Neoadjuvant Ipilimumab + Nivolumab for Melanoma

(NADINA Trial)

Not currently recruiting at 24 trial locations

Overseen By Christian Blank, Prof

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: The Netherlands Cancer Institute

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Metastatic melanoma, Autoimmune disease, 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)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for individuals with stage III melanoma, a type of skin cancer. It compares two approaches: one where patients receive a combination of immunotherapy drugs, ipilimumab and nivolumab, before surgery, and another where they undergo surgery first and then receive nivolumab. The goal is to determine which approach better prevents cancer recurrence. This trial may suit those diagnosed with stage III melanoma that can be surgically removed and who have not received certain cancer treatments before. As a Phase 3 trial, it represents the final step before FDA approval, offering patients early access to potentially effective treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take immunosuppressive medications or certain investigational drugs before joining. It's best to discuss your specific medications with the trial team.

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

Research shows that the combination of ipilimumab and nivolumab has been studied for safety in treating melanoma. In previous studies, this combination consistently showed safe results. For instance, only 2.5% of melanoma patients experienced infusion-related reactions, indicating that most patients tolerated the treatment well.

Additionally, the FDA has approved this combination for advanced melanoma, confirming it has passed strict safety checks for that use. However, like any treatment, side effects can occur. It's important to consider personal health and discuss potential risks with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of ipilimumab and nivolumab for melanoma because it represents a powerful one-two punch against cancer cells. Unlike traditional treatments that might focus on a single pathway, this combo unleashes the body's immune system to attack tumors from multiple angles. Ipilimumab boosts the immune response by blocking CTLA-4, while nivolumab targets the PD-1 pathway to prevent cancer cells from hiding. This dual action could potentially lead to more effective outcomes, particularly for patients who haven't responded well to existing therapies.

What evidence suggests that this trial's treatments could be effective for melanoma?

This trial will evaluate the combination of ipilimumab and nivolumab as a neoadjuvant treatment for melanoma. Research has shown that using these drugs together effectively treats melanoma, a type of skin cancer. One study found that patients taking both drugs had a 52% chance of surviving for five years, compared to only 26% for those taking ipilimumab alone. This combination has been proven to extend patients' lives. The FDA has approved it for treating advanced melanoma, and it consistently outperforms using either drug alone. Overall, evidence strongly supports the effectiveness of combining ipilimumab and nivolumab for treating melanoma. ^{1 2 4 6 7}

Who Is on the Research Team?

Christian Blank, Prof

Principal Investigator

Medical oncologist/researcher

Georgina Long, Prof

Principal Investigator

Medical oncologist/researcher

Are You a Good Fit for This Trial?

This trial is for adults and teens (16+) with stage III melanoma that can be surgically removed. Participants must not have used immunosuppressive drugs in the last 6 months, should have good health status, no history of certain cancers or treatments targeting BRAF/MEK or CTLA-4/PD-1/PD-L1, and no active infections or autoimmune diseases. Women who can bear children and sexually active men must use contraception.

Inclusion Criteria

I have no other cancers, or if I do, they are under control and not expected to affect my life expectancy significantly.

I understand and can follow the treatment plan.

I have not had immunotherapy targeting CTLA-4, PD-1, or PD-L1.

Exclusion Criteria

Subjects will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

I have undergone radiotherapy before.

I am not pregnant or breastfeeding.

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 every 3 weeks followed by a total lymph node dissection and, if applicable, resection of in-transit metastases

6 weeks

Adjuvant Treatment

Participants receive adjuvant nivolumab every 4 weeks for 11 cycles if pathologic partial or non-response in arm A, or 12 cycles in arm B. BRAF V600E/K mutation-positive patients in arm A receive adjuvant dabrafenib plus trametinib for 46 weeks

46 weeks

Follow-up

Participants are monitored with CT scans every 12 weeks until the end of year 3, and then according to the institute's standards until year 5

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab, Nivolumab
• Nivolumab

Trial Overview

The study compares two approaches: one group receives neoadjuvant ipilimumab + nivolumab before surgery followed by adjuvant nivolumab; the other has standard surgery first then adjuvant nivolumab. Some may get additional treatment if they don't respond well initially. The goal is to see which method works better for preventing cancer progression.

How Is the Trial Designed?

Group I: A: Neoadjuvant Experimental Treatment 1 Intervention

2 cycles of neoadjuvant ipilimumab (80mg) + nivolumab (240mg) every 3 weeks followed by a total lymph node dissection (TLND) and if applicable, resection of in-transit metastases. Patients with a pathologic partial or non-response in arm A will also receive adjuvant nivolumab 480 mg every 4 weeks 11 cycles. In case of BRAF V600E/K mutation-positivity, patients will be treated with adjuvant dabrafenib plus trametinib for 46 weeks instead.

Group II: B: Adjuvant Active Control 1 Intervention

Standard upfront total lymph node dissection (TLND) and if applicable, resection of in-transit metastases followed by 12 cycles adjuvant nivolumab 480 mg every 4 weeks

Ipilimumab, Nivolumab is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Yervoy for:

• Melanoma
• Colorectal cancer
• Renal cell carcinoma
• Hepatocellular carcinoma
• Non-small cell lung cancer

Approved in United States as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in European Union as Yervoy for:

• Melanoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in Canada as Yervoy for:

• Melanoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma

Approved in Japan as Yervoy for:

• Melanoma

Approved in Japan as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma

Who Is Running the Clinical Trial?

The Netherlands Cancer Institute

Lead Sponsor

Trials

308

Recruited

216,000+

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

Published Research Related to This Trial

In a phase 3 trial involving 906 patients with resected advanced melanoma, nivolumab demonstrated a significantly higher 12-month recurrence-free survival rate of 70.5% compared to 60.8% for ipilimumab, indicating it is more effective as adjuvant therapy.

Nivolumab also had a much lower incidence of severe treatment-related adverse events (14.4%) compared to ipilimumab (45.9%), suggesting it is a safer option for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. Weber, J., Mandala, M., Del Vecchio, M., et al.[2023]

In a phase 2 study of 23 patients with high-risk resectable melanoma, the combination of ipilimumab and nivolumab showed high response rates (73% overall response rate and 45% pathologic complete response) but also resulted in significant toxicity, with 73% of patients experiencing grade 3 treatment-related adverse events.

Nivolumab monotherapy had lower response rates (25% overall response rate and 25% pathologic complete response) but was associated with much lower toxicity (only 8% grade 3 treatment-related adverse events), suggesting that while combination therapy is effective, it comes with higher risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Amaria, RN., Reddy, SM., Tawbi, HA., et al.[2021]

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]

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 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]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

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]

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]

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]

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 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]

Citations

1.

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.

2.

opdivohcp.com

opdivohcp.com/efficacy/melanoma/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Efficacy in ...

In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC ...

3.

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 ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7352976/

Combination of Ipilimumab and Nivolumab in Cancers

Studies showed a positive effect of ipilimumab when combined with other agents, including vaccines or other immune checkpoint inhibitors against cancer. The FDA ...

5.

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 ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7757740/

Safety and efficacy of combination nivolumab plus ...

In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further ...

7.

opdivohcp.com

opdivohcp.com/safety/melanoma/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Safety in ...

In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC ...