Pembrolizumab + BCG for Bladder Cancer

Recruiting at 7 trial locations

Overseen By Eugene Pietzak, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Muscle invasive cancer, 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

Compensation: Varies

Number of Visits: 9

Duration: 48 weeks

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with high-grade bladder cancer or upper tract urothelial cancer. Researchers are testing whether combining pembrolizumab, an immune-boosting drug, with BCG, a type of immunotherapy, can be more effective than BCG alone. The trial seeks participants with high-grade cancer who have not yet tried BCG treatment and are considering alternatives to major surgery. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, providing an opportunity to explore new treatment options.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on medications for active infections, autoimmune diseases, or are receiving live vaccines, you may need to discuss this with the trial team.

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

Research shows that pembrolizumab, when used alone, effectively targets tumors in patients with high-risk bladder cancer who did not respond to BCG, a common treatment for this cancer type. This indicates that pembrolizumab generally has manageable side effects.

The FDA has already approved pembrolizumab for treating certain bladder cancers, so its safety in similar conditions is well-established. Researchers are now exploring whether combining pembrolizumab with BCG might be more effective than using each treatment alone.

Although detailed information about this specific combination is not yet available, pembrolizumab has been widely studied and is considered safe enough for testing with BCG. This trial is in Phase 2, focusing on how well patients tolerate a new treatment, making safety a key concern at this stage. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab and Bacillus Calmette-Guérin (BCG) for bladder cancer because it introduces a novel mechanism by combining an immunotherapy with a well-established vaccine. Pembrolizumab, an immune checkpoint inhibitor, enhances the body's immune response against cancer cells by blocking the PD-1 pathway, which tumors use to hide from immune attack. Meanwhile, BCG is a live vaccine that stimulates a broad immune response in the bladder. By combining these two, the treatment aims to prime and activate T cells more effectively, potentially enhancing the overall immune response against high-grade non-muscle-invasive bladder cancer. This approach could offer a more robust treatment option compared to the current standard of care that typically involves BCG alone.

What evidence suggests that pembrolizumab combined with BCG might be an effective treatment for bladder cancer?

Research shows that pembrolizumab alone has promising effects in shrinking tumors for patients with high-risk bladder cancer unresponsive to BCG treatment. Some studies found that pembrolizumab can completely eliminate tumors in certain patients with non-muscle invasive bladder cancer. In this trial, participants will receive a combination of pembrolizumab and BCG. Combining pembrolizumab with BCG has a scientific basis, as both treatments help the immune system fight cancer and might work better together. Early results suggest that this combination could enhance the body's immune response against the cancer. This approach aims to offer an effective alternative for high-risk patients when BCG alone is insufficient. ^{2 6 7 8 9}

Who Is on the Research Team?

Gopakumar Iyer, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with high-risk T1 bladder cancer or upper tract urothelial carcinoma who haven't had BCG therapy, are not candidates for certain surgeries, and have no evidence of metastasis. They must be able to consent, use birth control if applicable, and meet specific health criteria. Exclusions include recent heart attacks, major surgery within the last month, pregnancy, inability to follow procedures, live vaccines recently taken or needed soon.

Inclusion Criteria

Be willing and able to provide written informed consent/assent for the trial

I have T1 bladder cancer and have not had BCG therapy.

My bladder or urinary tract cancer was confirmed with specific tests at MSK.

Exclusion Criteria

Pregnant (positive pregnancy test) or lactating

Inability to comply with study and/or follow-up procedures

I have previously been treated with specific medications.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab (MK-3475) and BCG as first-line treatment for high-risk T1 bladder cancer or high-grade NMI-UTUC

48 weeks

9 visits (in-person) for pembrolizumab infusions, weekly visits for 6 weeks for BCG therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Bacillus Calmette-Guérin (BCG)
• Pembrolizumab (MK-3475)

Trial Overview The trial is testing pembrolizumab combined with BCG as a first-line treatment for patients with high-grade non-muscle-invasive bladder cancer at 'high risk' where BCG alone may fail. It aims to see if this combination can be an alternative to more invasive treatments like radical cystectomy.

