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    Summary
    EudraCT Number:2015-002469-41
    Sponsor's Protocol Code Number:EZH-202
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-27
    Trial 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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-002469-41
    A.3Full title of the trial
    A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
    Studio di fase II multicentrico sull¿inibitore di EZH2 tazemetostat in soggetti adulti affetti da tumori INI1-negativi o sarcoma sinoviale recidivato/refrattario
    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 INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
    Studio sugli effetti di Tazemetostat (farmaco in studio) in soggetti adulti affetti da tumori INI1-negativi o sarcoma sinoviale recidivato/refrattario
    A.3.2Name or abbreviated title of the trial where available
    A Study of the Effect of Tazemetostat (study drug) in Patients with INI1-Negative Tumors or Relapsed
    Studio sugli effetti di Tazemetostat (farmaco in studio) in soggetti adulti affetti da tumori INI1-n
    A.4.1Sponsor's protocol code numberEZH-202
    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 number0018555001011
    B.5.5Fax number000000
    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 Yes
    D.2.1.1.1Trade name TAZVERIK [Trademark]
    D.2.1.1.2Name of the Marketing Authorisation holderEpizyme, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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]
    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.3.9.1CAS number 1403254-99-8
    D.3.9.2Current sponsor codeEPZ-6438
    D.3.9.4EV Substance CodeSUB178719
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Cohort 1: Rhabdoid tumors
    Cohort 2: Relapsed/refractory synovial sarcoma with SS18-SSX rearrangement
    Cohort 3: Other INI1-negative tumors or any solid tumor with EZH2 GOF (gain of function) mutation
    Cohort 4: Renal medullary carcinoma
    Cohort 5: Epithelioid sarcoma
    Cohort 6: Epithelioid sarcoma undergoing optional tumor biopsy
    Cohort 7: Poorly differentiated chordoma
    Coorte 1: tumore rabdoide
    Coorte 2: Sarcoma sinoviale recidivante/refrattario con riarrangiamento SS18-SSX
    Coorte 3: Altri tumori INI-1 negativi o qualsiasi tumore solido con una mutazione di acquisizione di funzione del gene EZH2
    Coorte 4: Carcinoma midollare renale
    Coorte 5: Sarcoma epitelioide
    Coorte 5: Sarcoma epitelioide
    Coorte 6: sarcoma epitelioide sottoposto a biopsia tumorale facoltativa
    Coorte 7: cordoma scarsamente differenziato
    E.1.1.1Medical condition in easily understood language
    INI1-negative tumors and synovial sarcoma
    Sarcoma sinoviale e tumori INI-1 negativi
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10026667
    E.1.2Term Malignant peripheral nerve sheath 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 10008747
    E.1.2Term Chordoma
    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 10042863
    E.1.2Term Synovial sarcoma
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10064886
    E.1.2Term Renal medullary carcinoma
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10073134
    E.1.2Term Extraskeletal myxoid chondrosarcoma
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10073335
    E.1.2Term Rhabdoid 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 HLT
    E.1.2Classification code 10015100
    E.1.2Term Epithelioid sarcomas
    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 10007284
    E.1.2Term Carcinoma
    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
