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Locally Advanced Urothelial CarcinomaPhase 1/2NCT03854474

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

A Phase 1/2 study testing Biospecimen Collection, Computed Tomography and Magnetic Resonance Imaging in people with Locally Advanced Urothelial Carcinoma and Metastatic Urothelial Carcinoma, run by National Cancer Institute (NCI) at 34 sites in 2 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Biospecimen Collection, Computed Tomography and Magnetic Resonance Imaging
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
34 sitesin 2 countries
Study dates
18 Nov 2019to 30 Jun 2027
Phase
Phase 1/2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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
  • Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female patients of childbearing/reproductive potential must be willing to use an adequate method of contraception, for the course of the study through 6 months for females and 3 months for males, respectively, after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient
  • Male patients of reproductive potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 3 months after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient
  • Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Participants who have the ability to understand and the willingness to sign an Institutional Review Board (IRB) approved written informed consent document are eligible OR Participants with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver are eligible
  • Human immunodeficiency virus (HIV)-infected patients who do not have a history of Kaposi sarcoma and/or Multicentric Castleman Disease, who are on effective anti-retroviral therapy, and who have undetectable viral load within 6 months are eligible for this trial

Who cannot join

  • 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
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  • 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
  • Patients receiving any medications or substances that are strong or moderate inhibitors or inducers of CYP3A =< 14 days prior to study treatment are not eligible
  • Note: The study team should check a frequently-updated medical reference for a list of drugs to avoid or minimize use of. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • Patients who are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat are not eligible
  • Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, interstitial lung disease or active, non-infectious pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled arterial hypertension, stroke within 6 months prior to starting study treatment, or psychiatric illness/social situations that would limit compliance with study requirements are not eligible
  • Pregnant women are excluded from this study because pembrolizumab (MK-3475) and tazemetostat are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab (MK-3475) and tazemetostat, breastfeeding should be discontinued if the mother is treated with pembrolizumab (MK-3475) or tazemetostat
  • Pembrolizumab (MK-3475) may have adverse effects on a fetus in utero. Furthermore, it is not known if pembrolizumab (MK-3475) has transient adverse effects on the composition of sperm
  • Patients are excluded from this study if pregnant or breastfeeding, or expecting to conceive or father children (or donate sperm) within the projected duration of the trial, starting with the screening visit through 6 months after the last dose of trial treatment
  • Patients with a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection are not eligible
  • Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority
  • Patients who have received a live vaccine within 30 days of planned treatment start are not eligible
  • Note: seasonal flu vaccines that do not contain live virus are permitted

Trial locations and contacts

34 sites in 2 countries.

