Immunotherapy + Targeted Therapy for Genitourinary Cancers

Recruiting at 379 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Autoimmune disease, Active malignancy, 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: 24

Duration: Up to 2 years

314 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for rare genitourinary cancers that have metastasized. The study tests whether cabozantinib (a drug that inhibits tumor growth), combined with nivolumab and ipilimumab (drugs that enhance the immune system's ability to attack cancer), is more effective than using any of these drugs alone. It targets individuals with specific rare cancers, such as neuroendocrine carcinoma of the bladder, adenocarcinoma, or penile cancer, who have limited treatment options and have experienced cancer spreading beyond its original site. Participants must not have been previously treated with the drugs being tested. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot take certain medications like warfarin and strong CYP3A4 inducers or inhibitors. 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?

Research has shown that the three drugs in this trial—cabozantinib, nivolumab, and ipilimumab—are considered safe based on previous studies in various cancer types.

Cabozantinib has undergone thorough study in patients with advanced kidney cancer. The METEOR trial, for instance, found no new safety issues. Some patients experienced changes in lab results, but these were effectively managed.

Ipilimumab, often used with nivolumab, has a safety profile similar to its use alone or with other treatments in adults. Side effects can occur, but they are usually known and manageable.

Nivolumab is another well-researched drug, approved by the FDA for several cancers, including those of the urinary tract. Known side effects include immune system reactions where the body attacks healthy tissues. Although serious, these effects are understood and can be treated.

In summary, while each drug may have side effects, these are well-documented, and healthcare providers know how to manage them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cabozantinib, nivolumab, and ipilimumab for genitourinary cancers because it leverages both immunotherapy and targeted therapy in a novel way. Unlike current standard treatments such as chemotherapy and surgery, this combination aims to harness the body's immune system while simultaneously blocking pathways that help cancer cells grow. Cabozantinib targets specific proteins involved in tumor growth and blood vessel formation, while nivolumab and ipilimumab enhance the immune system's ability to detect and destroy cancer cells. This dual approach has the potential to improve outcomes by attacking cancer on multiple fronts, offering hope for more effective and durable responses.

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

Research has shown that the drugs cabozantinib, nivolumab, and ipilimumab hold promise in treating various types of cancer. In this trial, participants will receive a combination of these drugs. Cabozantinib, particularly when combined with other drugs like Opdivo (nivolumab), has effectively stopped tumors from growing over the long term. Studies have found that nivolumab can extend the lives of patients with certain urinary tract cancers. When combined with nivolumab, ipilimumab has significantly improved survival rates for kidney cancer patients. These drugs boost the immune system to attack cancer cells and prevent their growth, offering hope for treating challenging genitourinary tumors. ^{6 7 8 9 10}

Who Is on the Research Team?

Andrea B Apolo

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

This trial is for adults with rare genitourinary tumors that have spread, who can swallow pills and don't have active brain metastases or certain illnesses. They may have had up to two cancer treatments before or none at all. Participants must not be on warfarin, have a good performance status (Karnofsky >=80%), no recent major surgeries, no severe allergies to monoclonal antibodies, and controlled medical conditions are okay.

Inclusion Criteria

I haven't had any major surgeries recently.

My cancer's type and stage have been confirmed with a biopsy.

I do not have any severe illnesses that are not under control.

Exclusion Criteria

I have a history of certain cancers or health conditions.

I have had an organ or stem cell transplant.

Living outside the US

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive cabozantinib orally once daily and nivolumab and ipilimumab intravenously on day 1 of cycles 1-4, followed by nivolumab on day 1 of subsequent cycles. Treatment repeats every 21 days for cycles 1-4 and every 28 days for subsequent cycles for up to 2 years.

Up to 2 years

Every 21-28 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 5 years

Every 2 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib S-malate
• Ipilimumab
• Nivolumab

Trial Overview The study tests how well the combination of cabozantinib (a drug blocking enzymes needed for cell growth), nivolumab and ipilimumab (both immunotherapy drugs) works against advanced genitourinary cancers compared to each drug alone. It's a phase II trial where these drugs' effectiveness in stopping tumor growth will be observed using scans like PET, CT, MRI.

How Is the Trial Designed?

Group I: Treatment (cabozantinib, nivolumab, ipilimumab) Experimental Treatment 9 Interventions

Patients receive cabozantinib PO QD on days 1-21 of cycles 1-4 and on days 1-28 of subsequent cycles. Patients also receive nivolumab IV over 30 minutes on day 1 and ipilimumab IV over 90 minutes on day 1 of cycles 1-4. Patients then receive nivolumab IV over 30 minutes on day 1 of subsequent cycles. Treatment repeats every 21 days for cycles 1-4 and every 28 days for subsequent cycles for 2 years in the absence of disease progression or unacceptable toxicity. Patients may undergo echocardiography during screening and undergo CT or MRI, bone scan and blood and urine sample collection throughout the trial and may undergo PET/CT 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

In a study involving 132 patients with metastatic castration-resistant prostate cancer, the combination of cabozantinib and atezolizumab demonstrated an objective response rate of 23%, indicating promising antitumor activity after prior hormonal therapies.

