Nivolumab + Ipilimumab Timing for Kidney Cancer

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, Nivolumab and Ipilimumab, for advanced kidney cancer. Researchers aim to determine the effectiveness of these drugs when administered at different times. Participants will begin with Nivolumab and, depending on their response, may continue with just this drug or add Ipilimumab. The trial seeks individuals with advanced kidney cancer that cannot be surgically removed and who have not previously used certain immune therapies. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that patients taking nivolumab, or a combination of nivolumab and ipilimumab, generally tolerate these treatments well, though some risks exist. Serious side effects of nivolumab can include kidney problems, lung inflammation, and digestive issues like diarrhea.

The combination of nivolumab and ipilimumab has demonstrated promising results in treating advanced kidney cancer, reducing the risk of death by 28% compared to sunitinib. However, side effects include liver inflammation in about 7% of patients, with 1.2% experiencing a severe reaction.

Overall, these treatments have been studied extensively and have proven effective and reasonably safe for many patients. It is important to consider potential side effects and consult a healthcare professional to understand their implications. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using nivolumab and ipilimumab for kidney cancer because these immunotherapy drugs work by supercharging the body's immune system to attack cancer cells more effectively. Unlike traditional chemotherapy, which directly targets and kills all rapidly dividing cells, this combination specifically boosts the immune response to target cancer cells. Nivolumab blocks the PD-1 pathway, preventing cancer cells from evading the immune system, while ipilimumab targets CTLA-4, another immune checkpoint, enhancing the immune attack on the tumor. This dual mechanism offers a novel approach that could potentially improve outcomes for patients with certain types of kidney cancer.

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

Research shows that using the drugs nivolumab and ipilimumab together can greatly help people with advanced kidney cancer. In this trial, some participants will receive this combination therapy, which studies have shown reduces the risk of death by 28% compared to sunitinib. Patients on this combination also experienced better control over tumor growth. More than half of those on this treatment had a lower risk of dying compared to those on sunitinib. These findings suggest that this treatment pair can improve survival chances for individuals with advanced kidney cancer. ^{4 5 6 7 8}

Who Is on the Research Team?

Toni K Choueiri, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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 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]

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 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]

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 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]

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]

Citations

1. opdivohcp.com opdivohcp.com/efficacy/rcc

Efficacy Data for Renal Cell Carcinoma (RCC) - Opdivo In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%) ...

2. news.bms.com news.bms.com/news/details/2024/Eight-Year-Data-for-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-Continue-to-Demonstrate-Longest-Survival-Benefit-vs.-Sunitinib-Reported-in-Patients-with-Previously-Untreated-Advanced-or-Metastatic-Renal-Cell-Carcinoma/default.aspx

Eight-Year Data for Opdivo (nivolumab) Plus Yervoy ... Patients with previously untreated advanced or metastatic renal cell carcinoma treated with Opdivo plus Yervoy experienced a 28% reduction in the risk of death ...

3. ascopubs.org ascopubs.org/doi/10.1200/CCI.24.00132

Real-World Outcomes in Patients With Metastatic Renal ... This study provides data to support the understanding of the real-world utilization and long-term effectiveness of 1L NIVO + IPI in patients with I/P-risk mRCC.

4. esmoopen.com esmoopen.com/article/S2059-7029(24)01371-1/fulltext

Nivolumab in patients with advanced renal cell carcinoma ... Assuming a 1-year survival rate of 70% (based on CheckMate 025 results), we determined that a sample size of 323 patients for the nivolumab ...

5. opdivo.com opdivo.com/advanced-kidney-cancer/clinical-trial-results/immunotherapy-combination

Clinical trial results for advanced kidney cancer (renal cell ... In the clinical trial, people given OPDIVO + YERVOY had a 37% lower risk of dying than those given SUTENT, and more than half of the people given OPDIVO + ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5568541/

Safety and Efficacy of Nivolumab in Patients With Metastatic ... Only 12% of patients with mRCC are alive at 5 years and only 1 agent has shown an improvement in overall survival (OS) in a specific subgroup of patients, ...

7. opdivohcp.com opdivohcp.com/safety/rcc

Safety Profile for Renal Cell Carcinoma (RCC) - Opdivo The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39705641/

Real-World Outcomes in Patients With Metastatic Renal ... This study provides data to support the understanding of the real-world utilization and long-term effectiveness of 1L NIVO + IPI in patients ...