Tazemetostat + Pembrolizumab for Bladder Cancer

Not currently recruiting at 38 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors/inducers

Disqualifiers: Chemotherapy, Radiotherapy, Immunodeficiency, Autoimmune, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 24

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments—tazemetostat and pembrolizumab—for individuals with urothelial carcinoma, a type of bladder cancer that has metastasized. The researchers aim to determine the optimal dose and assess whether combining these drugs is more effective than using pembrolizumab alone. Tazemetostat works to inhibit cancer cell growth, while pembrolizumab (also known as KEYTRUDA) enhances the immune system's ability to attack cancer. Individuals with advanced bladder cancer who have previously undergone specific chemotherapy treatments may be suitable candidates for this trial. As a Phase 1/Phase 2 trial, this research seeks to understand the treatment's effects and measure its effectiveness in an initial group, offering participants an opportunity to contribute to groundbreaking cancer treatment advancements.

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

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking medications that strongly affect certain liver enzymes (CYP3A) within 14 days before starting the trial. It's best to discuss your current medications with the study team to ensure there are no interactions.

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

Research shows that using tazemetostat and pembrolizumab together is generally safe for patients. Studies indicate that most people tolerate this combination well, with the most common side effect being a low red blood cell count. This can cause fatigue or weakness, but these side effects are manageable.

In a study involving patients with advanced bladder cancer, 21% of participants responded positively to the treatment, indicating that the combination might help shrink tumors or stop their growth.

Overall, evidence suggests that tazemetostat and pembrolizumab can be safely used together, although side effects may occur. Discuss any concerns with a healthcare provider before joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining tazemetostat and pembrolizumab for bladder cancer because this duo offers a novel approach to treatment. Unlike current therapies, which often involve chemotherapy or solely immune checkpoint inhibitors like pembrolizumab, this combination includes tazemetostat, an EZH2 inhibitor. EZH2 is an enzyme that can drive cancer growth, and by inhibiting it, tazemetostat may enhance the immune system's ability to fight cancer. This unique mechanism has the potential to make the immune system's attack on cancer cells even more effective, offering hope for better outcomes.

What evidence suggests that tazemetostat and pembrolizumab could be effective for bladder cancer?

This trial will evaluate the combination of tazemetostat and pembrolizumab for advanced bladder cancer. Research has shown that using tazemetostat with pembrolizumab might improve treatment outcomes. Tazemetostat stops certain enzymes that help cancer cells grow, while pembrolizumab, a type of immunotherapy, helps the immune system attack cancer cells. Studies have found that this combination is generally well-tolerated by patients, with some experiencing long-lasting treatment effects. However, the improvement over using pembrolizumab alone appears to be small. ^{1 2 4 6 7}

Who Is on the Research Team?

Maha H Hussain

Principal Investigator

University Health Network Princess Margaret Cancer Center LAO

Are You a Good Fit for This Trial?

Adults (18+) with advanced urothelial carcinoma that hasn't spread to the brain, without prior treatment with PD-L1 or EZH2 inhibitors. They must have measurable disease, be in fairly good health (ECOG <=2), and have normal organ function tests. HIV-positive patients can join if they're on effective therapy with an undetectable viral load. Participants need to understand and sign consent forms and agree to use contraception.

Inclusion Criteria

I am HIV-positive, on effective treatment, and have no history of Kaposi sarcoma or Multicentric Castleman Disease.

Your absolute neutrophil count is at least 1500 per microliter.

Patients must agree to use adequate contraception

Exclusion Criteria

Your heart's electrical activity takes too long, as measured by the QT interval, which can be risky for the study.

My tests show genetic changes linked to certain blood disorders.

Patients who are currently participating and receiving study therapy or have participated in a study of an investigational agent within 4 weeks of the first dose of treatment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tazemetostat orally twice daily and pembrolizumab intravenously on day 1 of each 21-day cycle, repeated for up to 2 years

Up to 2 years

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

1 year

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Tazemetostat

Trial Overview The trial is testing how well tazemetostat works alongside pembrolizumab compared to just pembrolizumab for treating advanced urothelial carcinoma. Tazemetostat blocks enzymes that help cancer cells grow, while pembrolizumab boosts the immune system's ability to fight cancer.

How Is the Trial Designed?

