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

Trial Summary

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.

What data supports the effectiveness of the drug combination of cabozantinib, nivolumab, and ipilimumab for kidney cancer?

Research shows that cabozantinib combined with nivolumab improved survival rates in advanced kidney cancer compared to another drug, sunitinib. Additionally, cabozantinib has been recognized as a breakthrough drug for advanced kidney cancer due to its effectiveness in previous trials. ^{1 2 3 4 5}

Is the genetic-guided therapy for kidney cancer safe?

Cabozantinib, Nivolumab, and Ipilimumab have been studied for safety in treating advanced kidney cancer. Some studies have reported adverse events (side effects) when these drugs are used alone or in combination, but they are generally considered safe for use in humans with careful monitoring. ^{2 5 6 7 8}

What makes the drug combination of Cabozantinib, Ipilimumab, and Nivolumab unique for kidney cancer?

This drug combination is unique because it combines Cabozantinib, which targets multiple pathways involved in cancer growth, with Ipilimumab and Nivolumab, which are immune checkpoint inhibitors that help the immune system attack cancer cells. This approach is novel as it targets both the cancer cells directly and boosts the body's immune response against them. ^{2 5 7 9 10}

What is the purpose of this trial?

This phase II trial tests whether using genetic testing of tumor tissue to select the optimal treatment regimen works in treating patients with clear cell renal cell (kidney) cancer that has spread to other places in the body (advanced or metastatic). The current Food and Drug Administration (FDA)-approved regimens for advanced kidney cancer fall into two categories. One treatment combination includes two immunotherapy drugs (nivolumab plus ipilimumab), which are delivered by separate intravenous infusions into a vein. The other combination is one immunotherapy drug (nivolumab infusion) plus an oral pill taken by mouth (cabozantinib). Nivolumab and ipilimumab are "immunotherapies" which release the brakes of the immune system, thus allowing the patient's own immune system to better kill cancer cells. Cabozantinib is a "targeted therapy" specifically designed to block certain biological mechanisms needed for growth of cancer cells. In kidney cancer, cabozantinib blocks a tumor's blood supply. The genetic (DNA) makeup of the tumor may affect how well it responds to therapy. Testing the makeup (genes) of the tumor, may help match a treatment (from one of the above two treatment options) to the specific cancer and increase the chance that the disease will respond to treatment. The purpose of this study is to learn if genetic testing of tumor tissue may help doctors select the optimal treatment regimen to which advanced kidney cancer is more likely to respond.

Research Team

Brian I. Rini

Principal Investigator

Vanderbilt University/Ingram Cancer Center

Eligibility Criteria

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

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)

Treatment Details

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).

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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 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]

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 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]

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]

References

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

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. [2023]

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

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

3. Switzerland 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. [2023]

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

Cost-Effectiveness Analysis of First-Line Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma in the United States. [2021]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical use of cabozantinib in the treatment of advanced kidney cancer: efficacy, safety, and patient selection. [2022]

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

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

7. England pubmed.ncbi.nlm.nih.gov

CaboPoint: a phase II study of cabozantinib as second-line treatment in patients with metastatic renal cell carcinoma. [2022]

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

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. [2022]

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

Updated EAU Guidelines for Clear Cell Renal Cancer Patients Who Fail VEGF Targeted Therapy. [2018]

10. Switzerland 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. [2018]