Cabozantinib +/− Atezolizumab for Advanced Kidney Cancer

Recruiting at 214 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Brain metastases, Autoimmune diseases, 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: 21-day cycles, repeated until disease progression or unacceptable toxicity

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial compares the effect of atezolizumab in combination with usual treatment with cabozantinib to cabozantinib alone in patients with papillary renal cell carcinoma that has spread from where it first started (primary site) to other places in the body (metastatic). Papillary renal cell carcinoma (PRCC) is a type of kidney cancer that forms in the lining of the tiny tubes in the kidney that return filtered substances that the body needs back to the blood and remove extra fluid and waste as urine. Most papillary tumors look like long, thin finger-like growths under a microscope. It is also called papillary kidney cancer or PRCC. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the tumor and may interfere with the ability of tumor cells to grow and spread. Cabozantinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply and may also prevent the growth of new blood vessels that tumors need to grow. By these actions it may help slow or stop the spread of tumor cells. Combination therapy with atezolizumab and cabozantinib may shrink the tumor and allow a longer survival time in patients with metastatic renal cell carcinoma.

Will I have to stop taking my current medications?

The trial requires that participants do not take certain medications, specifically strong CYP3A4 inhibitors and inducers, within 14 days before starting the trial and during the trial. If you are on these medications, you may need to stop or switch them, but the protocol does not specify about other medications.

Is the combination of Cabozantinib and Atezolizumab safe for humans?

Cabozantinib, when used with other drugs like nivolumab, has shown a manageable safety profile with common side effects such as diarrhea, fatigue, and skin reactions, which can be managed with medical care and dose adjustments. Atezolizumab, used for various cancers, has also been approved with a known safety profile. While specific data on the combination of Cabozantinib and Atezolizumab is not provided, both drugs have been used safely in humans for other conditions. ^{1 2 3 4 5}

How does the drug combination of Cabozantinib and Atezolizumab differ from other treatments for advanced kidney cancer?

The combination of Cabozantinib and Atezolizumab is unique because Cabozantinib is a multi-tyrosine kinase inhibitor that targets specific proteins involved in kidney cancer growth, while Atezolizumab is an immunotherapy drug that helps the immune system attack cancer cells. This combination offers a novel approach by combining targeted therapy with immunotherapy, potentially improving outcomes for patients with advanced kidney cancer. ^{2 6 7 8 9}

What data supports the effectiveness of the drugs Cabozantinib and Atezolizumab for advanced kidney cancer?

Cabozantinib has been shown to help patients with advanced kidney cancer live longer without the disease getting worse compared to another drug, sunitinib. Atezolizumab, when combined with another drug, bevacizumab, has also shown benefits in patients with a specific type of kidney cancer, helping them live longer without disease progression and improving their ability to perform daily activities. ^{2 4 6 10 11}

Who Is on the Research Team?

Benjamin L Maughan

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

Adults with advanced papillary kidney cancer that has spread, who have not had certain treatments like PD-1/PD-L1 inhibitors in the past 6 months. They must be able to swallow pills, have no major health issues affecting trial participation, and agree to use effective contraception if of reproductive potential.

Inclusion Criteria

Your liver function test should not be more than 3 times the normal level, unless the liver is affected by the tumor, in which case it should not be more than 5 times the normal level.

Your white blood cell count is at least 1.5 x 10^3 per microliter.

If I can't make decisions, my legal representative can consent for me.

Exclusion Criteria

I do not need frequent procedures to remove excess fluid from my body.

Participants must not be pregnant or nursing, due to VEGF therapy being toxic to embryogenesis. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of 'reproductive potential.' In addition to routine contraceptive methods, 'effective contraception' also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen

I am not taking, nor will I take, strong medications that affect liver enzymes while on this treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib S-malate orally once daily on days 1-21 of each 21-day cycle, with or without atezolizumab intravenously on day 1 of each cycle. Imaging and sample collection occur throughout the trial.

21-day cycles, repeated until disease progression or unacceptable toxicity

1 visit per cycle (in-person for IV administration and assessments)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months for 2 years, then every 6 months for up to 5 years.

Up to 5 years

Every 3 months for 2 years, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Cabozantinib S-malate

Trial Overview The PAPMET2 trial is comparing cabozantinib alone versus combining it with atezolizumab in patients with metastatic papillary renal cell carcinoma. The goal is to see if adding the immunotherapy agent improves outcomes compared to just the kinase inhibitor.

How Is the Trial Designed?

Group I: Arm II (cabozantinib S-malate, atezolizumab) Experimental Treatment 6 Interventions

Patients receive cabozantinib S-malate PO QD on days 1-21 and atezolizumab IV over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI and blood and urine sample collection throughout the trial. Patients may also undergo bone scan throughout the trial.

Group II: Arm I (cabozantinib S-malate) Active Control 5 Interventions

Patients receive cabozantinib S-malate 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 scan or MRI and blood and urine sample collection throughout the trial. Patients may also undergo bone scan throughout the trial.

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

Cabozantinib (Cabometyx®) is now approved as a first-line treatment for advanced renal cell carcinoma (RCC) in treatment-naïve adults, expanding its use beyond patients who have already received VEGF-targeted therapy.

