Triple Drug Therapy for Melanoma

Not currently recruiting at 3 trial locations

Overseen By Sandra John-Henry

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: NYU Langone Health

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, Ocular melanoma, 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: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—tocilizumab (an immunosuppressive drug), ipilimumab, and nivolumab—to determine their safety and effectiveness in treating advanced melanoma, a serious type of skin cancer. The study has two phases: an initial phase where all three drugs are administered together, and a maintenance phase with just one drug. It aims to understand how these drugs interact and how patients tolerate them. Individuals without previous treatment for advanced melanoma and with Stage IIIb/c/d or Stage IV melanoma might be suitable candidates for this trial. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on systemic steroids or other immunosuppressive medications within 14 days of starting the study drugs, unless they are inhaled or topical.

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

In earlier studies, combining the drugs ipilimumab and nivolumab showed that up to 60% of patients experienced serious immune-related side effects. These side effects, though significant, can be managed with proper care. Researchers have added tocilizumab to this combination to study its safety. They are examining how often severe side effects occur when these three drugs are used together in people with advanced melanoma.

This drug combination can cause immune-related side effects, but researchers are closely monitoring them in studies like this one. This information aids doctors in managing and reducing risks during treatment. While side effects are a concern, this combination is being explored for its potential benefits in treating difficult cases of melanoma. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about this triple drug therapy for melanoma because it combines Ipilimumab, Nivolumab, and Tocilizumab, each bringing a unique mechanism to the table. Ipilimumab and Nivolumab are immunotherapy drugs that help the immune system recognize and attack cancer cells more effectively, a step beyond traditional treatments like chemotherapy. Tocilizumab, typically used in autoimmune conditions, is being explored here for its potential to reduce inflammation-related side effects, making the combination potentially less toxic. This multi-faceted approach aims to not only enhance the effectiveness of melanoma treatment but also improve the patient's quality of life during therapy.

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

Research shows that using ipilimumab and nivolumab together can help people with advanced melanoma live longer. One study found that 59% of patients who took these drugs survived, demonstrating their effectiveness. However, up to 60% of patients might experience serious immune-related side effects. This trial examines tocilizumab to see if it can manage these side effects while preserving the treatment's benefits. Early results suggest that adding tocilizumab might reduce these side effects while still supporting the cancer-fighting effects of ipilimumab and nivolumab. ^{2 3 6 7 8}

Who Is on the Research Team?

Janice M. Mehnert

Principal Investigator

New York Langone Health

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma that can't be removed by surgery. Participants must have a good performance status, meaning they're fairly active and able to care for themselves. They should not have had certain previous cancer treatments or serious health conditions like heart failure or uncontrolled disorders. Women who can become pregnant and men with partners of childbearing potential must agree to use contraception.

Inclusion Criteria

I haven't had cancer treatment for metastatic disease, with some exceptions.

I had surgery with general anesthesia over 4 weeks ago.

My cancer's current state is documented by recent exams and scans.

Exclusion Criteria

You have an ongoing autoimmune disease or are suspected to have one.

I don't have a history of heart rhythm problems or need drugs that affect heart rhythm.

I had cancer other than melanoma, was treated successfully over 2 years ago, and don't need more treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive tocilizumab, ipilimumab, and nivolumab for four induction doses over 12 weeks

12 weeks

2 induction treatment cycles of 42 days each

Maintenance

Participants receive maintenance nivolumab alone up to one year

up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 18 months

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Tocilizumab

Trial Overview The study tests Tocilizumab combined with Ipilimumab and Nivolumab in patients with stage III or IV melanoma. It's an open-label, single-arm Phase II trial where everyone gets the same treatment: Tocilizumab every 6 weeks for five doses plus four induction doses of the other two drugs until week 12, followed by maintenance Nivolumab alone up to one year.

How Is the Trial Designed?

Group I: Induction Phase, Maintenance Phase Experimental Treatment 3 Interventions

Induction Phase: 2 induction treatment cycles of 42 days (6 weeks) each, of which the first cycle of 6 weeks is the dose-limiting toxicity (DLT) period. Maintenance Phase: Consists of treatment cycles of 84 days (12 weeks) each, and may extend up to 1 year.

