Ipilimumab + Nivolumab for Melanoma

Recruiting at 17 trial locations

Overseen By Michael Postow, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Autoimmune disease, HIV, Hepatitis, 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

Compensation: Varies

Number of Visits: 7

70 Participants Needed

Trial Summary

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 systemic corticosteroids or other immunosuppressive medications, you may need to stop them at least 14 days before starting the study drugs.

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

Research shows that combining Ipilimumab and Nivolumab significantly improves the chances of tumor response and prolongs the time patients live without the disease getting worse, compared to using Ipilimumab alone in advanced melanoma. ^{1 2 3 4 5}

Is the combination of Ipilimumab and Nivolumab safe for humans?

The combination of Ipilimumab and Nivolumab can cause immune-related side effects, which are often mild to moderate but can be severe in some cases. These side effects are due to the drugs' action on the immune system, and they require careful monitoring and management. While more studies are needed, current data from real-world use and clinical trials suggest that the safety profile includes reactions from each drug when used alone. ^{5 6 7 8 9}

How is the drug combination of Ipilimumab and Nivolumab unique for treating melanoma?

The combination of Ipilimumab and Nivolumab is unique because it targets two different immune checkpoints, CTLA-4 and PD-1, enhancing the body's immune response against melanoma. This combination has shown better outcomes in terms of response rates and survival compared to using Ipilimumab alone. ^{1 3 4 10 11}

What is the purpose of this trial?

This study will help determine whether 2 doses of the combination (ipilimumab + nivolumab) is sufficient for patients with early benefit compared to the usual way of trying to give 4 doses. If patients do not show early benefit after 2 doses, patients will be able to continue with additional ipilimumab + nivolumab, even beyond the standard 4 doses if felt in the best interest of the patient.

Research Team

Michael A. Postow

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with unresectable stage III or IV melanoma who haven't had CTLA-4 or PD-1/PD-L1 therapy. They must have a life expectancy of at least 4 months, be in good physical condition (ECOG 0-1), and women must use effective contraception. Exclusions include severe allergies, mental impairments, other serious illnesses, active autoimmune diseases requiring steroids or immunosuppressants, certain neuropathies, another active cancer, known immunodeficiency or viral hepatitis.

Inclusion Criteria

My melanoma cannot be removed by surgery and is stage III or IV.

I haven't received CTLA-4 or PD-1/PD-L1 therapy for my metastatic disease.

I use two birth control methods and will continue for 23 weeks after my last treatment dose.

Exclusion Criteria

I don't have another cancer that needs treatment or affects melanoma tests.

I am able to understand and follow the study's requirements.

I do not have any serious illnesses like infections needing antibiotics or bleeding disorders.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Treatment

Participants receive 2 doses of ipilimumab 3mg/kg + nivolumab 1mg/kg every 3 weeks

6 weeks

2 visits (in-person)

Response Assessment

Participants are assessed for antitumor effect by RECIST at week 6

1 week

1 visit (in-person)

Maintenance Treatment

Participants with favorable response receive maintenance nivolumab 480mg every 4 weeks for 2 doses

4 weeks

2 visits (in-person)

Extended Treatment

Participants without favorable response receive additional ipilimumab + nivolumab every 3 weeks, reassessed at week 12

6 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ipilimumab and Nivolumab Combination Immunotherapy

Trial Overview The study tests if two doses of ipilimumab plus nivolumab are as effective as the usual four doses for patients showing early benefits from treatment. Patients without early benefit can continue receiving additional doses beyond the standard four if deemed beneficial.

Participant Groups

Group I: ipilimumab and nivolumab Experimental Treatment 2 Interventions

Pts will receive 2 doses of ipilimumab 3mg/kg + nivolumab 1mg/kg every 3 weeks. Week 6, if pts have achieved a favorable antitumor effect by RECIST will begin maintenance nivolumab alone at 480mg every 4 weeks for 2 doses (week 6 \& week 10) \& repeat response assessments at week 12. If pts don't achieve a favorable antitumor effect at week 6, pt will get 2 additional doses of ipilimumab + nivolumab every 3 weeks \& then will be assessed for response at week 12. If pts haven't achieved a favorable antitumor effect by week 12, if felt in the best interest for the pt as determined by the PI, pts may continue getting additional doses of ipilimumab + nivolumab with response reassessments after every 2 doses. Maintenance nivolumab will continued until unacceptable toxicity or confirmed disease progression. If pts have had an initial clinical benefit from therapy \& subsequently experience progressive disease at any time, reinduction with combination ipilimuma+ nivolumab will be allowed.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

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 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 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 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]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

In a meta-analysis of 2,946 cancer patients, the combination therapy of nivolumab and ipilimumab was found to significantly increase the risk of immune-related adverse events (irAEs) compared to nivolumab alone.

Patients receiving the combination therapy experienced higher rates of various irAEs, including skin reactions, gastrointestinal issues, and liver enzyme elevation, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of immune-related adverse events associated with ipilimumab-plus-nivolumab and nivolumab therapy in cancer patients. Zhou, S., Khanal, S., Zhang, H.[2022]

In a study of 1255 patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with nivolumab plus ipilimumab (NIVO+IPI) showed a high incidence of treatment-related adverse events (TRAEs), with 78% experiencing any-grade TRAEs and 34% experiencing severe (grade 3 or 4) TRAEs, but the treatment was generally well tolerated.

Patients who discontinued NIVO+IPI due to TRAEs still had a favorable long-term survival rate, with a 3-year overall survival of 50%, indicating that stopping treatment because of side effects did not negatively impact their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. Paz-Ares, LG., Ciuleanu, TE., Pluzanski, A., et al.[2023]

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]

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. 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]

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]

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

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

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

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

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

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

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Risk of immune-related adverse events associated with ipilimumab-plus-nivolumab and nivolumab therapy in cancer patients. [2022]

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

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. [2023]

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

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

11. Switzerland pubmed.ncbi.nlm.nih.gov

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