Surgery + Immunotherapy + Targeted Therapy for Kidney Cancer

(Cyto-KIK Trial)

Recruiting at 3 trial locations

Overseen By Research Nurse Navigator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mark Stein

Must not be taking: Anticoagulants, Corticosteroids, Immunosuppressives, others

Disqualifiers: Nephrectomy, Hypertension, Autoimmune disease, 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: 5

Duration: 12 weeks

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining immunotherapy (nivolumab) and targeted therapy (cabozantinib) before kidney surgery can eliminate kidney cancer that has spread. The researchers aim to determine if this combination makes the cancer disappear from scans during treatment. Participants will receive treatments through IV infusion and oral pills before undergoing kidney removal surgery. The trial seeks individuals diagnosed with metastatic renal cell carcinoma (kidney cancer that has spread) who have not received prior treatment for this condition. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on certain blood thinners or medications that suppress the immune system, you may need to adjust or stop them. 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?

Research has shown that cabozantinib and nivolumab safely treat advanced kidney cancer. Cabozantinib often extends patient survival and slows cancer growth. Some patients may experience side effects like diarrhea and tiredness, but these are usually manageable with proper care.

Studies have found that nivolumab is well-tolerated and is already FDA-approved for certain types of kidney cancer. Common side effects include fatigue and skin rash, while serious side effects, such as lung and kidney problems, are less common.

These treatments have been studied in many patients and have demonstrated a good safety record. While side effects can occur, they are often mild and treatable. ^{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 it offers a unique approach by combining two powerful treatments: immunotherapy and targeted therapy. Unlike standard treatments that typically focus on surgery or single-drug therapies, cabozantinib is a targeted therapy that inhibits pathways that help cancer cells grow, while nivolumab is an immunotherapy that boosts the body's immune system to fight cancer cells. This combination has the potential to enhance treatment effectiveness by addressing cancer through multiple mechanisms, possibly leading to better outcomes for patients.

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

Research shows that using cabozantinib and nivolumab together may help treat kidney cancer. In this trial, all participants will receive both cabozantinib and nivolumab, followed by nephrectomy. Studies have found that people taking these two drugs had a 49% lower chance of their cancer spreading or worsening compared to those taking another drug called sunitinib. About 39.6% of patients experienced tumor shrinkage, and 83% achieved some disease control. Additionally, surgery to remove the kidney can reduce the risk of cancer progression by about 30%, providing patients an average of 6 extra months of survival. These findings suggest that this combination of treatments might effectively manage kidney cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Mark N Stein, MD

Principal Investigator

Associate Professor of Medicine Division of Hematology/Oncology

Are You a Good Fit for This Trial?

Adults with kidney cancer that has spread, who haven't had treatment for metastatic renal cell carcinoma. They must be in good physical condition (ECOG 0-1), have a measurable tumor, and agree to use two forms of contraception if of childbearing potential. Excluded are those with recent significant bleeding or radiation therapy, active or progressive other cancers, certain heart conditions, uncontrolled hypertension, brain metastases, major surgery within the last 8 weeks, systemic infections within the last month or on immunosuppressants.

Inclusion Criteria

Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 6 months after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method

I am not pregnant and can prove it with a test, or I cannot have children due to surgery or menopause.

My kidney cancer has spread, and tests show it's the clear cell type.

Exclusion Criteria

I haven't had a severe infection needing treatment in the last 28 days.

I haven't had any serious wounds, ulcers, or bone fractures that haven't healed in the last 28 days.

I have been treated with PD-1/PD-L1 or anti-CTLA-4 inhibitors before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib and nivolumab for approximately 12 weeks prior to nephrectomy

12 weeks

Nivolumab administered every 4 weeks, cabozantinib daily

Surgery

Participants undergo cytoreductive nephrectomy to remove the kidney tumor

1 week

1 surgical visit

Post-Surgery Treatment

Participants may resume cabozantinib and nivolumab if benefiting from treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Cytoreductive Nephrectomy
• Nivolumab

Trial Overview The trial is testing whether combining nivolumab (an immunotherapy drug) and cabozantinib (a targeted therapy) before surgically removing the kidney can clear visible signs of kidney cancer more effectively than current treatments. Participants will receive these drugs prior to undergoing cytoreductive nephrectomy.

How Is the Trial Designed?

