Nivolumab + Ipilimumab + Cabozantinib for Melanoma

Recruiting at 2 trial locations

Overseen By Gayle Cramer, RN, MHS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Georgetown University

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

14 Participants Needed

Trial Summary

What is the purpose of this trial?

In this phase II advanced melanoma study, all patients will receive treatment with nivolumab/ipilimumab plus cabozantinib for a 12 week induction period followed by nivolumab plus cabozantinib maintanence to complete up to 2 years of therapy unless disease progression, dose limiting toxicity, provider/patient decision or patient withdrawal of consent occurs. The primary endpoint is the one year PFS rate. Patients will have staging scans at baseline and every 12 weeks during the first 2 years on study. Safety evaluations including labs, EKG and history and physical will occur at each visit. Baseline tumor sample is required and on treatment biopsy will be optional of superficial tumor in the skin, subcutaneous tissue or lymph node that is palpable.

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.

What data supports the effectiveness of the drug combination Nivolumab, Ipilimumab, and Cabozantinib for treating melanoma?

Research shows that combining nivolumab and ipilimumab significantly improves survival and response rates in advanced melanoma compared to ipilimumab alone. Additionally, cabozantinib has shown effectiveness in other cancers, suggesting potential benefits when combined with these drugs. ^{1 2 3 4 5}

Is the combination of Nivolumab, Ipilimumab, and Cabozantinib safe for humans?

The combination of Nivolumab and Ipilimumab is known to cause immune-related side effects, which can be serious but are manageable with prompt care. Cabozantinib, when combined with Nivolumab, has been studied for safety in other conditions like renal-cell carcinoma, but specific safety data for the three-drug combination in melanoma is limited. ^{4 6 7 8 9}

How is the drug combination of Nivolumab, Ipilimumab, and Cabozantinib unique for treating melanoma?

This drug combination is unique because it combines two immune-boosting drugs, Nivolumab and Ipilimumab, which help the body's immune system attack cancer cells, with Cabozantinib, which targets and inhibits pathways that help tumors grow. This combination aims to enhance the effectiveness of treatment by using different mechanisms to fight melanoma. ^{1 2 3 4 10}

Research Team

Geoffrey T Gibney, MD

Principal Investigator

MedStar Georgetown University Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

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]

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 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 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]

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 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]

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 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]

References

1. 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]

2. United States 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). [2023]

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

Nivolumab plus ipilimumab in advanced melanoma. [2022]

4. United States 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. [2023]

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

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. [2020]

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

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]

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

Ipilimumab-Based Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events With Ipilimumab Monotherapy and Combination Therapy With Nivolumab. [2018]

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

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

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

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. [2023]