Nivolumab + Ipilimumab + Cabozantinib for Melanoma

Not currently recruiting at 3 trial locations

Overseen By Gayle Cramer, RN, MHS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Georgetown University

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Brain metastases, Autoimmune disorders, 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: 27

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for advanced melanoma, a serious type of skin cancer. Participants will receive a mix of drugs—nivolumab, ipilimumab, and cabozantinib (also known as Cabometyx)—to evaluate their combined effectiveness over two years. The main goal is to determine if this approach can control the cancer for at least a year. People with advanced melanoma that can't be surgically removed may be suitable candidates, but those with a specific type of eye melanoma or who have had certain prior treatments are not eligible. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but certain treatments like small molecule kinase inhibitors, cytotoxic or biologic therapies, and some anticoagulants must be stopped before starting the trial. If you're on anticoagulants, some are allowed if you're stable on them for at least 6 weeks before the trial.

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

Research has shown that the FDA approves the combination of nivolumab and ipilimumab for treating advanced melanoma, indicating it has been tested for safety and effectiveness in other studies. Some patients have reported mild to moderate side effects, such as reactions during the infusion, occurring in about 2.5% of cases.

Studies have found that cabozantinib is active in treating melanoma and other types of cancer. While generally well-tolerated, it can have side effects, including fatigue, diarrhea, and changes in liver function.

Overall, the treatments tested in the trial have been used in other contexts and have demonstrated some level of safety. However, like any treatment, side effects can occur, and discussing these with a doctor is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Nivolumab, Ipilimumab, and Cabozantinib for melanoma because it offers a unique approach compared to standard treatments. Unlike traditional therapies that may focus on just one pathway, this combination utilizes a multi-targeted strategy. Nivolumab and Ipilimumab are immune checkpoint inhibitors that help the immune system recognize and attack cancer cells more effectively. Cabozantinib, on the other hand, is a tyrosine kinase inhibitor that blocks specific proteins that promote tumor growth and blood vessel formation. Together, these treatments not only enhance the immune response but also directly inhibit tumor growth, potentially leading to more comprehensive control of the cancer.

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

Research has shown that using nivolumab and ipilimumab together holds promise for treating melanoma, a type of skin cancer. One study found that patients with melanoma who received this combination had a survival rate of up to 52% over 10 years. In this trial, participants will receive a combination of nivolumab, ipilimumab, and cabozantinib. Previous studies have demonstrated that adding cabozantinib to treatment can help stop cancer from worsening in other advanced cancers, such as kidney cancer. This suggests that cabozantinib might also enhance the treatment's effectiveness for melanoma. These findings offer hope that this combination could effectively manage advanced melanoma. ^{6 7 8 9 10}

Who Is on the Research Team?

Geoffrey T Gibney, MD

Principal Investigator

MedStar Georgetown University Hospital

Are You a Good Fit for This Trial?

Adults over 18 with advanced melanoma that can't be surgically removed may join this trial. They should have recovered from previous treatments, have good organ and bone marrow function, not be pregnant, and agree to use contraception. Participants need measurable disease by certain criteria and a sample of their tumor available.

Inclusion Criteria

Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.

My organs and bone marrow are working well.

I agree to use effective birth control during and for 4 months after the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive nivolumab 3mg/kg IV plus ipilimumab 1mg/kg IV every 3 weeks for 4 cycles with cabozantinib 40mg PO daily for 12 weeks

12 weeks

4 visits (in-person)

Maintenance Treatment

Participants receive nivolumab 480mg IV every 4 weeks and cabozantinib 40mg PO daily for up to 92 weeks

92 weeks

23 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Ipilimumab, Nivolumab

Trial Overview The study tests Nivolumab/Ipilimumab combined with Cabozantinib in patients during a 12-week induction phase followed by maintenance therapy for up to two years unless there's disease progression or unacceptable side effects. The main goal is to see how many are free from disease progression after one year.

How Is the Trial Designed?

Group I: Single Arm Experimental Treatment 3 Interventions

Nivolumab 3mg/kg IV plus Ipilimumab 1mg/kg IV every 3 weeks x 4 cycles with Cabozantinib 40mg PO daily for 12 weeks (Induction); Followed by Maintenance therapy: Nivolumab 480mg IV every 4 weeks for up to 92 weeks; Cabozantinib 40mg PO daily for up to 92 weeks; Maintenance therapy will continue for up to 92 weeks to complete 2 years total of treatment if tolerating therapy well and disease is controlled.

