Stereotactic Radiation + Immunotherapy for Kidney Cancer

(SAMURAI Trial)

Recruiting at 225 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

Trial Summary

What is the purpose of this trial?

This phase II trial tests whether the addition of radiation to the primary tumor, typically given with stereotactic ablative radiation therapy (SABR), in combination with standard of care immunotherapy improves outcomes in patients with renal cell cancer that is not recommended for surgery and has spread to other places in the body (metastatic). Radiation therapy uses high energy photons to kill tumor cells and shrink tumors. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses of radiation over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab, avelumab, and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Axitinib, cabozantinib, and lenvatinib are in a class of medications called antiangiogenic agents. They work by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving SABR in combination with standard of care immunotherapy may help shrink or stabilize the cancer in patients with renal cell cancer.

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.

What data supports the effectiveness of this treatment for kidney cancer?

Research shows that the combination of axitinib and pembrolizumab has a 73% response rate in advanced kidney cancer, and the combination of avelumab and axitinib may increase the benefit compared to using these drugs alone. ^{1 2 3 4 5}

Is the combination of stereotactic radiation and immunotherapy safe for kidney cancer treatment?

The combination of avelumab and axitinib, used in treating advanced kidney cancer, has shown a tolerable safety profile with manageable side effects like diarrhea, liver issues, fatigue, and heart-related problems. These side effects are consistent with what is expected from the individual drugs used in the treatment. ^{2 6 7 8 9}

How does the treatment of stereotactic radiation combined with immunotherapy differ for kidney cancer?

This treatment is unique because it combines stereotactic radiation, which precisely targets kidney tumors, with immunotherapy drugs like Avelumab and Nivolumab that help the immune system fight cancer. This combination aims to improve outcomes by using both precise radiation and immune system activation, which is different from traditional chemotherapy or single-drug treatments. ^{10 11 12 13 14}

Research Team

William A Hall

Principal Investigator

NRG Oncology

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Arm II (SABR, standard of care immunotherapy) Experimental Treatment 8 Interventions

Patients undergo SABR on 3 different days over 1-3 weeks and receive immunotherapy as in Arm I.

Group II: Arm I (standard of care immunotherapy) Active Control 7 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.

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

2. England 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. [2023]

3. England 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. [2022]

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

Pembrolizumab for the treatment of renal cell carcinoma. [2022]

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

Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Avelumab and axitinib in the treatment of renal cell carcinoma: safety and efficacy. [2021]

7. England 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. [2021]

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

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

9. England 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. [2022]

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

Current immunotherapeutic strategies in renal cell carcinoma. [2009]

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

Image guidance and stabilization for stereotactic ablative body radiation therapy (SABR) treatment of primary kidney cancer. [2018]

12. Czech Republic pubmed.ncbi.nlm.nih.gov

[Immunotherapy of Renal Cell Carcinoma]. [2019]

13. England 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. [2021]

14. Switzerland 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. [2023]