Pembrolizumab Combinations for Bladder Cancer

Recruiting at 27 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Intravesical chemotherapy, Immunotherapy

Disqualifiers: Muscle-invasive cancer, Active infection, Autoimmune 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 24 months

320 Participants Needed

Trial Summary

What is the purpose of this trial?

In this study, participants with high risk non-muscle-invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette Guerin (BCG) therapy and who are considered ineligible for or have refused to undergo radical cystectomy, will receive pembrolizumab therapy or pembrolizumab in combination with other investigational agents. The primary study hypothesis is that treatment with pembrolizumab will result in a clinically meaningful response.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot have received chemotherapy, targeted therapy, or radiation therapy within 2 weeks before starting the study treatment, and you must not have received intravesical chemotherapy or immunotherapy after your most recent cystoscopy or TURBT.

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

The trial protocol does not specify if you need to stop your current medications. However, you cannot have received chemotherapy, targeted therapy, or radiation therapy within 2 weeks before starting the study treatment.

What data supports the idea that Pembrolizumab Combinations for Bladder Cancer is an effective drug?

The available research shows that pembrolizumab is effective for treating bladder cancer in several ways. It has been approved by the FDA for patients with a specific type of bladder cancer that doesn't respond to other treatments and who can't or don't want to have surgery. Studies also show that when combined with other drugs like gemcitabine and cisplatin, pembrolizumab can be used before surgery to help treat muscle-invasive bladder cancer. Additionally, pembrolizumab has been found to be beneficial as a second-line treatment for advanced bladder cancer, especially after initial chemotherapy. This suggests that pembrolizumab can be a valuable option for patients with different stages and types of bladder cancer. ^{1 2 3 4 5}

What data supports the effectiveness of the drug pembrolizumab for bladder cancer?

Pembrolizumab has been approved by the FDA for treating certain types of bladder cancer that do not respond to other treatments, and studies have shown it can improve survival in patients with advanced bladder cancer. ^{1 2 3 4 5}

What safety data is available for pembrolizumab in bladder cancer treatment?

Safety data for pembrolizumab in bladder cancer treatment includes its approval by the FDA for BCG-unresponsive, high-risk, non-muscle invasive bladder cancer, indicating an acceptable safety profile. Studies have evaluated immune-related adverse events (irAEs) in patients with advanced urothelial carcinoma treated with pembrolizumab, showing a relationship between irAEs and clinical outcomes. Research on older patients with chemoresistant urothelial carcinoma assessed the safety of pembrolizumab using real-world data. Additionally, pembrolizumab combined with lenvatinib demonstrated acceptable safety in patients with platinum-refractory urothelial carcinoma. Lastly, pembrolizumab was studied as neoadjuvant therapy before radical cystectomy in muscle-invasive bladder carcinoma, further contributing to its safety data. ^{3 5 6 7 8}

Is pembrolizumab safe for humans?

Pembrolizumab has been shown to have acceptable safety in patients with various types of bladder cancer, including those who are older or have advanced conditions. Some patients may experience immune-related side effects, which are reactions where the immune system attacks normal cells, but these are generally manageable. ^{3 5 6 7 8}

Is the drug Pembrolizumab a promising treatment for bladder cancer?

Yes, Pembrolizumab is a promising drug for bladder cancer. It has been approved by the FDA for certain types of bladder cancer that don't respond to other treatments. It has shown benefits in improving survival rates in advanced bladder cancer and is effective for patients who can't use standard chemotherapy. It is also being tested in combination with other treatments to enhance its effectiveness. ^{3 5 8 9 10}

How is the drug pembrolizumab unique for treating bladder cancer?

Pembrolizumab is unique because it is an immunotherapy drug that helps the body's immune system fight cancer by targeting a specific protein called PD-1, which can help stop cancer cells from hiding from the immune system. It is particularly used for patients with bladder cancer who cannot undergo surgery or are not responding to other treatments like BCG or platinum-based chemotherapy. ^{3 5 8 9 10}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with high-risk bladder cancer that hasn't spread into the muscle, who didn't respond to BCG therapy and can't or won't have their bladder removed. They need good organ function, no recent other treatments or active infections, and must agree to use contraception.

Inclusion Criteria

My cancer was completely removed surgically.

I cannot or will not undergo major bladder surgery.

I am a woman who can have children, not pregnant, and willing to use birth control.

Exclusion Criteria

I have received a transplant from another person.

I have no progressing cancer except skin cancer or treated in situ cervical or prostate cancer.

I have been treated with drugs targeting immune checkpoints.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab or pembrolizumab in combination with other investigational agents every 3 weeks for up to 24 months

24 months

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term Follow-up

Participants are monitored for progression-free survival and overall survival

60 months

Treatment Details

Interventions

• Pembrolizumab

Trial Overview The study tests pembrolizumab alone or combined with other investigational drugs in patients whose bladder cancer remains after BCG treatment. The goal is to see if these therapies can effectively treat the cancer without surgery.

Participant Groups

Group I: Pembrolizumab coformulation Experimental Treatment 2 Interventions

Participants with CIS with or without papillary tumors (Cohort C) will receive either pembrolizumab/vibostolimab or favezelimab/pembrolizumab coformulation intravenously Q3W for up to 24 months

Group II: Pembrolizumab Experimental Treatment 1 Intervention

Participants with carcinoma-in-situ (CIS) with or without papillary tumors (Cohort A) and participants with papillary tumors only, without CIS (Cohort B) will receive pembrolizumab, 200 mg, intravenously, every 3 weeks (Q3W) for up to 24 months.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

Engineering degree from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

J.D. from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a study comparing 121 patients treated with pembrolizumab to 67 patients receiving conventional chemotherapy for advanced urothelial carcinoma, pembrolizumab showed a significant improvement in overall survival with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death compared to chemotherapy.