    - To assess the overall response rate (ORR) in subjects with rhabdoid tumors (Cohort 1), other INI1-negative tumors or any solid tumor with EZH2 GOF mutation (Cohort 3), and renal medullary carcinoma (Cohort 4) and epithelioid sarcoma (Cohort 5), epithelioid sarcoma with optional tumor biopsy (Cohort 6) and chordoma (Cohort 7) following oral administration of tazemetostat 800 mg twice daily (BID)
    - To determine the progression-free survival (PFS) rate after 16 weeks of treatment with tazemetostat in subjects with relapsed/refractory synovial sarcoma (Cohort 2) following oral administration of tazemetostat 800 mg BID
    - To assess the safety and tolerability of tazemetostat 1600 mg QD (cohort 8)
    - Valutare ORR (Tasso di risposta complessiva) in soggetti affetti da tumori rabdoidi (Coorte 1), altri tumori INI1-negativi o qualsiasi tumore solido con mutazione di acquisizione di funzione del gene EZH2 (Coorte 3), carcinoma midollare renale (Coorte 4) e sarcoma epitelioide (Coorte 5), sarcoma epitelioide con biopsia tumorale facoltativa (Coorte 6) e cordoma (Coorte 7) dopo somministrazione orale di tazemetostat 800mg due volte al giorno (BID)
    - Determinare PFS (Tasso di sopravvivenza libera da progressione) dopo 16 settimane di trattamento con tazemetostat in soggetti affetti da sarcoma sinoviale recidivato/refrattario (Coorte 2) dopo somministrazione orale di tazemetostat 800 mg BID
    - determinare la sicurezza e tollerabilità di tazemetostat 1600 mg QD (coorte 8)
    E.2.2Secondary objectives of the trial
    -To evaluate duration of response in subjects from Cohorts 1 -7 and in Cohorts 1, 3, 4, 5, 6 and 7 combined for subjects achieving a complete response (CR) or partial response (PR) after oral admin of tazemetostat 800 mg BID and in subjects with epithelioid sarcoma in Cohort 8 at 1600 mg QD;
    -To assess: disease control rate (DCR) in subjects in Cohort 5 and 6 after oral admin of tazemetostat 800 mg BID and in subjects in Cohort 8 following oral admin of tazemetostat 1600 mg QD;
    -To assess the ORR in subjects in Cohort 2 after oral admin of tazemetostat 800 mg BID and in subjects in Cohort 8 following oral admin of tazemetostat 1600 mg QD;
    -To determine PFS and OS at Week 24,32&56&overall in subjects in Cohort 1-7 after oral admin of tazemetostat 800 mg BID and in subjects
    in Cohort 8 following oral admin of tazemetostat 1600 mg QD;
    - To assess: safety and tolerability of IMP (Cohort 1-7);
    -To assess PK of IMP;
    -To investigate the PD effects of IMP in tumor tissue.
    - Valutare durata risposta in sogg dalle Coorti 1-7 e nelle Coorti 1, 3, 4, 5, 6 e 7 accorpate per sogg che ottengono una Risposta complete (CR) o una Risposta parziale (PR) dopo somm orale di tazemetostat 800mg BID e nei sogg con sarcoma epitelioide nella Coorte 8 a 1600 mg QD
    - Valutare tasso di controllo della malattia (DCR) nei sogg nella Coorte 5 e Coorte 6 dopo somm orale di tazemetostat 800mg BID e nei soggetti nella Coorte 8 a seguito di somm orale di tazemetostat 1600mg QD
    - Valutare ORR nei soggetti nella Coorte 2 dopo somm orale di tazemetostat 800 mg BID e nei sogg nella Coorte 8 a seguito di somm orale di tazemetostat 1600mg QD
    - Determinare PFS e OS alle Settimane 24, 32 e 56 e complessivamente nei sogg nelle Coorti 1-7 dopo somm orale di tazemetostat 800mg BID e nei sogg nella Coorte 8 a seguito di somm orale di tazemetostat 1600mg QD
    - Valutare sicurezza e tollerabilità di IMP (Coorte 1-7)
    - Valutare PK di IMP
    - Analizzare gli effetti PD di IMP nel tessuto tumorale
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Age (at the time of consent/assent): major= 18 years of age
    2.Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
    NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is considered to be ambulatory for the purpose of assessing their performance status.
