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    Summary
    EudraCT Number:2016-001139-10
    Sponsor's Protocol Code Number:EZH-203
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-03-22
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-001139-10
    A.3Full title of the trial
    A Phase 2, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects with Relapsed or Refractory BAP1 deficientMalignant Mesothelioma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of the Effect of Tazemetostat (study drug) in Patients with Relapsed or Refractory Mesothelioma
    A.4.1Sponsor's protocol code numberEZH-203
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEpizyme, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEpizyme, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEpizyme, Inc.
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address400 Technology Square, 4th Floor
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number001855500-1011
    B.5.6E-mailclinicaltrials@epizyme.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTAZEMETOSTAT
    D.3.2Product code EPZ-6438 (E7438)
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTAZEMETOSTAT
    D.3.9.2Current sponsor codeEZPZ-6438
    D.3.9.3Other descriptive nameESQR
    D.3.9.4EV Substance CodeSUB178719
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Part 1 – Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status
    Part 2 – Subjects with relapsed or refractory BAP1-deficient malignant mesothelioma
    E.1.1.1Medical condition in easily understood language
    Malignant mesothelioma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10027414
    E.1.2Term Mesotheliomas malignant and unspecified
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10027407
    E.1.2Term Mesothelioma malignant
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10027406
    E.1.2Term Mesothelioma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027408
    E.1.2Term Mesothelioma malignant advanced
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10062474
    E.1.2Term Mesothelioma malignant localized
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10027411
    E.1.2Term Mesothelioma malignant recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLGT
    E.1.2Classification code 10027412
    E.1.2Term Mesotheliomas
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1 (Pharmacokinetics)
    To assess the pharmacokinetic (PK) and safety profile of single and repeated doses of 800 mg tazemetostat administered as 400 mg tablets in subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status
    Part 2 (Efficacy)
    To assess disease control rate (DCR) at 12 weeks [consisting of complete response (CR), partial response (PR) or stable disease (SD)] according to modified RECIST [Nowak, 2005] for thoracic disease or RECIST 1.1 elsewhere in subjects with relapsed or refractory BAP1-deficient malignant mesothelioma treated with tazemetostat
    E.2.2Secondary objectives of the trial
    Parts 1 and 2
    To assess the safety and tolerability of tazemetostat
    To assess the overall response rate (ORR) in subjects with relapsed or refractory malignant mesothelioma treated with tazemetostat
    To determine the progression-free survival (PFS) and overall survival (OS) at 12 weeks, 24 weeks and overall in subjects with relapsed or refractory malignant mesothelioma treated with tazemetostat
    To evaluate the duration of response (DOR) in subjects with relapsed or refractory malignant mesothelioma achieving a CR or PR according to disease-appropriate criteria treated with tazemetostat
    Part 1
    To assess DCR at 12 weeks (consisting of CR, PR, and SD) in subjects with relapsed or refractory malignant mesothelioma treated with tazemetostat
    Part 2
    To assess the population PK parameters of tazemetostat
    To investigate the pharmacodynamic (PD) effects of tazemetostat in tumor tissue before and after treatment with tazemetostat (optional)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age (at the time of consent) ≥18 years of age
    2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
    3. Has a life expectancy of >3 months
    4.Has mesothelioma (pleural, peritoneal, pericardial, tunica vaginalis) of any histology that is relapsed or refractory after treatment with at least one pemetrexed-containing regimen
    5.Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or equivalent laboratory certification
    6.Part 2: Molecular evidence of BAP1 loss of function mutation present on local pathology, e.g., lack of nuclear BAP1 staining by immunohistochemistry (IHC)
    7. Has sufficient archival tumor tissue (a minimum of 10 slides or tumor block) available for central retrospective testing of BAP1 status
    8. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are clinically stable and not clinically significant, at time of enrollment
    9. Prior therapy(ies), if applicable, must be completed according to the criteria below prior to first dose of tazemetostat:
    a. Cytotoxic chemotherapy; at least 21 days since last dose
    b. Non-cytotoxic chemotherapy (e.g., small molecule inhibitor); at least 14 days since last dose
    c. Monoclonal antibody; at least 28 days since the last dose
    d. Non-antibody immunotherapy (e.g., tumor vaccine); at least 42 days since last dose
    e. Radiotherapy, at least 14 days from last local site radiotherapy
    f. Hematopoietic growth factor; at least 14 days from last dose
    g. Investigational drug; 30 days or five half-lives, whichever is longer, from last dose
    10. Has measurable disease based on either modified RECIST [Nowak 2005] for thoracic disease or RECIST 1.1 elsewhere
    11. Has adequate hematologic (bone marrow and coagulation factors), renal, and hepatic function as defined by criteria below:
    a. Hemoglobin ≥9 mg/dL
    b. Platelets ≥100,000/mm3 (≥100 × 109/L) without platelet transfusion for 7 days
    c. ANC ≥1000/mm3 (≥1.0 × 109/L) without growth factor support for 14 days
    d. Coagulation: Prothrombin time (PT) <1.5 × ULN and partial thromboplastin time (PTT) <1.5 × ULN
    e. Creatinine < 2.0 × ULN
    f. Hepatic function: Conjugated bilirubin <1.5 × ULN and ALT and AST <3 × ULN
    12. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec
    13. Willing to provide tissue for translational research
    14. Female subjects of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study drug; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required and subject also should agree to use an adequate method of contraception starting with screening through 30 days after the last dose of study therapy (if sexually active).
