survival. Lohray, R., Verma, KK., Wang, LL., et al.[2023]

Axitinib combined with immune checkpoint inhibitors (ICI) like pembrolizumab or avelumab is now approved for treating advanced renal cell carcinoma, but distinguishing between adverse events (AEs) caused by each treatment is crucial for optimizing therapy.

Experts identified specific AEs such as diarrhea, hepatic toxicity, fatigue, and cardiovascular issues that require unique management strategies when using axitinib-ICI combinations, emphasizing the need for careful clinical monitoring and tailored treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events. Grünwald, V., Voss, MH., Rini, BI., et al.[2021]

The JAVELIN Ovarian 200 trial is the first Phase III study to investigate the effectiveness of avelumab, a PD-L1 checkpoint inhibitor, in treating women with platinum-resistant ovarian cancer, involving multiple treatment arms to assess its efficacy.

The trial will measure overall survival and progression-free survival as primary outcomes, providing valuable insights into the potential benefits of avelumab alone or in combination with doxorubicin compared to doxorubicin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design. Pujade-Lauraine, E., Fujiwara, K., Dychter, SS., et al.[2022]

In a phase II trial involving 116 patients with metastatic Merkel cell carcinoma (mMCC), first-line treatment with avelumab resulted in a 39.7% objective response rate and a 30.2% durable response rate, indicating its efficacy in this aggressive skin cancer.

The treatment was generally well-tolerated, with 81% of patients experiencing treatment-related adverse events, but only 18.1% had severe (grade 3/4) events, and there were no treatment-related deaths, highlighting its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study. D'Angelo, SP., Lebbé, C., Mortier, L., et al.[2022]

Avelumab is an antibody that blocks programmed cell death ligand-1 (PD-L1) and has received accelerated approval in the USA for treating metastatic Merkel cell carcinoma (mMCC) in both adults and children aged 12 and older.

The drug is also undergoing regulatory reviews for other cancer treatments, including urothelial carcinoma, indicating its potential as a versatile cancer therapy in various stages of development worldwide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab: First Global Approval. Kim, ES.[2022]

Avelumab, a monoclonal antibody targeting PD-L1, demonstrated an acceptable safety profile in a phase 1a trial with 53 patients, with only one dose-limiting toxicity observed at the highest dose of 20 mg/kg, indicating that the maximum tolerated dose was not reached.

The pharmacokinetic analysis showed a dose-proportional exposure and a half-life of approximately 4 days at higher doses, leading to the selection of 10 mg/kg every 2 weeks for further development, as it achieved over 90% target occupancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Heery, CR., O'Sullivan-Coyne, G., Madan, RA., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03357757

Avelumab With Valproic Acid in Virus-associated Cancer Avelumab prevents the deactivation of a lymphocyte, in effect "turning off the off-switch." This leads to a re-energizing of a person's immune system, hopefully ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11077001/

Transcriptomic profiling of peripheral blood cells in HPV‐ ... We hypothesized that valproic acid (VA) as an epigenetic agent combined with avelumab may enhance the antitumor immunity in HPV‐associated solid tumors.

3. app.trialscreen.org app.trialscreen.org/trials/phase-2-cancer-that-associated-chronic-viral-infection-avelumab-valproic-trial-nct03357757

Avelumab With Valproic Acid in Virus-associated Cancer Although Avelumab is an effective treatment for several cancers, its effectiveness in virus-associated cancer has not yet been studied. The ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6605872/

Product review: avelumab, an anti-PD-L1 antibody - PMC Avelumab was well-tolerated and the objective response rate (ORR) was 15% with 3 PRs. Avelumab monotherapy for Merkel cell carcinoma. MCC is a rare, aggressive, ...

5. clinicaltrials.gov clinicaltrials.gov/search?cond=%22Cervical%20Cancer%22&intr=%22Avelumab%22&viewType=Table&rank=3

Search for: "Cervical Cancer", "Avelumab" | Card Results Avelumab With Valproic Acid in Virus-associated Cancer. Conditions. Cancer That is Associated With a Chronic Viral Infection. EBER Positive Hodgkins and Non ...

6. clin.larvol.com clin.larvol.com/trial-detail/NCT03357757

Avelumab With Valproic Acid in Virus-associated Cancer SITC 2024 (Poster) - 617 - Combined histone deacetylase and PD-L1 inhibition is safe and efficacious for the treatment of virus-associated cancers: results ...

7. mdpi.com mdpi.com/2072-6694/17/18/2956

Evaluating the Evolving Treatment Landscape of Systemic ... By combining valproic acid with avelumab, investigators seek to enhance the immunologic response against viral-infected tumoral cells [47]. Interestingly, a ...