Group I: Treatment with cabozantinib and nivolumab with nephrectomy Experimental Treatment 3 Interventions

All study participants will receive the same study medications, cabozantinib and nivolumab. The study drug, nivolumab, will be administered through an IV infusion every 4 weeks and cabozantinib will be administered orally daily. Initially participants will receive study treatment for 12 weeks. The cabozantinib will then be stopped prior to the nephrectomy. Initially patients enrolled on the study will be assigned to cohort 1. Patients who are assigned to cohort 1 will be treated with cabozantinib until 21 days prior to surgery. A patient in cohort 1 will be evaluable for assessment of the cabozantinib washout interval ("evaluable patients") if they 1. complete at least 10 of the 14 scheduled cabozantinib doses in the two week period prior to stopping cabozantinib AND 2. have surgical resection of the primary tumor. In cohort 2, subjects will receive cabozantinib until 14 days prior to nephrectomy.

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?

Mark Stein

Lead Sponsor

Trials

4

Recruited

150+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

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

A 52-year-old male with a large inoperable tumor in a horseshoe kidney achieved a major partial response to neoadjuvant therapy with nivolumab and cabozantinib, allowing for successful radical tumor resection and maintaining mild renal function post-treatment.

Despite experiencing hepatotoxicity that led to early withdrawal of nivolumab, the combination of immune checkpoint inhibitors and tyrosine kinase inhibitors shows promise as a neoadjuvant treatment strategy for advanced renal cell carcinoma, particularly in challenging cases like horseshoe kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant nivolumab and cabozantinib in advanced renal cell carcinoma in a horseshoe kidney - how to achieve a safe and radical resection? a case report and review of the literature. Zemankova, A., Studentova, H., Kopova, A., et al.[2023]

Nivolumab plus cabozantinib significantly improved progression-free survival and overall survival compared to sunitinib in advanced renal cell carcinoma, as shown in the CheckMate 9ER study.

However, the combination treatment was found to be not cost-effective, with an incremental cost-effectiveness ratio of $863,720 per quality-adjusted life-year (QALY) gained, far exceeding the commonly accepted threshold of $150,000.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness Analysis of First-Line Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma in the United States. Liao, W., Lei, W., Feng, M., et al.[2021]

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]

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 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 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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04322955

CYTO Reductive Surgery in Kidney Cancer Plus ... The purpose of this study is to determine if the use of immunotherapy nivolumab and the targeted therapy cabozantinib prior to removal of the kidney,

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9775439/

Efficacy and Safety of Cabozantinib in Patients with ... The ORR and DCR were 39.6% and 83.0%, respectively. The median PFS was 11.0 months. PFS was significantly shorter in patients previously treated ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.6_suppl.TPS371

Phase II trial of cytoreductive surgery in kidney cancer plus ... Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over ...

4. urotoday.com urotoday.com/conference-highlights/esmo-2024/esmo-2024-kidney-cancer/154895-esmo-2024-the-role-of-cytoreductive-nephrectomy-in-the-immunotherapy-era.html

ESMO 2024: The Role of Cytoreductive Nephrectomy in ... These trials demonstrated an ~30% risk reduction benefit with cytoreductive nephrectomy, resulting in a 6-month survival advantage. The greatest ...

5. opdivo.com opdivo.com/advanced-kidney-cancer/clinical-trial-results/opdivo-cabometyx-immunotherapy-combination

Clinical trial results for advanced kidney cancer (renal cell ... People given OPDIVO + CABOMETYX had a 49% lower risk of their cancer spreading, growing, or getting worse than those given SUTENT. More people given OPDIVO + ...

6. 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 ...

7. cabometyx.com cabometyx.com/kidney-cancer/about-cabometyx

Learn about CABOMETYX in advanced kidney cancer See how CABOMETYX is used to treat a type of advanced kidney cancer known as advanced Renal Cell Carcinoma. See study results, side effects and important safety

8. sciencedirect.com sciencedirect.com/science/article/pii/S1558767323002173

Real-World Results of Cabozantinib Given as Alternative ... Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD- ...

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

The efficacy and safety of cabozantinib in patients ... Cabozantinib shows significant efficacy in extending overall survival, progression-free survival, and tumor objective response rate despite a potentially ...

10. cabometyx.com cabometyx.com/kidney-cancer

Advanced Kidney Cancer Treatment Option| CABOMETYX ... CABOMETYX is used to treat certain people with advanced kidney cancer (RCC) alone or in combination with OPDIVO. See indication and important safety ...