Nivolumab +/− Ipilimumab Before Surgery for Bladder Cancer

Recruiting at 8 trial locations

Overseen By Scott Niglio, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Corticosteroids, Immunosuppressives, Checkpoint inhibitors, others

Disqualifiers: Autoimmune disease, Heart failure, Stroke, 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: 5

Duration: 10 weeks

45 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test if immunotherapy with nivolumab alone or in combination with ipilimumab is safe and does not delay the planned bladder cancer surgery. The investigators want to see if treatment with these drugs prior to surgery may decrease the size of the bladder cancer and thus could help make the surgery more successful.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic corticosteroids or other immunosuppressive medications, you must stop them at least 14 days before starting the study treatment.

What data supports the effectiveness of the drug combination Nivolumab and Ipilimumab before surgery for bladder cancer?

Research shows that using Nivolumab and Ipilimumab before surgery in patients with advanced bladder cancer led to a complete response in 46% of patients, meaning no signs of cancer were found in the tissue removed during surgery. This suggests that the combination of these drugs can be an effective pre-surgery treatment option. ^{1 2 3 4 5}

Is the combination of Nivolumab and Ipilimumab safe for use before bladder cancer surgery?

In a trial with patients having advanced bladder cancer, 55% experienced severe immune-related side effects from the combination of Nivolumab and Ipilimumab, but the safety profile was considered acceptable in early trials, with severe side effects ranging from 6% to 41% in similar studies. ^{4 6 7 8 9}

How is the drug combination of Nivolumab and Ipilimumab unique for treating bladder cancer?

The combination of Nivolumab and Ipilimumab is unique because it uses two immune checkpoint inhibitors to enhance the body's immune response against cancer cells, which is different from traditional chemotherapy that directly targets cancer cells. This approach has shown promising results in other cancers like lung and kidney cancer, making it a novel option for bladder cancer treatment. ^{10 11 12 13 14}

Research Team

Scott Niglio, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with bladder cancer who can't have chemotherapy. They must have a certain type of bladder cancer that hasn't spread beyond the pelvis and be fit for surgery. People with prior systemic cancer treatments, active autoimmune diseases needing steroids, recent heart attacks or strokes, HIV/AIDS, or those unwilling to use contraception are excluded.

Inclusion Criteria

My bladder cancer diagnosis is mainly urothelial.

You are not eligible if you have moderate to severe kidney function, hearing loss, peripheral neuropathy, or if there is not enough tumor tissue available for testing. You must also be fit for surgery, be at least 18 years old, and have a certain level of physical ability.

Before joining the study, your blood tests need to show specific levels of white blood cells, platelets, bilirubin, and liver enzymes. If you are taking blood-thinning medication, your dose should be consistent.

Exclusion Criteria

I've had chemotherapy for bladder cancer, including treatments to boost my immune system.

I am a male willing to use contraception during and for 31 weeks after treatment.

You are being held against your will for treatment of a mental or physical illness.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive immunotherapy with nivolumab alone or in combination with ipilimumab prior to surgery

10 weeks

5 visits (in-person) for Cohort 1, 3 visits (in-person) for Cohort 3, 4 visits (in-person) for Cohort 2

Surgery

Planned bladder cancer surgery to assess the effect of the immunotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment and surgery

4-8 weeks

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Radical cystectomy

Trial Overview The study tests if immunotherapy drugs Nivolumab alone or combined with Ipilimumab are safe before surgery without delaying it. The goal is to see if these drugs shrink the tumor to aid surgical success in bladder cancer patients.

Participant Groups

Group I: Cohort U (UTUC patients) is independent from Cohorts 1 - 3. ( who are cisplatin-ineligible) Experimental Treatment 3 Interventions

Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg on day 1, of each cycle, followed by Nivolumab 3 mg/kg on day 22 and Ipilimumab 3mg/kg and Nivolumab 1mg/kg on day 45.

Group II: Cohort 3 Experimental Treatment 3 Interventions

Ipilimumab 3 mg/kg on day 1 each cycle and Nivolumab 1 mg/kg on day 1 of each cycle for a total of 3 cycles. Each cycle will be three weeks long and treatment will occur during weeks 0, 3, and 6.

