VO + Nivolumab for Advanced Melanoma

Recruiting at 52 trial locations

Overseen By Clinical Trials at Replimune

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Replimune Inc.

Must not be taking: Antivirals, Corticosteroids

Disqualifiers: Hepatitis, HIV, CNS metastases, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 55 months

400 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, VO (Vusolimogene Oderparepvec) and nivolumab (Opdivo, an immunotherapy drug), for individuals with advanced melanoma (a severe form of skin cancer) that cannot be surgically removed. The goal is to determine if this new combination is more effective than other treatments selected by a doctor. It suits patients whose melanoma has worsened despite previous treatments with drugs targeting PD-1 and CTLA-4, proteins that help the immune system fight cancer. Participants should have melanoma that has spread beyond the skin and have already tried specific medications without success. As a Phase 3 trial, this study represents the final step before FDA approval, offering patients a chance to access potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot use certain antivirals or systemic corticosteroids above a certain dose. 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 has shown that the combination of vusolimogene oderparepvec (VO) and nivolumab is generally safe for patients with advanced melanoma. In earlier studies, patients who did not respond to other treatments experienced positive outcomes without major safety issues. Importantly, this combination treatment proved safe, with manageable and not too severe side effects. While any treatment can have side effects, evidence so far suggests that this combination is relatively safe for most patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Vusolimogene Oderparepvec (VO) combined with Nivolumab for advanced melanoma because it introduces a novel approach to treatment. VO is a genetically modified oncolytic virus designed to selectively infect and kill cancer cells, sparking an immune response against the tumor. This is different from traditional treatments like single-agent chemotherapy or anti-PD-1 monotherapy, which primarily focus on inhibiting tumor growth. By combining VO with Nivolumab, an immune checkpoint inhibitor, the treatment aims to enhance the body's immune response to melanoma, potentially leading to more effective and durable outcomes.

What evidence suggests that this trial's treatments could be effective for advanced melanoma?

Research has shown that the combination of Vusolimogene Oderparepvec (VO) and nivolumab, which participants in this trial may receive, holds promise for treating advanced melanoma. Studies have found that this combination can lead to significant and lasting improvements in patients whose disease did not improve with previous treatments like anti–PD-1 therapy. The treatment appears effective even for those with a poor prognosis, demonstrating long-lasting effects against tumors. Additionally, it is generally safe, with patients usually tolerating it well. These findings suggest that VO combined with nivolumab could be a strong option for challenging cases of melanoma. ^{1 5 6 7 8}

Who Is on the Research Team?

Giuseppe Gullo, MD

Principal Investigator

Replimune Inc.

Are You a Good Fit for This Trial?

This trial is for adults and children over 12 with advanced melanoma that worsened after treatment with anti-PD-1 and anti-CTLA-4 drugs, or those unsuitable for anti-CTLA-4 therapy. Participants must have at least one measurable tumor, proper organ function, and a documented BRAF V600 mutation status.

Inclusion Criteria

My blood counts are within a healthy range.

I have a tumor larger than 1 cm that can be measured and injected.

I am 12 years old or older.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Vusolimogene Oderparepvec in combination with Nivolumab or treatment of Physician's Choice

Up to 55 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Vusolimogene Oderparepvec

Trial Overview The study compares VO (Vusolimogene Oderparepvec) combined with Nivolumab against treatments chosen by the patient's physician in cases of Stage IIIb to IV melanoma. It aims to find out if this combination is more effective than standard options after previous therapies fail.

How Is the Trial Designed?

Group I: VO + nivolumab Experimental Treatment 2 Interventions

Group II: Physicians Choice Active Control 4 Interventions

Choosing from 1 of the following (to be consistent with approved label and/or applicable local clinical guidelines): * Nivolumab + relatlimab (as Opdualag) * Anti-PD-1 monotherapy (nivolumab or pembrolizumab) * Single-agent chemotherapy (dacarbazine, temozolomide, or paclitaxel/albumin-bound paclitaxel)

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

Replimune Inc.