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

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

Georgetown University

Lead Sponsor

Trials

355

Recruited

142,000+

MedStar Franklin Square Medical Center

Collaborator

Trials

2

Recruited

110+

Hackensack Meridian Health

Collaborator

Trials

141

Recruited

42,900+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Published Research Related to This Trial

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 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 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 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]

In a study of 346 patients receiving cabozantinib (CABO) as second-line therapy after various first-line treatments, the median overall survival was 21.4 months for those who previously received ipilimumab-nivolumab (IPI-NIVO), indicating that CABO is effective regardless of the initial treatment.

The median time to treatment failure for CABO was 7.6 months, suggesting that it provides a clinically meaningful benefit as a second-line option after different first-line therapies, including immunotherapy and VEGF inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CABOSEQ: The Effectiveness of Cabozantinib in Patients With Treatment Refractory Advanced Renal Cell Carcinoma: Results From the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Navani, V., Wells, JC., Boyne, DJ., et al.[2023]

In a study of 71 patients with advanced hepatocellular carcinoma, the combination of nivolumab and cabozantinib showed promising antitumor activity, with an objective response rate of 17% for the doublet therapy and 29% for the triplet therapy including ipilimumab.

Both treatment combinations had manageable safety profiles, with 50% of patients in the doublet arm and 74% in the triplet arm experiencing grade 3-4 treatment-related adverse events, but no treatment-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial. Yau, T., Zagonel, V., Santoro, A., et al.[2023]

In a real-world analysis of adverse events from two combination therapies for advanced renal cell carcinoma, cabozantinib (CAB) plus nivolumab (NIVO) showed higher incidence rates of seven types of toxicities compared to ipilimumab (IPI) plus NIVO.

Conversely, IPI + NIVO was associated with higher rates of three types of toxicities and had a greater incidence of serious adverse events, suggesting that both therapies have distinct safety profiles that can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. Blas, L., Shiota, M., Tsukahara, S., et al.[2023]

In a phase 3 trial involving 855 patients with untreated advanced renal-cell carcinoma, the combination of cabozantinib with nivolumab and ipilimumab significantly improved progression-free survival compared to nivolumab and ipilimumab alone, with a 12-month progression-free survival rate of 57% versus 49%.

However, the experimental group experienced a higher incidence of severe adverse events (grade 3 or 4) at 79%, compared to 56% in the control group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Albiges, L., 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39282897/

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97 ...

2. onclive.com onclive.com/view/cabozantinib-plus-nivolumab-ipilimumab-sustains-pfs-benefit-in-advanced-rcc

Cabozantinib Plus Nivolumab/Ipilimumab Sustains PFS ... Cabozantinib combined with nivolumab and ipilimumab improved progression-free survival in advanced renal cell carcinoma compared to placebo.

3. opdivohcp.com opdivohcp.com/efficacy/rcc/opdivo-cabometyx

OPDIVO® (nivolumab) + CABOMETYX® (cabozantinib ... 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 ...

4. opdivo.com opdivo.com/advanced-kidney-cancer/clinical-trial-results/opdivo-cabometyx-immunotherapy-combination

Clinical trial results for advanced kidney cancer (renal cell ... People given OPDIVO + CABOMETYX had a 49% lower risk of their cancer spreading, growing, or getting worse than those given SUTENT. More people given OPDIVO + ...

5. 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 ... In addition, at 10 years of follow up, the Opdivo plus Yervoy combination showed melanoma-specific survival (MSS) rates of 52% (median not ...

6. ascopubs.org ascopubs.org/doi/10.1200/jco.2012.30.15_suppl.8531

Activity of cabozantinib (XL184) in metastatic melanoma Cabo demonstrates activity in metastatic melanoma pts, regardless of subtypes or BRAF mutation status, with improvement in PFS relative to placebo.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5318966/

Phase II randomised discontinuation trial of the MET/VEGF ... In a phase I clinical study, treatment with cabozantinib resulted in tumour reduction in multiple cancer types (Kurzrock et al, 2011).

8. onclive.com onclive.com/view/cabozantinib-pembrolizumab-trial-poised-to-improve-efficacy-safety-in-advanced-melanoma

Cabozantinib/Pembrolizumab Trial Poised to Improve ... Melanoma, when unresectable or metastatic, has an estimated 5-year survival rate of 17%. With the emergence of immunotherapy and BRAF/MEK ...

9. oncnursingnews.com oncnursingnews.com/view/cabozantinib-plus-pembrolizumab-may-improve-melanoma-outcomes

Cabozantinib Plus Pembrolizumab May Improve ... Melanoma, when unresectable or metastatic, has an estimated 5-year survival rate of 17%. With the emergence of immunotherapy and BRAF/MEK ...

10. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-cabozantinib-adults-and-pediatric-patients-12-years-age-and-older-pnet-and-epnet

FDA approves cabozantinib for pNET and epNET OS data were not mature with 83 (63% of patients enrolled) deaths in the cabozantinib arm and 40 (60% of patients enrolled) in the placebo arm ( ...