Immunotherapy + Targeted Therapy for Genitourinary Cancers

Recruiting at 357 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Autoimmune disease, Active malignancy, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well cabozantinib works in combination with nivolumab and ipilimumab in treating patients with rare genitourinary (GU) tumors that has spread from where it first started (primary site) to other places in the body. Cabozantinib 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. Giving cabozantinib, nivolumab, and ipilimumab may work better in treating patients with genitourinary tumors that have no treatment options compared to giving cabozantinib, nivolumab, or ipilimumab alone.

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.

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

Research shows that combining Cabozantinib and Nivolumab, with or without Ipilimumab, has been effective in treating advanced genitourinary cancers, including urothelial carcinoma. These drugs work by boosting the immune system to fight cancer, and they have shown promising results in improving patient outcomes. ^{1 2 3 4 5}

Is the combination of cabozantinib, nivolumab, and ipilimumab safe for humans?

Research shows that the combination of cabozantinib, nivolumab, and ipilimumab has been studied for safety in various cancers, including genitourinary tumors and renal cell carcinoma. While specific safety details are not provided, these studies indicate that the treatment has been evaluated for safety in humans. ^{1 6 7 8 9}

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

This drug combination is unique because it combines targeted therapy (Cabozantinib) with immunotherapy (Nivolumab and Ipilimumab), aiming to enhance the immune system's ability to fight cancer while also targeting specific cancer cell pathways. This approach is being explored for its potential to improve outcomes in genitourinary cancers, where traditional immunotherapy alone has shown limited success. ^{1 4 10 11 12}

Research Team

Andrea B Apolo

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

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

Trial Timeline

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)

Treatment Details

Interventions

• Cabozantinib S-malate (Tyrosine Kinase Inhibitor)
• Ipilimumab (Checkpoint Inhibitor)
• Nivolumab (Checkpoint Inhibitor)

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.

Participant Groups

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.

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]

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]

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]

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]

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 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]

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]

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]

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

Targeting the Tumor Microenvironment with Immunotherapy for Genitourinary Malignancies. [2019]

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

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

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

Immunotherapy in Genitourinary Malignancy: Evolution in Revolution or Revolution in Evolution. [2022]

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. England 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). [2022]

9. 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]

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

Blocking immune checkpoints in prostate, kidney, and urothelial cancer: An overview. [2023]

11. Netherlands pubmed.ncbi.nlm.nih.gov

The immune infiltrate in prostate, bladder and testicular tumors: An old friend for new challenges. [2017]

12. England pubmed.ncbi.nlm.nih.gov

The immunotherapy revolution in genitourinary malignancies. [2021]