Cabozantinib +/− Atezolizumab for Advanced Kidney Cancer

Recruiting at 220 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 trial tests a new combination of treatments for advanced papillary renal cell carcinoma (PRCC) that has spread to other parts of the body. It compares the effectiveness of the standard treatment, cabozantinib (a medication that blocks proteins aiding cancer cell growth), alone and with atezolizumab (an immunotherapy drug that helps the immune system attack cancer cells). Suitable participants have metastatic PRCC and have not previously received cabozantinib. The trial aims to determine if adding atezolizumab more effectively shrinks tumors and improves survival time. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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

Research has shown that cabozantinib, a treatment for advanced kidney cancer, is generally safe based on past trials. Most patients tolerate it well, though some may experience side effects such as diarrhea, tiredness, and high blood pressure, which are usually manageable.

When combined with atezolizumab, a drug that aids the immune system in fighting cancer, the safety profile remains similar. Studies have found this combination to be effective, with side effects typically mild. Common issues include fatigue, nausea, and changes in liver function, which can often be controlled with proper care.

Both treatments have been tested in advanced kidney cancer, and safety data suggest they are generally well-tolerated by most patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using cabozantinib with or without atezolizumab for advanced kidney cancer because these treatments offer new ways to fight the disease. Cabozantinib S-malate works by inhibiting tumor growth and spread through its action on multiple pathways, including VEGF, MET, and AXL, which are different from the traditional tyrosine kinase inhibitors typically used. When combined with atezolizumab, an immunotherapy drug that blocks the PD-L1 protein to help the immune system attack cancer cells, the treatment might enhance the body's natural defenses against tumors. This dual approach could potentially provide more effective results than current treatments that do not target these specific mechanisms.

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

Research has shown that cabozantinib, which participants in Arm I of this trial will receive, works well for advanced kidney cancer. It can shrink tumors and sometimes even make them disappear completely. Studies have also found that patients using cabozantinib tend to live longer. In Arm II of this trial, cabozantinib is combined with another drug, atezolizumab. However, one study found that adding atezolizumab did not help patients live longer compared to using cabozantinib alone. Both treatments are promising, but cabozantinib by itself has more consistent evidence supporting its effectiveness for kidney cancer. ^{6 7 8 9 10}

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, 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]

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]

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]

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 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]

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 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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6854754/

Cabozantinib for Renal Cell Carcinoma A phase I study in patients with advanced RCC reported in 2014 showed a promising activity in heavily pretreated patients with a partial response rate of 28% [ ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0929664625001172

Real-world study of cabozantinib treatment of advanced ... The 5-year survival rate for metastatic kidney cancer is poor (15 % in 2021 in the USA) [1,6]. Cabozantinib is an oral inhibitor of multiple ...

3. cancer.gov cancer.gov/news-events/cancer-currents-blog/2021/papillary-renal-cell-carcinoma-cabozantinib

Cabozantinib Slows Progression of Rare Kidney Cancer Two out of 44 people receiving cabozantinib (5%) had their tumors disappear entirely during treatment, known as a complete response. No complete ...

4. cabometyxhcp.com cabometyxhcp.com/rcc-treatment/monotherapy-1L/efficacy

CABOSUN study shows 1L CABOMETYX® (cabozantinib) ... CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC). CABOMETYX is indicated ...

5. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-and-its-partner-ipsen-announce-phase-3-trial-results

Exelixis and Its Partner Ipsen Announce Phase 3 Trial Results ... “Recent data from the METEOR trial confirms the benefit in median overall survival of almost 5 months that CABOMETYX can provide to patients with advanced renal ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf

CABOMETYX (cabozantinib) - accessdata.fda.gov The safety of CABOMETYX was evaluated in METEOR, a randomized, open-label trial in which 331 patients with advanced renal cell carcinoma received CABOMETYX 60 ...

7. cabometyxhcp.com cabometyxhcp.com/rcc-treatment/combo/efficacy

1L aRCC Efficacy & Safety for CABOMETYX® ... See the results from the CheckMate-9ER study - including efficacy, safety, and exploratory patient-reported quality of life data.

8. cabometyx.com cabometyx.com/kidney-cancer

Advanced Kidney Cancer Treatment Option| CABOMETYX ... ... CABOMETYX is safe and effective in children younger than 12 years of age. Indications. People with kidney cancer (renal cell carcinoma). CABOMETYX may be used:.

9. ema.europa.eu ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf

Cabometyx, INN-Cabozantinib - European Medicines Agency Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population. Hepatic ...

10. 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 ...