    3.Has provided signed written informed consent
    4.Has a life expectancy of >3 months
    5.Has a malignancy:
    •For which there are no standard therapies available (Cohorts 1, 3, 4 &5)
    •That is relapsed or refractory, defined as metastatic or nonresectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies), if therapy(ies) exists (Cohort 2)
    •That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion and Cohort 6 and 8 ONLY)
    6.Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or other Sponsor approved laboratory certification
    7.For Cohort 1 (subjects with rhabdoid tumors only): The following test results must be available by local laboratory:
    •Morphology and immunophenotypic panel consistent with rhabdoid tumors, and
    •Loss of INI1 or SMARCA4 confirmed by IHC, or
    •Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss or
    mutation when INI1 or SMARCA4 IHC is equivocal or unavailable
    8.For Cohort 2 (subjects with relapsed/refractory synovial sarcoma only): The following test results must be available by local laboratory:
    •Morphology consistent with synovial sarcoma, and
    •Cytogenetics or Fluorescence in situ hybridization (FISH) and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11)
    9.For Cohort 3,4, 5, 7& 8 (subjects with INI1-negative tumor or any solid tumor with EZH2 GOF mutation only): The following test results must be available by local laboratory:
    •Morphology and immunophenotypic panel consistent with INI1-negative tumors (not applicable for solid tumors with EZH2 GOF mutation), and
    •Loss of INI1 confirmed by IHC, or
    •Molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is equivocal or unavailable, or
    •Molecular evidence of EZH2 GOF mutation
    10.For Cohort 6 (subjects with epithelioid sarcoma undergoing optional tumor biopsy):
    •Morphology and immunophenotypic panel consistent with epithelioid sarcoma (e.g., CD34, EMA, Keratin, and INI1)
    •If providing optional biopsy: Willingness to provide informed consent to undergo pre- and post-dose biopsy
    11. 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
    12.Prior anti-cancer therapy(ies) according to the criteria described in the protocol.
    13.Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of IHC and/or cytogenetics/FISH and/or DNA mutation analysis (required for study entry but enrollment based on local results).
    14.Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors as defined in the protocol.
    Please, see Protocol Synopsis for other criteria and added changes
    1.Età (al momento del consenso/assenso): =maggiore 18 anni
    2.Punteggio della performance secondo la scala ECOG di 0, 1 o 2
    NB: se un soggetto non è in grado di camminare perché paralizzato, ma usa la sedia a rotelle, sarà considerato avente capacità di deambulazione ai fini della valutazione del performance status

    3.Ha consegnato una copia firmata del modulo di consenso informato
    4.Aspettativa di vita > 3 mesi
    5.Affetto da un tumore:
    •Per il quale non siano disponibili terapie standard (Coorti 1, 3, 4 e 5)
    •Recidivante o refrattario, definito metastatico o non operabile, localmente avanzato, sottoposto a pregresso trattamento e progredito a seguito di terapia/e approvata/e, ammesso che sia/siano disponibile/i (Coorte 2)
    •Progredito nei 6 mesi precedenti l’arruolamento dello studio (SOLO per espansione della Coorte 5, Coorte 6 e Coorte 8)
    6.Diagnosi documentata di un lab patologico locale, basata su una biopsia originaria e confermata da una certificazione di laboratorio Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) o rilasciato da un laboratorio approvato dallo sponsor
    7.Coorte 1 (soggetti con soltanto tumori rabdoidi): devono essere disponibili i risultati delle seguenti analisi effettuate da un lab locale:
    •Morfologia e pannello immunofenotipico coerente con tumori rabdoidi e
    •Perdita di INI1 o SMARCA4 confermata mediante IHC, o
    •Conferma molecolare della perdita INI1 o SMARCA4 bi-allelica o con mutazione di INI1 o SMARCA4 in cellule tumorali laddove l’esame IHC di INI1 dia risultati equivoci o non sia disponibile
    8.Coorte 2 (soltanto soggetti con sarcoma sinoviale recidivante/refrattario): devono essere disponibili i risultati delle seguenti analisi effettuate da un lab locale:
    •Morfologia coerente con sarcomi sinoviali, e
    •Conferma citogenetica o mediante FISH (Fluorescence In Situ Hybridization [Ibridazione fluorescente in situ]) e/o conferma molecolare (per es. sequenziamento del DNA) del riarrangiamento di SS18 t(X;18)(p11;q11)
    9.Coorti da 3, 4, 5, 7 e 8 (soggetti con tumore INI1-negativo o qualunque tumore solido con mutazione GOF a carico di EZH2): devono essere disponibili i risultati delle seguenti analisi effettuate da un lab locale:
    •Morfologia e pannello immunofenotipico coerente con tumori INI1-negativi (non applicabile per tumori solidi con mutazione GOF a carico di EZH2), e
