Testing the Addition of Tazemetostat to the Immunotherapy Drug, Pembrolizumab (MK-3475), in Advanced Urothelial Carcinoma

Running, not enrolling · Phase 1/Phase 2

Conditions studied: Locally Advanced Urothelial Carcinoma, Metastatic Urothelial Carcinoma, Stage III Bladder Cancer AJCC v8, Stage IV Bladder Cancer AJCC v8

In brief

This phase I/II trial studies the side effects and best dose of tazemetostat and how well it works when given together with pembrolizumab in treating patients with urothelial carcinoma that has spread to nearby tissue or lymph nodes (locally advanced ) or from where it first started (primary site) to other places in the body (metastatic). Tazemetostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving tazemetostat and pembrolizumab may work better in treating patients with urothelial carcinoma compared to pembrolizumab without tazemetostat.

Key facts

Study ID

NCT03854474

Run by

National Cancer Institute (NCI)

People needed

30

Starts

2019-11-18

Expected to finish

2027-06-30

Last updated by the study team

2026-07-31

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Patients must have pathologically confirmed urothelial carcinoma
• Note: Patients with mixed histology (with predominant urothelial carcinoma) are eligible
• Patients must have locally advanced or metastatic disease with either:
• Arm A: Disease progression during or following (within 12 months) platinum-based chemotherapy (cisplatin or carboplatin)
• Note: No minimum number of cycles on platinum-based chemotherapy are required. Patients who have had multiple rounds of platinum-based chemotherapy with events of intermittent progressive disease (PD) are eligible as long as progression has been confirmed while on or within 12 months from platinum based therapy OR
• Arm B: Platinum ineligible status (i.e., patients unable to receive platinum-containing chemotherapy, in the opinion of the treating investigator, regardless of PD-L1 status) or chemotherapy ineligible status (i.e., patients unable to receive treatment with any chemotherapy, in the opinion of the treating investigator, regardless of PD-L1 status)
• Note: The eligible patient population for Arm B was revised in protocol amendment 10 from 'cisplatin ineligible patients with PD-L1 positive disease' to 'platinum ineligible patients (i.e., unable to receive platinum-containing chemotherapy, in the opinion of the treating investigator, regardless of PD-L1 status) or chemotherapy ineligible patients (i.e., unable to receive treatment with any chemotherapy, in the opinion of the treating investigator, regardless of PD-L1 status).' This revision was made to align with the updated United States (U.S.) Food and Drug Administration (FDA) indications for pembrolizumab (MK-3475) that were released in August of 2021 for patients with locally advanced or metastatic urothelial carcinoma
• All patients must have measurable disease in accordance with RECIST criteria version (v) 1.1
• Note: radiological evaluation should occur within 28 days prior to study registration
• Patients must be naive to prior PD-L1 or EZH2 inhibitors
• Note: patients in Arm A should have received platinum-based chemotherapy only
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Leukocytes >= 3000/mcL (performed within 14 days prior to registration)
• Absolute neutrophil count (ANC) >= 1500/mcL (performed within 14 days prior to registration)
• Platelets >= 100 000/mcL (performed within 14 days prior to registration)
• Hemoglobin >= 9 g/dL or >= 4.9 mmol/L (performed within 14 days prior to registration)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (CrCl) >= 30 mL/min for patient with creatinine levels > 1.5 x institutional ULN (performed within 14 days prior to registration)
• Creatinine clearance (CrCl) should be calculated per institutional standard
• Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 x ULN (performed within 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for patients with liver metastases (performed within 14 days prior to registration)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 14 days prior to registration)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 14 days prior to registration)
• The effects of pembrolizumab (MK-3475) and tazemetostat on the developing human fetus are unknown. For this reason and because PD-1 inhibitors as well as EZH2 inhibitors are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation

You may not qualify if…

• Patients with disease that is suitable for local therapy administered with curative intent are not eligible
• Patients who have had chemotherapy, targeted small molecule therapy, or radiotherapy within 4 weeks prior to entering the study are not eligible
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1 per Common Terminology Criteria for Adverse Events [CTCAE] v.5 ) are not eligible
• Note: patients with =< grade 2 neuropathy or =< grade 2 alopecia or =< grade 3 audiometric hearing loss are an exception to this criterion and may qualify for the study
• Note: if patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Patients are not eligible who are currently participating and receiving study therapy or have participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Patients who have received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin) within 4 weeks prior to the first dose of treatment are not eligible
• Patients with a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment are not eligible
• Note: the use of physiologic doses of corticosteroids may be approved after consultation with the study principal investigator (PI)
• Patients with thrombocytopenia, neutropenia, or anemia of grade 3 (per CTCAE 5.0 criteria) are not eligible
• Patients with abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and myeloproliferative neoplasms (MPN, e.g. JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing are not eligible
• Patients with an ongoing or untreated hematologic malignancy or myeloproliferative disorder, or a prior history of a hematologic malignancy or myeloproliferative disorder are not eligible. (Examples of excluded malignancies/disorders include but are not limited to myelodysplastic syndrome [MDS], T cell lymphoblastic lymphoma (T-LBL), T cell acute lymphoblastic leukemia (T-ALL), and any other myeloid or lymphoid malignancy)
• Patients who have received prior PD-L1/PD-1/PD-L2 or EZH2 inhibitor therapy are not eligible
• Patients who have had a prior monoclonal antibody within 4 weeks prior to study day 1 are not eligible
• Patients must be disease-free of prior invasive malignancies for > 5 years, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. If there is a history of prior malignancy, patients must not be receiving other specific treatment for that cancer
• Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• Note: patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either magnetic resonance imaging (MRI) or computed tomography (CT) scan, for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab (MK-3475) or tazemetostat are not eligible
• Patients with an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) are not eligible
• Note: replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Patients with a history of (non-infectious) pneumonitis that required steroids or current pneumonitis are not eligible
• Patients with a prolongation of corrected QT interval (Fridericia's correction formula [QTcF]) of > 450 msec are not eligible
• Patients with major surgery within 3 weeks before the first dose of study drugs
• Note: minor surgery (e.g. minor biopsy of an extracranial site, central venous catheter placement, shunt revision) has no restriction
• Patients must not have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator

Where it is running

• Mayo Clinic Hospital in Arizona — Phoenix, Arizona, United States
• Mayo Clinic in Arizona — Scottsdale, Arizona, United States
• Smilow Cancer Hospital-Derby Care Center — Derby, Connecticut, United States
• Smilow Cancer Hospital Care Center-Fairfield — Fairfield, Connecticut, United States
• Smilow Cancer Hospital Care Center - Guilford — Guilford, Connecticut, United States
• Smilow Cancer Hospital Care Center at Saint Francis — Hartford, Connecticut, United States
• Smilow Cancer Center/Yale-New Haven Hospital — New Haven, Connecticut, United States
• Yale University — New Haven, Connecticut, United States
• Yale-New Haven Hospital North Haven Medical Center — North Haven, Connecticut, United States
• Smilow Cancer Hospital-Orange Care Center — Orange, Connecticut, United States
• Smilow Cancer Hospital-Torrington Care Center — Torrington, Connecticut, United States
• Smilow Cancer Hospital Care Center-Trumbull — Trumbull, Connecticut, United States
• Smilow Cancer Hospital-Waterbury Care Center — Waterbury, Connecticut, United States
• Smilow Cancer Hospital Care Center - Waterford — Waterford, Connecticut, United States
• Mayo Clinic in Florida — Jacksonville, Florida, United States
• Northwestern University — Chicago, Illinois, United States
• University of Kansas Clinical Research Center — Fairway, Kansas, United States
• HaysMed — Hays, Kansas, United States
• Lawrence Memorial Hospital — Lawrence, Kansas, United States
• The University of Kansas Cancer Center - Olathe — Olathe, Kansas, United States
• University of Kansas Cancer Center-Overland Park — Overland Park, Kansas, United States
• Mercy Hospital Pittsburg — Pittsburg, Kansas, United States
• Salina Regional Health Center — Salina, Kansas, United States
• University of Kansas Health System Saint Francis Campus — Topeka, Kansas, United States
• University of Kansas Hospital-Westwood Cancer Center — Westwood, Kansas, United States

Full record on ClinicalTrials.gov

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