Lead Sponsor

Trials

16

Recruited

1,700+

Published Research Related to This Trial

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Nivolumab significantly improved overall survival and progression-free survival in patients with unresectable or metastatic melanoma compared to dacarbazine, with hazard ratios of 0.42 and 0.43 respectively, based on a trial involving 418 patients.

The most common side effects of nivolumab included fatigue, diarrhea, and rash, but it was still considered to have a favorable benefit-risk profile compared to dacarbazine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. Beaver, JA., Theoret, MR., Mushti, S., et al.[2018]

The combination of talimogene laherparepvec (T-VEC) and ipilimumab in patients with advanced melanoma showed a tolerable safety profile, with no dose-limiting toxicities and a manageable rate of grade 3/4 treatment-related adverse events (26.3%).

The treatment resulted in a 50% objective response rate, with 44% of patients experiencing a durable response lasting 6 months or more, indicating that this combination therapy may be more effective than using either treatment alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma. Puzanov, I., Milhem, MM., Minor, D., et al.[2022]

In a study of 697 patients with advanced melanoma treated with ipilimumab and nivolumab, the combination therapy showed a median overall survival of 53.7 months for treatment-naïve patients without brain metastases, indicating strong efficacy in this group.

However, the treatment was associated with significant toxicity, with 44% of patients experiencing grade 3-4 treatment-related adverse events and 0.7% experiencing treatment-related deaths, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world outcomes with ipilimumab and nivolumab in advanced melanoma: a multicentre retrospective study. Serra-Bellver, P., Versluis, JM., Oberoi, HK., et al.[2022]

In a phase III study involving 692 patients with advanced melanoma, the combination of talimogene laherparepvec (T-VEC) and pembrolizumab did not significantly improve progression-free survival (PFS) or overall survival (OS) compared to pembrolizumab alone.

The combination therapy showed a higher objective response rate (48.6% vs. 41.3%) and a similar safety profile to the placebo group, with grade ≥ 3 treatment-related adverse events occurring in about 20% of patients in both treatment arms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. Chesney, JA., Ribas, A., Long, GV., et al.[2023]

Talimogene laherparepvec (T-VEC) is an effective oncolytic immunotherapy for advanced melanoma, showing potential to elicit systemic antitumor immune responses even in patients who have not responded to anti-PD-1 and anti-CTLA-4 therapies.

In a case study involving two female patients with advanced melanoma who had previously progressed on immune checkpoint inhibitors, T-VEC treatment demonstrated successful outcomes, suggesting it may provide a complementary treatment option for those resistant to conventional immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment with intralesional talimogene laherparepvec in two patients with immune checkpoint inhibitor-refractory, advanced-stage melanoma. Seremet, T., Planken, S., Schwarze, JK., et al.[2019]

In a phase 1b clinical trial involving 21 patients with advanced melanoma, the combination of oncolytic virotherapy using talimogene laherparepvec and the anti-PD-1 antibody pembrolizumab was well tolerated, with a 62% confirmed objective response rate and a 33% complete response rate.

The combination therapy led to increased infiltration of CD8+ T cells and elevated PD-L1 expression in tumors, suggesting that talimogene laherparepvec may enhance the effectiveness of anti-PD-1 therapy by modifying the tumor microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Ribas, A., Dummer, R., Puzanov, I., et al.[2022]

Nivolumab, an immune checkpoint inhibitor, shows strong antitumor activity but is associated with immune-related adverse events that can affect patient safety and treatment continuation, necessitating careful monitoring.

Long-term safety data, including a 5-year follow-up, suggests that nivolumab can be safely administered to various challenging patient subgroups, but identifying biomarkers for severe toxicity could improve patient selection for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. Czarnecka, AM., Rutkowski, P.[2021]

The combination of nivolumab and relatlimab shows a manageable safety profile for patients with advanced melanoma who have already undergone treatment.

This combination therapy may offer a new option for patients with pretreated melanoma, suggesting potential efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Relatlimab Is Safe and Efficacious in Pretreated Melanoma. [2023]

Ipilimumab, the first drug to improve survival in advanced melanoma, works by inhibiting CTLA-4 on T cells, but newer PD-1 inhibitors like nivolumab and pembrolizumab have shown better efficacy and safety.

