Stereotactic Radiation + Immunotherapy for Kidney Cancer

(SAMURAI Trial)

Recruiting at 329 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: NRG Oncology

Must be taking: Immunotherapy

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Brain metastases, Autoimmune disease, Hypertension, Heart failure, 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: 6

Duration: 1-3 weeks for SABR, ongoing for immunotherapy

240 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding a precise type of radiation therapy, Stereotactic Ablative Radiotherapy, to standard immunotherapy can help treat kidney cancer that has spread and is not suitable for surgery. The radiation targets the main tumor more accurately, potentially reducing side effects, while immunotherapy boosts the immune system to fight the cancer. Participants with metastatic kidney cancer who cannot or choose not to have surgery might be a good fit for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on systemic treatment for an active autoimmune disease or certain other conditions, you may need to discuss this with the trial team.

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

Research has shown that combining stereotactic ablative radiation therapy (SABR) with various immune-boosting drugs is generally safe. SABR uses focused radiation to target tumors accurately, aiming to destroy cancer cells while protecting nearby healthy tissue.

For the drug avelumab, studies found it is safe to use with SABR and effective against some tough cancers. Axitinib, when used with SABR, also showed promise in early research, with manageable safety concerns, though specific side effects weren't detailed.

There is limited data on using cabozantinib with radiation, but real-world experiences suggest it can be safely combined with radiotherapy. Ipilimumab, another immune-boosting drug, has been shown to be safe with SABR, provided normal tissue is carefully monitored.

Lenvatinib, when used with SABR, was found to be safe in studies without major issues. Nivolumab and SABR together did not cause significant safety problems in trials for other conditions. Lastly, pembrolizumab combined with SABR also showed a good safety profile, with a focus on protecting normal tissue.

Overall, these treatments appear well-tolerated, with radiation offering potential benefits without major safety concerns. However, monitoring for side effects remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining stereotactic ablative body radiotherapy (SABR) with immunotherapy for kidney cancer because it could offer a new approach to enhance treatment effectiveness. Unlike standard immunotherapy regimens that rely solely on drugs like nivolumab, ipilimumab, or pembrolizumab, this method incorporates precise, high-dose radiation delivered over a short period, potentially boosting the immune response against cancer cells. This dual approach might not only target tumors more effectively but also minimize damage to surrounding healthy tissue, offering hope for better outcomes and fewer side effects compared to traditional treatments.

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

Research has shown that stereotactic ablative body radiotherapy (SABR), a special type of radiation therapy, can effectively treat kidney cancer, even when it has spread. SABR precisely targets and destroys cancer cells while minimizing harm to nearby healthy tissue. In this trial, one group of participants will receive SABR combined with immunotherapy, which helps the body's immune system fight cancer. The immunotherapy drugs used, such as nivolumab, ipilimumab, avelumab, and pembrolizumab, have been shown to support the immune system in attacking cancer cells. Additionally, drugs like axitinib, cabozantinib, and lenvatinib prevent tumors from growing by stopping the formation of new blood vessels they need. Another group will receive immunotherapy without SABR. Together, these treatments aim to shrink or control kidney cancer that cannot be surgically removed. ^{6 7 8 9 10}

Who Is on the Research Team?

William A Hall

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

Adults with unresectable or metastatic renal cell cancer, eligible for standard immunotherapy or immunotherapy-VEGF combinations. They must have adequate organ function, no severe comorbidities, and not be recommended for kidney removal surgery. Prior cancers are okay if they don't affect the trial's safety or results. Participants need to use effective contraception and provide informed consent.

Inclusion Criteria

I can care for myself but may need occasional help.

My chronic hepatitis B virus infection is under control with treatment.

My kidney tumor is 8 cm or smaller in one specific measurement.

Exclusion Criteria

I have brain metastases that are either untreated or not stable.

My kidney was exposed to radiation during my cancer treatment.

I do not have severe health issues like uncontrolled high blood pressure, recent major surgery, serious heart problems, or untreated blood clots.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive immunotherapy with or without stereotactic ablative radiation therapy (SABR) for renal cell carcinoma

1-3 weeks for SABR, ongoing for immunotherapy

Multiple visits for immunotherapy administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 years

Every 6 months for 5 years, then annually for 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• Axitinib
• Cabozantinib
• Ipilimumab
• Lenvatinib
• Nivolumab
• Pembrolizumab
• Stereotactic Ablative Radiotherapy

Trial Overview The SAMURAI study is testing if adding Stereotactic Ablative Radiation Therapy (SABR) to standard immune therapies like nivolumab improves outcomes in patients with advanced kidney cancer. SABR targets tumors precisely with high-energy photons, potentially causing less damage to healthy tissue.

How Is the Trial Designed?

Group I: Arm II (SABR, standard of care immunotherapy) Experimental Treatment 12 Interventions

Patients undergo SABR on 3 different days over 1-3 weeks and receive immunotherapy as in Arm I. Patients also undergo CT scan or MRI throughout the trial. Patients may also undergo a bone scan as clinically indicated and blood sample collection throughout the trial.