    •Perdita di INI1 confermata mediante IHC, o
    •Conferma molecolare della perdita di INI1 bi-allelica o con mutazione di INI1 in cellule tumorali laddove l’esame IHC di INI1 dia risultati equivoci o non sia disponibile, o
    •Evidenza di mutazione GOF a carico di EZH2 alle analisi molecolari
    10.Coorte 6 (soggetti con sarcoma epitelioide sottoposto a biopsia tumorale facoltativa):
    •Morfologia e pannello immunofenotipico coerente con il sarcoma epitelioide (per es.CD34, EMA, cheratina e INI1)
    • Se è fornita biopsia facoltativa: disponibilità a fornire il consenso informato per essere sottoposti alla biopsia pre-dose e post-dose
    11.Tutti gli effetti tossici clinicamente significativi correlati ai trattamenti precedentemente ricevuti (es. chemioterapia, immunoterapia, radioterapia) devono essersi risolti a minore= Grado 1 in base ai CTCAE, versione 4.03 o sono clinicamente stabili e non clinicamente significativi all’atto dell’arruolamento
    12.Precedente/i terapia/e antitumorale/I secondo i criteri descritti nel protocollo
    13. Presenza di una quantità sufficiente di tessuto tumorale (vetrini o blocchi) per effettuare analisi di conferma presso il laboratorio centrale di tipo IHC e/o citogenetica/FISH e/o mutazioni del DNA (richieste per l’entrata nello studio, ma con l’arruolamento basato sui risultati ottenuti localmente).
    14.Presenza di una malattia misurabile sulla base dei criteri RECIST 1.1 per i tumori solidi o dei criteri RANO per i tumori dell’SNC come definito nel protocollo
    Si veda Sinossi del protocollo per altri criteri e modifiche introdotte
    E.4Principal exclusion criteria
    1.Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2)
    2.Has participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of tazemetostat 3. Has known active CNS or any leptomeningeal metastasis of primary extra-cranial tumor. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of study drug and any neurologic symptoms have stabilized), have no evidence of new or enlarging brain metastases, and are on stable or tapering doses of steroids for at least 7 days prior to first dose of study drug.
    NOTE: Subjects with asymptomatic brain metastases found on screening MRI may be entered into the study without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating Investigator and in the opinion of a radiation therapy or neurosurgical consultant.
    4.Has had a prior malignancy other than the malignancies under study Exception: 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.
    5.Has had major surgery within 3 weeks prior to enrollment
    NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment.
    6.Has thrombocytopenia, neutropenia, or anemia of Grade =3 (per CTCAE 4.03 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing.
    NOTE: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central laboratory. Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy.
    7.Has a prior history of T-LBL/T-ALL.
    8.Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study.
    9.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
    10.Is currently taking any prohibited medication(s) as described in the protocol.
    NOTE:Subjects with a history of hepatitis B or C with normal ALT and undetectable HBV DNA or HCV RNA are eligible for this study;
    11.Has an active infection requiring systemic treatment
    12.Is immunocompromised (ie has a congential immunodeficiency), including subjects known history of infection with human immunodeficiency virus (HIV)
    13.Has known active infection with hepatitis B virus or hepatitis C virus
    •Note - Subjects with a history of hepatitis B or C with normal ALT and undetectable HBV DNA or HCV RNA are eligible for this study
    14.Has had a symptomatic venous thrombosis within the 2 weeks prior to study enrollment.
    Please, see Protocol Synopsis for other criteria and added changes.
    1. Precedente esposizione a tazemetostat o ad altro/i inibitore/i di Enhancer of Zeste Homologue-2 [Potenziatore di zeste omologo-2] (EZH2)
    2. Precedente partecipazione a un altro studio clinico interventistico e assunzione di un farmaco sperimentale nei 30 giorni o 5 emivite, il periodo più lungo tra i due, precedenti la prima dose di tazemetostat
    3. Presenza di metastasi attive note dell’SNC o leptomeninge da tumore primario extracranico. I soggetti con metastasi cerebrali già trattate possono partecipare allo studio a condizione che siano stabili (senza segni di progressione alla scansione 4 settimane prima della prima dose del farmaco sperimentale e con stabilizzazione dei sintomi neurologici), nessuna evidenza di metastasi cerebrali di nuova formazione o in espansione, e terapia con dosi stabili o decrescenti di steroidi per almeno 7 giorni prima della prima dose del farmaco sperimentale.
    NB: è consentito arruolare soggetti con metastasi cerebrali asintomatiche evidenziate alla RMN in fase di screening senza pregressa radioterapia dell’encefalo se, a giudizio dello sperimentatore che li ha in carico e del radioterapista o del neurochirurgo, non necessitano di chirurgia o irradiazione immediata.
    4. Precedente tumore maligno diverso da quelli in studio
    Eccezione: sono eleggibili i soggetti liberi da malattia da 5 anni o con anamnesi di tumore cutaneo diverso dal melanoma completamente resecato o di carcinoma in situ trattato con successo.
    5. Intervento di chirurgia maggiore nelle 3 settimane precedenti l’arruolamento
    NB: interventi chirurgici minori (es. biopsia minore di sede extracranica, posizionamento di catetere venoso centrale, revisione di uno shunt) sono consentiti entro 3 settimane prima dell’arruolamento.
    6. Presenza di trombocitopenia, neutropenia o anemia di Grado =3 (in base ai criteri CTCAE 4.03) o eventuale anamnesi pregressa di neoplasie maligne di tipo mieloide, tra cui sindrome mielodisplastica (MDS). Presenza di anomalie note associate all’MDS (per es. del 5q, chr 7 abn) e all’MPN (per es. JAK2 V617F) osservate al test citogenetico e al sequenziamento del DNA.
    NB: l’aspirato/biopsia del midollo osseo sarà effettuato/a in presenza di una valutazione morfologica anomala di striscio di sangue periferico condotta dal laboratorio centrale. Il test citogenetico e il sequenziamento del DNA saranno condotti in presenza di un risultato anomalo dell’aspirato/biopsia del midollo osseo.
    7. Anamnesi pregressa di T-LBL/T-ALL.
    8. Riluttanza a escludere dalla dieta il succo di pompelmo, le arance amare e il pompelmo e tutti gli alimenti che contengono questi frutti, dal momento dell’arruolamento e per tutta la durata dello studio.
    9. Disfunzione cardiovascolare, anamnesi di insufficienza cardiaca congestizia di classe NYHA superiore a grado II, ipertensione arteriosa non controllata, angina instabile, infarto del miocardio o ictus nei 6 mesi precedenti la prima dose programmata di tazemetostat, oppure aritmia ventricolare cardiaca che richieda una terapia medica
    10. Terapia in atto con uno o più medicinale/i proibito/i come descritto nel protocollo
    NB: Soggetti con anamnesi di epatite B o C con valori normali di ALT e HBV DNA o HCV RNA non rilevabile sono idonei per questo studio;
    11. Presenza di un’infezione attiva che richieda una terapia per via sistemica
    12. Immunocompromissione (ovvero immunodeficienza congenita), compresi i soggetti con anamnesi di infezione da Human Immunodeficiency Virus [Virus dell’immunodeficienza umana]) (HIV)
    13. Infezione attiva da virus dell’epatite B o da virus dell’epatite C
    • NB: Soggetti con anamnesi di epatite B o C con valori normali di ALT e HBV DNA o HCV RNA non rilevabile sono idonei per questo studio
    14. Trombosi venosa sintomatica nelle 2 settimane precedenti l’arruolamento nello studio.
    Si veda Sinossi del protocollo per altri criteri e modifiche introdotte.
    E.5 End points
    E.5.1Primary end point(s)
    Cohorts 1 , 3, 4, 5,6 and 7 ORR (confirmed CR+PR) for tazemetostat in subjects with INI1-negative tumors using disease-appropriate standardized response criteria (primary CNS tumors: Response Assessment for Neuro-Oncology [RANO] and all others: RECIST 1.1).

    Cohort 2: PFS rate after 16 weeks of treatment with tazemetostat. This is the number of subjects with confirmed CR or PR, or stable disease (SD) at the Week 16 assessment.

    Cohort 8: Assessment of safety and tolerability of tazemetostat following 1600 mg oral administration QD
    Coorti 1, 3, 4, 5, 6 e 7: ORR (CR+PR confermate) per tazemetostat in soggetti affetti da tumori INI1-negativi utilizzando appropriati criteri di valutazione della risposta standardizzati (tumori primari dell’SNC: Response Assessment for Neuro-Oncology [RANO]; tutti gli altri: RECIST 1.1)

    Coorte 2: tasso di PFS dopo 16 settimane di trattamento con tazemetostat. Questo è il numero di soggetti con CR o PR o SD (Stable Disease [Malattia stabile]) confermata alla valutazione della Settimana 16

    Coorte 8: valutazione della sicurezza e della tollerabilità di tazemetostat a seguito della somministrazione orale di 1600 mg QD
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Cohorts 1 (rhabdoid tumors), 3 (other INI1-negative tumors), 4 (renal medullary carcinoma), 5 (epithelioid sarcoma), 6 (epithelioid sarcoma undergoing optional tumor biopsy and 7- ORR: every 8 weeks for tumor response until disease progression;

    - Cohort 2 (synovial sarcoma) – PFS: every 8 weeks until disease progression;

    - Cohort 8 assessment of AEs and clinical laboratory tests.
    Coorte 1 (tumori rabdoidi), 3 (altri tumori INI-1 negativi), 4 (carcinoma midollare renale) e 5 (sarcoma epitelioide), 6 (sarcoma epitelioide sottoposto a biopsia tumorale facoltativa e 7 - ORR: ogni 8 settimane dalla risposta del tumore fino a progressione della malattia;

    Coorte 2 (sarcoma sinoviale) - PFS: ogni 8 settimane fino a progressione della malattia;

    Coorte 8 valutazione di AEs e test clinici di laboratorio.
    E.5.2Secondary end point(s)
    - Duration of response for each cohort and for Cohorts 1, 3, 4, 5, 6, and 7 combined and Cohort 8. Duration of response, for the subset of subjects with a confirmed CR or PR, is defined as the time from the first documented evidence of confirmed CR or PR to the time of first documented disease progression or death due to any cause, whichever comes first, using disease-appropriate standardized response criteria;
    - Cohorts 5, 6 and 8: Disease control rate (DCR) for tazemetostat. This is defined as the number of subjects who achieve confirmed response (CR+PR) or who have SD lasting at least 32 weeks;
    - Cohorts 2 and 8: ORR (confirmed CR+PR, RECIST 1.1) for tazemetostat; PFS at Weeks 24, 32, and 56 and overall for each cohort. PFS is defined as the time from the 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 Weeks 24, 32, and 56 and overall for each cohort. OS is defined as the time from the date of the first dose of study treatment to the date of death due to any cause;
    - Cohort 1-7: Safety and tolerability of orally administered tazemetostat 800 mg BID;
    - Population PK parameters including but not limited to oral clearance (CL/F), oral volume of distribution (Vd/F), and first-order absorption rate constant (Ka), AUC and CMAX and apparent half-life; PD effects of tazemetostat in tumor tissue in IHC assessments of changes in the level of H3K27me3 following tazemetostat dosing.
    -Durata della risposta per ciascuna coorte e per le Coorti 1, 3, 4, 5, 6, e 7 accorpate e per la Coorte 8. La durata della risposta, per il sottogruppo di soggetti con una CR o una PR confermate, è definita come il tempo che intercorre dalla prima evidenza documentata di CR o PR confermata al momento della prima progressione della malattia documentata o al decesso per qualsiasi causa, a seconda di quale evento avviene per primo, utilizzando gli appropriati criteri standardizzati di valutazione della risposta
    - Coorti 5, 6 e 8: tasso di controllo della malattia (DCR) per tazemetostat, che è definito come il numero di soggetti che raggiungono una risposta confermata (CR+PR) o che presentano una SD che dura almeno 32 settimane.
