Nivolumab + Ipilimumab for Melanoma

Overseen By kayla Rosati, EdM

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Maria Constantinou

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Brain metastases, Autoimmune disease, Hepatitis, HIV, others

Stay on Your Current Meds You can continue your current medications while participating

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 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), to determine if they can prevent melanoma, a type of skin cancer, from returning after surgery. The goal is to find a treatment that is more effective and has fewer side effects than the current, often harsh, option. The trial targets individuals who have had melanoma completely removed by surgery but remain at high risk of recurrence. Participants should not have received any treatment for melanoma other than surgery or radiation and must currently be disease-free. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to potentially groundbreaking advancements in melanoma care.

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

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic corticosteroids or other immunosuppressive medications, you must stop them at least 14 days before starting the trial treatment.

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

Research has shown that the combination of nivolumab and ipilimumab is generally well-tolerated, though some patients experience side effects. In a study with 709 patients using this combination, about 51% had severe side effects, known as grade 3-4 adverse events. These side effects can be serious but are often manageable with medical care.

This treatment is not new in the medical field and has demonstrated long-term benefits for patients with advanced melanoma, indicating that its safety is well understood. While awareness of possible side effects is important, the combination has proven effective in helping patients live longer, healthier lives. ^{1 2 3 4 5}

Why are researchers excited about this possible treatment for melanoma?

Unlike the standard treatments for melanoma, which often involve surgery, chemotherapy, or radiation, Nivolumab and Ipilimumab are immunotherapy drugs that harness the body’s own immune system to fight cancer. Nivolumab is a PD-1 inhibitor, while Ipilimumab is a CTLA-4 inhibitor; together, they work by blocking proteins that prevent the immune system from attacking cancer cells, thereby boosting the immune response against melanoma. Researchers are excited about these treatments because they offer a targeted approach that can potentially lead to longer-lasting remissions and improved survival rates compared to traditional therapies.

What evidence suggests that nivolumab and ipilimumab could be effective for melanoma?

Research has shown that using nivolumab and ipilimumab together effectively treats advanced melanoma, a type of skin cancer. In studies, 96% of patients who were alive and had no disease progression three years after treatment remained alive 10 years later. Another study found that 59% of patients with advanced melanoma who received this combination survived. The five-year survival rate for this combination was 52%, compared to 44% for nivolumab alone and 26% for ipilimumab alone. This trial will evaluate the combination of nivolumab and ipilimumab as an adjuvant treatment, suggesting that using them together can greatly improve survival chances for melanoma patients. ^{1 3 4 6 7}

Who Is on the Research Team?

Howard Safran, MD

Principal Investigator

BrUOG Study Chair

Are You a Good Fit for This Trial?

Adults over 18 with high-risk melanoma that's been surgically removed can join. They should be healthy enough for treatment (ECOG 0-1), not have had other cancer treatments except surgery or radiation, and must agree to use birth control. People with certain medical conditions, previous immunotherapy, active infections like hepatitis B/C or HIV, pregnant/breastfeeding women, and those with brain metastases cannot participate.

Inclusion Criteria

You are not pregnant or breastfeeding. If you can have children, you need a negative pregnancy test before starting the treatment. If you have not had a period for over a year or had surgery that caused menopause, you do not need a pregnancy test.

My cancer was surgically removed, it had spread to my lymph nodes but I am now disease-free.

My blood, liver, and kidney functions meet the study's required levels.

Exclusion Criteria

I have been treated with drugs targeting PD-1, PD-L1, or CTLA-4.

I am currently undergoing treatment for cancer.

I have tested positive for HIV/AIDS.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab 3mg/kg every 2 weeks and ipilimumab 1mg/kg every 6 weeks for a total of 6 months

6 months

12 visits (in-person) for nivolumab, 4 visits (in-person) for ipilimumab

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab

Trial Overview The trial is testing a combination of two drugs: Nivolumab (3mg/kg every 2 weeks) and Ipilimumab (1mg/kg every 6 weeks) as an adjuvant therapy for six months in patients who've had their melanoma surgically removed but are at high risk of it coming back. The goal is to see if this regimen can prevent the cancer from returning better than current standard care.

How Is the Trial Designed?

