SBRT + Immunotherapy for Kidney Cancer

(CYTOSHRINK Trial)

Recruiting at 7 trial locations

Overseen By Lisa Rudd-Scott, RN BScN MN

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Ontario Clinical Oncology Group (OCOG)

Must be taking: Ipilimumab, Nivolumab

Must not be taking: Chronic corticosteroids, Herbal preparations

Disqualifiers: Large renal lesion, Auto-immune disorder, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

66 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those on chronic corticosteroids or immune suppressive therapy, except for certain low-dose or topical forms. It also excludes those using medicinal herbal preparations unless prescribed by a doctor.

What data supports the effectiveness of the treatment SBRT + Immunotherapy for Kidney Cancer?

Research shows that the combination of nivolumab and ipilimumab, which are part of the immunotherapy treatment, has been effective in treating advanced kidney cancer, producing positive responses in patients. Additionally, combining radiotherapy with immunotherapy may enhance the treatment's effectiveness. ^{1 2 3 4 5}

Is the combination of SBRT and immunotherapy safe for kidney cancer patients?

The combination of nivolumab and ipilimumab, which are types of immunotherapy, can cause immune-related side effects like colitis (inflammation of the colon), hepatitis (liver inflammation), dermatitis (skin inflammation), and thyroiditis (thyroid inflammation). Rare but serious side effects include myocarditis (heart inflammation) and pneumonitis (lung inflammation). These side effects are important to monitor and manage during treatment. ^{6 7 8 9 10}

How is the SBRT + Ipilimumab/Nivolumab treatment different for kidney cancer?

The combination of stereotactic body radiotherapy (SBRT) with the immunotherapy drugs Ipilimumab and Nivolumab is unique because it aims to enhance the immune system's ability to fight kidney cancer by potentially overcoming resistance to immunotherapy. This approach uses SBRT to improve drug delivery and activate antitumor immune cells, which may lead to better outcomes compared to using immunotherapy alone. ^{3 11 12 13 14}

What is the purpose of this trial?

This trial is testing if adding targeted radiation therapy to standard immunotherapy drugs can better treat advanced kidney cancer. It focuses on patients with advanced kidney cancer who can't have surgery. The treatment works by boosting the immune system and directly targeting the tumor with radiation. Evidence suggests that targeted radiation therapy can impact anti-tumor immune responses, and may potentially be combined with immunotherapy for synergistic effect.

Research Team

Aly-Khan Lalani, MD

Principal Investigator

Juravinski Cancer Centre

Eligibility Criteria

This trial is for adults with biopsy-proven metastatic kidney cancer, who haven't had systemic therapy for it and can lie still for at least 30 minutes. They should be at an intermediate/poor risk level and have a primary kidney lesion small enough (<20 cm) to be treated with SBRT. Patients must not have plans for nephrectomy, previous abdominal radiation that prevents SBRT use, severe autoimmune disorders, or be on chronic immune suppressive drugs.

Inclusion Criteria

My kidney cancer diagnosis was confirmed with a biopsy.

My kidney tumor can be treated with targeted radiation.

My condition is considered intermediate or poor risk.

Exclusion Criteria

I've had radiation in my abdomen that prevents further targeted radiation.

I only use herbal medicines if they are prescribed by my doctor.

I have an autoimmune disease that prevents me from taking certain cancer treatments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Induction ipilimumab combined with nivolumab every 3 weeks for cycles 1-4

12 weeks

4 visits (in-person)

Radiation (Experimental Arm)

SBRT to the primary disease in-situ, delivered between cycles 1 and 2 of I/N

1.5 weeks

5 visits (in-person)

Maintenance Treatment

Nivolumab maintenance treatment every 2 or 4 weeks until disease progression or intolerance

Until disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Clinic visits every 3 months for 1 year, then at 18 and 24 months

Treatment Details

Interventions

• Ipilimumab/Nivolumab
• SBRT

Trial Overview The study compares two approaches: one group will receive standard care ipilimumab/nivolumab (I/N) treatment alone; the other group will get I/N plus stereotactic body radiation therapy (SBRT). The goal is to see if adding SBRT improves outcomes in metastatic kidney cancer patients.

