Sequential Therapy for Kidney Cancer

Overseen By Che-Kai Tsao, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: Anticoagulants, Immunosuppressants

Disqualifiers: Brain metastases, Autoimmune disease, 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: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore a new treatment plan for individuals with advanced kidney cancer that cannot be surgically removed. Participants will initially receive Cabozantinib (Cabometyx), followed by a combination of two immunotherapy drugs, Ipilimumab (Yervoy) and Nivolumab (Opdivo). Depending on the cancer's response, further treatments may include Nivolumab alone or other medications. Individuals with advanced kidney cancer of the clear cell type who have not previously received these specific drugs might be suitable for this trial. As an Early Phase 1 trial, this research focuses on understanding how the treatment works in participants, offering them a chance to be among the first to receive this new treatment approach.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot have received certain cancer treatments or immunosuppressive medications recently, and some anticoagulants are not allowed. It's best to discuss your specific medications with the trial team.

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

A previous study found cabozantinib safe for patients with kidney cancer, even those with cancer that had spread to the brain. Most patients tolerated the treatment well, with tiredness and diarrhea as common side effects.

Research has shown that the combination of ipilimumab and nivolumab is generally safe for advanced kidney cancer. Patients did not encounter any unexpected safety issues, indicating it is as safe as anticipated. Common side effects included tiredness and skin rash.

Studies have shown promising results for the combination of lenvatinib and everolimus in patients with advanced kidney cancer. This combination was safe for most people, although some experienced high blood pressure and tiredness.

Overall, these treatments have been studied in other settings and are generally well-tolerated. While side effects can occur, they are usually manageable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for kidney cancer?

Researchers are excited about this treatment for metastatic or unresectable clear cell renal cell carcinoma because it combines targeted therapy and immunotherapy in a unique sequence. Unlike standard treatments, which often rely on single-drug regimens, this approach starts with Cabozantinib, a tyrosine kinase inhibitor that targets specific proteins involved in tumor growth. After 12 weeks, it transitions to a powerful duo of immunotherapies, Ipilimumab and Nivolumab, which work together to enhance the body's immune response against cancer cells. This sequential strategy aims to improve treatment effectiveness and adaptability based on individual patient responses, offering a potentially more dynamic and personalized cancer-fighting approach.

What evidence suggests that this trial's treatments could be effective for kidney cancer?

In this trial, participants with metastatic or unresectable clear cell renal cell carcinoma will receive a sequential treatment strategy. Research has shown that cabozantinib, administered initially, effectively treats advanced kidney cancer, known as metastatic renal cell carcinoma (RCC). It slows the disease by 40% and shrinks tumors in 23% of patients. After cabozantinib, participants will receive a combination of ipilimumab and nivolumab, which also shows promise for advanced RCC, reducing the risk of death by 28% and achieving a 70% response rate in some patients. Additionally, for those whose disease progresses, the combination of lenvatinib and everolimus has demonstrated good results, especially for patients who have not succeeded with other treatments. Together, these treatments offer hope for managing advanced kidney cancer. ^{1 6 7 8 9}

Who Is on the Research Team?

Che-Kai Tsao

Principal Investigator

Investigator

Are You a Good Fit for This Trial?

Adults with advanced or metastatic clear cell renal cell carcinoma that can't be surgically removed. They should have a life expectancy of at least 12 weeks, measurable disease, and good organ function. Participants must not be pregnant, have had certain cancers within the last 3 years, or received specific treatments for kidney cancer before.

Inclusion Criteria

Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception during the course of the study and for 4 months after the last dose of study treatment

Capable of understanding and complying with the protocol requirements and must have signed the informed consent document

I had kidney cancer, underwent kidney removal, and now it has spread.

Exclusion Criteria

I haven't taken any kinase inhibitor medication in the last 2 weeks.

I haven't had recent radiation or radionuclide treatments and have no ongoing complications from them.

You have had a bad reaction to certain medications or their ingredients in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Cabozantinib

Participants receive Cabozantinib for 12 weeks

12 weeks

Treatment - Ipilimumab + Nivolumab

Participants receive Ipilimumab plus Nivolumab immunotherapy for 12 weeks

12 weeks

Treatment - Response-based

Participants receive Nivolumab for CR/PR/SD, or Cabozantinib or Lenvatinib/Everolimus for PROG for 12 weeks

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Everolimus
• Ipilimumab
• Lenvatinib
• Nivolumab

Trial Overview The study tests a sequence of drugs: Cabozantinib for 12 weeks followed by Ipilimumab plus Nivolumab immunotherapy over another 12 weeks. Depending on response, treatment may continue with either Nivolumab alone or in combination with Lenvatinib/Everolimus.

How Is the Trial Designed?

Group I: Patients with metastatic or unresectable clear cell renal cell carcinoma Experimental Treatment 5 Interventions

Patients with metastatic or unresectable clear cell renal cell carcinoma to receive same sequential treatment strategy. (Cabozantinib for 12 weeks, then proceed with Ipilimumab plus Nivolumab immunotherapy x4 over 12 weeks, then subsequent therapies depending on treatment response for another 12 weeks \[Nivolumab for CR/PR/SD, Cabozantinib or Lenvatinib/Everolimus for PROG\]).

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?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

Published Research Related to This Trial

In clear cell renal cell carcinoma, combining immunotherapy (like nivolumab/ipilimumab or axitinib/pembrolizumab) is effective as a first-line treatment, enhancing patient outcomes and quality of life.

