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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the combined effects of ipilimumab and nivolumab in treating melanoma that has recurred during or after other treatments. Participants will receive these drugs before their scheduled surgery, followed by regular follow-up treatment. The trial seeks individuals whose melanoma can be surgically removed and who experienced a recurrence while on or shortly after completing anti-PD-1 therapy. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that combining ipilimumab and nivolumab effectively treats advanced melanoma. However, this treatment often causes serious side effects. Studies have found that many patients experience strong negative reactions to this combination.

Despite these side effects, the treatment has been successfully used for advanced melanoma and is FDA-approved for this purpose. This approval indicates that, while risks exist, the potential benefits are recognized.

Prospective trial participants should consider the potential side effects and benefits. Always consult a healthcare provider to make the best decision for your situation. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for melanoma?

Unlike standard melanoma treatments that often include surgery, chemotherapy, or radiation, Ipilimumab and Nivolumab are immune checkpoint inhibitors that work by unleashing the body's own immune system to attack cancer cells. These drugs target specific proteins (CTLA-4 and PD-1) that usually act as brakes on the immune system, effectively allowing the immune cells to recognize and destroy melanoma cells more effectively. Researchers are excited about these treatments because they have shown potential for longer-lasting responses compared to traditional therapies, and they might also be effective against tumors that have spread to other parts of the body.

What evidence suggests that this treatment might be an effective treatment for melanoma?

Research has shown that using ipilimumab and nivolumab together effectively treats advanced melanoma, a type of skin cancer. Studies found that after five years, 52% of patients who received both drugs were still alive, compared to 26% of those who only received ipilimumab. This combination proves more effective than using either drug alone for advanced melanoma. While not everyone benefits from the treatment, it significantly increases survival rates for many patients. The FDA has approved this combination for treating advanced melanoma, confirming its effectiveness. Participants in this trial will receive the combination of ipilimumab and nivolumab as part of the study treatment. ^{2 3 4 6 7}

Who Is on the Research Team?

Siwen Hu-Lieskovan

Principal Investigator

Huntsman Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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 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]

Citations

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

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... Further, even with available immune checkpoint inhibitor combinations, ~40% of patients do not respond to treatment, and half die from melanoma.

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

Advanced Melanoma Skin Cancer | Clinical Trial Results OPDIVO + YERVOY is FDA approved to treat advanced melanoma regardless of your test results. More people given OPDIVO + YERVOY were alive compared to YERVOY ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1910836

Five-Year Survival with Combined Nivolumab and ... Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group.

4. curemelanoma.org curemelanoma.org/patient-eng/melanoma-treatment/options/nivolumab-opdivo-ipilimumab-yervoy

Nivolumab (Opdivo) + Ipilimumab (Yervoy) When used together, nivolumab and ipilimumab can treat advanced melanoma more effectively than each drug on its own.

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

Pooled Long-Term Outcomes With Nivolumab Plus ... In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment–naïve ...

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

Real-world Outcomes of Ipilimumab Plus Nivolumab ... Ipilimumab plus nivolumab combination therapy is highly efficacious for advanced melanoma, despite many treatment-related grades 3-4 adverse events.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.02229

Long-Term Outcomes With Nivolumab Plus Ipilimumab or ... Five-year OS rates were 52%, 44%, and 26% in the three groups, respectively, and among patients with BRAF-mutant advanced melanoma, 5-year OS ...