Participant Groups

Group I: Standard of Care I/N plus primary disease SBRT Experimental Treatment 1 Intervention

induction ipilimumab 1 mg/kg combined with nivolumab 3 mg/kg (I/N) every 3 weeks for one cycle, followed by SBRT to the primary disease in-situ, prior to cycle 2-4 of I/N. Patients randomized to SBRT will undergo radiation planning during the first cycle of I/N to their primary kidney mass, and then the radiation will be delivered between cycles 1 and 2 to a dose of 30-40 Gy in 5 fractions every other day over 1.5 weeks. Approximately one week following completion of SBRT, patients will start cycle 2 of immunotherapy as per standard of care. The total time elapsed between the start of cycle 1 and 2 of I/N should be no more than 6 weeks. After completion of up to four cycles of I/N, patients will proceed to standard of care maintenance treatment with nivolumab 240mg every 2 weeks or 480mg every 4 weeks until disease progression (as determined by RECIST 1.1), intolerance, or patient/physician decision to stop treatment.

Group II: Standard of Care I/N alone Active Control 1 Intervention

induction ipilimumab 1 mg/kg combined with nivolumab 3 mg/kg (I/N) every 3 weeks for cycles 1-4 followed by maintenance treatment with nivolumab 240mg every 2 weeks or 480mg every 4 weeks until disease progression (as determined by RECIST 1.1), intolerance, or patient/physician decision to stop treatment.

Ipilimumab/Nivolumab is already approved in United States, European Union, Japan, Canada for the following indications:

Approved in United States as Yervoy/Opdivo for:

• Melanoma
• Non-Small Cell Lung Cancer (NSCLC)
• Hepatocellular Carcinoma (HCC)
• Colorectal Cancer (MSI-H or dMMR)

Approved in European Union as Yervoy/Opdivo for:

• Melanoma
• Non-Small Cell Lung Cancer (NSCLC)
• Hepatocellular Carcinoma (HCC)
• Colorectal Cancer (MSI-H or dMMR)

Approved in Japan as Yervoy/Opdivo for:

• Melanoma
• Non-Small Cell Lung Cancer (NSCLC)
• Hepatocellular Carcinoma (HCC)

Approved in Canada as Yervoy/Opdivo for:

• Melanoma
• Non-Small Cell Lung Cancer (NSCLC)
• Hepatocellular Carcinoma (HCC)
• Colorectal Cancer (MSI-H or dMMR)

Who Is Running the Clinical Trial?

Ontario Clinical Oncology Group (OCOG)

Lead Sponsor

Trials

65

Recruited

42,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

In a phase 3 trial involving 1096 patients with untreated advanced renal-cell carcinoma, nivolumab plus ipilimumab significantly improved overall survival rates (75% at 18 months) compared to sunitinib (60% at 18 months), indicating a more effective treatment option for patients with intermediate or poor prognostic risk.

The objective response rate was also higher with nivolumab plus ipilimumab (42%) compared to sunitinib (27%), although both treatments had a high incidence of treatment-related adverse events, with nivolumab plus ipilimumab showing a slightly lower rate of severe (grade 3 or 4) events (46% vs. 63%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. Motzer, RJ., Tannir, NM., McDermott, DF., et al.[2022]

In a study of 45 Japanese patients with untreated metastatic renal cell carcinoma, the combination therapy of nivolumab and ipilimumab showed a 41.5% objective response rate and a median progression-free survival of 17.8 months over a 2-year follow-up period.

The 2-year analysis indicated that nivolumab plus ipilimumab therapy's effectiveness aligns with previous studies, and second-line therapy following this combination also demonstrated a 20% objective response rate with a median progression-free survival of 9.8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of nivolumab plus ipilimumab and second-line therapy in Japanese untreated patients with metastatic renal cell carcinoma: 2-year analysis from a multicenter retrospective clinical study (J-cardinal study). Kojima, T., Kato, R., Sazuka, T., et al.[2022]

In a study of 74 patients with metastatic renal cell carcinoma, adding stereotactic body radiotherapy (SBRT) to non-first-line PD-1 inhibitors and targeted agents significantly improved overall survival, with a median of 38.5 months compared to 15.4 months for those receiving only anti-PD-1/TA therapy.

