Ipilimumab + Nivolumab for Melanoma

(NeoRelapse Trial)

Overseen By Kaitlin Stephens

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Utah

Must be taking: Anti-PD1 therapy

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Active infection, Brain metastases, Cardiovascular disorders, 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: Unknown

25 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol mentions that participants must stop taking certain prohibited medications for a period of at least five half-lives before starting the treatment. However, it does not specify which medications are prohibited, so you should discuss your current medications with the study team to see if any need to be stopped.

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

Research shows that combining Ipilimumab and Nivolumab leads to better responses and longer survival in patients with advanced melanoma compared to using Ipilimumab alone. This combination has been shown to improve the chances of the cancer not getting worse and increases the number of patients who respond to the treatment. ^{1 2 3 4 5}

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

The combination of Ipilimumab and Nivolumab for melanoma can cause immune-related side effects, which are common and sometimes severe, leading to treatment discontinuation in 30-40% of patients. While most side effects are mild to moderate, some can be serious, affecting multiple organs, and may require treatment with steroids or other medications. Despite these risks, the combination is used because it can be effective, and patients who stop treatment due to side effects may still have good outcomes. ^{6 7 8 9 10}

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

The combination of Ipilimumab and Nivolumab is unique because it uses two different types of immune checkpoint inhibitors that work together to enhance the body's immune response against melanoma. Ipilimumab targets CTLA-4, while Nivolumab targets PD-1, and together they have shown to improve survival rates and response in patients with advanced melanoma compared to using Ipilimumab alone. ^{1 2 3 11 12}

What is the purpose of this trial?

The goal of this clinical trial is to study the impact of Neoadjuvant ipilimumab and nivolumab for melanoma patients that had recurrence during or after adjuvant anti-PD-1 therapy. Participants will receive 2 cycles of treatment prior to their standard of care surgery. After surgery participants will receive standard of care adjuvant therapy and be followed for response.

Research Team

Siwen Hu-Lieskovan

Principal Investigator

Huntsman Cancer Institute

Eligibility Criteria

This trial is for melanoma patients who have experienced a recurrence during or after initial treatment with anti-PD-1 therapy. Participants will undergo surgery as part of their standard care and must be suitable candidates for this procedure.

Inclusion Criteria

I can carry out all my self-care activities without assistance.

Negative pregnancy test or evidence of post-menopausal status or evidence of permanent surgical sterilization for subjects of childbearing potential

Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines

Exclusion Criteria

Receiving other investigational agents currently or within 28 days of study treatment

I have another cancer, but it won't affect this trial's safety evaluation.

Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive 2 cycles of neoadjuvant Ipilimumab and Nivolumab prior to surgery

2 months

Surgery

Participants undergo standard of care surgery

Adjuvant Therapy

Participants receive standard of care adjuvant therapy post-surgery

Follow-up

Participants are monitored for response, safety, and effectiveness after treatment

11 years

Treatment Details

Interventions

• Ipilimumab/Nivolumab

Trial Overview The trial tests the effect of two drugs, Ipilimumab and Nivolumab, given in cycles before surgery. After surgery, participants continue with standard post-surgery treatments and are monitored to see how well they respond.

Participant Groups

Group I: Treatment: All Patients Experimental Treatment 2 Interventions

Neoadjuvant Ipilimumab and Nivolumab

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Findings from Research

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]

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]

The combination of ipilimumab and nivolumab is more effective in treating advanced melanoma compared to ipilimumab alone, leading to better patient responses.

However, this two-drug combination significantly increases the likelihood of side effects compared to using ipilimumab as a single treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab + ipilimumab ups melanoma response. [2018]

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 study of 448 patients treated with ipilimumab and nivolumab for metastatic melanoma, 30-40% discontinued treatment due to immune-related adverse events (irAEs), but this did not significantly affect their progression-free survival (PFS).

Interestingly, patients who discontinued treatment due to irAEs actually experienced a significantly longer overall survival (OS) compared to those who completed the full treatment, suggesting that early discontinuation may not negatively impact treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study. Fink, M., Vittrup, AS., Bastholt, L., et al.[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]

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]

A patient with advanced melanoma experienced severe immune-related adverse events (irAEs) after receiving a single treatment of combined immunotherapy with ipilimumab and nivolumab, which are known to block PD-1 and CTLA-4 checkpoints.

Despite the severe irAEs leading to early discontinuation of therapy, the patient achieved a durable complete response, suggesting that irAEs may be associated with better long-term outcomes in some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable Complete Response in a Melanoma Patient With Unknown Primary, Associated With Sequential and Severe Multi-Organ Toxicity After a Single Dose of CTLA-4 Plus PD-1 Blockade: A Case Report. Matull, J., Livingstone, E., Wetter, A., et al.[2020]

In a study of 2834 melanoma patients treated with immune checkpoint inhibitors, 82 developed rare immune-related adverse events (RirAEs), with a higher incidence in those receiving combination therapy (4.6%) compared to anti-PD-1/L1 agents (2.8%).

Most RirAEs were of moderate severity (grade 2 and 3), and while steroid re-escalation and additional immunosuppression were often needed, fatal events were relatively rare, indicating that while RirAEs can occur, they are manageable in most cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rare immune-related adverse events in patients with melanoma: incidence, spectrum, and clinical presentations. Park, BC., Narayanan, S., Gavraldis, A., et al.[2023]

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

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]

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

Nivolumab + ipilimumab ups melanoma response. [2018]

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

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

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

Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study. [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

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

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

Durable Complete Response in a Melanoma Patient With Unknown Primary, Associated With Sequential and Severe Multi-Organ Toxicity After a Single Dose of CTLA-4 Plus PD-1 Blockade: A Case Report. [2020]

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

Rare immune-related adverse events in patients with melanoma: incidence, spectrum, and clinical presentations. [2023]

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]