How Is the Trial Designed?

Group I: High Risk T1 Bladder Cancer Cohort Experimental Treatment 2 Interventions

Pts will receive pembrolizumab/MK-3475 after transurethral resection of bladder tumor/TURBT in comb w/BCG as initial therapy. Pembrolizumab (MK-3475) will be administered as a 400 mg IV infusion at 6-wk intervals for 9 doses over a 48-wk period, unless there is unacceptable toxicity or other reasons to discontinue treatment occur. Intravesical BCG therapy (TICE strain, 50 mg) will be given 1x-weekly for 6 consecutive wks as a standard induction course, followed by maintenance BCG consistent w/standard clinical practice. BCG will start on wk 3 after the first infusion of pembrolizumab (400 mg) to allow for initial priming of T cells to further enhance the effects of BCG treatment.

Group II: Exploratory cohort for high-grade non-muscle-invasive upper tract urothelial carcinoma Experimental Treatment 2 Interventions

Pts will receive pembrolizumab (MK-3475) administered after ureteroscopy/laser ablation in comb w/BCG as initial therapy. Pembrolizumab (MK-3475) will be administered as 400 mg IV infusion at 6-week intervals for 9 doses over a 48-week period, unless there is unacceptable toxicity or other reasons that would warrant the discontinuation of treatment. Pts will receive once-weekly BCG therapy (TICE strain, 50 mg) for 6 consecutive wks as a standard induction course administered through a percutaneous nephrostomy tube in antegrade fashion for patients with high-grade NMI-UTUC, consistent with standard clinical practice. BCG will start on wk 3 after the first infusion of pembrolizumab (400 mg) to allow for initial priming of T cells to further enhance the effects of BCG treatment.

Bacillus Calmette-Guérin (BCG) is already approved in United States, Canada, European Union for the following indications:

Approved in United States as TheraCys for:

• Non-muscle invasive bladder cancer
• Upper tract urothelial carcinoma

Approved in Canada as Immun BCG for:

• Non-muscle invasive bladder cancer

Approved in European Union as TICE BCG for:

• Non-muscle invasive bladder cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Merck Sharp & Dohme LLC

Industry 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

Published Research Related to This Trial

The KEYNOTE-676 study aims to evaluate the safety and efficacy of pembrolizumab combined with Bacillus Calmette-Guérin (BCG) therapy in patients with high-risk nonmuscle-invasive bladder cancer (NMIBC) who have not responded to initial BCG treatment.

This Phase III trial is significant as it addresses the need for effective treatment options for patients with recurrent or BCG-unresponsive NMIBC, a group that currently has limited therapeutic alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-676: Phase III study of BCG and pembrolizumab for persistent/recurrent high-risk NMIBC. Kamat, AM., Shore, N., Hahn, N., et al.[2020]

In a study of 755 patients with metastatic, chemo-resistant urothelial carcinoma treated with pembrolizumab, a history of non-muscle invasive bladder cancer (NMIBC) treatment, including BCG therapy, did not significantly impact overall survival or treatment response outcomes.

Patients with a history of BCG treatment had a lower objective response rate compared to those without an NMIBC history, but overall disease control rates were similar, indicating that prior NMIBC treatment does not adversely affect the efficacy of pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of prior intravesical bacillus Calmette-Guerin therapy on the effectiveness of pembrolizumab for patients with metastatic urothelial carcinoma. Taoka, R., Kobayashi, T., Hidaka, Y., et al.[2022]

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 involving 101 patients with BCG-unresponsive non-muscle-invasive bladder cancer, pembrolizumab showed a promising clinical complete response rate of 41% at 3 months, indicating its potential as an effective treatment option for patients who cannot undergo surgery.

The treatment was generally well-tolerated, with only 13% of patients experiencing grade 3 or 4 adverse events, suggesting that pembrolizumab is a safe alternative for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Balar, AV., Kamat, AM., Kulkarni, GS., et al.[2022]

This study aims to systematically evaluate the efficacy and safety of Bacillus Calmette-Guerin (BCG) treatment for bladder cancer by reviewing high-quality trials from various databases, ensuring a comprehensive analysis.

