Immunotherapy + Cabozantinib for Advanced Kidney Cancer

Not currently recruiting at 1007 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Coumarin agents

Disqualifiers: Autoimmune disease, Hepatitis B/C, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 4

Duration: Ongoing until disease progression or unacceptable toxicity

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether adding cabozantinib to the usual immunotherapy can more effectively combat advanced kidney cancer that has spread. The standard treatment involves ipilimumab and nivolumab, which help the immune system attack cancer cells. Researchers aim to determine if cabozantinib, which targets enzymes necessary for cancer cell growth, can improve outcomes. This trial targets individuals with untreated kidney cancer that has spread, particularly those with conditions like a clear cell component or sarcomatoid features. As a Phase 3 trial, it represents the final step before FDA approval, offering patients early access to potentially effective treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, certain medications like immunosuppressive drugs and specific anticoagulants are not allowed. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

A previous study tested the combination of nivolumab and cabozantinib for advanced kidney cancer. This research showed that patients had a 40% lower risk of dying compared to those who received SUTENT. The study's safety information indicates that the combination is generally well-tolerated, though some patients experienced side effects.

Nivolumab, an FDA-approved treatment for kidney cancer, is known to be safe for many patients. Serious side effects can include hormone production issues and inflammation of certain glands, but these occur in only a small percentage of patients.

Cabozantinib, the other part of the treatment, blocks enzymes that help cancer grow. It has been studied with nivolumab, and results suggest it can be used safely, although some patients may experience side effects.

Overall, both treatments have been studied and are generally considered safe, with known side effects that are manageable in most cases. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for advanced kidney cancer because they combine immunotherapy with targeted therapy for potentially better outcomes. Ipilimumab and Nivolumab work by boosting the immune system to attack cancer cells, which is different from many existing treatments that directly target the cancer cells themselves. Cabozantinib, a targeted therapy, inhibits cancer cell growth and blood vessel formation, adding another layer of attack. This combination approach could offer a more comprehensive treatment, potentially leading to better control of the disease compared to standard therapies that typically focus on one pathway.

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

Studies have shown that using nivolumab and ipilimumab together can lower the risk of death by 28% for patients with advanced kidney cancer. This combination also reduces the risk of death by 37% compared to sunitinib. In this trial, participants in Arm A will receive nivolumab, while those in Arm B will receive a combination of nivolumab and cabozantinib. Research indicates that adding cabozantinib to nivolumab can reduce the risk of the cancer spreading or worsening by 49%. This suggests that using nivolumab and cabozantinib together might benefit patients with advanced kidney cancer. Overall, these treatments have shown promising results in combating advanced kidney cancer. ^{5 6 7 8 9}

Who Is on the Research Team?

Tian Zhang

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

This trial is for adults with advanced kidney cancer that hasn't been treated yet. Participants should have a certain level of physical fitness (Karnofsky performance status >= 70%), measurable disease, and be at an intermediate or poor risk according to specific criteria. They can't join if they've had certain treatments before, have active autoimmune diseases, uncontrolled conditions like hypertension or infections like HIV with detectable viral load, or are pregnant.

Inclusion Criteria

You have a disease that can be measured according to the study's guidelines.

My kidney cancer is classified as intermediate or poor risk.

Your hemoglobin level is at least 8 grams per deciliter.

Exclusion Criteria

I haven't had serious stomach or bowel problems in the last 6 months.

I am currently being treated for an autoimmune disease.

Your blood pressure is too high and not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive nivolumab and ipilimumab intravenously every 21 days for up to 4 cycles

12 weeks

4 visits (in-person)

Treatment

Patients receive either nivolumab alone or nivolumab with cabozantinib based on randomization, with treatment repeating every 28 days

Ongoing until disease progression or unacceptable toxicity

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Ipilimumab
• Nivolumab

Trial Overview

The study compares standard immunotherapy treatment using Nivolumab and Ipilimumab followed by Nivolumab alone versus the same regimen followed by a combination of Nivolumab with Cabozantinib. The goal is to see if adding Cabozantinib improves outcomes in untreated renal cell carcinoma that has spread.

How Is the Trial Designed?

