Cabozantinib + Nivolumab + Ipilimumab for Kidney Cancer

Not currently recruiting at 3 trial locations

Overseen By Bradley McGregor, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Bradley A. McGregor, MD

Must not be taking: Corticosteroids, Hydroxychloroquine, Warfarin, others

Disqualifiers: Untreated brain metastases, Cardiovascular disorders, Autoimmune disease, 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: 12

Duration: 21 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy)—to determine if they can safely and effectively slow the growth of advanced kidney cancer that has spread. The researchers aim to discover if these drugs can work together to manage the disease. Individuals with a confirmed diagnosis of certain types of advanced kidney cancer and measurable disease may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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

The trial protocol does not specify if you must stop all current medications. However, you cannot take certain medications like small molecule tyrosine kinase inhibitors, hydroxychloroquine, or systemic immunosuppressive medications within two weeks of starting the trial. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, certain medications like small molecule tyrosine kinase inhibitors, hydroxychloroquine, and some systemic immunosuppressive medications must be stopped at least 2 weeks before starting the trial. It's best to discuss your current medications with the trial team.

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

Research has shown that the combination of cabozantinib, nivolumab, and ipilimumab has been tested for safety in people with kidney cancer. One study found that this combination slowed cancer growth more effectively than other treatments. However, side effects must be considered.

Serious side effects occurred in 79% of patients taking this combination. Another study found that starting with a lower dose of cabozantinib, reducing it from 40 mg to 20 mg per day, led to fewer severe side effects.

These findings suggest that while the treatment can effectively control cancer growth, careful dose adjustment may help reduce the risk of serious side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cabozantinib, nivolumab, and ipilimumab for kidney cancer because it offers a fresh approach to treatment. Unlike typical treatments that might focus solely on targeting cancer cells, this combination leverages both targeted therapy and immunotherapy. Cabozantinib inhibits pathways that help tumors grow and spread, while nivolumab and ipilimumab work by boosting the body's immune response to fight cancer more effectively. This dual approach not only aims to directly attack the cancer but also empowers the immune system, potentially leading to more comprehensive and durable treatment outcomes.

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

Research has shown that combining the drugs cabozantinib, nivolumab, and ipilimumab can help treat advanced kidney cancer. Some studies have significantly reduced the risk of death with this combination compared to standard treatments. For instance, patients taking cabozantinib and nivolumab had a 40% lower risk of dying than those on another treatment. This trial will evaluate the effectiveness of this combination, which could potentially slow cancer growth and improve survival rates. This is encouraging news for people with advanced kidney cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

Bradley A McGregor, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with advanced or metastatic non-clear cell renal cell carcinoma (nccRCC) who haven't had certain previous treatments can join. They must be able to provide a fresh tumor biopsy, use contraception, and have normal organ/marrow function. Excluded are those with specific heart diseases, autoimmune conditions, lung fibrosis, bleeding disorders without therapeutic anticoagulation, severe infections or on strong CYP3A4 inhibitors/inducers.

Inclusion Criteria

My organ and bone marrow functions are normal.

Ability to understand and willingness to sign a written informed consent document

I will have a new tumor biopsy before starting treatment unless it's unsafe.

Exclusion Criteria

I haven't taken cancer drugs or tyrosine kinase inhibitors in the last 4 weeks.

I have a bleeding disorder not caused by blood thinners.

I have had a previous transplant of an organ or stem cells from a donor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Cabozantinib, Nivolumab, and Ipilimumab in cycles of 21 days for the first 4 cycles, followed by cycles of 28 days

21 months

Every 3 weeks for the first 4 cycles, then every 4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

21 months

Every 8 weeks for the first 6 months, then every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing the combination of Cabozantinib with immunotherapy drugs Nivolumab and Ipilimumab for effectiveness in slowing kidney cancer growth. Participants will receive all three medications to see if they work better together than current standard treatments.

How Is the Trial Designed?

Group I: Cabozantinib Experimental Treatment 3 Interventions

Eligible patients will be enrolled and receive treatment with * Cycle 1-4 (cycles of 21 days) * Cabozantinib predetermined protocol dosage po daily * Nivolumab predetermined protocol dosage via IV every 3 weeks * Ipilimumab predetermined protocol dosage via IV every 3 weeks * After the first four cycles of therapy, * Cabozantinib determined protocol dosage po daily * Nivolumab predetermined protocol dosage via IV every 3 weeks (cycles of 28 days)

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?

Bradley A. McGregor, MD

Lead Sponsor

Trials

3

Recruited

100+

Bradley A. McGregor

Lead Sponsor

Trials

3

Recruited

100+

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

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

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]

Cabozantinib combined with nivolumab is shown to be superior in terms of progression-free survival (PFS) compared to axitinib + pembrolizumab and nivolumab + ipilimumab for the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC), based on a systematic review of four randomized controlled trials involving treatment-naïve patients.