Despite the older age and poorer health status of patients receiving pembrolizumab, the treatment demonstrated a clinical benefit over traditional chemotherapy, suggesting its effectiveness as a second-line therapy in real-world settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of pembrolizumab with conventional chemotherapy after first-line platinum-based chemotherapy for advanced urothelial carcinoma in real-world practice: A multicenter retrospective study. Narita, T., Hatakeyama, S., Numakura, K., et al.[2021]

In a study of 164 patients with metastatic urothelial carcinoma who received pembrolizumab as second-line therapy, nearly 46% were found to be ineligible based on KEYNOTE-045 trial criteria, primarily due to low hemoglobin levels.

The results indicated that ineligible patients had similar overall survival and progression-free survival compared to eligible patients, suggesting that pembrolizumab remains effective even in those who do not meet traditional trial criteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of pembrolizumab in trial-ineligible patients with metastatic urothelial carcinoma. Fukuokaya, W., Yanagisawa, T., Hashimoto, M., et al.[2023]

Pembrolizumab (Keytruda) has been approved by the FDA for treating high-risk, non-muscle invasive bladder cancer (NMIBC) in patients who are unresponsive to BCG therapy and are either ineligible for or have opted not to undergo cystectomy.

This approval specifically targets patients with carcinoma in situ (CIS) with or without papillary tumors, highlighting its role as a treatment option for those with limited surgical options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. Wright, KM.[2021]

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]

In the PURE-01 study involving 50 patients with muscle-invasive bladder carcinoma, neoadjuvant treatment with pembrolizumab resulted in a pathologic complete response (pT0) in 42% of patients, demonstrating its efficacy as a pre-surgery immunotherapy.

The study found that patients with high PD-L1 expression (CPS ≥ 10%) had a significantly higher rate of pT0 (54.3%) compared to those with lower expression (13.3%), suggesting that pembrolizumab may be particularly effective in patients with PD-L1-positive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. Necchi, A., Anichini, A., Raggi, D., et al.[2021]

In a study of 105 advanced urothelial carcinoma patients treated with pembrolizumab, those who experienced immune-related adverse events (irAEs) had significantly better clinical outcomes, including higher objective response rates and longer overall survival compared to those without irAEs.

An increase in the relative eosinophil count (REC) three weeks after starting pembrolizumab was not linked to the occurrence of irAEs, suggesting that while irAEs are associated with improved survival, changes in REC may not be a reliable predictor of irAE incidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Immune-Related Adverse Events and Efficacy and Changes in the Relative Eosinophil Count Among Patients with Advanced Urothelial Carcinoma Treated by Pembrolizumab. Furubayashi, N., Minato, A., Negishi, T., et al.[2022]

In a study of 608 patients with advanced urothelial carcinoma treated with pembrolizumab, the overall survival was similar for patients aged under 75 (7.8 months) and those aged 75 and older (10.4 months), indicating that age does not significantly impact treatment efficacy.

Older patients (≥75 years) experienced a higher rate of any-grade adverse events (55.3%) compared to younger patients (<75 years, 41.9%), suggesting that while pembrolizumab is effective across age groups, older patients may require closer monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pembrolizumab for older patients with chemoresistant urothelial carcinoma assessed using propensity score matching. Nishiyama, N., Kobayashi, T., Narita, S., et al.[2022]

In a phase 3 study involving 487 patients with advanced urothelial carcinoma, the combination of pembrolizumab and lenvatinib did not show improved progression-free survival (4.5 months) or overall survival (11.8 months) compared to pembrolizumab with placebo.

The combination treatment resulted in a higher rate of severe adverse events (51%) compared to the placebo group (27%), leading to the conclusion that the benefit-to-risk ratio was not favorable for using lenvatinib with pembrolizumab as first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. Matsubara, N., de Wit, R., Balar, AV., et al.[2023]

In the Phase III KEYNOTE-045 trial, pembrolizumab significantly improved overall survival in patients with second-line metastatic urothelial carcinoma compared to standard treatments like docetaxel, paclitaxel, and vinflunine.

Early results from the Phase II KEYNOTE-052 trial suggest that pembrolizumab is effective for first-line treatment in patients with metastatic urothelial carcinoma who are not eligible for cisplatin, leading to its FDA approval for these indications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the treatment of advanced urothelial cancer. Lundgren, KT., Farina, MS., Bellmunt, J.[2018]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Comparison of pembrolizumab with conventional chemotherapy after first-line platinum-based chemotherapy for advanced urothelial carcinoma in real-world practice: A multicenter retrospective study. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Effectiveness of pembrolizumab in trial-ineligible patients with metastatic urothelial carcinoma. [2023]

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

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. [2021]

4. 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]

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

Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. [2021]

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

Association Between Immune-Related Adverse Events and Efficacy and Changes in the Relative Eosinophil Count Among Patients with Advanced Urothelial Carcinoma Treated by Pembrolizumab. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pembrolizumab for older patients with chemoresistant urothelial carcinoma assessed using propensity score matching. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the treatment of advanced urothelial cancer. [2018]

10. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]