VO + Nivolumab for Advanced Melanoma

Recruiting at30 trial locations

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Replimune Inc.

Must not be taking: Antivirals, Corticosteroids

Disqualifiers: Hepatitis, HIV, CNS metastases, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This is a randomized, controlled, multicenter, open-label Phase 3 clinical study comparing VO in combination with nivolumab versus Physician's Choice treatment for patients with unresectable Stage IIIb-IV cutaneous melanoma whose disease progressed on an anti PD-1 and an anti-CTLA-4 containing regimen (administered either as a combination regimen or in sequence) or who are not candidates for treatment with an anti-CTLA-4 therapy.

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.

What data supports the effectiveness of the drug Nivolumab for advanced melanoma?

Research shows that Nivolumab, when combined with another drug called ipilimumab, improves survival and response rates in patients with advanced melanoma compared to using ipilimumab alone. This combination has been shown to help patients live longer and slow down the progression of the disease. ^{1 2 3 4 5}

Is the combination of VO and Nivolumab safe for treating advanced melanoma?

Nivolumab, also known as Opdivo, is generally safe but can cause immune-related side effects like fatigue, diarrhea, and rash. When combined with other drugs like ipilimumab, the risk of these side effects can increase. Safety data for Vusolimogene Oderparepvec (RP1) is not detailed here, but Nivolumab has been studied extensively and is considered to have a manageable safety profile. ^{6 7 8 9 10}

How is the VO + Nivolumab treatment different from other treatments for advanced melanoma?

The VO + Nivolumab treatment is unique because it combines nivolumab, an immune checkpoint inhibitor, with Vusolimogene Oderparepvec, an oncolytic virus therapy. This combination aims to enhance the immune response against melanoma by using the virus to directly attack cancer cells and potentially improve the effectiveness of nivolumab, which helps the immune system recognize and fight cancer cells. ^{11 12 13 14 15}

Research Team

Giuseppe Gullo, MD

Principal Investigator

Replimune Inc.

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Nivolumab (Checkpoint Inhibitor)
• Vusolimogene Oderparepvec (Virus Therapy)

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.

Participant Groups

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 Canada, Switzerland for the following indications:

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+

Findings from Research

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 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 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]

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]

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]

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 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]

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 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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in metastatic melanoma: a critical appraisal focused on specific subpopulations. [2023]

2. England 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. [2022]

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

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Real-world outcomes with ipilimumab and nivolumab in advanced melanoma: a multicentre retrospective study. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. [2018]

6. England pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

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

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. [2018]

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

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? [2018]

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

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

11. Germany 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. [2020]

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

Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma. [2022]

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

Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. [2023]

14. England pubmed.ncbi.nlm.nih.gov

Successful treatment with intralesional talimogene laherparepvec in two patients with immune checkpoint inhibitor-refractory, advanced-stage melanoma. [2019]

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

Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. [2022]