Triple Drug Therapy for Kidney Cancer

Recruiting at 11 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Immunostimulants

Disqualifiers: Autoimmune disease, Active infection, 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: 4

Duration: Up to 2 years

65 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial studies the effects of combination therapy with bevacizumab, erlotinib, and atezolizumab in treating patients with hereditary leiomyomatosis and kidney cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Bevacizumab is in a class of medications called antiangiogenic agents. They work by stopping the formation of blood vessels that bring oxygen and nutrients to tumors. This may slow the growth and spread of tumors. Erlotinib is in a class of medications called kinase inhibitors. It works by blocking the action of a protein called EGFR that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Combination therapy with bevacizumab, erlotinib, and atezolizumab may stabilize or shrink advanced hereditary leiomyomatosis and kidney cancer.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot have had any systemic therapy for kidney cancer within 4 weeks before starting the trial, and certain medications like herbal therapies must be stopped at least 1 week before. It's best to discuss your specific medications with the trial team.

Is the triple drug therapy for kidney cancer safe for humans?

The safety of the drugs Atezolizumab, Bevacizumab, and Erlotinib has been studied in various conditions. Bevacizumab, for example, has been approved for use in kidney cancer and is generally safe, but it can cause side effects like bleeding, high blood pressure, and blood clots. Managing these side effects is important to ensure patient safety and quality of life during treatment. ^{1 2 3 4 5}

How is the triple drug therapy for kidney cancer unique?

The triple drug therapy for kidney cancer combines Atezolizumab, Bevacizumab, and Erlotinib, which is unique because it targets multiple pathways involved in cancer growth and spread, including the immune system, blood vessel formation, and cell growth signals, potentially offering a more comprehensive approach than single or dual therapies. ^{6 7 8 9 10}

What data supports the effectiveness of the drugs Atezolizumab, Tecentriq, Bevacizumab, Avastin, Erlotinib, and Tarceva for kidney cancer?

Bevacizumab, one of the drugs in the treatment, has shown effectiveness in improving progression-free survival in patients with metastatic renal cell carcinoma when combined with interferon, according to a phase 3 study. ^{1 6 7 11 12}

Who Is on the Research Team?

Ramaprasad Srinivasan

Principal Investigator

National Cancer Institute LAO

Are You a Good Fit for This Trial?

This trial is for individuals aged 12 or older with advanced kidney cancer, including hereditary leiomyomatosis and renal cell carcinoma. Participants must have measurable disease, acceptable organ function, no more than two prior VEGF-targeted treatments, and no recent use of certain medications or therapies. Those with treated brain metastases stable for at least 3 months can join. Pregnant women and tobacco users who cannot quit are excluded.

Inclusion Criteria

Your bilirubin levels need to be within a certain range, unless you have Gilbert's disease.

I can provide a tissue sample from my tumor or am willing to have a biopsy.

I have had 2 or fewer treatments targeting VEGF but no bevacizumab for my advanced cancer.

Exclusion Criteria

I haven't had radiotherapy for kidney cancer in the last 2 weeks.

I haven't taken any immune-weakening medications in the last 2 weeks.

I have not had major surgery in the last 28 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive bevacizumab, erlotinib, and atezolizumab in 21-day cycles

Up to 2 years

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 6 months

2 visits per year (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Bevacizumab
• Erlotinib

Trial Overview The study tests a combination therapy using bevacizumab (stops blood vessels from feeding tumors), erlotinib (blocks proteins that signal cancer cells to multiply), and atezolizumab (boosts the immune system to fight cancer). The goal is to see if this trio can stabilize or shrink advanced-stage kidney cancers.

How Is the Trial Designed?

Group I: Treatment (bevacizumab, atezolizumab, erlotinib) Experimental Treatment 11 Interventions

Patients receive bevacizumab IV over 30-90 minutes and atezolizumab IV over 30-60 minutes on day 1 of each cycle. Patients also receive erlotinib PO QD on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT with or without contrast and MRI throughout the trial. Patients undergo collection of blood throughout the trial, and may undergo a biopsy during screening, as well as a brain MRI/CT scan with contrast, bone scan, and/or F-18 sodium fluoride PET scan as clinically indicated.

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 3 trial involving 628 patients with metastatic renal cell carcinoma, the combination of bevacizumab and interferon (BEV+IFN) significantly improved progression-free survival (PFS) compared to interferon alone, with median PFS of 10.2 months versus 4.6 months (p < 0.001).

A new predictive model based on factors like age and performance status showed better ability to predict individual PFS than the existing Motzer criteria, indicating it could help identify patients who would benefit most from BEV+IFN treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prediction of progression-free survival rates after bevacizumab plus interferon versus interferon alone in patients with metastatic renal cell carcinoma: comparison of a nomogram to the Motzer criteria. Karakiewicz, PI., Sun, M., Bellmunt, J., et al.[2015]

Targeted therapies, including multikinase inhibitors like sunitinib and sorafenib, have become the primary treatment options for metastatic renal cell carcinoma (RCC), showing significant efficacy in clinical trials compared to traditional immunotherapy.

Sunitinib is the first-line treatment for metastatic RCC, while temsirolimus is recommended for poor-prognosis patients, highlighting the importance of personalized treatment approaches based on patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New treatment approaches in renal cell carcinoma. Facchini, G., Perri, F., Caraglia, M., et al.[2021]

Recent advances in understanding the molecular mechanisms of renal cell carcinoma have led to the development of targeted therapies, including VEGF inhibitors like bevacizumab and tyrosine kinase inhibitors such as sunitinib and pazopanib, which have shown efficacy in Phase III trials.

