Nivolumab + Ipilimumab Timing for Kidney Cancer

Recruiting at 7 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Toni Choueiri, MD

Must not be taking: Checkpoint inhibitors, Immunosuppressants, RANKL inhibitors

Disqualifiers: Active metastases, Autoimmune disease, Severe infections, Cardiovascular disease, 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: 13

85 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing two drugs, Nivolumab and Ipilimumab, to treat advanced kidney cancer. These drugs help the immune system fight cancer cells. The study aims to find better treatment strategies for patients who do not respond well to standard treatments. Nivolumab and Ipilimumab have been used in combination to treat various cancers, including metastatic melanoma and advanced renal cell carcinoma, showing promising results in improving patient outcomes.

Do I need to stop my current medications to join the trial?

The trial requires stopping certain medications before starting, such as small molecule kinase inhibitors and some immunosuppressive drugs, at least 2-4 weeks prior. However, some medications like low-dose steroids and certain topical treatments are allowed. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for kidney cancer?

The combination of nivolumab and ipilimumab has been shown to improve survival in patients with advanced renal cell carcinoma, with more patients responding to the treatment and experiencing longer progression-free survival compared to those receiving sunitinib. This was demonstrated in a phase III trial and supported by real-world data from the Canadian Kidney Cancer Information System. ^{1 2 3 4 5}

Is the combination of Nivolumab and Ipilimumab safe for humans?

The combination of Nivolumab (Opdivo) and Ipilimumab (Yervoy) has been studied for safety in patients with advanced kidney cancer. Some patients may experience immune-related side effects, which are reactions where the immune system attacks normal organs and tissues. These side effects can vary in severity, so it's important to discuss potential risks with your healthcare provider. ^{1 6 7 8 9}

How is the drug combination of nivolumab and ipilimumab unique for kidney cancer?

The combination of nivolumab and ipilimumab is unique for treating advanced kidney cancer because it uses two drugs that help the immune system attack cancer cells more effectively, leading to better survival rates and fewer side effects compared to the standard drug sunitinib. ^{1 2 3 10 11}

Research Team

Toni K Choueiri, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults with advanced kidney cancer, including those who haven't had their cancer surgically removed or have metastatic RCC. Participants can be new or previously treated but not with certain immune checkpoint inhibitors. They must have measurable disease, good organ function, and provide a tissue sample. Women of childbearing age need a negative pregnancy test and agree to use contraception.

Inclusion Criteria

I may or may not have had previous cancer treatments, including adjuvant therapy.

My cancer can be measured by scans according to RECIST 1.1.

My recent tests show my organs are functioning well.

Exclusion Criteria

I haven't taken steroids or immunosuppressants for an autoimmune disease in the last 6 months.

I have a serious wound or ulcer that is not healing.

Your heart's electrical activity, as measured by a test, is too slow.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Initial primary treatment with Nivolumab IV every 2 weeks, with serial imaging assessments every 8 weeks

7 months

Every 2 weeks (in-person)

Arm A: Observation

Patients with persistent response to induction nivolumab are observed with serial imaging every 8 weeks. Nivolumab is resumed if progressive disease develops.

12 months

Every 8 weeks (in-person)

Arm B: Combination Therapy

Patients with SD/PD to induction nivolumab receive combination therapy with nivolumab and ipilimumab, followed by nivolumab alone until disease progression.

22 months

Every 3 weeks (in-person) for combination, then every 4 weeks (in-person) for nivolumab alone

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ipilimumab
• Nivolumab

Trial Overview The OMNIVORE Study is testing the timing and effectiveness of two drugs, Nivolumab and Ipilimumab, in treating advanced renal cell carcinoma (RCC). The study aims to optimize how these drugs are administered based on patient response to treatment.

Participant Groups

Group I: Overall cohort: Initial Primary Treatment with Nivolumab (induction phase) Experimental Treatment 1 Intervention

* Therapy with nivolumab IV every 2 weeks * Serial imaging assessments every 8 weeks * After confirmatory scans, patients are assigned to Arm A or Arm B.

Group II: Arm B: Nivolumab+Ipilimumab then nivolumab alone (for patients with SD/PD to induction nivolumab) Experimental Treatment 2 Interventions

Patients with confirmed SD/PD to induction nivolumab are allocated to Arm B (Combination Therapy Arm). * In combination therapy, patients received nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for two doses. * After then nivolumab will be continued at 480 mg IV every 4 weeks until disease progression. * Arm B patients undergo imaging at 12 weeks and then every 8 weeks.

Group III: Arm A: Observation Arm (for patients with persistent response to induction nivolumab) Experimental Treatment 2 Interventions

Patients with persistent response (complete or partial response) to induction nivolumab are assigned to Arm A (Observation Arm). * Patients discontinued nivolumab after allocation to Arm A. * Serial imaging assessments every 8 weeks. * If scans persistently show PR/CR, patients remained on observation. * If progressive disease develops, therapy with nivolumab (480 mg IV every 4 weeks) will be resumed. * If there is subsequent progression on nivolumab monotherapy, ipilimumab (1 mg/kg IV every 3 weeks x 2 doses) is added. * If progression after nivolumab + ipilimumab, therapy discontinued. If SD/PR/CR, nivolumab is continued until progression.

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

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Toni Choueiri, MD

Lead Sponsor

Trials

3

Recruited

120+

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

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

In a real-world study of 195 patients with metastatic renal cell carcinoma (mRCC) treated with ipilimumab plus nivolumab, the estimated median overall survival was 54.5 months, indicating a significant survival benefit similar to that seen in clinical trials.

The treatment was generally well-tolerated, but 45% of patients discontinued due to disease progression and 18% due to toxicity, with colitis being the most common adverse event, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilization and Safety of Ipilimumab Plus Nivolumab in a Real-World Cohort of Metastatic Renal Cell Carcinoma Patients. Thana, M., Basappa, NS., Ghosh, S., et al.[2022]

In a phase III trial, the combination of nivolumab and ipilimumab resulted in a higher response rate (over 41%) compared to sunitinib (26.5%) in patients with intermediate or high-risk renal cell carcinoma.

Patients treated with the immunotherapy combination not only had longer progression-free survival but also experienced fewer side effects, indicating a potentially safer and more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checkpoint Inhibitor Combo Effective for RCC. [2019]

In a pooled analysis of 410 patients with advanced clear cell renal cell carcinoma, nivolumab plus ipilimumab showed a modest objective response rate of 12.6% in patients who did not respond to prior nivolumab treatment, indicating that a small subset may still benefit from this combination therapy.

The study found that the overall survival rate at three years was 59%, suggesting that while the response to salvage therapy is limited, the combination can still provide significant long-term survival benefits for some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma. McKay, RR., Leucht, K., Xie, W., et al.[2023]

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 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 35 patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab, 62.9% experienced immune-related adverse events, which were associated with significantly longer progression-free and overall survival rates.

The presence of immune-related adverse events, particularly skin reactions, was identified as an independent predictor of better clinical outcomes, suggesting that these events could serve as effective biomarkers for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-related adverse events are clinical biomarkers to predict favorable outcomes in advanced renal cell carcinoma treated with nivolumab plus ipilimumab. Ueda, K., Suekane, S., Kurose, H., et al.[2022]

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]

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]

A patient on hemodialysis with advanced clear-cell renal cell carcinoma successfully received combined immune checkpoint blockade therapy with nivolumab and ipilimumab, showing no significant immune-related adverse events.

This case supports the safety and efficacy of using nivolumab and ipilimumab in patients on hemodialysis, suggesting that renal function does not significantly impact the treatment's pharmacokinetics or safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and ipilimumab immunotherapy for hemodialysis patients with advanced renal cell carcinoma. Kobayashi, Y., Arai, H., Honda, M.[2023]

In a study of 41 patients with metastatic renal cell carcinoma treated with nivolumab and ipilimumab, deferred cytoreductive nephrectomy led to significant tumor shrinkage in both primary kidney and metastatic lesions, with 86% of patients showing at least 30% reduction.

Patients who underwent deferred nephrectomy had a higher overall survival rate (100% at 1 year) compared to those who had upfront nephrectomy (72.4%) or no nephrectomy (58.2%), suggesting a potential therapeutic benefit of this approach after immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Yoshino, M., Ishihara, H., Nemoto, Y., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. [2021]

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

Utilization and Safety of Ipilimumab Plus Nivolumab in a Real-World Cohort of Metastatic Renal Cell Carcinoma Patients. [2022]

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

Checkpoint Inhibitor Combo Effective for RCC. [2019]

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

A Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma. [2023]

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

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

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

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

7. England pubmed.ncbi.nlm.nih.gov

Immune-related adverse events are clinical biomarkers to predict favorable outcomes in advanced renal cell carcinoma treated with nivolumab plus ipilimumab. [2022]

8. 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]

9. 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]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Nivolumab and ipilimumab immunotherapy for hemodialysis patients with advanced renal cell carcinoma. [2023]

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

Therapeutic role of deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. [2022]