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Tazemetostat and Pembrolizumab in Treating Patients With Locally Advanced or Metastatic Urothelial Carcinoma

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ClinicalTrials.gov Identifier: NCT03854474
Recruitment Status : Recruiting
First Posted : February 26, 2019
Last Update Posted : November 21, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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 or other places in the body (locally advanced/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.

Condition or disease Intervention/treatment Phase
Advanced Urothelial Carcinoma Locally Advanced Urothelial Carcinoma Metastatic Bladder Urothelial Carcinoma Metastatic Urothelial Carcinoma Stage III Bladder Cancer AJCC v8 Stage IIIA Bladder Cancer AJCC v8 Stage IIIB Bladder Cancer AJCC v8 Stage IV Bladder Cancer AJCC v8 Stage IVA Bladder Cancer AJCC v8 Stage IVB Bladder Cancer AJCC v8 Biological: Pembrolizumab Drug: Tazemetostat Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVES:

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

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

CORRELATIVE OBJECTIVES:

I. 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.

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of Tazemetostat and MK-3475 (Pembrolizumab) in Advanced Urothelial Carcinoma
Actual Study Start Date : May 17, 2019
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (tazemetostat, pembrolizumab)
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.
Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Tazemetostat
Given PO
Other Names:
  • E7438
  • EPZ-6438
  • EPZ6438




Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: Up to 1 year ]
    Response rates will be summarized in each cohort by proportions and 95% exact confidence intervals. Time to progression will be summarized using the Kaplan-Meier product limit curve.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 30 days after treatment discontinuation ]
    Will be assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5. All adverse events will be summarized as to type, grade, timing, frequency and attribution using frequencies and percentages


Other Outcome Measures:
  1. EZH2 and H3K27me3 chromatin methylation and mutations in genes associated with histone methylation [ Time Frame: Baseline ]
    Will determine if EZH2, H3K27me3 and mutations in genes associated with histone methylation determine disease response to EZH2 and PD1. Each gene will be related to response using Fisher's exact test.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients in Arm A may begin treatment after this registration
  • Patients in Arm B will be required to undergo a second registration by meeting PD-L1 eligibility criteria. A tissue sample must be submitted for central analysis of PD-L1 after eligibility are confirmed
  • 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: cisplatin ineligible as defined by the following criteria:

      • Impaired renal function with measured or calculated creatinine clearance (CrCl) < 60 mL/min (calculated by Cockcroft-Gault method or measured by 24 hour urine collection)
      • Eastern Cooperative Oncology Group (ECOG) performance status >= 2
      • Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4 grade >= 2 audiometric hearing loss (25 dB in two consecutive wave ranges)
      • CTCAE v.4 grade >= 2 peripheral neuropathy
      • New York Heart Association (NYHA) class III heart failure
    • Patients must undergo central analysis of tissue for PD-L1 status
    • Patients must be positive for PD-L1
    • If archival tissue is unavailable or insufficient for PD-L1 central analysis, a new biopsy must be performed
  • All patients must have measurable disease in accordance with RECIST criteria v1.1

    • 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
  • ECOG performance status =< 2
  • Patients must have a blood smear or manual differential performed at screening showing no significant morpholic abnormalities on complete blood count (CBC) testing
  • Leukocytes >= 3000/mcL (within 10 days of treatment initiation)
  • Absolute neutrophil count (ANC) >= 1500/mcL (within 10 days of treatment initiation)
  • Platelets >= 100 000/mcL (within 10 days of treatment initiation)
  • Hemoglobin >= 9 g/dL or >= 4.9 mmol/L (within 10 days of treatment initiation)
  • 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 (within 10 days of treatment initiation)

    • 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 (within 10 days of treatment initiation)
  • 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 (within 10 days of treatment initiation)
  • 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 (within 10 days of treatment initiation)
  • 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 (within 10 days of treatment initiation)
  • The effects of 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 potential must be willing to use an adequate method of contraception for the course of the study through 120 days 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 childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MK-3475 or tazemetostat administration
  • Ability to understand and the willingness to sign an Institutional Review Board (IRB) approved written informed consent document
  • Participants with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver are eligible

Exclusion Criteria:

  • 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) are not eligible

    • Note: patients with =< grade 2 neuropathy or =< grade 2 alopecia 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) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS) 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 a prior history of T-cell lymphoblastic lymphoma (T-LBL) or T-cell acute lymphoblastic leukemia (T-ALL) are not eligible
  • 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 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events (AEs) due to agents administered more than 4 weeks earlier are not eligible
  • Patients with a known additional malignancy that is progressing or requires active treatment are not eligible. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical 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 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 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 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 MK-3475 and tazemetostat, breastfeeding should be discontinued if the mother is treated with MK-3475 or tazemetostat

    • MK-3475 may have adverse effects on a fetus in utero. Furthermore, it is not known if 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 within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
  • Patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements:

    • They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective
    • They must have a CD4 count of greater than 250 cells/mcL
    • They must not be receiving prophylactic therapy for an opportunistic infection
  • 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
  • PD-L1 ELIGIBILITY (ARM B ONLY):
  • Patients in Arm B must have positive PD-L1 status as confirmed by central analysis prior to second step registration and treatment initiation

    • NOTE: positive PD-L1 expression is defined as a combined positive score (CPS) >= 10 and will be confirmed in a report from HistoGeneX

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03854474


Locations
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United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Site Public Contact    312-695-1301    cancer@northwestern.edu   
Principal Investigator: Maha H. Hussain         
United States, Kentucky
University of Kentucky/Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Site Public Contact    859-257-3379      
Principal Investigator: Zin W. Myint         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Maha H Hussain Northwestern University EDDOP

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03854474     History of Changes
Other Study ID Numbers: NCI-2019-01035
NCI-2019-01035 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ETCTN 10183
10183 ( Other Identifier: Northwestern University EDDOP )
10183 ( Other Identifier: CTEP )
P30CA060553 ( U.S. NIH Grant/Contract )
First Posted: February 26, 2019    Key Record Dates
Last Update Posted: November 21, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents