Genetic-Guided Therapy for Kidney Cancer

Recruiting at 5 trial locations

Overseen By Vanderbilt-Ingram Service for Timely Access

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Vanderbilt-Ingram Cancer Center

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Hypertension, Active infection, Cardiovascular, 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: 5

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether genetic testing on tumor tissue can tailor treatment for advanced kidney cancer that has spread. It compares two treatment options: one uses a pair of immunotherapy drugs, nivolumab and ipilimumab, administered intravenously, and the other combines the immunotherapy drug nivolumab with a targeted therapy pill, cabozantinib (Cabometyx), which blocks the tumor's blood supply. The goal is to determine if matching the treatment to the tumor's genetic makeup improves outcomes. Individuals with advanced or metastatic clear cell kidney cancer who have not received prior systemic therapy for this cancer may be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications. However, it allows the use of anti-hypertensive medications and certain corticosteroids, so you may be able to continue some treatments. It's best to discuss your specific medications with the trial team.

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

Studies have shown that the combination of nivolumab and ipilimumab is generally well-tolerated in patients with advanced kidney cancer. Research found no new safety concerns, and the treatment showed promise in controlling the disease. Common side effects included diarrhea and tiredness.

For the nivolumab and cabozantinib combination, studies indicate it can be effective but may have some side effects. The most common serious issues were diarrhea, fever, and lung inflammation. Despite these, many patients lived longer compared to those on other treatments.

The FDA has approved both treatment combinations for advanced kidney cancer. This approval means they are considered safe enough for use, although side effects can still occur. Always consult a healthcare provider about potential risks when considering joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for kidney cancer because they offer a fresh approach to combating the disease. While traditional treatments often rely on surgery or chemotherapy, these investigational therapies utilize the body's immune system. Arm I harnesses the power of two immunotherapy drugs, ipilimumab and nivolumab, to activate the immune system against cancer cells. Arm II combines nivolumab with cabozantinib, a medication known to interfere with cancer cell growth by blocking specific pathways. This unique combination and mechanism of targeting cancer make these treatments promising for more effective and personalized care.

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

This trial will compare two treatment combinations for advanced kidney cancer. Participants in one arm will receive nivolumab and ipilimumab together. Research has shown that this combination can significantly help people with advanced kidney cancer by lowering the risk of death by 28% compared to other treatments. Participants in another arm will receive nivolumab and cabozantinib, which has also demonstrated good results, reducing the risk of death by 40% compared to a standard treatment. Both combinations boost the immune system and cut off the cancer's blood supply, making them effective options for treating advanced kidney cancer. ^{2 4 6 7 8}

Who Is on the Research Team?

Brian I. Rini

Principal Investigator

Vanderbilt University/Ingram Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced or metastatic clear cell renal cell carcinoma, who haven't had systemic therapy for RCC and have a Karnofsky performance status of >=70%. Participants need measurable lesions per RECIST 1.1, adequate organ function, and must consent to genetic testing of their tumor tissue. Women must not be pregnant and agree to contraception.

Inclusion Criteria

I am a woman who can still have children and have not had surgery to remove my reproductive organs.

I am a woman over 45 and have not had a period for 12 months due to menopause.

You have at least one tumor that can be measured according to specific guidelines.

Exclusion Criteria

I am currently receiving treatment through an IV for an infection.

I have not had major surgery within the last 14 days.

I use low-dose steroids or hormone replacement without having an active autoimmune disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive ipilimumab and nivolumab intravenously on day 1. Cycles repeat every 21 days for 4 cycles.

12 weeks

4 visits (in-person)

Maintenance

Patients receive nivolumab intravenously on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Variable, up to 4 years

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing if genetic testing can help choose better treatment for kidney cancer that has spread. It compares two FDA-approved treatments: one combines two immunotherapies (nivolumab plus ipilimumab) via IV infusions; the other pairs nivolumab infusion with an oral pill (cabozantinib).

How Is the Trial Designed?

Group I: Arm II (nivolumab, cabozantinib) Experimental Treatment 2 Interventions

Patients receive nivolumab IV on day 1 and cabozantinib PO QD. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (ipilimumab, nivolumab) Experimental Treatment 2 Interventions

INDUCTION: Patients receive ipilimumab and nivolumab IV on day 1. Cycles repeat every 21 days for 4 cycles. MAINTENANCE: Patients receive nivolumab IV on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

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?

Vanderbilt-Ingram Cancer Center

Lead Sponsor

Trials

221

Recruited

64,400+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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]

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]

A 52-year-old male with a large inoperable tumor in a horseshoe kidney achieved a major partial response to neoadjuvant therapy with nivolumab and cabozantinib, allowing for successful radical tumor resection and maintaining mild renal function post-treatment.

Despite experiencing hepatotoxicity that led to early withdrawal of nivolumab, the combination of immune checkpoint inhibitors and tyrosine kinase inhibitors shows promise as a neoadjuvant treatment strategy for advanced renal cell carcinoma, particularly in challenging cases like horseshoe kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant nivolumab and cabozantinib in advanced renal cell carcinoma in a horseshoe kidney - how to achieve a safe and radical resection? a case report and review of the literature. Zemankova, A., Studentova, H., Kopova, A., et al.[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]

The European Association of Urology now recommends nivolumab and cabozantinib as preferred treatments for patients with renal cancer who have not responded to previous vascular endothelial growth factor-targeted therapies.

Recent data indicate that cabozantinib offers a survival benefit, reinforcing its efficacy as a treatment option in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Association of Urology Guidelines for Clear Cell Renal Cancers That Are Resistant to Vascular Endothelial Growth Factor Receptor-Targeted Therapy. Powles, T., Staehler, M., Ljungberg, B., et al.[2018]

Nivolumab plus cabozantinib significantly improved progression-free survival and overall survival compared to sunitinib in advanced renal cell carcinoma, as shown in the CheckMate 9ER study.

However, the combination treatment was found to be not cost-effective, with an incremental cost-effectiveness ratio of $863,720 per quality-adjusted life-year (QALY) gained, far exceeding the commonly accepted threshold of $150,000.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness Analysis of First-Line Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma in the United States. Liao, W., Lei, W., Feng, M., et al.[2021]

The updated European Association of Urology guidelines now recommend nivolumab and cabozantinib as preferred treatments for renal cancer patients who have not responded to one or more lines of VEGF-targeted therapy.

This change reflects a shift from the previous standard of care, highlighting the improved efficacy of nivolumab and cabozantinib in managing renal cancer after prior treatments have failed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated EAU Guidelines for Clear Cell Renal Cancer Patients Who Fail VEGF Targeted Therapy. Powles, T., Staehler, M., Ljungberg, B., et al.[2018]

Cabozantinib was designated as a breakthrough drug by the FDA and approved in 2016 for treating advanced clear cell renal cell carcinoma (ccRCC), which is the most common kidney cancer type, accounting for about 90% of cases.

The METEOR trial demonstrated significant efficacy for cabozantinib in advanced RCC, and ongoing studies like the CABOSUN trial will further clarify its effectiveness compared to other treatments like sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of cabozantinib in the treatment of advanced kidney cancer: efficacy, safety, and patient selection. Yu, SS., Quinn, DI., Dorff, TB.[2022]

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 CaboPoint trial is a phase II study designed to assess the efficacy and safety of cabozantinib, a multi-tyrosine kinase inhibitor, in patients with advanced renal cell carcinoma who have not responded to previous checkpoint inhibitor therapies.

Patients will receive cabozantinib for up to 18 months, with the primary goal of measuring the objective response rate, while also evaluating overall survival and progression-free survival as secondary outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CaboPoint: a phase II study of cabozantinib as second-line treatment in patients with metastatic renal cell carcinoma. Albiges, L., Schmidinger, M., Taguieva-Pioger, N., et al.[2022]

Citations

1. 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 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39705641/

Real-World Outcomes in Patients With Metastatic Renal ... This study provides data to support the understanding of the real-world utilization and long-term effectiveness of 1L NIVO + IPI in patients ...

3. ascopubs.org ascopubs.org/doi/10.1200/CCI.24.00132

Real-World Outcomes in Patients With Metastatic Renal ... This study provides data to support the understanding of the real-world utilization and long-term effectiveness of 1L NIVO + IPI in patients with I/P-risk mRCC.

4. 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 + ...

5. cancerdiagnosisprognosis.org cancerdiagnosisprognosis.org/article/500/analysis-of-early-progression-in-advanced-renal-cell-carcinoma-treated-with-nivolumab-plus-ipilimumab

Analysis of Early Progression in Advanced Renal Cell ... This retrospective study aimed to identify predictive factors for EDP among patients with aRCC treated with NIVO + IPI.

6. 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.

7. 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 ...

8. jitc.bmj.com jitc.bmj.com/content/10/2/e003844

Safety and efficacy of nivolumab plus ipilimumab in ... Nivolumab plus ipilimumab for previously untreated advanced nccRCC showed no new safety signals and encouraging antitumor activity.