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

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

NYU Langone Health

Lead Sponsor

Trials

1,431

Recruited

838,000+

Published Research Related to This Trial

Combining ipilimumab with nivolumab can significantly improve treatment outcomes for advanced melanoma patients, but ipilimumab alone is not effective for those resistant to nivolumab.

A case study demonstrated that a nivolumab-resistant patient with multiple in-transit melanomas responded well to a combination of ipilimumab and topical imiquimod, suggesting a potential new treatment strategy for similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod. Fujimura, T., Kambayashi, Y., Sato, Y., et al.[2020]

In a study analyzing 2,088 individual case safety reports (ICSRs) related to immune checkpoint inhibitors (ICIs) in Italy, 801 reports documented serious immune-related adverse drug reactions (irADRs), primarily affecting male patients with gastrointestinal and skin toxicities.

Among the ICIs, nivolumab and pembrolizumab were most frequently associated with irADRs, with significant risks identified for pembrolizumab and ipilimumab, highlighting the need for oncologists to recognize and manage these serious side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database. Ruggiero, R., Fraenza, F., Scavone, C., et al.[2022]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

The CheckMate 511 study found that using nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) resulted in a significantly lower incidence of severe treatment-related adverse events (34%) compared to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) which had a 48% incidence (P = .006).

While the efficacy outcomes such as objective response rate (45.6% for NIVO3+IPI1 vs. 50.6% for NIVO1+IPI3) and median progression-free survival (9.9 months vs. 8.9 months) were similar between the two groups, the NIVO3+IPI1 regimen showed a better safety profile without compromising effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. Lebbé, C., Meyer, N., Mortier, L., et al.[2020]

A 45-year-old male with metastatic melanoma experienced severe immune-related adverse events from ipilimumab, leading to its discontinuation, but successfully transitioned to pembrolizumab.

After over 20 months of treatment with pembrolizumab, the patient has shown no major toxicities and has achieved an ongoing partial response, suggesting that pembrolizumab may be a safe and effective option for patients with prior severe adverse events from other immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab. Aya, F., Fernández-Martínez, A., Gaba, L., et al.[2017]

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]

Ipilimumab, the first drug to improve survival in advanced melanoma, works by inhibiting CTLA-4 on T cells, but newer PD-1 inhibitors like nivolumab and pembrolizumab have shown better efficacy and safety.

The combination of ipilimumab and nivolumab enhances response rates and progression-free survival in advanced melanoma patients, but it also increases the risk of immune-related toxicities, leading to its FDA approval in 2015 for BRAF wild-type cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? Carlino, MS., Long, GV.[2018]

Citations

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

Advanced Melanoma Skin Cancer | Clinical Trial Results 59% of those given OPDIVO® + YERVOY® for advanced melanoma survived, versus ... In the clinical trial, people given OPDIVO + YERVOY had a 58% lower risk of ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.9553

Phase II trial of weekly or bi-weekly tocilizumab with ... However, up to 60% of patients (pts) receiving ipilimumab (ipi) plus nivolumab (nivo) experience grade 3/4 (G 3/4) immune-related adverse events ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9954703/

Immunotherapy in Melanoma: Recent Advances and ... Immunotherapy has demonstrated the ability to reduce the risk of recurrence for melanoma following surgical resection and improve survival ...

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

Five-Year Survival with Combined Nivolumab and ... Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial ...

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)03654-1/fulltext

1040O Phase II trial of ipilimumab, nivolumab and ... Immunotherapy with ipilimumab and nivolumab has response rates of 45-55%, but 50% of patients (pts) suffer grade 3-5 immune-related adverse events.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40684089/

Comparative safety of nivolumab plus ipilimumab versus ... Conclusion: NIVO-IPI is linked with a broader range of immune-related toxicities, whereas NIVO-RELA presents higher cardiac-specific risks.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04940299

NCT04940299 | Tocilizumab, Ipilimumab, and Nivolumab ... To determine the grade 3 or higher toxicity rate of Tocilizumab in combination with Ipilimumab and nivolumab for patients with advanced cutaneous melanoma.

8. esmoiotech.org esmoiotech.org/article/S2590-0188(22)00194-0/fulltext

151P Clinical outcome and preliminary immune analysis of ... We conducted this trial to assess the safety and efficacy of IL-6 blockade, using Tocilizumab, in combination with ipilimumab and nivolumab in melanoma ...