Group I: Adjuvant treatment Experimental Treatment 2 Interventions

Ipilumumab:1mg/kg q6weeks (1 dose per cycle, 4 planned treatments over 6 months total) Nivolumab:3mg/kg q2weeks (3 doses per cycle, 12 planned treatments over 6 months total)

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?

Maria Constantinou

Lead Sponsor

Trials

2

Recruited

30+

Brown University

Lead Sponsor

Trials

480

Recruited

724,000+

Rhode Island Hospital

Collaborator

Trials

275

Recruited

71,400+

The Miriam Hospital

Collaborator

Trials

252

Recruited

39,200+

Published Research Related to This Trial

In a phase 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

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 the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

The combination of nivolumab and ipilimumab, two immune checkpoint inhibitors, is a promising treatment for advanced melanoma, enhancing the body's immune response against the cancer.

Adding denosumab to this treatment may further improve anti-tumor effects by counteracting the immunosuppressive environment created by CD8+ T cells, as suggested by recent reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. Yoshida, S., Fujimura, T., Kambayashi, Y., et al.[2020]

In a study of 945 patients with untreated metastatic melanoma, the combination of nivolumab and ipilimumab significantly improved progression-free survival to a median of 11.5 months compared to just 2.9 months with ipilimumab alone.

For patients with PD-L1-negative tumors, the combination therapy was particularly effective, showing a progression-free survival of 11.2 months compared to 5.3 months with nivolumab alone, highlighting the potential of dual checkpoint inhibition in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

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]

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]

Combined immune checkpoint blockade (ICB) using nivolumab and ipilimumab shows significant efficacy in treating advanced melanoma, but it also leads to a higher frequency and severity of adverse drug reactions (ADRs) compared to single-agent therapies, based on pooled safety data from 1551 patients.

Most immune-related ADRs are reversible with glucocorticoids, but due to the increased risk and rapid onset of these toxicities, clinicians must be well-trained to monitor and manage these side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Hassel, JC., Heinzerling, L., Aberle, J., et al.[2022]

In a study of 142 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a significantly higher objective response rate of 61% compared to 11% for ipilimumab alone, indicating that the combination therapy is much more effective for treating this type of cancer.

While the combination therapy showed promising efficacy, it also had a higher incidence of severe adverse events (54% vs. 24% for monotherapy), but most of these side effects were manageable with immune-modulating medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. Postow, MA., Chesney, J., Pavlick, AC., et al.[2022]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12080919/

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... In patients who were progression-free at 3-years, 10-year melanoma-specific survival rates were 96% with nivolumab-plus-ipilimumab, 97% with ...

2. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2407417

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab ... Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97 ...

3. opdivo.com opdivo.com/melanoma/clinical-trial-results/advanced-immunotherapy-combination

Advanced Melanoma Skin Cancer | Clinical Trial Results 59% of those given OPDIVO® + YERVOY® for advanced melanoma survived, versus ... OPDIVO and OPDIVO + YERVOY can cause serious side effects, including: See ...

4. news.bms.com news.bms.com/news/details/2019/Five-Year-Outcomes-for-Opdivo-nivolumab-in-Combination-with-Yervoy-ipilimumab-Demonstrate-Durable-Long-Term-Survival-Benefits-in-Patients-with-Advanced-Melanoma/default.aspx

Five-Year Outcomes for Opdivo (nivolumab) in ... Five-year overall survival rates were 52% for the Opdivo plus Yervoy combination, 44% for Opdivo alone, and 26% for Yervoy alone.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.00400

Pooled Long-Term Outcomes With Nivolumab Plus ... Six-year OS was 52% with NIVO + IPI and 41% with NIVO, with a median OS of 84.6 months (95% CI, 59.5 to not reached [NR]) and 36.9 months (95% ...

6. news.bms.com news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-Landmark-10-Year-Follow-Up-Data-from-CheckMate--067-Which-Showed-Continued-Durable-Long-Term-Survival-Benefit-with-Opdivo-plus-Yervoy-in-Advanced-Melanoma/default.aspx

067 Which Showed Continued Durable Long-Term ... With a minimum follow up of 10 years, median overall survival (OS) was 71.9 months with Opdivo plus Yervoy (95% CI: 38.2-114.4) - the longest ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37103470/

Real-world Outcomes of Ipilimumab Plus Nivolumab ... In total, 709 patients received first-line ipilimumab plus nivolumab. Three hundred sixty (50.7%) patients experienced grade 3-4 adverse events, ...