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    Summary
    EudraCT Number:2012-004083-21
    Sponsor's Protocol Code Number:E7438-G000-101
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-02-12
    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 ConcernedGermany - BfArM
    A.2EudraCT number2012-004083-21
    A.3Full title of the trial
    An Open-Label, Multicenter, Phase 1/2 Study of Tazemetostat (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid Tumors or With B Cell Lymphomas and Tazemetostat in Combination With Prednisolone in Subjects With Diffuse Large B Cell Lymphoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study on the Effect of Tazametostat (study drug) in Patients with Advanced Solid Tumors or with B Cell Lymphomas
    A.4.1Sponsor's protocol code numberE7438-G000-101
    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 number+1855500-1011
    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.3.4Pharmaceutical 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 codeEPZ-6438
    D.3.9.3Other descriptive nameE7438
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Relapsed or refractory Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Advanced solid tumor
    E.1.1.1Medical condition in easily understood language
    Cancer of a specific type of lymphocytes (white blood cells) that has not responded to, or stopped responding to other treatments
    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 LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    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 10003899
    E.1.2Term B-cell lymphoma
    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
    Phase 1
     To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of tazemetostat as a single agent administered orally twice daily (BID), continuously in 28-day cycles, in subjects with advanced solid tumors or with relapsed and/or refractory B cell lymphomas
    Phase 2
     To determine the objective response rate (ORR; complete response + partial response [CR + PR]) of tazemetostat in subjects with enhancer of zeste homolog 2 (EZH2) gene mutation positive or negative (wild-type) with histologically confirmed diffuse large B cell lymphoma (DLBCL) or follicular lymphomas (FL), with relapsed or refractory disease and the ORR of tazemetostat in combination with prednisolone in subjects with EZH2 wild-type DLBCL
    E.2.2Secondary objectives of the trial
    Phase 1
     To assess the effect of a high-fat meal on the bioavailability of tazemetostat
     To assess the effect of tazemetostat on exposure of midazolam, a cytochrome P450 (CYP)3A4 substrate
     To assess the preliminary activity of tazemetostat
    Phase 2
     To assess the effect of tazemetostat monotherapy and tazemetostat in combination with prednisolone on progression-free survival (PFS)
     To assess the effect of tazemetostat monotherapy and tazemetostat in combination with prednisolone on duration of response (DOR)
    All Phases and Cohorts
     To assess the safety and tolerability of tazemetostat monotherapy and tazemetostat in combination with prednisolone
     To assess the pharmacokinetic (PK) profile of tazemetostat monotherapy and tazemetostat in combination with prednisolone
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All Subjects:
    1. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Phase 2: ECOG performance status of 0 to 2.
    2. Life expectancy ≥ 3 months before starting tazemetostat.
    3. Subjects with a history of Hepatitis B or C are eligible on the condition that subjects have adequate liver function as defined by Inclusion Criterion #6 and are hepatitis B surface antigen negative and/or have undetectable hepatitis C virus (HCV RNA).
    4. Adequate renal function defined as calculated creatinine clearance ≥ 40 mL/min per the Cockcroft and Gault formula or local institutional standard formula.
    5. Adequate bone marrow function:
    a. Absolute neutrophil count (ANC)≥ 750/mm3 (≥ 0.75 × 109/L)
    b. Platelets ≥ 75,000/mm3 (≥ 75 × 10*9/L)
    c. Hemoglobin ≥ 9.0 g/dL
    6. Adequate liver function:
    a. Total bilirubin ≤ 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert’s syndrome
    b. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases)
    7. Time between prior anticancer therapy and first dose of tazemetostat as indicated in the protocol.
    8. Males or females aged ≥18 years at the time of informed consent (Phase 2). Males and females aged ≥16 years of age at time of informed consent (Phase 1).
    9. Females must not be lactating or pregnant at screening or baseline (as documented by a negative beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. All females will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutively amenorrheic, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). Females of childbearing potential must not have had unprotected sexual intercourse within 30 days prior to study entry and must agree to use a highly effective method of contraception(as per protocol), from the last menstrual period prior to randomization, during Treatment Cycles, and for 30 days after the final dose of study drug, and have a male partner who uses a condom.
    10. Male subjects must have had either a successful vasectomy OR they and their female partner must meet the criteria above (ie, not of childbearing potential OR practicing highly effective contraception and use a condom throughout the study period and for 30 days after study drug discontinuation).
    11. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.
    Phase 1 only (IGR and IB sites in France only):
    12. Histologically and/or cytologically confirmed advanced or metastatic solid tumor or B cell lymphomas that have progressed after treatment with approved therapies or for which there are no standard therapies available.
