Triple Drug Therapy for Melanoma

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

71 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the triple drug therapy for melanoma?

Research shows that combining nivolumab and ipilimumab, two of the drugs in the therapy, significantly improves survival rates and response in advanced melanoma compared to using ipilimumab alone. This suggests that the combination of these drugs can be more effective in treating melanoma. ^{1 2 3 4 5}

Is the triple drug therapy for melanoma safe for humans?

The drugs ipilimumab and nivolumab, used in melanoma treatment, have been associated with serious immune-related side effects, but they are generally considered safe with a favorable safety profile. Common side effects include fatigue, rash, itching, and diarrhea, while less common ones include thyroid issues, colitis, liver inflammation, and lung inflammation. ^{1 6 7 8 9}

How is the triple drug therapy for melanoma different from other treatments?

The triple drug therapy for melanoma combines ipilimumab and nivolumab, which are known to improve survival in advanced melanoma, with tocilizumab, potentially offering a novel approach by targeting different immune pathways. This combination may enhance the effectiveness of treatment but could also lead to unique immune-related side effects. ^{1 5 10 11 12}

What is the purpose of this trial?

This is a Phase II, open-label, single arm study. The study will consist of an assessment of the safety and tolerability of tocilizumab administered concurrently at 4 mg/kg every 6 weeks for 5 doses in combination with ipilimumab and nivolumab for four induction doses to week 12, then maintenance nivolumab alone up to one year to patients with advanced melanoma. Treatment will be divided into induction and maintenance phases. It is anticipated that this clinical study will inform the use of this 3-drug combination for further phase II and/or phase III clinical testing. The trial will include an assessment of the pharmacodynamic activity of tocilizumab administered in combination with ipilimumab and nivolumab.

Research Team

Janice M. Mehnert

Principal Investigator

New York Langone Health

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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]

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]

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]

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]

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]

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]

References

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

Checkpoint inhibitors for malignant melanoma: a systematic review and meta-analysis. [2022]

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

Checkpoint modulation in melanoma: an update on ipilimumab and future directions. [2022]

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

A Three-Drug Combo for Multiple Myeloma. [2017]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod. [2020]

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

Immune Checkpoint Inhibitors and Immune-Related Adverse Drug Reactions: Data From Italian Pharmacovigilance Database. [2022]

7. United States 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. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in a BRAF-mutant metastatic melanoma patient following a severe immune-related adverse event with ipilimumab. [2017]

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

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? [2018]

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

Pharmacological interventions for melanoma: Comparative analysis using bayesian meta-analysis. [2022]

12. Czech Republic pubmed.ncbi.nlm.nih.gov

[Side effects of Modern Immunotherapy and How to Solve Them in the Clinics]. [2018]