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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, pembrolizumab (an immunotherapy drug) and entinostat (a type of histone deacetylase inhibitor), for individuals with muscle-invasive bladder cancer who can't or choose not to use traditional chemotherapy. The researchers aim to assess how these treatments affect specific immune system markers, potentially enhancing the body's ability to fight cancer. Participants will receive either pembrolizumab alone or with entinostat to compare the effects. Suitable candidates have bladder cancer that has spread into the muscle and are planning surgery or specific therapy but can't use cisplatin-based chemotherapy. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research shows that pembrolizumab, used alone or with entinostat, is generally safe for people with muscle-invasive bladder cancer. Studies have found that pembrolizumab, a treatment that helps the immune system fight cancer, can improve survival rates for patients with high-risk bladder cancer, with about 61% of patients still alive after three years.

Entinostat has a few side effects, with mild tiredness being the most common. At higher doses than those used in this study, some people experienced lower levels of certain blood cells, such as white blood cells (neutropenia) and red blood cells (anemia). However, at the dose used in this study, these side effects have been less frequent.

Overall, participants have tolerated the treatments well. It's important for participants to discuss possible side effects and benefits with their healthcare provider before joining any clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab and entinostat for bladder cancer because it offers a fresh approach to treatment. Pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells, and it's already a standard option for bladder cancer. The addition of entinostat is what makes this combination special. Entinostat is a histone deacetylase inhibitor, which can alter the expression of certain genes to make cancer cells more vulnerable to immune attack. This dual-action approach could potentially enhance the effectiveness of treatment compared to standard options like chemotherapy alone, offering hope for better outcomes.

What evidence suggests that this trial's treatments could be effective for bladder cancer?

Research shows that pembrolizumab, a drug that aids the immune system in fighting cancer, effectively treats muscle-invasive bladder cancer (MIBC). Studies have found that about 61% of patients receiving pembrolizumab survive three years after starting treatment. Additionally, pembrolizumab reduces tumor size in about 29% of patients, indicating effectiveness for nearly a third of those treated.

In this trial, participants will receive either pembrolizumab alone or combined with entinostat. When combined with entinostat, a drug that alters gene activity to boost the immune response against cancer, animal studies have shown promising results. This combination is believed to enhance the immune system's ability to combat bladder cancer. These findings suggest that pembrolizumab, both alone and with entinostat, could effectively treat MIBC. ^{5 6 7 8 9}

Who Is on the Research Team?

Tracy L Rose, MD

Principal Investigator

UNC- Chapel HIll

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 (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 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]

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 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 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 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 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]

Citations

1. cancer.gov cancer.gov/news-events/press-releases/2024/high-risk-bladder-cancer-pembrolizumab

Pembrolizumab improves outcomes in high-risk bladder ... In preliminary data on overall survival, at three years, about 61% of patients in the pembrolizumab group were still alive, compared with about ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6452591/

Pembrolizumab in the treatment of locally advanced or ... An updated efficacy analysis with all patients having ⩾6 months of follow up demonstrated an ORR of 29% (95 CI, 24–34%) and a CR rate of 7%. The median time to ...

3. merck.com merck.com/news/mercks-keytruda-pembrolizumab-significantly-improved-disease-free-survival-dfs-as-adjuvant-therapy-versus-observation-in-high-risk-patients-with-localized-muscle-invasive-and-locall/

Merck's KEYTRUDA® (pembrolizumab) Significantly ... After a median follow-up of 36.9 months, median OS was 50.9 months (95% CI, 43.8-NE) for KEYTRUDA versus 55.8 months (95% CI, 53.3-NE) for observation. “Even ...

4. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35601

Efficacy and safety of pembrolizumab in patients with ... In the phase 2 KEYNOTE-052 trial, first-line pembrolizumab monotherapy was found to demonstrate antitumor activity and acceptable tolerability ...

5. onclive.com onclive.com/view/perioperative-enfortumab-vedotin-plus-pembrolizumab-displays-positive-topline-data-in-muscle-invasive-bladder-cancer

Perioperative Enfortumab Vedotin Plus Pembrolizumab ... Enfortumab vedotin plus pembrolizumab significantly improved survival outcomes in patients with muscle-invasive bladder cancer who were ...

6. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.4603

Pathologic response and safety of neoadjuvant ... Neoadjuvant pembrolizumab with or without entinostat is active in MIUC with an acceptable safety profile.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03978624

Study Details | NCT03978624 | Window of Opportunity ... Phase I data identified grade 1/2 fatigue as the most common entinostat-related toxicity, with neutropenia and anemia only occurring at doses exceeding those ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03765229

NCT03765229 | An Exploratory Study of Pembrolizumab ... The study will determine how many subjects cancer has become better or not changed 6 months after subjects have started treatment on the study. We will also ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8363284/

Entinostat induces antitumor immune responses through ... We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment.