Cabozantinib + Nivolumab +/- Ipilimumab for Genitourinary Cancers

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

152 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Cabozantinib, Nivolumab, and Ipilimumab for genitourinary cancers?

Research shows that the combination of cabozantinib and nivolumab, with or without ipilimumab, has been assessed for safety and effectiveness in treating advanced genitourinary cancers. Additionally, cabozantinib and nivolumab are recommended for patients with renal cancer who have not responded to other treatments, indicating their potential benefit in similar conditions. ^{1 2 3 4 5}

Is the combination of Cabozantinib, Nivolumab, and Ipilimumab safe for humans?

The combination of Cabozantinib, Nivolumab, and Ipilimumab has been studied for safety in people with various types of genitourinary cancers, including advanced renal-cell carcinoma. While specific safety details are not provided, these treatments are generally evaluated for safety in clinical trials, which means they are monitored for any harmful effects in humans. ^{1 6 7 8 9}

How is the drug combination of Cabozantinib, Nivolumab, and Ipilimumab unique for genitourinary cancers?

This drug combination is unique because it combines Cabozantinib, which targets cancer cell growth, with Nivolumab and Ipilimumab, which help the immune system attack cancer cells. This approach is different from traditional treatments as it uses both targeted therapy and immunotherapy to potentially improve outcomes for patients with genitourinary cancers. ^{1 4 5 6 9}

What is the purpose of this trial?

This phase I trial studies the side effects and best doses of cabozantinib s-malate and nivolumab with or without ipilimumab in treating patients with genitourinary (genital and urinary organ) tumors that have spread from where it first started (primary site) to other places in the body (metastatic). Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving cabozantinib s-malate and nivolumab alone or with ipilimumab works better in treating patients with genitourinary tumors.

Research Team

Andrea B Apolo

Principal Investigator

National Cancer Institute LAO

Eligibility Criteria

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 metastatic genitourinary cancer with at least one measurable tumor or a new bone lesion.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

References

1. United States 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. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

[Mode of action, new targets and potential biomarkers in modern immunotherapy]. [2019]

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

Characterization of outcomes in patients with advanced genitourinary malignancies treated with immune checkpoint inhibitors. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

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

5. 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]

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

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

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

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

8. 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]

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

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