Group II: Arm I (standard of care immunotherapy) Active Control 11 Interventions

Patients receive one of the following immunotherapy regimens per physician discretion: nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes every 3 weeks for 4 doses followed by nivolumab IV over 30 minutes every 2 or 4 weeks; pembrolizumab IV over 30 minutes every 3 or 6 weeks and axitinib PO BID; avelumab IV over 60 minutes every 2 weeks and axitinib PO BID; nivolumab IV over 30 minutes every 2 or 4 weeks and cabozantinib PO QD; OR pembrolizumab IV over 30 minutes every 3 or 6 weeks and lenvatinib PO QD. Treatment with immunotherapy continues in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan or MRI throughout the trial. Patients may also undergo a bone scan as clinically indicated and blood sample collection throughout the trial.

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

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

NRG Oncology

Lead Sponsor

Trials

242

Recruited

105,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a clinical trial involving 32 patients with primary kidney cancer, stereotactic ablative body radiation therapy was successfully delivered with minimal intrafraction motion, showing a mean target displacement of only 1.3 mm during treatment.

The study demonstrated that kidney motion was not significantly affected by the presence of tumors, indicating that the treatment can be accurately administered without major adjustments for tumor-related movement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Image guidance and stabilization for stereotactic ablative body radiation therapy (SABR) treatment of primary kidney cancer. Pham, D., Kron, T., Bressel, M., et al.[2018]

Cabozantinib combined with nivolumab is shown to be superior in terms of progression-free survival (PFS) compared to axitinib + pembrolizumab and nivolumab + ipilimumab for the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC), based on a systematic review of four randomized controlled trials involving treatment-naïve patients.

While cabozantinib + nivolumab demonstrated effectiveness, the combination of lenvatinib + pembrolizumab showed numerical superiority in overall survival, indicating that while cabozantinib + nivolumab is a strong option, other combinations may also be effective and warrant consideration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma-A network meta-analysis. Focus on cabozantinib combined with nivolumab. Niewada, M., Macioch, T., Konarska, M., 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 the phase III JAVELIN Renal 101 trial, the combination of avelumab and axitinib showed improved progression-free survival (PFS) and objective response rates (ORR) compared to sunitinib across all age groups, including patients aged 75 and older, indicating its efficacy in treating advanced renal cell carcinoma (aRCC).

The safety profile of avelumab plus axitinib was consistent across different age groups, with a high incidence of grade ≥3 adverse events, suggesting that while the treatment is effective, careful monitoring for side effects is necessary, especially in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of avelumab plus axitinib in elderly patients with advanced renal cell carcinoma: extended follow-up results from JAVELIN Renal 101. Tomita, Y., Motzer, RJ., Choueiri, TK., et al.[2022]

In the phase III JAVELIN Renal 101 trial, avelumab plus axitinib demonstrated significantly improved progression-free survival (PFS) of 13.9 months compared to 8.5 months for sunitinib, indicating better efficacy in treating advanced renal cell carcinoma.

The overall survival (OS) trend also favored avelumab plus axitinib, with a hazard ratio of 0.79 compared to sunitinib, although the data is still immature and requires further follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma. Haanen, JBAG., Larkin, J., Choueiri, TK., et al.[2023]

Axitinib combined with immune checkpoint inhibitors (ICI) like pembrolizumab or avelumab is now approved for treating advanced renal cell carcinoma, but distinguishing between adverse events (AEs) caused by each treatment is crucial for optimizing therapy.

Experts identified specific AEs such as diarrhea, hepatic toxicity, fatigue, and cardiovascular issues that require unique management strategies when using axitinib-ICI combinations, emphasizing the need for careful clinical monitoring and tailored treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events. Grünwald, V., Voss, MH., Rini, BI., et al.[2021]

Targeted therapies and immune checkpoint inhibitors, such as anti-PD-1 antibodies, have significantly improved response rates and survival outcomes for patients with renal cell carcinoma compared to traditional treatments like cytokines and chemotherapy.

Combination therapies, including treatments like axitinib with pembrolizumab and nivolumab with ipilimumab, have shown promising efficacy with response rates between 70-100%, although high toxicity and costs remain challenges in their widespread use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy of Renal Cell Carcinoma]. Poprach, A., Lakomý, R., Büchler, T.[2019]

The ATLAS trial, involving 724 patients with locoregional renal cell carcinoma, found that axitinib did not significantly improve disease-free survival compared to placebo, leading to the trial's early termination due to futility.

However, in the highest-risk subgroup, axitinib showed a promising reduction in the risk of disease-free survival events, suggesting potential benefits for specific patients, despite similar rates of adverse events compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Gross-Goupil, M., Kwon, TG., Eto, M., et al.[2023]

In a study involving 28 patients undergoing stereotactic body radiation therapy (SBRT) for primary kidney cancer, no significant long-term reduction in quality of life (QoL) metrics was observed, indicating that SBRT is a safe treatment option for maintaining QoL post-therapy.

