Cabozantinib + Nivolumab for Kidney Cancer

Overseen By Amy Rowell, MBA,CCRP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Texas Southwestern Medical Center

Must be taking: Cabozantinib

Must not be taking: Warfarin, Dabigatran, Clopidogrel

Disqualifiers: Brain metastases, Uncontrolled hypertension, 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: Unknown

Duration: Up to 24 months

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effects of a higher dose of the drug cabozantinib (Cabometyx) combined with nivolumab (Opdivo) for individuals with advanced kidney cancer. The researchers aim to determine if increasing the cabozantinib dose benefits patients whose cancer progressed after initial cabozantinib treatment. This trial suits those with advanced kidney cancer unresponsive to standard cabozantinib treatment for six months or more and who can tolerate the side effects of their current dose. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant findings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but there is no washout period required for cabozantinib. For other cancer treatments, a washout period of 4 weeks or 4 half-lives, whichever is shorter, is needed. Some anticoagulants are not allowed, so check with the trial team about your specific medications.

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

Research has shown that cabozantinib is generally safe for people with kidney cancer. Although some side effects occur, they are usually mild, and most patients manage the treatment well. Its safety in everyday use aligns with findings from earlier studies.

Nivolumab, another kidney cancer treatment, is also typically well-tolerated. However, some serious side effects, such as diarrhea, fever, and pneumonia, have been reported. Despite this, it remains a common treatment choice.

Both cabozantinib and nivolumab are used to treat renal cell carcinoma, a type of kidney cancer. This indicates they are generally safe, though side effects can vary among individuals. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Cabozantinib and Nivolumab for kidney cancer because these drugs work together in a unique way. Most treatments for kidney cancer, like sunitinib or pazopanib, target tumor growth by blocking certain pathways. Cabozantinib, however, targets multiple pathways involved in tumor growth and blood vessel formation, potentially making it more effective. Meanwhile, Nivolumab is an immunotherapy that helps the immune system recognize and attack cancer cells. This combination could offer a more comprehensive approach to fighting kidney cancer than existing treatments.

What evidence suggests that this treatment might be an effective treatment for kidney cancer?

Research has shown that cabozantinib, which participants in this trial may receive, effectively treats advanced kidney cancer. Studies have found that it can slow the disease or reduce the risk of death by 34% and improve tumor response to treatment by 33% compared to treatments like sunitinib. In another study, cabozantinib kept the cancer from worsening for an average of 7.4 months, longer than the 3.8 months observed with everolimus. Meanwhile, nivolumab, another treatment option in this trial, helps the immune system better identify and destroy cancer cells. Combining cabozantinib and nivolumab is believed to enhance these benefits, potentially leading to better outcomes for patients with advanced kidney cancer. ^{1 2 5 6 7}

Who Is on the Research Team?

Tian Zhang, MD

Principal Investigator

UT Southwestern Medical Center

Are You a Good Fit for This Trial?

Adults with advanced kidney cancer who've seen their disease progress after cabozantinib treatment can join. They must have used cabozantinib for over 6 months, be able to take it without severe side effects, and not be on certain medications or have specific health conditions. Participants need measurable cancer growth, good organ function, and a performance status indicating they can walk and care for themselves.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

My advanced kidney cancer responded to cabozantinib treatment for over 6 months.

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

Exclusion Criteria

I don't have another cancer needing treatment right now, except for certain exceptions.

Active, known, or suspected autoimmune diseases except for specific exceptions

My brain metastases are treated and have been stable.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib 80mg PO daily for dose escalation after progression on cabozantinib monotherapy

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 36 months

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Nivolumab

Trial Overview The trial is testing two approaches in patients whose kidney cancer has worsened despite previous treatment: one group will receive a high dose of cabozantinib alone, while the other will get a lower dose combined with nivolumab. The choice between these options depends on what dosage participants tolerated before.

How Is the Trial Designed?

Group I: Cabozantinib Dose Escalation Experimental Treatment 1 Intervention

cabozantinib 80mg PO daily

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?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Published Research Related to This Trial

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]

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]

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 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]

Cabozantinib combined with nivolumab is shown to be superior in terms of progression-free survival (PFS) compared to axitinib + pembrolizumab and nivolumab + ipilimumab for the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC), based on a systematic review of four randomized controlled trials involving treatment-naïve patients.

While cabozantinib + nivolumab demonstrated effectiveness, the combination of lenvatinib + pembrolizumab showed numerical superiority in overall survival, indicating that while cabozantinib + nivolumab is a strong option, other combinations may also be effective and warrant consideration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma-A network meta-analysis. Focus on cabozantinib combined with nivolumab. Niewada, M., Macioch, T., Konarska, M., 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]

A 77-year-old male with metastatic papillary renal cell carcinoma and inferior vena cava tumor thrombus was successfully treated with nivolumab plus cabozantinib, leading to significant regression of all lesions.

Following treatment, the patient underwent radical nephrectomy and other surgeries, with no viable cancer cells found and no recurrence of the disease for 9 months, indicating the potential efficacy of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete response of metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus to nivolumab plus cabozantinib. Hayashida, M., Miura, Y., Yamaguchi, T., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6854754/

Cabozantinib for Renal Cell Carcinoma A phase I study in patients with advanced RCC reported in 2014 showed a promising activity in heavily pretreated patients with a partial response rate of 28% [ ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0929664625001172

Real-world study of cabozantinib treatment of advanced ... The 5-year survival rate for metastatic kidney cancer is poor (15 % in 2021 in the USA) [1,6]. Cabozantinib is an oral inhibitor of multiple ...

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

The efficacy and safety of cabozantinib in patients ... The cabozantinib group showed a 34% reduction in disease progression or death and higher tumor response rates (33%) compared to the sunitinib ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa1510016

Cabozantinib versus Everolimus in Advanced Renal-Cell ... The efficacy with cabozantinib was robust, with an estimated median progression-free survival of 7.4 months, as compared with 3.8 months with ...

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. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e16538

Cabozantinib outcomes for metastatic renal cell carcinoma ... Conclusions: Overall, Cabozantinib showed better than expected response rates, and the toxicities in our NHS tertiary hospital were less severe ...

7. 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 ...