In a phase 2 trial, cabozantinib significantly improved median progression-free survival and objective response rates compared to the standard treatment sunitinib, while its side effects are manageable, similar to other tyrosine kinase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use. Lyseng-Williamson, KA.[2020]

Cabozantinib is an effective multi-tyrosine kinase inhibitor approved for advanced renal cell carcinoma, showing significant benefits in progression-free and overall survival in two major clinical trials.

The phase III METEOR trial demonstrated cabozantinib's superiority over everolimus, while the phase II CABOSUN trial showed it outperformed sunitinib as a first-line treatment, highlighting its role in current treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib for the Management of Metastatic Clear Cell Renal Cell Carcinoma. Vecchio, SJD., Ellis, RJ.[2020]

In a phase 3 trial involving patients with metastatic renal cell carcinoma with sarcomatoid features, the combination of atezolizumab and bevacizumab significantly improved median progression-free survival compared to sunitinib (8.3 months vs 5.3 months).

Patients receiving the atezolizumab and bevacizumab combination also had a higher objective response rate (49% vs 14%) and reported better symptom improvements, indicating enhanced efficacy of this treatment for this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus Bevacizumab Versus Sunitinib for Patients with Untreated Metastatic Renal Cell Carcinoma and Sarcomatoid Features: A Prespecified Subgroup Analysis of the IMmotion151 Clinical Trial. Rini, BI., Motzer, RJ., Powles, T., et al.[2022]

In a phase 3 trial involving 522 patients with metastatic renal cell carcinoma, adding atezolizumab to cabozantinib did not significantly improve progression-free survival or overall survival compared to cabozantinib alone, indicating that this combination may not be effective for patients whose disease progressed after immune checkpoint inhibitors.

The combination treatment with atezolizumab and cabozantinib resulted in higher rates of serious adverse events (48% vs. 33% for cabozantinib alone), suggesting increased toxicity without clinical benefit, which raises concerns about its use outside of clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Pal, SK., Albiges, L., Tomczak, P., et al.[2023]

Atezolizumab is a monoclonal antibody that targets PD-L1, which is being developed for treating various blood cancers and solid tumors, showing promise in cancer immunotherapy.

It has already been approved in the US as a second-line treatment for urothelial carcinoma and is pending approval for non-small cell lung cancer, highlighting its potential efficacy in these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab: First Global Approval. Markham, A.[2019]

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]

Cabozantinib is a new multikinase inhibitor that has shown superior efficacy compared to everolimus in treating metastatic renal cell carcinoma (RCC) in a randomized phase III study, indicating its effectiveness for patients who have already undergone antiangiogenic therapy.

The safety profile of cabozantinib is comparable to other multikinase inhibitors used for RCC, suggesting it has a similar risk of side effects while providing effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib use in renal cell carcinoma. Neuwelt, AJ., Mathur, S., Johnson, AT., et al.[2021]

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 phase 3 trial involving 658 patients with advanced renal cell carcinoma, cabozantinib significantly improved overall survival (21.4 months) compared to everolimus (16.5 months), indicating its efficacy as a treatment option.

Cabozantinib also demonstrated better progression-free survival and objective response rates, but it was associated with more frequent severe adverse events like hypertension and diarrhea, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Choueiri, TK., Escudier, B., Powles, T., et al.[2022]

In a phase 3 trial involving 658 patients with metastatic renal-cell carcinoma, cabozantinib significantly improved progression-free survival (7.4 months) compared to everolimus (3.8 months), indicating its greater efficacy after VEGFR-targeted therapy.

Cabozantinib also showed a higher objective response rate (21% vs. 5% for everolimus) and a lower risk of progression or death (42% reduction), although both treatments had similar rates of treatment discontinuation due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. Choueiri, TK., Escudier, B., Powles, T., et al.[2022]

Cabozantinib, a tyrosine kinase inhibitor, has shown significant efficacy in treating metastatic renal cell carcinoma (RCC), demonstrating improved response rates, progression-free survival, and overall survival compared to everolimus in the METEOR trial.

In the CABOSUN trial, cabozantinib outperformed sunitinib in progression-free survival for untreated metastatic RCC patients, indicating its potential as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib for the treatment of kidney cancer. Abdelaziz, A., Vaishampayan, U.[2020]

Citations

1. New Zealand pubmed.ncbi.nlm.nih.gov

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use. [2020]

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

Cabozantinib for the Management of Metastatic Clear Cell Renal Cell Carcinoma. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Atezolizumab plus Bevacizumab Versus Sunitinib for Patients with Untreated Metastatic Renal Cell Carcinoma and Sarcomatoid Features: A Prespecified Subgroup Analysis of the IMmotion151 Clinical Trial. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Atezolizumab: First Global Approval. [2019]

6. Netherlands pubmed.ncbi.nlm.nih.gov

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

7. Spain pubmed.ncbi.nlm.nih.gov

Cabozantinib use in renal cell carcinoma. [2021]

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

Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. [2022]

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

Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Cabozantinib for the treatment of kidney cancer. [2020]