Group III: Cohort 2 Experimental Treatment 3 Interventions

Ipilimumab 3 mg/kg and Nivolumab 1 mg/kg on day 1 of each cycle, followed by Nivolumab 3 mg/kg on day 22 of each cycle for a total of 2 cycles. Each cycle will be six weeks long. Ipilimumab and Nivolumab will occur on weeks 0 and 6 while Nivolumab alone will occur on weeks 3 and 9.

Group IV: Cohort 1 Experimental Treatment 2 Interventions

Nivolumab 3 mg/kg on day 1 of each cycle for a total of 5 cycles. Each cycle will be two weeks long and treatment will occur during weeks 0, 2, 4, 6, and 8.

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

In a study of 39 patients with muscle-invasive bladder cancer, the combination of gemcitabine, cisplatin, and the immune checkpoint inhibitor pembrolizumab was effective, achieving pathologic downstaging in 56% of patients and complete pathologic response in 36%.

The treatment was generally safe, with common side effects including thrombocytopenia, anemia, and neutropenia, but no severe immune-related adverse events were reported, indicating a manageable safety profile for this neoadjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. Rose, TL., Harrison, MR., Deal, AM., et al.[2022]

Immune checkpoint inhibitors (ICIs) have shown promising efficacy and low toxicity in the neoadjuvant treatment of muscle invasive bladder cancer (MIBC), suggesting they could be a beneficial option compared to traditional chemotherapy.

However, results from large trials in the adjuvant setting have been conflicting, and there is a need for more long-term survival and toxicity data to fully understand the benefits of ICIs in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Perioperative Immune Checkpoint Inhibitors in Muscle Invasive Bladder Cancer. Chhaya, S., Watts, I., Ng, K., et al.[2023]

Immunotherapy using immune checkpoint inhibitors has shown promise in treating muscle-invasive bladder cancer, both in neoadjuvant (before surgery) and adjuvant (after surgery) settings, with studies like PURE and ABACUS demonstrating their effectiveness in certain patient groups.

A Phase III study (CheckMate 247) indicated that adjuvant nivolumab therapy can be beneficial for high-risk urothelial cancer patients post-chemotherapy, achieving similar pathologic complete response rates as traditional cisplatin-based chemotherapy, suggesting a potential alternative for patients who cannot tolerate chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant or adjuvant immunotherapy in bladder cancer: biological opportunity or clinical utility? Petrelli, F., Perego, G., Vavassori, I., et al.[2022]

In a trial involving 24 patients with stage III urothelial cancer, 96% were able to undergo surgery within 12 weeks after receiving preoperative immunotherapy with ipilimumab and nivolumab, demonstrating the treatment's feasibility.

The combination therapy resulted in a 46% rate of pathological complete response (pCR) and 58% of patients had no remaining invasive disease, suggesting that this approach is effective regardless of the patients' baseline CD8+ T cell levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. van Dijk, N., Gil-Jimenez, A., Silina, K., et al.[2022]

Cisplatin-based chemotherapy is currently the standard treatment for muscle-invasive bladder cancer, but recent studies suggest that immune checkpoint inhibitors may offer a promising alternative with better safety and efficacy, especially in patients with higher disease stages and specific biomarkers.

Pathological responses to immunotherapy have been particularly encouraging in patients with high PD-L1 expression and certain gene signatures, indicating that biomarker selection could enhance treatment outcomes in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Immunotherapy: The Next Gold Standard Before Radical Surgery for Urothelial Cancer. Raggi, D., Moschini, M., Necchi, A.[2022]

In a study of 95 patients with muscle-invasive bladder cancer receiving two cycles of neoadjuvant atezolizumab before surgery, 44% experienced treatment-related adverse events, but no surgeries were delayed due to these toxicities.

The use of neoadjuvant atezolizumab was found to be well tolerated, with surgical complication rates not significantly impacted, indicating its safety in the pre-surgical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and Surgical Complication Rates of Neoadjuvant Atezolizumab in Patients with Muscle-invasive Bladder Cancer Undergoing Radical Cystectomy: Updated Safety Results from the ABACUS Trial. Szabados, B., Rodriguez-Vida, A., Durán, I., et al.[2022]

In a retrospective study of 31 patients with locally advanced or metastatic bladder cancer, the combination of tislelizumab and chemotherapy (TGC) showed a median progression-free survival (PFS) of 36 weeks, significantly better than the 29 weeks observed with chemotherapy alone (GC).