The findings will provide crucial evidence to determine the effectiveness of BCG in treating bladder cancer, potentially influencing treatment decisions for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of Bacillus Calmette-Guerin for bladder cancer: A protocol of systematic review. Zhang, ZH., Yin, L., Zhang, LL., et al.[2023]

The combination of intravesical Bacillus Calmette-Guérin (BCG) and systemic pembrolizumab was found to be safe in a phase I trial involving 18 patients with high-grade non-muscle-invasive bladder cancer, with 69% of treated patients showing no evidence of disease after 3 months.

Despite some treatment-related adverse events, including one severe case of adrenal insufficiency and several grade 3 adverse events, the overall safety profile supports further investigation, leading to the initiation of a phase III trial to evaluate the efficacy of this combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous Bacillus Calmette-Guérin treatment. Alanee, S., Sana, S., El-Zawahry, A., et al.[2022]

Infantile BCG vaccination is associated with a 35-37% lower incidence of bladder cancer later in life, based on preliminary data analysis of various factors including gender and socio-economic status.

Despite the promising findings, there is limited existing literature on the relationship between BCG vaccination and bladder cancer incidence, indicating a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bacillus Calmette-Guerin vaccine and bladder cancer incidence: Scoping literature review and preliminary analysis. Trigo, S., Gonzalez, K., Di Matteo, L., et al.[2021]

Citations

1. keytruda.com keytruda.com/non-muscle-invasive-bladder-cancer/clinical-trial-results/

Clinical Trial Results in Some Patients With Non-Muscle ... KEYTRUDA helped completely shrink tumors in some patients with high-risk, non-muscle invasive bladder cancer. Results are from a clinical trial that ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03711032

NCT03711032 | Efficacy and Safety of Pembrolizumab (MK ... High-risk means NMIBC may have a high chance of getting worse or coming back after treatment. The goals of this study are to learn: 1. If more people who ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32162533/

KEYNOTE-676: Phase III study of BCG and pembrolizumab ... Phase III KEYNOTE-676 study, which will evaluate the efficacy and safety of pembrolizumab in combination with BCG in patients with persistent/recurrent high- ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1558767325001454

A Systematic Review and Meta-Analysis of the ... Pembrolizumab monotherapy showed antitumor activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4597

Outcomes of patients with bacillus Calmette-Guérin ... Background: The phase 2 KEYNOTE-057 trial (NCT02625961) demonstrated that pembrolizumab can serve as a bladder-sparing option for patients (pts) ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03504163

Study Details | NCT03504163 | Pembrolizumab (MK-3475) ... The combination of pembrolizumab with BCG will also be evaluated in an exploratory cohort of patients with upper tract urothelial cancer. Detailed Description.

7. urotoday.com urotoday.com/conference-highlights/asco-gu-2024/asco-gu-2024-bladder-cancer/149535-asco-gu-2024-phase-3-keynote-676-cohort-a-bacillus-calmette-guerin-with-or-without-pembrolizumab-for-high-risk-non-muscle-invasive-bladder-cancer-that-persists-recurs-after-bcg-induction.html

ASCO GU 2024: Phase 3 KEYNOTE-676 Cohort A However, many patients have persistent/recurrent HR NMIBC after BCG induction and are at a particularly increased risk for disease progression.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6924696/

Combination of pembrolizumab and BCG treatment after ... The primary objective is to determine the safety and efficacy of administering MK-3475 at a fixed dose of 200 mg every 3 weeks in conjunction with intrapelvic ...

9. merck.com merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-for-patients-with-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer-with-carcinoma-in-situ-with-or-without-papillary-tumors-wh/

FDA Approves Merck's KEYTRUDA® (pembrolizumab) for ... FDA Approves Merck's KEYTRUDA® (pembrolizumab) for Patients With BCG-Unresponsive, High-Risk, Non-Muscle Invasive Bladder Cancer With Carcinoma ...