Group I: Treatment (tazemetostat, pembrolizumab) Experimental Treatment 5 Interventions

Patients receive tazemetostat PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI throughout the trial and undergo collection of blood samples on study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 115 patients with metastatic urothelial carcinoma treated with atezolizumab (ATZ) after failing first-line chemotherapy, the objective response rate was 28.7%, indicating that ATZ is effective in this patient population.

The treatment was well tolerated, with 98% of patients experiencing adverse events, but only 21.2% had severe (grade 3-4) treatment-related adverse events, suggesting a manageable safety profile similar to previous clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences. Tural, D., Ölmez, ÖF., Sümbül, AT., et al.[2022]

Atezolizumab, an anti-PD-L1 therapy, showed long-term safety and efficacy in patients with metastatic urothelial carcinoma, with a median follow-up of 37.8 months and a low incidence of severe treatment-related adverse events (9%).

The treatment resulted in a 26% objective response rate, with a median duration of response of 22.1 months, and median overall survival of 10.1 months, particularly benefiting patients with higher PD-L1 expression on immune cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab (MPDL3280A) Monotherapy for Patients With Metastatic Urothelial Cancer: Long-term Outcomes From a Phase 1 Study. Petrylak, DP., Powles, T., Bellmunt, J., et al.[2022]

Atezolizumab is an FDA-approved treatment for advanced bladder cancer that works by blocking the PD-L1/PD-1 immune checkpoint, enhancing T-cell immunity against tumors.

In clinical trials, atezolizumab showed a 15% objective response rate in patients whose cancer progressed after chemotherapy, and a 24% response rate in chemotherapy-naïve patients, with a favorable safety profile compared to other second-line treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab: A PD-L1-Blocking Antibody for Bladder Cancer. Inman, BA., Longo, TA., Ramalingam, S., 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]

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]

Atezolizumab and pembrolizumab received accelerated FDA approval in 2017 for treating advanced urothelial carcinoma in patients who cannot receive cisplatin, showing objective response rates of 23.5% and 28.6%, respectively, in single-arm trials with a total of 746 patients.

Due to preliminary concerns from ongoing trials, the FDA revised the indications for these drugs, now specifying they are for patients not eligible for any platinum-based chemotherapy or those with high PD-L1 expression, ensuring a more targeted treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Atezolizumab or Pembrolizumab for the Treatment of Patients with Advanced Urothelial Carcinoma Ineligible for Cisplatin-Containing Chemotherapy. Suzman, DL., Agrawal, S., Ning, YM., et al.[2020]

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]

Citations

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A pilot study of tazemetostat and pembrolizumab in ... In this pilot study, improvement in efficacy relative to historical controls of pembrolizumab alone appears to be modest. Response in tumors ...

2. onclive.com onclive.com/view/tazemetostat-plus-pembrolizumab-is-tolerable-in-advanced-urothelial-carcinoma

Tazemetostat Plus Pembrolizumab Is Tolerable in ... Tazemetostat (Tazverik) in combination with pembrolizumab (Keytruda) demonstrated tolerability in patients with advanced urothelial carcinoma.

3. bcan.org bcan.org/clinicaltrials/tazemetostat-and-pembrolizumab-in-treating-patients-with-locally-advanced-or-metastatic-urothelial-carcinoma/

Tazemetostat and Pembrolizumab in Treating Patients With ... Tazemetostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.6_suppl.506

A pilot study of tazemetostat and pembrolizumab in ... The RP2D dose for tazemetostat is 800 mg + 200 mg Pembrolizumab q 3 weeks. The combination was feasible, well tolerated, and resulted in durable responses.

5. researchgate.net researchgate.net/publication/339387595_A_pilot_study_of_tazemetostat_and_MK-3475_pembrolizumab_in_advanced_urothelial_carcinoma_ETCTN_10183

A pilot study of tazemetostat and MK-3475 (pembrolizumab ... One clinical study reported the results of tazemetostat in combination with pembrolizumab for the treatment of urothelial carcinoma [174] (Table 2). However, ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-01035

Testing the Addition of Tazemetostat to the Immunotherapy ... Giving tazemetostat and pembrolizumab may work better in treating patients with urothelial carcinoma compared to pembrolizumab without tazemetostat. Eligibility ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11816339/

Tazemetostat, a Selective EZH2 Inhibitor, in Combination with ... We found that the 800 mg dose level of tazemetostat given with pembrolizumab was safe and tolerable. The most common side effects were a low red blood cell ...