The combination of ipilimumab and nivolumab enhances response rates and progression-free survival in advanced melanoma patients, but it also increases the risk of immune-related toxicities, leading to its FDA approval in 2015 for BRAF wild-type cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? Carlino, MS., Long, GV.[2018]

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 retrospective study of 14 melanoma patients treated with talimogene laherparepvec (T-VEC) from 2016 to 2018, 64% of patients benefited from the therapy, demonstrating its effectiveness in overcoming loco-regional recurrence after systemic treatment.

T-VEC was found to be a tolerable treatment option for patients with stable or regressive systemic metastases who developed loco-regional resistance to immune checkpoint blockade or targeted therapy, with a durable response rate of 36%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talimogene laherparepvec treatment to overcome loco-regional acquired resistance to immune checkpoint blockade in tumor stage IIIB-IV M1c melanoma patients. Fröhlich, A., Niebel, D., Fietz, S., et al.[2020]

Nivolumab combined with ipilimumab has been established as a first-line treatment for advanced melanoma, showing significant efficacy based on results from the phase III CheckMate 067 trial.

While this combination therapy is effective, it is also associated with severe immune-related toxicities, highlighting the need to identify patient subgroups, such as those with BRAF mutations or asymptomatic brain metastases, who may benefit most from this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in metastatic melanoma: a critical appraisal focused on specific subpopulations. Vázquez-Montero, L., de la Gala, MDCÁ., de la Cruz-Merino, L.[2023]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

In a phase 3 trial with patients suffering from advanced melanoma, the combination of nivolumab and ipilimumab resulted in significantly longer overall survival rates (58% at 3 years) compared to ipilimumab alone (34%).

The safety profile of the combination therapy was consistent with previous reports, showing that 59% of patients experienced severe treatment-related adverse events, indicating that while effective, the combination therapy has a higher risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Wolchok, JD., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-01346

RP1 Combined With Nivolumab in Advanced Anti–PD-1– ... RP1 combined with nivolumab provided deep and durable systemic responses in patients with anti–PD-1–failed melanoma, including those with poor prognostic ...

2. ascopost.com ascopost.com/news/august-2025/nivolumab-plus-rp1-shows-durable-responses-in-advanced-melanoma-after-pd-1-inhibitor-resistance/

Nivolumab Plus RP1 Shows Durable Responses in ... “This study provides evidence that the combination of intratumoral RP1 and intravenous nivolumab is effective in patients with advanced melanoma ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06264180

Study Details | NCT06264180 | VO and Nivolumab vs ... This is a randomized, controlled, multicenter, open-label Phase 3 clinical study comparing VO in combination with nivolumab versus Physician's Choice treatment.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.9517

Efficacy and safety of RP1 combined with nivolumab in ... The updated data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed ...

5. targetedonc.com targetedonc.com/view/rp1-nivolumab-combo-shows-durable-responses-favorable-safety-in-melanoma

RP1/Nivolumab Combo Shows Durable Responses ... RP1 with nivolumab treatment for patients with melanoma after progression on anti–PD-1 offers durable responses and a favorable safety profile.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40627813/

RP1 Combined With Nivolumab in Advanced Anti-PD-1- ... RP1 combined with nivolumab provided deep and durable systemic responses in patients with anti-PD-1-failed melanoma, including those with poor prognostic ...

7. ir.replimune.com ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics

Replimune Receives Complete Response Letter from FDA ... We strongly believe that RP1 in combination with nivolumab can bring substantial benefit to advanced melanoma patients.” About RP1 RP1 ( ...

8. targetedonc.com targetedonc.com/view/rp1-combination-shows-response-safety-in-advanced-melanoma

RP1 Combination Shows Response, Safety in Advanced ... Vusolimogene oderparepvec plus nivolumab showed responses and a favorable safety profile in advanced melanoma post-anti–PD-1 therapy, per phase 2 IGNYTE trial ...