Cabozantinib + Nivolumab +/- Ipilimumab for Genitourinary Cancers

Not currently recruiting at 8 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inducers, Warfarin

Disqualifiers: Active brain metastases, Autoimmune disease, Hepatitis, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 21

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal doses and understand the side effects of combining cabozantinib, nivolumab, and possibly ipilimumab to treat genitourinary cancers that have metastasized. Cabozantinib (also known as Cabometyx or Cometriq) blocks certain enzymes to halt tumor growth, while nivolumab and ipilimumab are immunotherapies that enhance the body's cancer-fighting ability. The trial will evaluate cabozantinib and nivolumab, both alone and with ipilimumab, to identify the most effective combination. Suitable patients have metastatic genitourinary tumors and have not responded to previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering patients a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you have taken certain treatments like cytotoxic chemotherapy, biologic agents, or small molecule kinase inhibitors within a specific timeframe before the study. It's best to discuss your current medications with the study team to understand any potential interactions.

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

Research has shown that using cabozantinib, nivolumab, and ipilimumab together raises some safety concerns. In studies, cabozantinib with nivolumab did not perform as well as other treatments. However, nivolumab combined with ipilimumab proved to be safer.

Cabozantinib and nivolumab have approval for treating certain advanced cancers, indicating their safety has been well-studied, though side effects can still occur. Some patients have experienced serious side effects, but many tolerate the treatment well.

When using cabozantinib, nivolumab, and ipilimumab together, patients have responded to treatment but also experienced some side effects. While these treatments can be effective, it is important to consider all possible side effects and discuss them with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine multiple pathways to target genitourinary cancers more effectively. Most treatments for these cancers rely on either inhibiting tumor growth or boosting the immune system separately. However, cabozantinib, nivolumab, and ipilimumab work together to not only block signals that tumors use to grow but also enhance the body's immune response to attack cancer cells. This combination approach aims to improve outcomes by tackling the cancer from different angles simultaneously, potentially leading to better results compared to standard treatments.

What evidence suggests that this trial's treatments could be effective for genitourinary cancers?

Research has shown that combining the drugs cabozantinib, nivolumab, and ipilimumab may help treat advanced urinary system cancers. In this trial, some participants will receive cabozantinib and nivolumab, while others will receive the combination of cabozantinib, nivolumab, and ipilimumab. Previous studies have found that adding ipilimumab to cabozantinib and nivolumab is safe and effective, offering significant benefits for patients with these cancers. Specifically, one study found that cabozantinib with nivolumab improved survival in patients with advanced kidney cancer, reducing the risk of death by 23%. This combination has shown lasting benefits over time, confirmed by extensive follow-ups. Overall, these treatments work by stopping tumor growth and helping the immune system fight cancer. ^{1 2 5 6 7}

Who Is on the Research Team?

Andrea B Apolo

Principal Investigator

National Cancer Institute LAO

Are You a Good Fit for This Trial?

Adults with advanced genitourinary cancers, who are in good physical condition (Karnofsky performance status >= 70%), and have not recently received certain treatments. Women must test negative for pregnancy and agree to contraception. Participants need available tissue for PD-L1 testing and understand the study's consent.

Inclusion Criteria

Women of childbearing potential must have a negative pregnancy test at screening and agree to use adequate contraception

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

I have a confirmed diagnosis of a specific type of metastatic genitourinary cancer with new or worsening lesions.

Exclusion Criteria

You have certain reproductive, infectious, or autoimmune conditions.

I have not had certain cancer treatments recently.

I do not have active brain tumors, serious heart, stomach, or other major health issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part I

Patients receive cabozantinib s-malate orally once daily and nivolumab intravenously on days 1 and 15 of each 28-day cycle. After 21 cycles, nivolumab is administered every 4 weeks.

21 cycles (approximately 84 weeks)

Bi-weekly visits for IV administration, monthly visits post-cycle 21

Treatment Part II

Patients receive cabozantinib s-malate orally once daily, nivolumab intravenously, and ipilimumab intravenously on day 1 of each 21-day cycle for up to 4 cycles. After 4 cycles, treatment continues with cabozantinib and nivolumab as in Part I.

