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

22 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Nivolumab and Ipilimumab for treating melanoma?

Research shows that combining Nivolumab and Ipilimumab leads to better outcomes for patients with advanced melanoma, including higher response rates and longer survival times, compared to using Ipilimumab alone. ^{1 2 3 4 5}

Is the combination of Nivolumab and Ipilimumab safe for treating melanoma?

The combination of Nivolumab and Ipilimumab for melanoma can lead to increased risk of immune-related side effects, which can be more frequent and severe than when using each drug alone. Common side effects include fatigue, diarrhea, and skin reactions, but most are reversible with treatment. Close monitoring by experienced healthcare providers is important to manage these side effects effectively. ^{6 7 8 9 10}

How is the drug Nivolumab + Ipilimumab unique for treating melanoma?

Nivolumab and ipilimumab work together to boost the immune system's ability to fight melanoma by targeting different pathways, leading to better response rates and longer survival compared to using ipilimumab alone. This combination is unique because it uses two different types of immune checkpoint inhibitors to enhance the body's natural defenses against cancer. ^{2 3 4 11 12}

What is the purpose of this trial?

Effective adjuvant treatment can increase cure in patients with high-risk resected melanoma. High dose interferon is a standard of care in the adjuvant setting but is highly toxic and marginally effective. The combination of ipilimumab and nivolumab is the most active regimen in patients with advanced melanoma so there is clear rationale to test this regimen in the adjuvant setting. Investigators are testing if nivolumab 3mg/kg every 2 weeks with 1mg/kg ipilimumab every 6 weeks in the high risk adjuvant setting. The duration of therapy will be six months.

Research Team

Howard Safran, MD

Principal Investigator

BrUOG Study Chair

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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 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]

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]

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 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]

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]

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]

References

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

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. [2022]

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

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

3. 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]

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]

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

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

6. Netherlands pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. [2022]

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

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

8. England pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

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

10. 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]

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

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. [2020]