The review also highlights the importance of optimizing treatment management strategies, including determining the appropriate timing for starting and stopping therapy, as well as exploring alternative dosing schedules for sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical management of metastatic kidney cancer: the role of new molecular drugs. Vitale, MG., Cartenì, G.[2021]

The standard treatment for metastatic renal cell carcinoma involves using targeted therapies like VEGF inhibitors and mTOR inhibitors, emphasizing the importance of understanding their tolerability profiles to enhance patient adherence and clinical outcomes.

Effective management of adverse events (AEs) associated with these therapies is crucial, as it can significantly improve patients' quality of life during treatment, highlighting the important role of nurses in educating patients about AEs and their management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing patient adherence to targeted therapies in renal cell carcinoma. Creel, PA.[2014]

Tivozanib is a highly potent and selective VEGF tyrosine kinase inhibitor (TKI) with a long half-life, making it a promising candidate for treating renal cell carcinoma (RCC) with potentially fewer off-target effects compared to existing TKIs.

The drug shows potential for effective combination therapies, which could lead to better treatment outcomes for RCC patients, although its overall clinical and market relevance is still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress and contrasts of the development of tivozanib for therapy of kidney cancer. Gupta, S., Fishman, M.[2014]

The introduction of antiangiogenic agents, including sorafenib, sunitinib, bevacizumab, and temsirolimus, has significantly changed the treatment landscape for renal cell carcinoma, with approvals occurring in less than two years.

Effective management of the adverse events associated with these new treatments is crucial for maintaining patient compliance and quality of life, highlighting the need for clinicians to be well-informed about potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of side effects associated with antiangiogenic treatment in renal cell carcinoma]. Fléchon, A., Boyle, H., Négrier, S.[2018]

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 study of 988 patients with metastatic renal cell carcinoma, over 65% of those new to VEGFR-TKIs experienced anti-angiogenesis-related adverse events, with hypertension being the most common side effect.

Patients who experienced these adverse events were 1.6 times more likely to receive a lower dose intensity of their VEGFR-TKI treatment, indicating that side effects can impact the effectiveness of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of Anti-Angiogenesis-Related Adverse Events Associated with Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors (VEGFR-TKIs) in Patients with Metastatic Renal Cell Carcinoma. Lee, N., Lee, JL., Lee, JY.[2023]

In a clinical trial involving 649 patients with metastatic renal cell carcinoma, the combination of bevacizumab and interferon-alpha2a significantly improved progression-free survival (PFS) compared to placebo, with median PFS times of 10.2 months versus 5.4 months, respectively.

While bevacizumab showed efficacy in delaying disease progression, it did not provide a survival advantage and was associated with a higher incidence of serious adverse events, including bleeding, hypertension, and thromboembolic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma. Summers, J., Cohen, MH., Keegan, P., et al.[2021]

Targeted therapies have significantly changed the treatment landscape for metastatic clear cell renal cell carcinoma, with four main drugs currently available: bevacizumab, sunitinib, sorafenib, and temsirolimus.

Ongoing research is exploring new molecules and combination therapies that target key pathways involved in cancer growth, such as vascular endothelial growth factor, mammalian target of rapamycin, and the epithelial growth factor cascade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapies in metastatic renal cancer in 2009. Bastien, L., Culine, S., Paule, B., et al.[2018]

Clear-cell renal cell carcinoma is driven by the inactivation of the von Hippel-Lindau tumor suppressor gene, leading to increased vascular endothelial growth factor (VEGF) production, which promotes tumor growth and spread.

Several treatments, including sunitinib, sorafenib, bevacizumab, and temsirolimus, have shown improved clinical outcomes by targeting the pathways involved in tumor angiogenesis, and ongoing clinical trials are necessary to explore these and other potential therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting growth factor and antiangiogenic pathways in clear-cell renal cell carcinoma: rationale and ongoing trials. Hutson, TE., Sonpavde, G., Galsky, MD.[2019]

Recent advancements in treating metastatic renal cell carcinoma (mRCC) have significantly improved patient outcomes, with anti-angiogenic drugs like sunitinib, sorafenib, and bevacizumab showing increased progression-free and overall survival rates in pivotal phase III trials.

Targeted therapies for mRCC focus on two main pathways: angiogenesis and mTOR, allowing for flexible treatment strategies that can involve using these drugs alone, in combination, or sequentially to enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on the medical treatment of metastatic renal cell carcinoma. Ravaud, A., Wallerand, H., Culine, S., et al.[2008]

Citations

1. Switzerland pubmed.ncbi.nlm.nih.gov

Prediction of progression-free survival rates after bevacizumab plus interferon versus interferon alone in patients with metastatic renal cell carcinoma: comparison of a nomogram to the Motzer criteria. [2015]

2. England pubmed.ncbi.nlm.nih.gov

New treatment approaches in renal cell carcinoma. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Clinical management of metastatic kidney cancer: the role of new molecular drugs. [2021]

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

Optimizing patient adherence to targeted therapies in renal cell carcinoma. [2014]

5. England pubmed.ncbi.nlm.nih.gov

Progress and contrasts of the development of tivozanib for therapy of kidney cancer. [2014]

6. France pubmed.ncbi.nlm.nih.gov

[Management of side effects associated with antiangiogenic treatment in renal cell carcinoma]. [2018]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. [2023]

8. France pubmed.ncbi.nlm.nih.gov

Analysis of Anti-Angiogenesis-Related Adverse Events Associated with Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors (VEGFR-TKIs) in Patients with Metastatic Renal Cell Carcinoma. [2023]

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

FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma. [2021]

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

Targeted therapies in metastatic renal cancer in 2009. [2018]

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

Targeting growth factor and antiangiogenic pathways in clear-cell renal cell carcinoma: rationale and ongoing trials. [2019]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Update on the medical treatment of metastatic renal cell carcinoma. [2008]