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

NCT03854474 | Active Not Recruiting Phase 1 FDA Drug

• 4 other identifiers: NCI-2019-01035ETCTN 1018310183P30CA060553
• Study Type: interventional
• Target: 30
• Locations: 2 countries
• Sites: 34

Brief Summary

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.

Conditions

Locally Advanced Urothelial Carcinoma; Metastatic Urothelial Carcinoma; Stage III Bladder Cancer AJCC v8; Stage IV Bladder Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• Recommended phase 2 dose (RP2D) of tazemetostat in combination with pembrolizumab

  The 3+3 rule will be used to define the RP2D, such that for each cohort, the highest level in which =\< 1 out of 6 patients experienced dose limiting toxicity (DLT), at or below the maximum administered dose, would constitute the RP2D. If =\< 1 of 6 patients experienced DLTs at the maximum administered dose, then the maximum administered dose will be declared RP2D for that cohort.

  Up to 21 days following the first dose of tazemetostat

Secondary Outcomes (4)

• Incidence of adverse events

  Up to 30 days after treatment discontinuation

• Objective response rate (ORR)

  Up to 1 year

• Progression free survival

  From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

• Response rate

  Up to 1 year

Other Outcomes (2)

• EZH2 and H3K27me3 chromatin methylation and mutations in genes associated with histone methylation

  Baseline

• Immune response

  Up to 1 year

Study Arms (1)

Treatment (tazemetostat, pembrolizumab)

EXPERIMENTAL

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.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Biological: Pembrolizumab; Drug: Tazemetostat

Interventions

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (tazemetostat, pembrolizumab)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: BCD-201, GME 751, GME751, Keytruda, Lambrolizumab, MK 3475, MK-3475, MK3475, Pembrolizumab Biosimilar BCD-201, Pembrolizumab Biosimilar GME751, Pembrolizumab Biosimilar QL2107, Pembrolizumab Biosimilar RPH-075, Pembrolizumab Biosimilar SB27, QL2107, RPH 075, RPH-075, RPH075, SB 27, SB-27, SB27, SCH 900475, SCH-900475, SCH900475

Treatment (tazemetostat, pembrolizumab)

Tazemetostat DRUG

Given PO

Also known as: E 7438, E-7438, E7438, EPZ 6438, EPZ-6438, EPZ6438

Treatment (tazemetostat, pembrolizumab)

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (tazemetostat, pembrolizumab)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Treatment (tazemetostat, pembrolizumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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)

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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (34)

Mayo Clinic Hospital in Arizona

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic in Arizona

Scottsdale, Arizona, 85259, United States

Location

Smilow Cancer Hospital-Derby Care Center

Derby, Connecticut, 06418, United States

Location

Smilow Cancer Hospital Care Center-Fairfield

Fairfield, Connecticut, 06824, United States

Location

Smilow Cancer Hospital Care Center - Guilford

Guilford, Connecticut, 06437, United States

Location

Smilow Cancer Hospital Care Center at Saint Francis

Hartford, Connecticut, 06105, United States

Location

Smilow Cancer Center/Yale-New Haven Hospital

New Haven, Connecticut, 06510, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

Yale-New Haven Hospital North Haven Medical Center

North Haven, Connecticut, 06473, United States

Location

Smilow Cancer Hospital-Orange Care Center

Orange, Connecticut, 06477, United States

Location

Smilow Cancer Hospital-Torrington Care Center

Torrington, Connecticut, 06790, United States

Location

Smilow Cancer Hospital Care Center-Trumbull

Trumbull, Connecticut, 06611, United States

Location

Smilow Cancer Hospital-Waterbury Care Center

Waterbury, Connecticut, 06708, United States

Location

Smilow Cancer Hospital Care Center - Waterford

Waterford, Connecticut, 06385, United States

Location

Mayo Clinic in Florida

Jacksonville, Florida, 32224-9980, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Kansas Clinical Research Center

Fairway, Kansas, 66205, United States

Location

HaysMed

Hays, Kansas, 67601, United States

Location

Lawrence Memorial Hospital

Lawrence, Kansas, 66044, United States

Location

The University of Kansas Cancer Center - Olathe

Olathe, Kansas, 66061, United States

Location

University of Kansas Cancer Center-Overland Park

Overland Park, Kansas, 66210, United States

Location

Mercy Hospital Pittsburg

Pittsburg, Kansas, 66762, United States

Location

Salina Regional Health Center

Salina, Kansas, 67401, United States

Location

University of Kansas Health System Saint Francis Campus

Topeka, Kansas, 66606, United States

Location

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas, 66205, United States

Location

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

University Health Truman Medical Center

Kansas City, Missouri, 64108, United States

Location

University of Kansas Cancer Center - North

Kansas City, Missouri, 64154, United States

Location

University of Kansas Cancer Center - Lee's Summit

Lee's Summit, Missouri, 64064, United States

Location

University of Kansas Cancer Center at North Kansas City Hospital

North Kansas City, Missouri, 64116, United States

Location

Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center

Lebanon, New Hampshire, 03756, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

University Health Network-Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms

Interventions

Specimen Handling; Magnetic Resonance Spectroscopy; pembrolizumab; tazemetostat

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Maha H Hussain

  University Health Network Princess Margaret Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 25, 2019
• First Posted: February 26, 2019
• Study Start: November 18, 2019
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: April 13, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share

Locations

CA (1); US (33)