While the treatment showed efficacy, 55% of patients experienced grade 3-4 treatment-related adverse events, with pulmonary embolism and diarrhea being the most common, suggesting that while the combination is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Agarwal, N., McGregor, B., Maughan, BL., et al.[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 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]

Cancer immunotherapy, particularly with immune checkpoint inhibitors, has shown promise in treating urothelial carcinoma and renal cell carcinoma, leading to durable responses in some patients who previously had poor prognoses.

Despite these advancements, many patients do not respond to these therapies, highlighting the need for new treatment strategies and better biomarkers to identify which patients will benefit most from immunotherapy in genitourinary cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Tumor Microenvironment with Immunotherapy for Genitourinary Malignancies. Marciscano, AE., Madan, RA.[2019]

Current immunotherapy treatments for genitourinary cancers have not been successful in curing these malignancies, highlighting the need for new approaches.

Recent focus on immune checkpoints has led to the development of monoclonal antibodies that block these checkpoints, showing promising results in early trials for metastatic melanoma and generating interest in similar strategies for genitourinary cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blocking immune checkpoints in prostate, kidney, and urothelial cancer: An overview. Alme, AK., Karir, BS., Faltas, BM., et al.[2023]

Immunotherapy has been effectively used in genito-urinary tumors, with treatments like Calmette-Guèrin Bacillus for bladder cancer and Sipuleucel-T for prostate cancer showing significant benefits, including a 22% reduction in mortality risk for certain patients.

Recent advancements in targeting immune checkpoint molecules have improved outcomes in various cancers, but their effectiveness varies among patients, highlighting the importance of optimizing patient selection based on immune infiltrate characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The immune infiltrate in prostate, bladder and testicular tumors: An old friend for new challenges. Solinas, C., Chanzá, NM., Awada, A., et al.[2017]

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 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]

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]

Immune checkpoint inhibitors and therapeutic cancer vaccines have shown significant survival benefits and long-lasting responses in patients with renal cell cancer, prostate cancer, and bladder cancer, although their effectiveness is limited in testicular cancer.

Research is ongoing to explore the combination of immunotherapy with chemotherapy or targeted therapies in various treatment settings, including neo-adjuvant, adjuvant, and metastatic stages of genitourinary cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The immunotherapy revolution in genitourinary malignancies. U Gandhy, S., Madan, RA., Aragon-Ching, JB.[2021]

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]

Immunotherapy, particularly immune checkpoint inhibitors, is showing promising survival benefits and durable responses in patients with genitourinary cancers, such as renal cell carcinoma and urothelial carcinoma, marking a significant advancement in cancer treatment.

Despite these advancements, the effectiveness of immune checkpoint inhibitors is currently limited to a small group of patients, highlighting the need for further research to identify biomarkers for patient selection and to develop strategies that enhance treatment responses and overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy in Genitourinary Malignancy: Evolution in Revolution or Revolution in Evolution. Lu, K., Chiu, KY., Cheng, CL.[2022]

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. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.479

Cabozantinib real-world effectiveness in the second-line ... Conclusions: This study demonstrates that cabozantinib maintains efficacy comparable to that observed in the METEOR trial in a real-world ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38954785/

Final Results From a Phase I Trial and Expansion Cohorts of ... CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1558767325001028

Effectiveness and Safety of Cabozantinib Treatment in ... Median overall survival (OS) was 15.36 months (95% CI, 11.58-19.11); objective response rate (ORR), 29.5% (95% CI, 24.0-35.4); median time to first response, ...

5. clinical-genitourinary-cancer.com clinical-genitourinary-cancer.com/article/S1558-7673(23)00217-3/fulltext

Real-World Results of Cabozantinib Given as Alternative ... The aim of this retrospective study was to analyze the pattern of cabozantinib treatment and its efficacy in a real-world cohort of patients ...

6. cabometyxhcp.com cabometyxhcp.com/rcc-treatment/monotherapy/safety

CABOSUN & METEOR show similar safety results for ... No new safety signals observed between METEOR and CABOSUN trials · Laboratory abnormalities occurring in ≥25% of patients in the CABOMETYX arm of the METEOR ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5905684/

Management of Adverse Events Associated with ... This review reports on the safety profile of cabozantinib in patients with advanced renal cell carcinoma and offers guidance on the management of adverse ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf

CABOMETYX (cabozantinib) - accessdata.fda.gov The safety of CABOMETYX was evaluated in METEOR, a randomized, open-label trial in which 331 patients with advanced renal cell carcinoma received CABOMETYX 60 ...

9. oncologynewscentral.com oncologynewscentral.com/drugs/monograph/163010-313027/cabozantinib-oral

Cabozantinib Oral Cabozantinib S-malate tablets (Cabometyx®) are used as a single agent for the treatment of patients with advanced renal cell carcinoma (RCC); the drug also is ...

10. ema.europa.eu ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf

Cabometyx, INN-Cabozantinib - European Medicines Agency Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population. Hepatic ...