Pembrolizumab + BCG for Bladder Cancer

Recruiting at 234 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme Corp.

Must be taking: BCG

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

Disqualifiers: Metastatic UC, Active autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: Up to 2 years

1397 Participants Needed

Trial Summary

What is the purpose of this trial?

Researchers are looking for new ways to treat high-risk non muscle invasive bladder cancer (HR NMIBC). NMIBC is cancer in the tissue that lines the inside of the bladder but has not spread to the bladder muscle or outside of the bladder. 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 receive pembrolizumab with Bacillus Calmette-Guerin (BCG) have no signs of cancer in their body and live longer without the cancer growing, spreading, or coming back compared to people who receive BCG alone. 2. About the safety and how well people tolerate BCG alone or in combination with pembrolizumab.

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 chronic systemic steroid therapy or any other form of immunosuppressive therapy, you must stop these at least 7 days before starting the study treatment.

What data supports the effectiveness of the drug Pembrolizumab + BCG for bladder cancer?

The FDA has approved pembrolizumab for patients with bladder cancer that does not respond to BCG treatment, showing it can be effective in these cases. Additionally, studies like KEYNOTE-676 are exploring the combination of pembrolizumab and BCG for persistent high-risk bladder cancer, suggesting potential benefits of this drug combination. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and BCG safe for humans?

Research has been conducted to evaluate the safety of combining Pembrolizumab (Keytruda) and BCG for bladder cancer. A Phase I trial focused on the safety of this combination in patients with high-grade non-muscle-invasive bladder cancer, and the FDA has approved Pembrolizumab for certain bladder cancer cases, indicating it has been deemed safe for use in humans. ^{1 2 3 4 6}

How is the drug pembrolizumab combined with BCG unique for treating bladder cancer?

This treatment is unique because it combines pembrolizumab, an immune system booster, with BCG, a standard bladder cancer therapy, to help patients who don't respond to BCG alone. Pembrolizumab targets a specific pathway (PD-1) that may be involved in BCG resistance, offering a new option for those with persistent or recurrent high-risk bladder cancer. ^{1 2 3 4 5}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with high-risk non-muscle invasive bladder cancer (HR NMIBC) that's persistent or recurrent after BCG therapy, or who haven't had BCG treatment. Participants need good organ function, must not be pregnant or breastfeeding, and agree to use contraception. Exclusions include active tuberculosis, recent other cancers, HIV infection, certain prior treatments including anti-PD-1/L1/L2 agents, and specific contraindications to BCG.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

My bladder cancer returned or persisted after BCG therapy.

I've had surgery to remove bladder tumors.

Exclusion Criteria

I have not had any cancer treatment or experimental drugs in the last 4 weeks.

I have an immune system disorder or have been on steroids or other immune-weakening medicines recently.

Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of start of study treatment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BCG (Induction and Maintenance) in combination with pembrolizumab administered intravenously

Up to 2 years

Every 3 weeks for 35 doses or every 6 weeks for 9 doses

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• BCG
• Pembrolizumab

Trial Overview The study tests the effectiveness of pembrolizumab combined with BCG against BCG alone in HR NMIBC patients. It aims to see if the drug duo works better for complete response rate in those previously treated with BCG (Cohort A), and event-free survival in new patients (Cohort B).

Participant Groups

Group I: BCG plus Pembrolizumab: Post-induction Cohort A (Arm A-1) Experimental Treatment 2 Interventions

Participants receive BCG (Induction and Maintenance) in combination with 200 mg pembrolizumab administered intravenously (IV) every 3 weeks (Q3W) for 35 doses (\~2 years).

Group II: BCG plus Pembrolizumab: BCG Naïve Cohort B-Reduced Maintenance (Arm B-1) Experimental Treatment 2 Interventions

Participants receive BCG (Induction and reduced Maintenance) in combination with 400 mg pembrolizumab administered IV every 6 weeks (Q6W) for 9 doses (\~1 year).

Group III: BCG plus Pembrolizumab: BCG Naïve Cohort B-Full Maintenance (Arm B-2) Experimental Treatment 2 Interventions

Participants receive BCG (Induction and full Maintenance) in combination with 400 mg pembrolizumab administered IV Q6W for 9 doses (\~1 year).

Group IV: BCG Monotherapy: Post-induction Cohort A (Arm A-2) Experimental Treatment 1 Intervention

Participants receive BCG monotherapy (Induction and Maintenance).

Group V: BCG Monotherapy: BCG Naïve Cohort B (Arm B-3) Experimental Treatment 1 Intervention

Participants receive BCG monotherapy (Induction and Maintenance).

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

Approved in United States as Bacillus Calmette-Guérin for:

• Non-muscle invasive bladder cancer

Approved in European Union as Bacillus Calmette-Guérin for:

• Non-muscle invasive bladder cancer

Approved in Canada as Bacillus Calmette-Guérin for:

• Non-muscle invasive bladder cancer

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

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]

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]

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]

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]

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]

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]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

KEYNOTE-676: Phase III study of BCG and pembrolizumab for persistent/recurrent high-risk NMIBC. [2020]

3. Germany 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. [2022]

4. England 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. [2022]

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

Impact of prior intravesical bacillus Calmette-Guerin therapy on the effectiveness of pembrolizumab for patients with metastatic urothelial carcinoma. [2022]

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

Efficacy and safety of Bacillus Calmette-Guerin for bladder cancer: A protocol of systematic review. [2023]