<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03010982</url>
  </required_header>
  <id_info>
    <org_study_id>EZH-103</org_study_id>
    <nct_id>NCT03010982</nct_id>
  </id_info>
  <brief_title>Open-Label, Multi-Center, Two-Part, Ph1 Study to Characterize the PKs of an Intravenous Micro-Dose of [14C]-Tazemetostat (EPZ 6438) and the ADME of an Oral [14C]-Labeled Dose of Tazemetostat in Subjects With B-Cell Lymphomas or Adv Solid Tumors</brief_title>
  <official_title>An Open-Label, Multi-Center, Two-Part, Phase 1 Study to Characterize the Pharmacokinetics of an Intravenous Micro-Dose of [14C]-Tazemetostat (EPZ 6438) and the Absorption, Distribution, Metabolism and Elimination of an Oral [14C]-Labeled Dose of Tazemetostat in Subjects With B-Cell Lymphomas or Advanced Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Epizyme, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ipsen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase 1, open-label, two-part study designed to characterize the PK of an IV dose&#xD;
      of approximately 12 µg tazemetostat that contains approximately 500 nCi of [14C] tazemetostat&#xD;
      and the ADME of an oral dose of 800 mg tazemetostat that contains approximately 400 µCi of&#xD;
      [14C]-labeled tazemetostat in three subjects with B-cell lymphomas or advanced solid tumors.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 20, 2018</start_date>
  <completion_date type="Actual">January 8, 2019</completion_date>
  <primary_completion_date type="Actual">January 8, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Plasma PK of [14C] tazemetostat, tazemetostat, and its metabolite EPZ-6930 after IV administration of approximately 12 µg of [14C] tazemetostat containing approximately 500 nCi of radioactivity and oral BID administration of 800 mg tazemetostat (AUC 0-7)</measure>
    <time_frame>Day 15</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Total recovery and relative excretion of radioactivity in urine and feces after an oral 800 mg dose of [14C] tazemetostat containing approximately 400 µCi (14.8 MBq) of radioactivity</measure>
    <time_frame>Day 16</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Estimate tazemetostat absolute bioavailability (F) after repeated oral administration of 800 mg BID (AUC 0-12 and AUC 0-~)</measure>
    <time_frame>Day 15</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare the total radioactivity concentration-time profiles in blood and plasma after oral administration of [14C] tazemetostat (AUC 0-t, AUC 0-12, AUC 0-~)</measure>
    <time_frame>Day 16</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine peak plasma concentration (Cmax) after oral administration of [14C] tazemetostat</measure>
    <time_frame>Day 16</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine the plasma terminal half-life (t1/2) after oral administration of [14C] tazemetostat</measure>
    <time_frame>Day 16</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma PK of tazemetostat and EPZ6930 after administration of an oral 800 mg dose of [14C] tazemetostat containing approximately 400 µCi (14.8 MBq) of radioactivity (Plasma AUC 0-t, AUC 0-12)</measure>
    <time_frame>Day 16</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine the peak plasma concentration (Cmax) of tazemetostat and EPZ6930 after administration of an oral 800 mg dose of [14C] tazemetostat containing approximately 400 µCi (14.8 MBq) of radioactivity</measure>
    <time_frame>Day 16</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine the time to peak plasma concentration (Tmax) tazemetostat and EPZ6930 after administration of an oral 800 mg dose of [14C] tazemetostat containing approximately 400 µCi (14.8 MBq) of radioactivity</measure>
    <time_frame>Day 16</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Diffuse Large B Cell Lymphoma</condition>
  <condition>Primary Mediastinal Lymphoma</condition>
  <condition>Mantle-Cell Lymphoma</condition>
  <condition>Follicular Lymphoma</condition>
  <condition>Marginal Zone Lymphoma</condition>
  <condition>Advanced Solid Tumors</condition>
  <arm_group>
    <arm_group_label>Tazemetostat and [14C] Tazemetostat</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tazemetostat 800 mg BID orally as tablets continuously starting on Day 1, with the exception of the morning dose on Day 16;&#xD;
A single IV dose of approximately 12 µg tazemetostat that contains approximately 500 nCi of [14C] tazemetostat on Day 15;&#xD;
A single oral dose of 800 mg tazemetostat as a solution containing approximately 400 µCi (14.8 MBq) of [14C] tazemetostat on Day 16.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tazemetostat and [14C] Tazemetostat</intervention_name>
    <description>Tazemetostat is a selective oral small molecule inhibitor of EZH2.</description>
    <arm_group_label>Tazemetostat and [14C] Tazemetostat</arm_group_label>
    <other_name>E7438, EPZ-6438</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male ≥ 18 years of age at time of consent&#xD;
&#xD;
          2. Female ≥ 18 years of age at time of consent and of non-childbearing potential. A woman&#xD;
             is considered to be of non-childbearing potential if she has reached a postmenopausal&#xD;
             state (≥ 12 continuous months of amenorrhea with no identified cause other than&#xD;
             menopause) or has undergone surgical sterilization (removal of ovaries and/or uterus).&#xD;
             Note: Postmenopausal state will be confirmed with FSH test completed during the&#xD;
             screening period.&#xD;
&#xD;
          3. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2&#xD;
&#xD;
          4. Has a life expectancy of &gt;3 months&#xD;
&#xD;
          5. Has EITHER histologically confirmed B-cell lymphomas including but not limited to&#xD;
             diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), primary mediastinal&#xD;
             B-cell lymphoma (PMBCL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), or&#xD;
             Hodgkin lymphoma (HL) and has relapsed or refractory disease following at least two&#xD;
             lines of prior standard therapy, including alkylator/anthracycline (unless&#xD;
             anthracycline-based chemotherapy is contraindicated)/anti-CD20-based therapy (R-CHOP,&#xD;
             rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone or&#xD;
             dexamethasone, or equivalent for non-Hodgkin lymphoma), AND must be considered unable&#xD;
             to benefit from intensification treatment with autologous hematopoietic stem cell&#xD;
             transplantation (ASCT) , as defined by meeting at least one of the following criteria:&#xD;
&#xD;
               -  Relapsed following, or refractory to, previous ASCT&#xD;
&#xD;
               -  Did not achieve at least a partial response to a standard salvage regimen (e.g.,&#xD;
                  R-ICE, rituximab, ifosfamide, carboplatin, etoposide, or R-DHAP, rituximab,&#xD;
                  dexamethasone, cytarabine, cisplatin)&#xD;
&#xD;
               -  Ineligible for intensification treatment due to age or significant comorbidity&#xD;
&#xD;
               -  Ineligible for intensification treatment due to failure to mobilize an acceptable&#xD;
                  number of hematopoietic stem cells&#xD;
&#xD;
               -  Refused intensification treatment and/or ASCT&#xD;
&#xD;
             OR&#xD;
&#xD;
          6. Histologically and/or cytologically confirmed advanced or metastatic solid tumor that&#xD;
             has progressed after treatment with approved therapies or for which there are no&#xD;
             standard therapies available&#xD;
&#xD;
          7. May have evaluable or measurable disease&#xD;
&#xD;
          8. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related&#xD;
             clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are&#xD;
             clinically stable, at time of consent&#xD;
&#xD;
          9. Time between the last dose of the latest therapy and the first dose of study drug:&#xD;
&#xD;
               1. Chemotherapy: cytotoxic - at least 21 days&#xD;
&#xD;
               2. Chemotherapy: nitrosureas - at least 6 weeks&#xD;
&#xD;
               3. Chemotherapy: non-cytotoxic (e.g. small molecule inhibitor) - at least 14 days&#xD;
&#xD;
               4. Monoclonal antibody (ies) - at least 28 days&#xD;
&#xD;
               5. Immunotherapy (e.g. tumor vaccine) - at least 28 days&#xD;
&#xD;
               6. Radiotherapy (RT) - at least 21 days for stereotactic radiosurgery, at least 12&#xD;
                  weeks for craniospinal, ≥50% radiation of pelvis, or total body irradiation&#xD;
&#xD;
               7. High dose therapy with autologous hematopoietic cell infusion - at least 60 days&#xD;
&#xD;
               8. Hematopoietic growth factor - at least 14 days&#xD;
&#xD;
         10. Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic&#xD;
             function as defined by criteria below:&#xD;
&#xD;
               1. Hemoglobin ≥9 g/dL&#xD;
&#xD;
               2. Platelet ≥75,000/mm3 (≥75 × 10^9/L)&#xD;
&#xD;
               3. ANC ≥750/mm3 (≥0.75 × 10^9/L)&#xD;
&#xD;
               4. PT&lt; 1.5 ULN&#xD;
&#xD;
               5. PTT&lt; 1.5 ULN&#xD;
&#xD;
               6. Creatinine &lt; 2.0 ULN&#xD;
&#xD;
               7. Conjugated bilirubin &lt; 1.5 × ULN&#xD;
&#xD;
               8. AST &lt;3 × ULN I. ALT &lt;3 × ULN NOTE: Laboratory results obtained during screening&#xD;
                  should be used to determine eligibility criteria. In situations where laboratory&#xD;
                  results are outside the permitted range, the investigator may retest the subject&#xD;
                  and the subsequent within range screening result may be used to determine the&#xD;
                  subject's eligibility&#xD;
&#xD;
         11. Subjects with a history of Hepatitis B or C are eligible on the condition that&#xD;
             subjects have adequate liver function as defined the protocol and are hepatitis B&#xD;
             surface antigen negative and/or have undectable HCV RNA.&#xD;
&#xD;
         12. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec&#xD;
&#xD;
         13. Subject must have regular bowel movements (minimum of 1 bowel movement every day or&#xD;
