Pembrolizumab + Entinostat for Bladder Cancer

Recruiting at 1 trial location

Overseen By Shamina Williams

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must not be taking: Immunosuppressants, Steroids, HDAC inhibitors, others

Disqualifiers: Immunodeficiency, Active tuberculosis, Autoimmune disease, others

Stay on Your Current Meds You can continue your current medications while participating

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: 1

Duration: Up to 3 months

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open-label, window of opportunity platform study for subjects with muscle-invasive bladder cancer (MIBC) who are deemed ineligible or refuse cisplatin-based neoadjuvant chemotherapy and are scheduled to undergo definitive surgery (radical cystectomy), or are planning to undergo trimodality therapy (maximal transurethral resection of the bladder tumor followed by concurrent chemoradiation). The primary objective of this study is to assess changes to immunogenomic markers after treatment with pembrolizumab alone and in combination with the selective class I histone deacetylase (HDAC) inhibitor (entinostat).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain immunosuppressive therapies, systemic steroids, or specific drugs that interact with the trial medications. It's best to discuss your current medications with the trial team.

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

Pembrolizumab has been approved for use in certain types of bladder cancer, such as BCG-unresponsive non-muscle invasive bladder cancer, and has shown effectiveness in advanced urothelial carcinoma, making it a promising component of the treatment. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and Entinostat safe for humans?

Pembrolizumab has been studied in various bladder cancer treatments and is generally considered safe, but it can cause immune-related side effects, such as muscle weakness and heart inflammation. There is no specific safety data available for the combination of Pembrolizumab and Entinostat in the provided research. ^{1 4 6 7 8}

What makes the drug Pembrolizumab unique for bladder cancer treatment?

Pembrolizumab is unique because it is approved for patients with high-risk, non-muscle invasive bladder cancer (NMIBC) who do not respond to BCG treatment and are ineligible for surgery. It works by helping the immune system recognize and attack cancer cells, offering an alternative for those who cannot undergo traditional surgery. ^{1 4 9 10 11}

Research Team

Tracy L Rose, MD

Principal Investigator

UNC- Chapel HIll

Eligibility Criteria

Adults with muscle-invasive bladder cancer who can't or won't take cisplatin-based chemo and are set for surgery or trimodality therapy. They must be able to provide tissue samples, have a life expectancy over 3 months, and show adequate organ function. Women of childbearing age need to use contraception.

Inclusion Criteria

I am a woman who can have children and have a recent negative pregnancy test.

My bladder cancer diagnosis includes urothelial carcinoma.

My bladder cancer is at a stage where it has grown but not spread to distant parts.

Exclusion Criteria

I am taking medication that affects P-gp for my treatment.

Subject has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

I have an active tuberculosis infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab alone or in combination with entinostat prior to surgery

Up to 3 months

Pembrolizumab on day 1 and day 22; Entinostat on day 1, 8, and 15

Surgery

Participants undergo radical cystectomy or maximal TURBT followed by chemoradiation

Immediate post-treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 months

Long-term Follow-up

Participants are monitored for event-free survival and overall survival

Up to 3 years

Treatment Details

Interventions

• Entinostat
• Pembrolizumab

Trial Overview The study is testing the effects of Pembrolizumab alone and combined with Entinostat on immune markers in bladder cancer patients ineligible for certain chemotherapy before their scheduled surgeries.

Participant Groups

Group I: B: Pembrolizumab plus Entinostat Experimental Treatment 3 Interventions

Subjects will be administered pembrolizumab on day 1 and day 22 and entinostat 5 mg given orally on day 1, day 8 and day 15

Group II: A: Pembrolizumab alone Experimental Treatment 2 Interventions

Subjects will be administered pembrolizumab alone 200 mg IV on day 1 and day 22

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?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

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

Syndax Pharmaceuticals

Industry Sponsor

Trials

49

Recruited

2,700+

Syndax Pharmaceuticals, Inc.

Collaborator

Trials

5

Recruited

220+

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]

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 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 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]

Pembrolizumab, an immunotherapy for advanced bladder cancer, led to significant tumor shrinkage after just one injection, demonstrating its efficacy in treating this type of cancer.

The patient experienced immune-related adverse events, specifically myasthenia gravis and myocarditis, which were effectively managed with early corticosteroid treatment, highlighting the importance of monitoring and addressing side effects in immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-induced myasthenia gravis with myositis and presumable myocarditis in a patient with bladder cancer. Todo, M., Kaneko, G., Shirotake, S., et al.[2022]

In a study involving 33 patients with advanced urothelial cancer, pembrolizumab demonstrated anti-tumor activity, with a 26% overall response rate, including 11% complete responses and 15% partial responses, after a median follow-up of 13 months.

The treatment was found to have an acceptable safety profile, with common side effects including fatigue and peripheral edema, and no treatment-related deaths reported, supporting further investigation in larger phase 2 and 3 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. Plimack, ER., Bellmunt, J., Gupta, S., et al.[2022]

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 78 patients with advanced urothelial carcinoma treated with pembrolizumab, the median overall survival was 7.3 months, and the estimated survival rate at 6 months was 61.5%, indicating its efficacy in a real-life setting.

The treatment was generally well-tolerated, with the most common side effects being fatigue and gastrointestinal issues, but no severe adverse events occurred in more than 5% of patients, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Benefit of Pembrolizumab in Advanced Urothelial Cancer Patients in Real-Life Setting: An Efficacy and Safety Monocentric Study. Dang, E., Vallée, A., Lepage-Seydoux, C., et al.[2022]

References

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

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

2. 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]

3. Iran pubmed.ncbi.nlm.nih.gov

Favorable Response of Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma with Only Small Lesions to not be Considered Measurable by RECIST. [2022]

4. 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]

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. Australia pubmed.ncbi.nlm.nih.gov

Pembrolizumab-induced myasthenia gravis with myositis and presumable myocarditis in a patient with bladder cancer. [2022]

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

Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study. [2022]

8. 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]

9. Greece pubmed.ncbi.nlm.nih.gov

Initial Experience of Pembrolizumab Therapy in Japanese Patients With Metastatic Urothelial Cancer. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Benefit of Pembrolizumab in Advanced Urothelial Cancer Patients in Real-Life Setting: An Efficacy and Safety Monocentric Study. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Pembrolizumab as Second-line Therapy for the Treatment of Locally Advanced or Metastatic Urothelial Carcinoma in Sweden. [2021]