    - Coorti 2 e 8: ORR (CR+PR confermate, RECIST 1.1) per tazemetostat;
    PFS alle Settimane 24, 32 e 56 e complessivamente per ciascuna coorte. Si definisce PFS il tempo che intercorre dalla data della prima dose del trattamento in studio alla data di progressione della malattia documentata o alla data di decesso per qualsiasi causa, a seconda di quale evento avviene per primo.
    - OS alle Settimane 24, 32 e 56 e complessivamente per ciascuna coorte. La OS è definita come il tempo che intercorre dalla data della prima dose del trattamento in studio alla data di decesso per qualsiasi causa.
    - Coorti 1-7: sicurezza e tollerabilità di tazemetostat somministrato per via orale 800 mg BID
    - Parametri di PK di popolazione inclusi, a titolo non esaustivo: clearance orale (CL/F), volume di distribuzione orale (Vd/F) e costante della velocità di assorbimento di primo ordine (Ka), AUC e CMAX ed emivita apparente
    Effetti PD di tazemetostat nel tessuto tumorale nelle valutazioni IHC dei cambiamenti dei livelli di H3K27me3 dopo somministrazione di tazemetostat.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Cohort 2 (synovial sarcoma) - ORR: every 8 weeks until disease progression
    All Cohorts -
    - PFS: every 8 weeks until disease progression and analyzed at 24 and 56 weeks. OS: continuously throughout the treatment period and then every 16 weeks until death or study completion
    - Response duration: every 8 weeks from the time of confirmed response (CR or PR) until disease progression or death.
    - Safety: At each visit or required timepoint during treatment and until for 30 days after last treatment or until new anti-cancer therapy
    - PK: Days 1, 15, 29, 43 and 57
    - PD: Any time after week 8
    Coorte 2 (sarcoma sinoviale) - ORR: ogni 8 settimane fino a progressione della malattia
    Tutte le Coorti -
    - PFS: ogni 8 settimane fino a progressione della malattia e analizzata a 24 e 56 settimane. OS: in maniera continuativa durante il trattamento e poi ogni 16 settimane fino a morte o completamento dello studio
    -Durata della risposta: ogni 8 settimane dal momento della conferma della risposta (CR o PR) fino a progressione dalla malattia o morte.
    - Sicurezza: Ad ogni visita o timepoint richiesto durante il trattamento e fino a 30 giorni dopo l'ultimo trattamento o fino a nuova terapia anti-tumorale
    -PK: Giorno 1, 15, 29, 43 e 57
    -PD: ogni momento dopo la settimana 8
    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 No
    E.8.1.2Open No
    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 trial8
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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 Information not present in EudraCT
    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
    Taiwan
    United States
    Belgium
    France
    Germany
    Italy
    United Kingdom
    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
    The end of study will occur when the last subject discontinues the study treatment and has had to opportunity to complete the safety follow-up
    visit or the long-term survival follow-up period, whichever is later. The study may end prior to this if 80% of enrolled subjects are deceased prior to the collection of the last survival follow-up.
    La fine dello studio avverrà quando l'ultimo soggetto interromperà il trattamento dello studio e avrà avuto l'opportunità di completare il la visita di follow-up di sicurezza o il periodo di follow-up di sopravvivenza a lungo termine, se successivo. Lo studio può terminare prima di questa data se l'80% dei soggetti arruolati è deceduto prima della raccolta dell'ultimo follow-up di sopravvivenza.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 266
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 291
    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)
    Subjects will be followed for safety for approximately 30 days after the last dose of tazemetostat. For subjects that discontinue dosing, participation will continue for survival follow- up and response for 2
    years from first dose of tazemetostat.
    I soggetti saranno seguiti per sicurezza per circa 30 giorni dopo l'ultima dose di tazemetostat. Per i soggetti che interrompono il dosaggio, la partecipazione continuerà per il follow-up di sopravvivenza e la risposta per 2 anni dalla prima dose di tazemetostat.
    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 Decision2016-02-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-09
    P. End of Trial
    P.End of Trial StatusOngoing
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