34 sites in 2 countries

United States33 sites

  • Northwestern University

    Chicago, Illinois, 60611

  • Smilow Cancer Hospital-Derby Care Center

    Derby, Connecticut, 06418

  • Smilow Cancer Hospital Care Center-Fairfield

    Fairfield, Connecticut, 06824

  • University of Kansas Clinical Research Center

    Fairway, Kansas, 66205

  • Smilow Cancer Hospital Care Center - Guilford

    Guilford, Connecticut, 06437

  • Smilow Cancer Hospital Care Center at Saint Francis

    Hartford, Connecticut, 06105

  • HaysMed

    Hays, Kansas, 67601

  • Mayo Clinic in Florida

    Jacksonville, Florida, 32224-9980

  • University Health Truman Medical Center

    Kansas City, Missouri, 64108

  • University of Kansas Cancer Center - North

    Kansas City, Missouri, 64154

  • Lawrence Memorial Hospital

    Lawrence, Kansas, 66044

  • Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center

    Lebanon, New Hampshire, 03756

  • University of Kansas Cancer Center - Lee's Summit

    Lee's Summit, Missouri, 64064

  • University of Kentucky/Markey Cancer Center

    Lexington, Kentucky, 40536

  • Smilow Cancer Center/Yale-New Haven Hospital

    New Haven, Connecticut, 06510

  • Yale University

    New Haven, Connecticut, 06520

  • Yale-New Haven Hospital North Haven Medical Center

    North Haven, Connecticut, 06473

  • University of Kansas Cancer Center at North Kansas City Hospital

    North Kansas City, Missouri, 64116

  • The University of Kansas Cancer Center - Olathe

    Olathe, Kansas, 66061

  • Smilow Cancer Hospital-Orange Care Center

    Orange, Connecticut, 06477

  • University of Kansas Cancer Center-Overland Park

    Overland Park, Kansas, 66210

  • Mayo Clinic Hospital in Arizona

    Phoenix, Arizona, 85054

  • Mercy Hospital Pittsburg

    Pittsburg, Kansas, 66762

  • UPMC Hillman Cancer Center

    Pittsburgh, Pennsylvania, 15232

  • Mayo Clinic in Rochester

    Rochester, Minnesota, 55905

  • Salina Regional Health Center

    Salina, Kansas, 67401

  • Mayo Clinic in Arizona

    Scottsdale, Arizona, 85259

  • University of Kansas Health System Saint Francis Campus

    Topeka, Kansas, 66606

  • Smilow Cancer Hospital-Torrington Care Center

    Torrington, Connecticut, 06790

  • Smilow Cancer Hospital Care Center-Trumbull

    Trumbull, Connecticut, 06611

  • Smilow Cancer Hospital-Waterbury Care Center

    Waterbury, Connecticut, 06708

  • Smilow Cancer Hospital Care Center - Waterford

    Waterford, Connecticut, 06385

  • University of Kansas Hospital-Westwood Cancer Center

    Westwood, Kansas, 66205

Other trials in United States

Canada1 site

  • University Health Network-Princess Margaret Hospital

    Toronto, Ontario, M5G 2M9

Other trials in Canada

About this study

Official title: A Pilot Study of Tazemetostat and Pembrolizumab (MK-3475) in Advanced Urothelial Carcinoma

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To conduct a safety lead-in phase that identifies the safe recommended phase II dose for combination tazemetostat and pembrolizumab (MK-3475).

SECONDARY OBJECTIVES:

  1. To assess the safety and tolerability of pembrolizumab (MK-3475) in combination with tazemetostat.

II. To evaluate the objective disease response rate of combination tazemetostat and pembrolizumab (MK-3475) in patients with advanced urothelial carcinoma that is cisplatin resistant (Arm A) or cisplatin ineligible (Arm B).

III. To evaluate the progression free survival to combination tazemetostat and pembrolizumab (MK-3475) in patients with advanced urothelial carcinoma that is cisplatin resistant (Arm A) or cisplatin ineligible (Arm B).

IV. To evaluate immune-related response using tumor response by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) in combination tazemetostat and pembrolizumab (MK-3475) in patients with advanced urothelial carcinoma that is cisplatin resistant (Arm A) or cisplatin ineligible (Arm B) based on irRECIST criteria.

CORRELATIVE OBJECTIVES:

  1. To determine if EZH2 and H3K27me3 chromatin methylation determines disease response to EZH2 and PD1 inhibition in metastatic urothelial carcinoma by analyzing baseline tissue samples.

II. To determine if mutations in genes associated with histone methylation determine disease response to EZH2 and PD1 inhibition in metastatic urothelial carcinoma by analyzing baseline tissue samples.

III. To identify the immune response (T cell phenotypes), T-cell clonality with comparison to T-cell infiltrating lymphocytes and neoantigen profile of responsive and resistant urothelial carcinoma treated with combination anti-PD1 and EZH2i by analyzing blood and tissue samples throughout the study.

OUTLINE:

Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-21 and pembrolizumab intravenously (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 computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial and undergo collection of blood samples on study.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Being tested
Biospecimen Collection, Computed Tomography, Magnetic Resonance Imaging, Pembrolizumab, Tazemetostat
Medical subject headings
Carcinoma, Transitional Cell, Urinary Bladder Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

    Undergo collection of blood samples

  • Computed TomographyProcedure or surgery

    Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography

    Undergo CT

  • Magnetic Resonance ImagingProcedure or surgery

    Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan

    Undergo MRI

  • PembrolizumabBiological

    Also called BCD-201, GME 751, GME751, Keytruda

    Given IV

  • TazemetostatDrug

    Also called E 7438, E-7438, E7438, EPZ 6438

    Given PO

Study groups in NCT03854474
Study groupRoleWhat they receive
Treatment (tazemetostat, pembrolizumab)ExperimentalPatients 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.
Receives: Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Biological: Pembrolizumab; Drug: Tazemetostat

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to 21 days following the first dose of tazemetostat

Secondary outcomes (4)

  1. Incidence of adverse events

    Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5. All adverse events will be summarized as to type, grade, timing, frequency and attribution using frequencies and percentages

    Measured: Up to 30 days after treatment discontinuation

  2. Objective response rate (ORR)

    Response rates will be summarized in each cohort by proportions and 95% exact confidence intervals.

    Measured: Up to 1 year

  3. Progression free survival

    Will be summarized using the Kaplan-Meier product limit curve.

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

  4. Response rate

    Assessed by immune related Response Evaluation Criteria in Solid Tumors (irRECIST) for investigational purposes. Tumor response by irRECIST is defined as an immune-related partial response or complete response over a period of at least 4 weeks. Will define immune-related clinical benefit rate as immune-related stable disease, partial response, or complete response. Response rate by irRECIST will be summarized in each cohort by proportions and 95% exact confidence intervals.

    Measured: Up to 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Feb 2019
  2. Study start18 Nov 2019
  3. Primary completion30 Jun 2027 (estimated)
  4. Study completion30 Jun 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
30 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03854474
Sponsor's protocol ID
NCI-2019-01035
Other IDs
NCI-2019-01035, ETCTN 10183, 10183, 10183, P30CA060553
Status last verified
Jun 2026
First submitted
25 Feb 2019
Last updated
31 Jul 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

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