    Phase 2:
    13. Subjects must satisfy all of the following criteria:
    a. Have histologically confirmed DLBCL (including primary mediastinal B cell lymphoma), with relapsed or refractory disease following at least 2 lines of prior standard therapy, including alkylator/anthracycline (unless anthracycline–based chemotherapy is contraindicated)/anti-CD20-based therapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or equivalent) AND must be considered unable to benefit from intensification treatment with autologous hematopoietic stem cell transplantation (ASCT), as defined by meeting at least 1 of the following criteria:
     Relapsed following, or refractory to, previous ASCT
     Did not achieve at least a partial response to a standard salvage regimen(eg, rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE] or rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP])
     Ineligible for intensification treatment due to age or significant comorbidity
     Ineligible for intensification treatment due to failure to mobilize an acceptable number of hematopoietic stem cells
     Refused intensification treatment and/or ASCT
    OR
    b. Have histologically confirmed FL, all grades.
    c. Have provided sufficient archival tumor tissue that has been successfully tested for EZH2 mutation status and cell of origin (DLBCL only) at study specific laboratories allowing for allocation into an open cohort.
    d. Have measurable disease as defined by International Working Group-Non-Hodgkin’s Lymphoma
    E.4Principal exclusion criteria
    All Subjects:
    1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
    2. Subjects with known leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
    3. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) and any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
    4. Has a prior history of T-LBL/T-ALL.
    5. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors (including St John's Wort)
    6. Subjects unwilling to exclude Seville oranges, grapefruit juice, and grapefruit from their diet.
    7. Any prior treatment-related (ie, chemotherapy, immunotherapy, radiotherapy), clinically significant toxicities have not resolved to ≤ Grade 1 per CTCAE version 4.03, or prior treatment-related toxicities are clinically unstable and clinically significant at time of enrollment.
    8. Major surgery within 4 weeks before the first dose of study drug.
    9. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might impair the bioavailability of tazemetostat.
    10. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac ventricular arrhythmia.
    11. Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to > 480 msec.
    12. Venous thrombosis or pulmonary embolism within the last 3 months before starting tazemetostat.
    13. Active infection requiring systemic therapy.
    14. Known hypersensitivity to any component of tazemetostat, prednisolone/prednisone (combination cohort only), or inability to be treated with a Pneumocystis prophylaxis medication (combination cohort only).
    15. Immunocompromised subjects, including subjects known to be infected with human immunodeficiency virus (HIV).
    16. Any other major illness that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in this study.
    17. Females who are pregnant or breastfeeding.
    18. Subjects who have undergone a solid organ transplant.
    Phase 2 only:
    19. Subjects with noncutaneous malignancies other than B cell lymphomas.
     Exception: Subjects with another malignancy who have been disease-free for 5 years, or subjects with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1:
    The MTD and/or RP2D of tazemetostat as a single agent administered orally, b.i.d. continuously in 28-day cycles in subjects with advanced solid tumors or with relapsed and/or refractory B cell lymphomas.
    Phase 2:
    The objective response rate (ORR), defined as the proportion of complete response + partial response [CR + PR]) with tazemetostat in EZH2 mutation positive and negative (wild-type) subjects with histologically confirmed DLBCL or FL with relapsed or refractory disease. The 95% confidence interval (CI) of ORR will be based on a Clopper–Pearson exact formula. Each cohort will be evaluated separately.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1: Dose escalation will continue until the MTD is reached, or up to a maximum feasible dose of 1600 mg BID, whichever comes first. If no DLTs are observed, the RP2D will be determined based on safety, tolerability, activity, PK, and PD assessments.
    Phase 2: after end of trial database lock.
    E.5.2Secondary end point(s)
    Phase 1:
    • Preliminary efficacy (e.g., best overall response [BOR]) will be assessed in subjects in the Safety Analysis Set.
    • Food effect on bioavailability (AUC and Cmax) of tazemetostat.
    • Effect of tazemetostat on exposure (AUC and Cmax) to midazolam, its metabolites and 4β-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity.
    Phase 2:
    - PFS, defined as the time from the date of first dose to the date of first documentation of relapse, disease progression, or date of death, whichever occurs first.
    - DOR, defined as time from the first date of response (CR or PR, whichever is first recorded) to recurrence, objectively documented disease progression, or death.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The food effect and drug-drug interaction will be assessed after cycle 1.

    Other endpoints assessed after end of trial database lock.
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Food effect and drug-drug interaction.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial6
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    Australia
    Canada
    France
    Germany
    Italy
    Netherlands
    Poland
    Taiwan
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    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 years7
    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: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 50
    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 Yes
    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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 240
    F.4.2.2In the whole clinical trial 350
    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)
    All subjects in Phase 1 who remain on tazemetostat for 9 months or longer AND all subjects in Phase 2 who remain on tazemetostat for 24 months or longer (and are eligible to continue receiving tazemetostat) will transfer to a Rollover Study for monitoring and continued study drug at the Investigator’s and the Medical Monitor’s discretion.
    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 Decision2016-04-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-11-02
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