Triple Drug Therapy for Kidney Cancer with Brain Metastases

Overseen By Jianbo Wang

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Chemotherapy, Hormonal therapy

Disqualifiers: Symptomatic brain metastases, Leptomeningeal disease, Autoimmune disease, Active infections, 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: Until progression or intolerable toxicities

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new triple drug treatment for individuals with kidney cancer that has spread to the brain. The research aims to assess the effectiveness of combining three drugs—Nivolumab (an immunotherapy drug), Ipilimumab (another immunotherapy drug), and Cabozantinib (a targeted therapy drug)—against this cancer type. Suitable candidates are those with kidney cancer that has metastasized to the brain, who have not previously received these specific drugs, and are not experiencing severe symptoms. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to significant advancements in cancer treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had any approved anticancer therapy, including chemotherapy and hormonal therapy, within 4 weeks prior to starting the study treatment, except for hormone-replacement therapy or oral contraceptives. Herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to the study. Please consult with the trial coordinators for specific guidance on your medications.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had any approved anticancer therapy, including chemotherapy and hormonal therapy, within 4 weeks before starting the study treatment, except for hormone-replacement therapy or oral contraceptives.

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

Research shows that the combination of nivolumab, ipilimumab, and cabozantinib has been tested for safety in patients with kidney cancer that has spread to the brain. Studies have found that nivolumab and ipilimumab together are generally well-tolerated, meaning they don't usually cause severe side effects. Cabozantinib has also been evaluated for safety when used with these two drugs in similar conditions.

Previous research indicates that using these drugs together can help slow the growth of kidney cancer. The safety data suggest that people taking this combination might experience side effects, but these are usually manageable. This trial is in phase 2, indicating that the treatment has shown sufficient safety and effectiveness in earlier trials to continue.

Patients should discuss any concerns with their doctor, who can provide more personalized advice. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this triple drug therapy for kidney cancer with brain metastases because it combines Nivolumab and Ipilimumab, which are both immunotherapy drugs that help the body's immune system attack cancer cells more effectively. Unlike traditional treatments that might only target cancer cells directly, this combination boosts the body's natural defenses. Cabozantinib, the third component, is a targeted therapy that blocks cancer cell growth and spread by cutting off their blood supply. Together, this regimen offers a multi-faceted approach that could potentially be more effective than existing treatments like sunitinib or pazopanib, which typically focus on single pathways. This combination could lead to improved outcomes by addressing multiple aspects of tumor growth and immune evasion.

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

Research shows that using the drugs nivolumab, ipilimumab, and cabozantinib together may help treat advanced kidney cancer. This trial will evaluate each drug separately: Nivolumab is administered intravenously every 3 weeks for 4 doses, Ipilimumab is given intravenously over 30 minutes every 3 weeks for 4 doses, and Cabozantinib is taken orally as tablets once daily. Studies have found that this combination can slow cancer growth in patients who have not yet received treatment for kidney cancer. Specifically, cabozantinib, when used with nivolumab and ipilimumab, has led to better results compared to other treatments. The combination of nivolumab and ipilimumab has already shown long-term effectiveness in similar cases. These findings suggest that this treatment could also work for kidney cancer that has spread to the brain. ^{1 2 3 5 6}

Who Is on the Research Team?

Jianbo Wang, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with untreated brain metastases from renal cell carcinoma. Participants should have a measurable brain lesion, be in good physical condition (ECOG 0-2), and not need immediate local therapy. They must have normal organ function and agree to contraception if applicable. Exclusions include recent radiation or systemic cancer treatments, significant liver disease, metal implants preventing MRI scans, symptomatic brain metastases needing urgent treatment, certain infections or vaccinations recently, other cancers within the last 5 years, autoimmune diseases.

Inclusion Criteria

I agree to use effective birth control during and for 12 months after treatment.

The size of the tumor is between 5mm and 30mm, as seen on an MRI scan with a special dye.

I have had treatments for kidney cancer that has spread, but not with anti-CTLA-4, cabozantinib, or MET inhibitors.

Exclusion Criteria

I have cancer that has spread to the lining of my brain and spinal cord.

I have never had lung conditions like pulmonary fibrosis or pneumonitis.

My side effects from cancer treatment are mild, except for hair loss.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive nivolumab and ipilimumab IV every 3 weeks for 4 doses, and cabozantinib daily. After 4 doses, treatment continues with nivolumab every 4 weeks and cabozantinib daily until progression or intolerable toxicities.

Until progression or intolerable toxicities

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab, Ipilimumab, Cabozantinib

Trial Overview The study tests a combination of Nivolumab (an immunotherapy drug), Ipilimumab (another immunotherapy), and Cabozantinib (a medication targeting specific proteins in cancer cells) on patients who haven't treated their kidney cancer's spread to the brain yet. It aims to see how well this combo works together.

How Is the Trial Designed?

Group I: Nivolumab Experimental Treatment 3 Interventions

by vein every 3 weeks for 4 doses

Group II: Ipilimumab Experimental Treatment 3 Interventions

by vein over 30 minutes every 3 weeks for 4 doses

Group III: Cabozantinib Experimental Treatment 3 Interventions

tablets by mouth 1 time every day.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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 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]

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 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]

The combination of cabozantinib and nivolumab has emerged as a promising treatment for metastatic renal cell carcinoma (mRCC), showing improved outcomes in clinical trials compared to traditional therapies like sunitinib.

While dual immune checkpoint inhibition and combinations with VEGF inhibitors have demonstrated efficacy in phase III trials, there is currently no direct comparison of these therapies, and no biomarkers exist to help determine the best first-line treatment for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib and nivolumab as first-line treatment in advanced renal cell carcinoma. Vitale, MG., Nasso, C., Oltrecolli, M., et al.[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]

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]

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 of 711 renal cell carcinoma patients with new brain metastases, the median survival improved from 9.6 months to 12 months over time, indicating better outcomes for patients diagnosed more recently.

Cytokine therapy after the diagnosis of brain metastases was the only treatment associated with improved survival, while the use of whole-brain radiation therapy decreased and stereotactic radiosurgery became more common, reflecting evolving treatment patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Targeted Therapies on Prognostic Factors, Patterns of Care, and Survival in Patients With Renal Cell Carcinoma and Brain Metastases. Sperduto, PW., Deegan, BJ., Li, J., et al.[2022]

Cabozantinib demonstrated remarkable efficacy in treating renal cell carcinoma with brain metastases, leading to complete remission in one patient within 2 weeks and significant regression in another after combination therapy.

The cases suggest that cabozantinib, especially when used with immune checkpoint inhibitors like nivolumab, could be a promising treatment option for patients with advanced renal cell carcinoma and brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of cabozantinib therapy for brain metastases from renal cell carcinoma. Nakagawa, T., Kijima, T., Imasato, N., et al.[2022]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2212851

Cabozantinib plus Nivolumab and Ipilimumab in Renal- ... Cabozantinib improved outcomes as compared with sunitinib in previously untreated patients with advanced renal-cell carcinoma when administered ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9298991/

Safety and efficacy of nivolumab plus ipilimumab in patients ... Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long‐term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC) ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04413123

NCT04413123 | Cabozantinib In Combo With NIVO + IPI In ... This research study will assess whether cabozantinib, nivolumab and ipilimumab in combination are safe and effective in slowing down the growth of kidney ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0959804922007602

Nivolumab plus ipilimumab plus cabozantinib triplet ... These results suggest that the nivolumab plus ipilimumab plus cabozantinib triplet combination has clinical activity in patients with previously untreated aRCC.

5. ascopubs.org ascopubs.org/doi/10.1200/CCI.24.00132

Real-World Outcomes in Patients With Metastatic Renal ... This study provides data to support the understanding of the real-world utilization and long-term effectiveness of 1L NIVO + IPI in patients with I/P-risk mRCC.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9249636/

Efficacy of cabozantinib therapy for brain metastases from ... Cabozantinib, alone or in combination with immune checkpoint inhibitors, may be a viable option for clear cell renal cell carcinoma with brain metastases.