Nivolumab alone is a promising second-line treatment option for patients who have previously received targeted therapies, supported by both clinical data and mechanistic rationale.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequencing Therapies for Metastatic Renal Cell Carcinoma. Dizman, N., Arslan, ZE., Feng, M., et al.[2020]

Nivolumab (Opdivo®) has been established as an effective second-line treatment for metastatic renal cell carcinoma (mRCC), showing improved overall survival (26 months vs. 19.7 months) and response rates compared to Everolimus, based on the CheckMate 025 trial with 1,080 participants.

The combination of Nivolumab and Ipilimumab has demonstrated a significantly higher objective response rate (42% vs. 27%) and better overall survival in intermediate and high-risk patients compared to Sunitinib, while also improving quality of life, despite an increase in immune-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy for renal cell carcinoma - current status]. Grimm, MO., Foller, S.[2019]

The combination of cabozantinib (a TKI) and nivolumab (an anti-PD-1 antibody) is an effective first-line treatment for previously-untreated advanced renal cell carcinoma (RCC), showing significantly longer progression-free and overall survival compared to sunitinib monotherapy in the CheckMate 9ER trial.

Patients receiving cabozantinib plus nivolumab reported better health-related quality of life, although the combination therapy had a higher incidence of serious adverse events compared to sunitinib, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab: A Review in Advanced Renal Cell Carcinoma. Markham, A.[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 combination of cabozantinib (a tyrosine kinase inhibitor) and nivolumab (an immune checkpoint inhibitor) significantly improved progression-free survival, overall survival, and objective response rates in patients with untreated advanced renal cell carcinoma compared to sunitinib, supporting its approval as a first-line therapy.

While the safety profile of the combination treatment is generally manageable, it requires careful monitoring and management of overlapping adverse events, such as diarrhea and hepatotoxicity, to maintain patient tolerability and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. McGregor, B., Mortazavi, A., Cordes, L., et al.[2023]

In a phase 3 trial involving 522 patients with metastatic renal cell carcinoma, adding atezolizumab to cabozantinib did not significantly improve progression-free survival or overall survival compared to cabozantinib alone, indicating that this combination may not be effective for patients whose disease progressed after immune checkpoint inhibitors.

The combination treatment with atezolizumab and cabozantinib resulted in higher rates of serious adverse events (48% vs. 33% for cabozantinib alone), suggesting increased toxicity without clinical benefit, which raises concerns about its use outside of clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Pal, SK., Albiges, L., Tomczak, P., 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]

A patient with refractory metastatic renal cell carcinoma achieved 22 months of disease control using a combination of cabozantinib and nivolumab after previously failing multiple treatments, including both drugs as monotherapies.

This case highlights the potential of combining cabozantinib, a vascular endothelial growth factor inhibitor, with nivolumab, an immune checkpoint inhibitor, to enhance treatment efficacy, suggesting a promising avenue for ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Illustrative Case of Combination Cabozantinib/Nivolumab for Progressive Metastatic Renal Cell Carcinoma (mRCC). Kao, C., George, DJ., Zhang, T.[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]

The COSMIC-313 phase 3 trial demonstrated that the triplet combination of cabozantinib, nivolumab, and ipilimumab may offer a new first-line treatment option for patients with metastatic clear cell renal cell carcinoma, marking a significant advancement in therapy.

The results presented at the 2022 European Society of Medical Oncology Congress suggest that triplet combinations could enhance treatment efficacy compared to the standard dual therapy of nivolumab and ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Less is More? First Impressions From COSMIC-313. Msaouel, P.[2023]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11332639/

The efficacy and safety of cabozantinib in patients ... Positive results were observed for cabozantinib, with a 40% reduction in disease progression or death and a 23% tumor response rate compared to ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1558767325000825

Cabozantinib in the First-Line Treatment of Patients With ... Here we analyze the outcome of metastatic RCC patients treated with first-line cabozantinib in a retrospective cohort from the Czech Republic and Poland.

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

Cabozantinib real-world effectiveness in the second-line ... Background: Cabozantinib is approved as a subsequent therapy for patients with metastatic renal cell carcinoma (mRCC) based on the METEOR trial.

4. cancer.gov cancer.gov/news-events/cancer-currents-blog/2021/papillary-renal-cell-carcinoma-cabozantinib

Cabozantinib Slows Progression of Rare Kidney Cancer Two out of 44 people receiving cabozantinib (5%) had their tumors disappear entirely during treatment, known as a complete response. No complete ...

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

Real-World Results of Cabozantinib Given as Alternative ... At the timepoint when cabozantinib was started, most patients presented with an ECOG performance status of 0 (50.7%), followed by 1 (32,4%), 2 ( ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36328934/

Results from the International Metastatic Renal Cell ... Our study reports the real-world experience of using radiotherapy in patients receiving cabozantinib for metastatic kidney cancer.

7. sciencedirect.com sciencedirect.com/science/article/pii/S1558767323002379

Cabozantinib in the Routine Management of Renal Cell ... Cabozantinib is approved for use in renal cell carcinoma (RCC) as both monotherapy,, based on data from the pivotal METEOR17, 18, 19 and CABOSUN trials,, and as ...

8. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2784989

Activity and Safety of Cabozantinib for Brain Metastases in ... These findings show considerable intracranial activity and an acceptable safety profile of cabozantinib in patients with renal cell carcinoma and brain ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03945773

NCT03945773 | Study of Cabozantinib as 2nd Line ... The overall objective of this study is to evaluate the efficacy and safety of cabozantinib as 2nd line treatment in subjects with unresectable, locally ...