While cabozantinib + nivolumab demonstrated effectiveness, the combination of lenvatinib + pembrolizumab showed numerical superiority in overall survival, indicating that while cabozantinib + nivolumab is a strong option, other combinations may also be effective and warrant consideration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma-A network meta-analysis. Focus on cabozantinib combined with nivolumab. Niewada, M., Macioch, T., Konarska, M., 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]

The COSMIC-313 phase 3 trial demonstrated that the triplet combination of cabozantinib, nivolumab, and ipilimumab may offer a new first-line treatment option for patients with metastatic clear cell renal cell carcinoma, marking a significant advancement in therapy.

The results presented at the 2022 European Society of Medical Oncology Congress suggest that triplet combinations could enhance treatment efficacy compared to the standard dual therapy of nivolumab and ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Less is More? First Impressions From COSMIC-313. Msaouel, P.[2023]

In a phase 3 trial involving 651 patients with untreated advanced renal-cell carcinoma, the combination of nivolumab and cabozantinib significantly improved progression-free survival (16.6 months) compared to sunitinib (8.3 months), with a hazard ratio of 0.51, indicating a 49% reduction in the risk of disease progression or death.

Patients receiving nivolumab plus cabozantinib also had a higher overall survival rate at 12 months (85.7%) compared to those on sunitinib (75.6%), and a greater objective response rate (55.7% vs. 27.1%), although adverse events were common in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Burotto, M., et al.[2022]

A 77-year-old male with metastatic papillary renal cell carcinoma and inferior vena cava tumor thrombus was successfully treated with nivolumab plus cabozantinib, leading to significant regression of all lesions.

Following treatment, the patient underwent radical nephrectomy and other surgeries, with no viable cancer cells found and no recurrence of the disease for 9 months, indicating the potential efficacy of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete response of metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus to nivolumab plus cabozantinib. Hayashida, M., Miura, Y., Yamaguchi, T., et al.[2023]

In a phase II trial involving 47 patients with advanced non-clear-cell renal cell carcinoma, the combination of cabozantinib and nivolumab showed a promising objective response rate of 47.5% in patients with papillary, unclassified, or translocation-associated RCC, along with a median progression-free survival of 12.5 months.

The treatment was less effective in chromophobe RCC, with no objective responses observed, highlighting the need for further research into genomic predictors of response, particularly mutations like NF2 and FH that were associated with better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. Lee, CH., Voss, MH., Carlo, MI., et al.[2023]

The combination of cabozantinib (a tyrosine kinase inhibitor) and nivolumab (an immune checkpoint inhibitor) significantly improved progression-free survival, overall survival, and objective response rates in patients with untreated advanced renal cell carcinoma compared to sunitinib, supporting its approval as a first-line therapy.

While the safety profile of the combination treatment is generally manageable, it requires careful monitoring and management of overlapping adverse events, such as diarrhea and hepatotoxicity, to maintain patient tolerability and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. McGregor, B., Mortazavi, A., Cordes, L., et al.[2023]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2212851

Cabozantinib plus Nivolumab and Ipilimumab in Renal- ... The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated ...

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

Clinical trial results for advanced kidney cancer (renal cell ... In a clinical trial, people given OPDIVO + CABOMETYX had a 40% lower risk of dying than those given SUTENT. Words to know.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.4539

Analysis of phase II study of cabozantinib (Cabo) with ... Reduction of the starting dose of Cabo to 20 mg/d in combination with Nivo/Ipi results in numerically lower ≥ grade 3 TrAEs than starting at 40 mg/d.

4. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/n/tr826967112990312/

Cabozantinib (Cabometyx) - NCBI Bookshelf - NIH After 10 years' predictive time horizon, the results favoured ipilimumab plus nivolumab followed by cabozantinib plus nivolumab. ... renal cell carcinoma.

5. news.bms.com news.bms.com/news/details/2024/Opdivo-nivolumab-in-Combination-with-CABOMETYX-cabozantinib-Demonstrates-Long-Term-Survival-Benefits-After-Four-Years-of-Follow-Up-in-the-CheckMate--9ER-Trial-in-First-Line-Advanced-Renal-Cell-Carcinoma/default.aspx

9ER Trial in First-Line Advanced Renal Cell Carcinoma Opdivo in combination with CABOMETYX reduced the risk of death by 23% in the first-line treatment of advanced renal cell carcinoma vs.

6. news.bms.com news.bms.com/news/details/2024/Eight-Year-Data-for-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-Continue-to-Demonstrate-Longest-Survival-Benefit-vs.-Sunitinib-Reported-in-Patients-with-Previously-Untreated-Advanced-or-Metastatic-Renal-Cell-Carcinoma/default.aspx

Eight-Year Data for Opdivo (nivolumab) Plus Yervoy ... Patients with previously untreated advanced or metastatic renal cell carcinoma treated with Opdivo plus Yervoy experienced a 28% reduction in the risk of death ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37163623/

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell ... Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall ...