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

11 Participants Needed

Trial Summary

What is the purpose of this trial?

A Phase II Study of Nivolumab with Ipilimumab and Cabozantinib in Patients with Untreated Renal Cell Carcinoma Brain Metastases

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.

What data supports the idea that Triple Drug Therapy for Kidney Cancer with Brain Metastases is an effective treatment?

The available research shows that cabozantinib, one of the drugs in the Triple Drug Therapy, has shown remarkable responses in two cases of kidney cancer with brain metastases. This suggests that the therapy could be effective for this condition. However, there is no specific data comparing this therapy to other treatments for kidney cancer with brain metastases in the provided information. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination Nivolumab, Ipilimumab, and Cabozantinib for kidney cancer with brain metastases?

There is some evidence that cabozantinib alone has shown positive responses in cases of kidney cancer with brain metastases, suggesting potential effectiveness when used in combination with other drugs. ^{1 2 3 4 5}

What safety data exists for the combination of Nivolumab, Ipilimumab, and Cabozantinib in kidney cancer treatment?

The safety data for the combination of Nivolumab, Ipilimumab, and Cabozantinib in kidney cancer treatment is explored in several studies. One study compares adverse events between Cabozantinib plus Nivolumab and Ipilimumab plus Nivolumab, highlighting differences in safety profiles. Another study assesses the safety of Cabozantinib plus Nivolumab in a phase II trial for non-clear-cell renal cell carcinoma. However, the safety of the triple combination specifically in kidney cancer with brain metastases is not directly addressed in the provided research. ^{1 2 6 7 8}

Is the combination of Nivolumab, Ipilimumab, and Cabozantinib generally safe for humans?

Studies have looked at the safety of combining these drugs for kidney cancer, showing that they can cause side effects, but the specific safety details for brain metastases are not clear from the available data. ^{1 2 6 7 8}

Is the drug combination of Nivolumab, Ipilimumab, and Cabozantinib a promising treatment for kidney cancer with brain metastases?

Yes, the combination of Nivolumab, Ipilimumab, and Cabozantinib is considered promising for kidney cancer, especially with new research showing potential benefits in treating advanced cases. This combination is seen as a potential new option for patients, marking a significant step forward in treatment possibilities. ^{1 2 4 9 10}

What makes the triple drug therapy of Nivolumab, Ipilimumab, and Cabozantinib unique for kidney cancer with brain metastases?

This triple drug therapy is unique because it combines two immune checkpoint inhibitors (Nivolumab and Ipilimumab) with a targeted therapy (Cabozantinib), potentially offering a more comprehensive approach by both boosting the immune system to fight cancer and directly targeting cancer cell growth, which is a novel strategy for treating kidney cancer with brain metastases. ^{1 2 4 9 10}

Research Team

Jianbo Wang, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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]

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]

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 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]

References

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

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. [2023]

2. Australia pubmed.ncbi.nlm.nih.gov

Complete response of metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus to nivolumab plus cabozantinib. [2023]

3. Australia pubmed.ncbi.nlm.nih.gov

Efficacy of cabozantinib therapy for brain metastases from renal cell carcinoma. [2022]

4. United States 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. [2022]

5. Switzerland 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. [2023]

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

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]

7. 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]

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

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Cabozantinib and nivolumab as first-line treatment in advanced renal cell carcinoma. [2022]