             every other day; no more than 3 bowel movements per day) for the past 2 weeks without&#xD;
             diarrhea (&gt;4 bowel movements per day) or constipation (fewer than 3 bowel movements in&#xD;
             1 week). No known medical history of a disease or syndrome that affects bowel function&#xD;
             (e.g., irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis,&#xD;
             etc.), fecal incontinence, and no history of significant opioid induced constipation&#xD;
             within the past 3 months&#xD;
&#xD;
         14. Subject must have the ability to regularly void urine with no current evidence of&#xD;
             urinary incontinence, urinary retention, uncorrected congenital defects that interfere&#xD;
             with normal urinary system function, chronic urinary tract infections, or other&#xD;
             conditions that may interfere with normal urinary bladder emptying. In the past 3&#xD;
             months, no obstructive uropathy, surgery affecting urinary system (e.g., radical&#xD;
             prostatectomy, TURP, etc.), urinary tract infection. Subjects with solitary kidney are&#xD;
             excluded from the study&#xD;
&#xD;
         15. Male subjects must refrain from donating sperm starting at the planned first dose of&#xD;
             study drug until 30 days following the last dose of study drug. Male subjects with a&#xD;
             female partner of childbearing potential must be vasectomized, or remain abstinent or&#xD;
             use a condom as defined in Section 8.3.8, starting at the planned first dose of study&#xD;
             drug until 30 days following the last dose of study drug. The reliability of sexual&#xD;
             abstinence should be evaluated in relation to the duration of the clinical trial and&#xD;
             the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar,&#xD;
             ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable&#xD;
             methods of contraception. Female partners of male subjects who are of childbearing&#xD;
             potential must also adhere to one of the following:&#xD;
&#xD;
               -  Placement of an intrauterine device or intrauterine system.&#xD;
&#xD;
               -  Established use of oral, injected or implanted hormonal methods of contraception.&#xD;
&#xD;
               -  Progesterone only oral contraception, where inhibition of ovulation is not the&#xD;
                  primary mode of action.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Subjects meeting ANY of the following criteria must NOT be enrolled in this study:&#xD;
&#xD;
          1. Has participated in a study in which [14C] was administered within the last 6 months&#xD;
             prior to screening for this study&#xD;
&#xD;
          2. Has CNS or leptomeningeal metastasis&#xD;
&#xD;
          3. Has had a prior malignancy other than the malignancies under study Exception: Subject&#xD;
             who has been disease-free for 3 years, or a subject with a history of a completely&#xD;
             resected non-melanoma skin cancer or successfully treated in situ carcinoma are&#xD;
             eligible&#xD;
&#xD;
          4. Has had major surgery within 3 weeks prior to enrollment NOTE: Minor surgery (e.g.,&#xD;
             minor biopsy, central venous catheter placement) is permitted within 3 weeks prior to&#xD;
             enrollment&#xD;
&#xD;
          5. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet&#xD;
             and all foods that contain those fruits from time of enrollment to while on study&#xD;
&#xD;
          6. Has cardiovascular impairment, history of congestive heart failure greater than NYHA&#xD;
             Class II uncontrolled arterial hypertension, unstable angina, myocardial infarction,&#xD;
             or stroke within 6 months prior to the planned first dose of tazemetostat; or&#xD;
             ventricular cardiac arrhythmia requiring medical treatment&#xD;
&#xD;
          7. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors&#xD;
             (including St. John's Wort) from 14 days prior to the first dose of study medications&#xD;
             (see&#xD;
             http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti&#xD;
             onsLabeling/ucm080499.htm; or http://medicine.iupui.edu/clinpharm/ddis/ for a list of&#xD;
             potent CYP3A4 inducers and inhibitors).&#xD;
&#xD;
          8. Has an active infection requiring systemic treatment&#xD;
&#xD;
          9. Is immunocompromised, including subjects with known history of infection with human&#xD;
             immunodeficiency virus (HIV)&#xD;
&#xD;
         10. Has known history of chronic infection with hepatitis B virus (hepatitis B surface&#xD;
             antigen positive) or hepatitis C virus (detectable HCV RNA)&#xD;
&#xD;
         11. Has had a venous thrombosis or pulmonary embolism within the 3 months prior to study&#xD;
             enrollment.&#xD;
&#xD;
             NOTE: Subjects with a history of a deep vein thrombosis &gt;3 months prior to study&#xD;
             enrollment who are on anticoagulation therapy with low molecular weight heparin are&#xD;
             eligible for this study.&#xD;
&#xD;
         12. Has known hypersensitivity to any of the components of study drug&#xD;
&#xD;
         13. Is unable to take oral medications, malabsorption syndrome or any other uncontrolled&#xD;
             gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that might impair the&#xD;
             bioavailability of study drug&#xD;
&#xD;
         14. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled&#xD;
             infection, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
         15. Is unwilling to adhere to contraception criteria from time of enrollment in study to&#xD;
             at least 30 days after last dose of study drug&#xD;
&#xD;
         16. Clinical history, current alcohol (ethanol), or illicit drug use which, in the&#xD;
             judgment of the investigator, will interfere with the subject's ability to comply with&#xD;
             the dosing schedule and protocol-specified evaluations&#xD;
&#xD;
         17. A history of bleeding (i.e., hemoptysis, hematuria, GI blood loss, epistaxis, or&#xD;
             others with greater than Grade 1 according to National Cancer Institute Common&#xD;
             Terminology Criteria Version 4.0 [NCI-CTC v4.0]) within 1 month prior to beginning&#xD;
             therapy or any clinical indications of current active bleeding&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>The Clatterbridge Cancer Centre NHS Foundation Trust</name>
      <address>
        <city>Bebington</city>
        <state>Wirral</state>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Liverpool and Broadgreen University Hospital Trust</name>
      <address>
        <city>Liverpool</city>
        <zip>L7 8XP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>December 19, 2016</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <last_update_submitted>June 23, 2023</last_update_submitted>
  <last_update_submitted_qc>June 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Mantle-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03010982
org study id: EZH-103
nct id: NCT03010982
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This is a Phase 1, open-label, two-part study designed to characterize the PK of an IV dose
      of approximately 12 µg tazemetostat that contains approximately 500 nCi of [14C] tazemetostat
      and the ADME of an oral dose of 800 mg tazemetostat that contains approximately 400 µCi of
      [14C]-labeled tazemetostat in three subjects with B-cell lymphomas or advanced solid tumors.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Plasma PK of [14C] tazemetostat, tazemetostat, and its metabolite EPZ-6930 after IV administration of approximately 12 µg of [14C] tazemetostat containing approximately 500 nCi of radioactivity and oral BID administration of 800 mg tazemetostat (AUC 0-7)
time frame: Day 15
measure: Total recovery and relative excretion of radioactivity in urine and feces after an oral 800 mg dose of [14C] tazemetostat containing approximately 400 µCi (14.8 MBq) of radioactivity
time frame: Day 16
measure: Estimate tazemetostat absolute bioavailability (F) after repeated oral administration of 800 mg BID (AUC 0-12 and AUC 0-~)
time frame: Day 15
measure: Compare the total radioactivity concentration-time profiles in blood and plasma after oral administration of [14C] tazemetostat (AUC 0-t, AUC 0-12, AUC 0-~)
time frame: Day 16
measure: Determine peak plasma concentration (Cmax) after oral administration of [14C] tazemetostat
time frame: Day 16
measure: Determine the plasma terminal half-life (t1/2) after oral administration of [14C] tazemetostat
time frame: Day 16
measure: Plasma PK of tazemetostat and EPZ6930 after administration of an oral 800 mg dose of [14C] tazemetostat containing approximately 400 µCi (14.8 MBq) of radioactivity (Plasma AUC 0-t, AUC 0-12)
time frame: Day 16
measure: Determine the peak plasma concentration (Cmax) of tazemetostat and EPZ6930 after administration of an oral 800 mg dose of [14C] tazemetostat containing approximately 400 µCi (14.8 MBq) of radioactivity
time frame: Day 16
measure: Determine the time to peak plasma concentration (Tmax) tazemetostat and EPZ6930 after administration of an oral 800 mg dose of [14C] tazemetostat containing approximately 400 µCi (14.8 MBq) of radioactivity
time frame: Day 16
arm group label: Tazemetostat and [14C] Tazemetostat
arm group type: Experimental
description: Tazemetostat 800 mg BID orally as tablets continuously starting on Day 1, with the exception of the morning dose on Day 16;
A single IV dose of approximately 12 µg tazemetostat that contains approximately 500 nCi of [14C] tazemetostat on Day 15;
A single oral dose of 800 mg tazemetostat as a solution containing approximately 400 µCi (14.8 MBq) of [14C] tazemetostat on Day 16.
intervention type: Drug
intervention name: Tazemetostat and [14C] Tazemetostat
description: Tazemetostat is a selective oral small molecule inhibitor of EZH2.
arm group label: Tazemetostat and [14C] Tazemetostat
other name: E7438, EPZ-6438
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Mantle-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
sharing ipd: No