    15. Male subjects should agree to use condoms starting with the first dose of study therapy through 30 days after the last dose of study therapy if sexually active with a female of childbearing potential
    E.4Principal exclusion criteria
    1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2)
    2. Has a history of known central nervous system metastasis
    3. Has had a prior malignancy other than the malignancies under study
    Exception: A subject who has been disease-free for 5 years, or a subject with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible.
    4. Has had major surgery within 3 weeks prior to enrollment (a percutaneous biopsy, pleural catheter insertion, placement of central venous catheter or other minor procedure are permitted)
    5. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment throughout their time on study
    6. Has cardiovascular impairment, history of congestive heart failure greater than NYHA Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical treatment
    7. Is currently taking any prohibited medication(s)
    8. Has an active infection requiring systemic treatment
    9. Has a congenital or acquired immunodeficiency, including subjects with known history of infection with human immunodeficiency virus (HIV)
    NOTE: HIV-positive subjects who are taking antiretroviral therapy are ineligible due to potential PK interactions with tazemetostat.
    10. Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable anti-hepatitis C circulating viral RNA)
    11. Has had a deep venous thrombosis (DVT) or pulmonary embolism within the 2 weeks prior to study enrollment.
    NOTE: Subjects with a history of a DVT or pulmonary embolism >2 weeks prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study.
    12. Is pregnant or breastfeeding
    E.5 End points
    E.5.1Primary end point(s)
    Part 1
    Adverse events (AE) and clinical laboratory tests
    Maximum plasma concentration (Cmax), time of Cmax (Tmax), area under the plasma concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0-t), AUC from time 0 extrapolated to infinity (AUC0-∞) (single dose only), and the apparent terminal elimination half-life (t1/2) of tazemetostat after administration as 400-mg tablets.
    Part 2
    DCR (CR+PR+SD) at Week 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1
    End of Cycle 1

    Part 2
    DCR (CR+PR+SD) at Week 12
    E.5.2Secondary end point(s)
    Parts 1 and 2
    AE and clinical laboratory tests
    ORR (confirmed CR+PR) to tazemetostat in subjects with relapsed/refractory malignant mesothelioma using disease-appropriate standardized response criteria (modified RECIST or RECIST 1.1)
    PFS at 12 weeks, 24 weeks, and overall (defined as the time from date of first dose of study treatment to the earlier of the date of first documented disease progression or date of death due to any cause)
    OS at 12 weeks, 24 weeks, and overall (defined as the time from the date of the first dose of study treatment to the date of death due to any cause)
    DOR, for the subset of subjects with a confirmed CR or PR (defined as the time from the first documented evidence of CR or PR to the time of first documented disease progression or death due to any cause, using disease-appropriate standardized response criteria)
    Part 1
    DCR (CR+PR+SD) at Week 12
    Part 2
    Population PK parameters oral clearance (CL/F), oral volume of distribution (Vd/F), and first-order absorption rate constant (Ka) for tazemetostat
    Changes in H3K27me3 levels between pre- and post-dose tumor tissue
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part 1 and 2
    DCR (CR+PR+SD) at Week 12 and 24
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Trial will end when the last patient has been followed for 12 months survival or 80% of the patients are deceased
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 41
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state33
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 45
    F.4.2.2In the whole clinical trial 66
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Any subject continuing to receive clinical benefit may rollover and continue to receive treatment on an extension study.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-06-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-19
    P. End of Trial
    P.End of Trial StatusCompleted
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