While TGC treatment resulted in a higher incidence of grade ≥3 treatment-related adverse events (35.7% vs 23.5% for GC), this increase was not statistically significant, indicating that TGC is generally well tolerated while providing promising antitumor activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab in combination with gemcitabine plus cisplatin chemotherapy as first-line adjuvant treatment for locally advanced or metastatic bladder cancer: a retrospective study. Ren, X., Tian, Y., Wang, Z., et al.[2022]

Thirteen clinical trials are currently investigating the use of immune checkpoint inhibitors as a treatment for high-risk non-muscle-invasive bladder cancer, particularly in patients who have not responded to Bacillus Calmette-Guérin (BCG) therapy.

Preliminary results from trials like SWOG S1605 and Keynote-057 indicate that checkpoint inhibitors, such as Pembrolizumab, show promising antitumor activity and are generally well-tolerated, suggesting they could be a viable alternative for patients with BCG-unresponsive bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoints inhibitors in the management of high-risk non-muscle-invasive bladder cancer. A scoping review. García-Perdomo, HA., Sánchez, AL., Spiess, PE.[2022]

Neoadjuvant immunotherapy using immune checkpoint inhibitors (ICIs) like anti-PD-(L)1 and anti-CTLA-4 antibodies shows promising efficacy in localized muscle-invasive bladder cancer, with pathological complete response rates between 31% and 46%.

The safety profile of these treatments is generally acceptable, with severe adverse events reported in 6% to 41% of patients, indicating that while there are risks, the potential benefits warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer. Peyrottes, A., Ouzaid, I., Califano, G., et al.[2021]

Nivolumab, an anti-PD-1 antibody, was administered to a 63-year-old female patient with metastatic melanoma after renal transplantation, highlighting the potential for anti-tumor activity in high-risk patients, despite the challenges of concurrent immunosuppression.

The patient experienced acute renal allograft rejection and renal failure shortly after starting nivolumab, indicating significant risks associated with this treatment in transplant recipients, but she later showed a positive clinical response after re-challenging with nivolumab while on hemodialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. Ong, M., Ibrahim, AM., Bourassa-Blanchette, S., et al.[2023]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

In a study of 44 patients with resectable stage IB to IIIA non-small cell lung cancer, both neoadjuvant chemotherapy combined with nivolumab and with ipilimumab showed high surgical resection rates, with 100% of patients in the nivolumab group and 90.9% in the ipilimumab group undergoing successful surgeries.

Despite the complexity of the procedures, with about half of the cases rated as challenging, the safety profile was acceptable, with 18.2% of nivolumab patients and 20% of ipilimumab patients experiencing significant complications (grade 3 or greater).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgical outcomes after chemotherapy plus nivolumab and chemotherapy plus nivolumab and ipilimumab in patients with non-small cell lung cancer. Feldman, H., Sepesi, B., Leung, CH., et al.[2023]

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]

Nivolumab (Opdivo) significantly improves overall survival and response rates in previously-treated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CheckMate 057 trial.

Nivolumab has a manageable adverse event profile and is better tolerated than docetaxel, making it a valuable treatment option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. Keating, GM.[2018]

References

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

Phase II Study of Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Role of Perioperative Immune Checkpoint Inhibitors in Muscle Invasive Bladder Cancer. [2023]

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

Neoadjuvant or adjuvant immunotherapy in bladder cancer: biological opportunity or clinical utility? [2022]

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

Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Neoadjuvant Immunotherapy: The Next Gold Standard Before Radical Surgery for Urothelial Cancer. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Toxicity and Surgical Complication Rates of Neoadjuvant Atezolizumab in Patients with Muscle-invasive Bladder Cancer Undergoing Radical Cystectomy: Updated Safety Results from the ABACUS Trial. [2022]

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

Tislelizumab in combination with gemcitabine plus cisplatin chemotherapy as first-line adjuvant treatment for locally advanced or metastatic bladder cancer: a retrospective study. [2022]

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

Immune checkpoints inhibitors in the management of high-risk non-muscle-invasive bladder cancer. A scoping review. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. [2023]

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

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. [2021]

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

Surgical outcomes after chemotherapy plus nivolumab and chemotherapy plus nivolumab and ipilimumab in patients with non-small cell lung cancer. [2023]

13. 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]

14. New Zealand pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. [2018]