Group I: Arm B (nivolumab, cabozantinib) Experimental Treatment 8 Interventions

INDUCTION: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. TREATMENT: Patients with iuPD with clinical instability receive cabozantinib PO daily on days 1-28. Treatment repeats every 28 days until further disease progression or unacceptable toxicity. Patients with iCR receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients with non-CR/non-PD rwith clinical stability eceive nivolumab IV over 30 minutes on day 1 and cabozantinib PO daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood and urine sample collection, and may also undergo a bone scan as clinically indicated throughout the study.

Group II: Arm A (nivolumab) Active Control 8 Interventions

INDUCTION: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. TREATMENT: Patients with iuPD with clinical instability receive cabozantinib PO daily on days 1-28. Treatment repeats every 28 days until further disease progression or unacceptable toxicity Patients with iCR receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients with non-CR/non-PD with clinical stability receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI and blood and urine sample collection, and may also undergo a bone scan as clinically indicated throughout the study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 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]

In a phase 3 trial involving 522 patients with metastatic renal cell carcinoma, adding atezolizumab to cabozantinib did not significantly improve progression-free survival or overall survival compared to cabozantinib alone, indicating that this combination may not be effective for patients whose disease progressed after immune checkpoint inhibitors.

The combination treatment with atezolizumab and cabozantinib resulted in higher rates of serious adverse events (48% vs. 33% for cabozantinib alone), suggesting increased toxicity without clinical benefit, which raises concerns about its use outside of clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Pal, SK., Albiges, L., Tomczak, P., 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]

The combination of cabozantinib (a TKI) and nivolumab (an anti-PD-1 antibody) is an effective first-line treatment for previously-untreated advanced renal cell carcinoma (RCC), showing significantly longer progression-free and overall survival compared to sunitinib monotherapy in the CheckMate 9ER trial.

Patients receiving cabozantinib plus nivolumab reported better health-related quality of life, although the combination therapy had a higher incidence of serious adverse events compared to sunitinib, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab: A Review in Advanced Renal Cell Carcinoma. Markham, A.[2022]

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]

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]

Citations

1.

opdivohcp.com

opdivohcp.com/efficacy/rcc

Efficacy Data for Renal Cell Carcinoma (RCC) - Opdivo

In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%) ...

2.

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 ...

3.

actionkidneycancer.org

actionkidneycancer.org/effectiveness-of-nivolumab-persists-long-term-in-advanced-renal-cell-carcinoma/

Effectiveness of nivolumab persists long-term in advanced ...

In the phase I study, the 5-year overall survival (OS) rate was 34%. In the phase II study, 29% of patients remained alive at 4 years. In addition, further ...

4.

esmoopen.com

esmoopen.com/article/S2059-7029(24)01371-1/fulltext

Nivolumab in patients with advanced renal cell carcinoma ...

Assuming a 1-year survival rate of 70% (based on CheckMate 025 results), we determined that a sample size of 323 patients for the nivolumab ...

5.

opdivo.com

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

Clinical trial results for advanced kidney cancer (renal cell ...

In the clinical trial, people given OPDIVO + YERVOY had a 37% lower risk of dying than those given SUTENT, and more than half of the people given OPDIVO + ...

6.

opdivohcp.com

opdivohcp.com/safety/rcc

Safety Profile for Renal Cell Carcinoma (RCC) - Opdivo

The most frequent serious adverse reactions reported in ≥1% of patients who received OPDIVO with ipilimumab were adrenal insufficiency (2.8%), hypophysitis (2.8 ...

7.

opdivo.com

opdivo.com/advanced-kidney-cancer

Advanced Kidney Cancer (RCC) Cancer Treatment

OPDIVO® (nivolumab) is an FDA-approved immunotherapy. This cancer treatment is the foundation for three different treatments to fight against RCC.

8.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5568541/

Safety and Efficacy of Nivolumab in Patients With Metastatic ...

Safety and efficacy of nivolumab in patients with metastatic renal cell carcinoma treated beyond progression: a subgroup analysis of a randomized clinical ...

9.

sciencedirect.com

sciencedirect.com/science/article/pii/S1558767320301415

Original Study Safety and Efficacy of Nivolumab in Patients ...

This study validates the safety and efficacy of nivolumab 240 mg Q2W flat-dose monotherapy for previously treated advanced ccRCC.