4 cycles (approximately 12 weeks) followed by continuation

Tri-weekly visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 16 weeks post-treatment and every 3 months thereafter.

16 weeks initial follow-up, then every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib S-malate
• Ipilimumab
• Nivolumab

Trial Overview The trial is examining the effectiveness of Cabozantinib S-malate combined with Nivolumab, an immunotherapy drug, with or without another immunotherapy called Ipilimumab in patients whose cancer has spread beyond its original location.

How Is the Trial Designed?

Group I: Part II (cabozantinib s-malate, nivolumab, ipilimumab) Experimental Treatment 8 Interventions

See detailed description.

Group II: Part I (cabozantinib s-malate, nivolumab) Experimental Treatment 7 Interventions

Patients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 21 cycles, patients receive nivolumab IV over 30 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles followed by cabozantinib s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-cycle 21 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography or magnetic resonance imaging and collection of blood samples throughout the trial. Patients may also undergo echocardiography at baseline and biopsies throughout the trial.

Cabozantinib S-malate is already approved in United States, European Union for the following indications:

Approved in United States as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Approved in United States as Cometriq for:

• Medullary thyroid cancer

Approved in European Union as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

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

Cabozantinib combined with nivolumab (CaboNivo) and with ipilimumab (CaboNivoIpi) showed manageable safety profiles, with 75% and 87% of patients experiencing grade 3 or 4 treatment-related adverse events, respectively, including fatigue and hypertension.

The treatment demonstrated promising efficacy, with an overall response rate of 30.6% and a median overall survival of 12.6 months for all patients, while patients with metastatic urothelial carcinoma had even better outcomes, with a median overall survival of 25.4 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors. Apolo, AB., Nadal, R., Girardi, DM., 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]

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 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]

Immune checkpoint inhibitors (ICIs) like nivolumab, pembrolizumab, and atezolizumab have been approved for treating metastatic urothelial carcinoma and renal cell carcinoma, significantly improving systemic therapy outcomes.

Future strategies aim to combine ICIs with targeted therapies to boost immune responses against tumors, while there is a critical need for biomarkers to predict patient responses and resistance to ICI therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Mode of action, new targets and potential biomarkers in modern immunotherapy]. Bedke, J., Stühler, V., Todenhöfer, T., et al.[2019]

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 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]

Citations

1. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-announces-final-five-year-follow-results-checkmate-9er

9ER Trial Evaluating CABOMETYX® (cabozantinib ... - Exelixis After more than five years of follow-up, the findings demonstrated that efficacy benefits with CABOMETYX in combination with Opdivo were sustained long term.

2. cabometyxhcp.com cabometyxhcp.com/rcc-treatment/combo/efficacy

1L aRCC Efficacy & Safety for CABOMETYX® ... See the results from the CheckMate-9ER study - including efficacy, safety, and exploratory patient-reported quality of life data.

3. ipsen.com ipsen.com/press-releases/cabometyx-in-combination-with-opdivo-demonstrated-continued-survival-and-quality-of-life-benefits-with-over-two-years-of-follow-up-in-the-phase-iii-checkmate-9er-trial-2/

Cabometyx® in combination with Opdivo® demonstrated ... Cabometyx® in combination with Opdivo® demonstrated continued survival and quality of life benefits with over two years of follow-up in the Phase III CheckMate ...

4. 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.

5. sciencedirect.com sciencedirect.com/science/article/pii/S1558767323002173

Real-World Results of Cabozantinib Given as Alternative ... Based on this data the combination of cabozantinib and nivolumab received treatment authorization by the EMA in March 2021 for the first-line treatment of ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02496208

Study Details | NCT02496208 | Cabozantinib S-malate and ... The safety and tolerability of a novel dose of cabozantinib, nivolumab and ipilimumab in patients with genitourinary cancer will be assessed. Up to 30 days post ...

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

Cabozantinib (Cabometyx) - NCBI Bookshelf - NIH Evidence from a clinical trial demonstrated that people with advanced or metastatic RCC treated with Cabometyx in combination with Opdivo experienced a delay in ...