The combination of SBRT with anti-PD-1/TA therapy was found to be safe and tolerable, with a similar rate of severe toxicities (54.8% in the SBRT group vs. 65.6% in the anti-PD-1/TA alone group), suggesting that this approach could be beneficial for patients, especially those with clear-cell type renal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiotherapy in combination with non-frontline PD-1 inhibitors and targeted agents in metastatic renal cell carcinoma. Liu, Y., Zhang, Z., Liu, R., et al.[2023]

In a study of 52 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, the 1-year progression-free survival rate was 55% and the overall survival rate was 75%, indicating promising efficacy of this treatment combination.

The treatment was associated with a 39% objective response rate, and while 69% of patients experienced immune-related adverse events, the incidence of severe events was lower compared to previous studies, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of first-line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study. Tanaka, T., Hatakeyama, S., Numakura, K., et al.[2021]

In a study of 69 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, those who experienced immune-related adverse events (irAEs) had significantly better overall survival (OS) and progression-free survival compared to those without irAEs, suggesting that irAEs may be a positive indicator of treatment response.

The study identified three key factors influencing OS: the presence of irAEs, C-reactive protein levels, and performance status, indicating that monitoring these factors could help predict patient outcomes in mRCC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study. Nukaya, T., Takahara, K., Yoshizawa, A., 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 a study of 46 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, 72% experienced immune-related adverse events (irAEs), which were linked to significantly longer progression-free survival (PFS) compared to those without irAEs.

While irAE development was an independent predictor of longer PFS, it did not affect overall survival (OS), suggesting that irAEs could serve as a useful prognostic marker for treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Ikeda, T., Ishihara, H., Nemoto, Y., et al.[2022]

References

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

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. [2022]

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

Real-world effectiveness of nivolumab plus ipilimumab and second-line therapy in Japanese untreated patients with metastatic renal cell carcinoma: 2-year analysis from a multicenter retrospective clinical study (J-cardinal study). [2022]

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

Stereotactic body radiotherapy in combination with non-frontline PD-1 inhibitors and targeted agents in metastatic renal cell carcinoma. [2023]

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

Tailored immunotherapy approach with nivolumab with or without nivolumab plus ipilimumab as immunotherapeutic boost in patients with metastatic renal cell carcinoma (TITAN-RCC): a multicentre, single-arm, phase 2 trial. [2023]

5. Australia pubmed.ncbi.nlm.nih.gov

Efficacy and safety of first-line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study. [2021]

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

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study. [2023]

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

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

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

Comparison of the Impact of Immune-Related Adverse Events Due to Immune Checkpoint Inhibitor Dual Combination Therapy and Immune Checkpoint Inhibitor Plus Tyrosine Kinase Inhibitor Combination Therapy in Patients with Advanced Renal Cell Carcinoma. [2023]

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

Immune Related Adverse Events: Classification and Management Approaches in Advanced Kidney Cancer. [2021]

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

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. [2022]

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

A rapid and systemic complete response to stereotactic body radiation therapy and pembrolizumab in a patient with metastatic renal cell carcinoma. [2020]

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

Survival After Combining Stereotactic Body Radiation Therapy and Tyrosine Kinase Inhibitors in Patients With Metastatic Renal Cell Carcinoma. [2022]

13. Canada pubmed.ncbi.nlm.nih.gov

Cytoreductive stereotactic body radiotherapy (SBRT) and combination SBRT with immune checkpoint inhibitors in metastatic renal cell carcinoma. [2021]

14. Egypt pubmed.ncbi.nlm.nih.gov

Combination with Stereotactic Body Radiotherapy Offers a Promising Strategy to Overcome Resistance to Immunotherapy in Advanced Renal Cell Cancer. [2020]