While some patients experienced a temporary decline in global QoL and fatigue at one week post-treatment, most reported stable or improved scores in pain, appetite, and nausea over time, suggesting that SBRT can lead to symptom relief and overall well-being in the months following treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported Quality of Life following Stereotactic Body Radiation Therapy for Primary Kidney Cancer - Results from a Prospective Cohort Study. Swaminath, A., Cheung, P., Glicksman, RM., et al.[2021]

The combination of avelumab and axitinib has shown superior response rates and progression-free survival in treatment-naïve patients with metastatic renal cell carcinoma compared to sunitinib, based on the Javelin 101 phase III trial.

Despite the improved response rates, there was no significant difference in overall survival after 11.6 months of follow-up, and the safety profile of avelumab/axitinib was found to be tolerable with manageable adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab and axitinib in the treatment of renal cell carcinoma: safety and efficacy. Leslie, I., Boos, LA., Larkin, J., et al.[2021]

Advanced renal cell carcinoma is resistant to many traditional therapies, but new immunotherapeutic approaches, including monoclonal antibodies and kinase inhibitors, are being explored, showing good tolerance and stable disease rates.

Two recently approved agents, a kinase inhibitor and an mTOR inhibitor, are now recommended as first-line treatments, while sorafenib is suggested for second-line therapy, highlighting the need for further research on their combinations and sequential use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current immunotherapeutic strategies in renal cell carcinoma. Amato, RJ.[2009]

The anti-PD-1 monoclonal antibody pembrolizumab has shown clinical efficacy in treating metastatic renal cell carcinoma (mRCC), making it a promising option in both first- and second-line therapies.

Combining pembrolizumab with tyrosine kinase inhibitors like axitinib is a new strategy for treating mRCC, but more research is needed to identify the best treatment combinations and to evaluate long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of renal cell carcinoma. Di Bona, C., Stühler, V., Rausch, S., et al.[2022]

The combination of axitinib and pembrolizumab shows a high response rate of 73% in patients with previously untreated advanced renal cell carcinoma, indicating strong efficacy for this treatment regimen.

This finding suggests that the dual approach of targeting both tumor growth and immune response may be effective in managing advanced kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma. [2019]

The combination of avelumab and axitinib showed promising antitumor activity in treatment-naive patients with advanced renal-cell carcinoma, with 58% of patients achieving confirmed objective responses in the study involving 55 participants.

The safety profile of the combination treatment was manageable, with adverse events similar to those seen with each drug alone, and the maximum tolerated dose was established as avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Choueiri, TK., Larkin, J., Oya, M., et al.[2022]

Citations

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Dose-response of localized renal cell carcinoma after ... This comprehensive meta-analysis of 724 patients across 22 studies evaludated the impact of BED escalation in SBRT on outcomes in primary RCC.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40907772/

Efficacy of Stereotactic Ablative Body Radiotherapy (SABR) ... SABR provides excellent oncologic outcomes, irrespective of ccRCC or nccRCC histology.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10698523/

Stereotactic ablative radiotherapy for primary renal cell ... 5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis ...

4. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00656-8/abstract

5-year outcomes after stereotactic ablative body ... The primary aim of this study was to report on long-term efficacy and safety of SABR for localised renal cell carcinoma. Methods. This study was ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0360301625061929

Efficacy of Stereotactic Ablative Body Radiotherapy (SABR) ... SABR provides excellent oncologic outcomes, irrespective of ccRCC or nccRCC histology. Introduction. Renal cell carcinoma (RCC) is divided into ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34493414/

The Phase 2 ICE-PAC Clinical Trial Avelumab with SABR demonstrated encouraging activity and acceptable toxicity in treatment-refractory mCRPC. This combination warrants further investigation.

7. europeanurology.com europeanurology.com/article/S0302-2838(21)01979-5/fulltext

Avelumab Combined with Stereotactic Ablative Body ... Avelumab combined with stereotactic ablative body radiotherapy in metastatic castration-resistant prostate cancer: the Phase 2 ICE-PAC clinical trial.

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0302283821019795

Avelumab Combined with Stereotactic Ablative Body ... Avelumab combined with SABR demonstrated encouraging activity in treatment-refractory mCRPC, with durable disease control in nearly half of the patients.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03158883

NCT03158883 | UCDCC#270: Avelumab and Stereotactic ... Stereotactic ablative radiotherapy (SAR) (also known as stereotactic body radiotherapy or SBRT) has emerged as a potentially curative treatment option for ...

10. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.6_suppl.86

ICEPAC: A phase II multicenter study of avelumab ... Avelumab with SABR demonstrated durable disease control in treatment-refractory mCRPC with an acceptable toxicity profile.