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    Summary
    EudraCT Number:2016-002044-16
    Sponsor's Protocol Code Number:20150292
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-10-25
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-002044-16
    A.3Full title of the trial
    A Phase 2/3 Multi-center Study of Evaluate the Safety and Efficacy of Blinatumomab in Subjects with Relapsed/Refractory Aggressive B-Cell Non Hodgkin Lymphoma
    Studio multicentrico di fase 2/3 volto a valutare la sicurezza e l’efficacia di blinatumomab nei soggetti con linfoma non Hodgkin a cellule B aggressivo recidivante/refrattario.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical phase 2/3 study to investigate the safety and efficacy of Blinatumomab in subjects with Non Hodgkin Lymphoma that did not respond to previous therapy or that relapsed after initially successful previous therapy
    Studio clinico di fase 2/3 volto a valutare la sicurezza e l’efficacia di blinatumomab per studiare la sicurezza e l’efficacia di blinatumomab in soggetti con linfoma non Hodgkin che non rispondono a precedenti terapie o che recidivano dopo il precedente trattamento inizialmente efficace.
    A.3.2Name or abbreviated title of the trial where available
    Studio clinico di fase 2/3 per studiare la sicurezza e l’efficacia di blinatumomab in soggetti con l
    A.4.1Sponsor's protocol code number20150292
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02910063
    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 SponsorAmgen 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 supportAmgen Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (EUROPE) GmbH
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.O. Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post codeCH-6300
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number0041413690300
    B.5.5Fax number0041413690400
    B.5.6E-mailMedinfoInternational@amgen.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/08/548
    D.3 Description of the IMP
    D.3.1Product nameBlinatumomab
    D.3.2Product code AMG 103, MT103
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBlinatumomab
    D.3.9.1CAS number 853426-35-4
    D.3.9.2Current sponsor codeAMG 103
    D.3.9.4EV Substance CodeSUB35403
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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
    Subjects with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (B-NHL)
    Soggetti affetti da linfoma non-Hodgkin da cellule B aggressive recidivante/refrattario
    E.1.1.1Medical condition in easily understood language
    Subjects with Non-Hodgkin Lymphoma which did not completely respond to treatment or has relapsed after first responding to therapy
    Soggetti affetti da linfoma non-Hodgkin che non hanno risposto pienamente al trattamento o che si è ripresentato dopo la prima risposta alla terapia
    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 PT
    E.1.2Classification code 10020067
    E.1.2Term High grade B-cell lymphoma Burkitt-like lymphoma
    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 10036710
    E.1.2Term Primary mediastinal large B-cell lymphoma
    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 10063908
    E.1.2Term Non-Hodgkin's lymphoma unspecified histology aggressive
    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 10012818
    E.1.2Term Diffuse large 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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 2:
    • estimate the complete metabolic response (CMR) rate following blinatumomab monotherapy administered in the second salvage (S2) treatment of transplant-eligible subjects with relapsed or refractory (R/R) aggressive B-NHL who have not achieved CMR1 following 2 cycles of standard platinum-based first salvage (S1) chemotherapy
    Phase 3:
    • compare the CMR rates following blinatumomab to those following investigator’s choice (IC) S2 chemotherapy
    Fase 2: Stimare il tasso di risposta metabolica completa (CMR) in seguito a blinatumomab in monoterapia somministrato nell’ambito del
    secondo trattamento di salvataggio (S2) di soggetti con B-NHL aggressivo recidivante o refrattario (R/R) idonei al trapianto che non hanno raggiunto una CMR1 dopo 2 cicli della prima chemioterapia di salvataggio (S1) standard a base di platino
    Fase 3:
    Confrontare i tassi di CMR dopo il trattamento a base di blinatumomab con quelli in seguito alla chemioterapia S2 scelta dallo sperimentatore
    E.2.2Secondary objectives of the trial
    Phase 2:
    • To evaluate the efficacy parameters following blinatumomab treatment, of:
    - Response duration
    - The rate of successful hematopoietic stem cell mobilization
    • To evaluate the safety of blinatumomab in the S2 setting
    Phase 3:
    • To compare the efficacy of blinatumomab to investigator’s choice chemotherapy (ICC) in:
    - Overall survival
    - Response duration
    - Rate of successful HSCs mobilisation
    - Ability to proceed to hematopoietic stem cell transplant (both autologous and allogeneic) rates among responding subjects (CMR) or those in sustained partial metabolic response (PMR)
    - Objective response rate (ORR; CMR + PMR)
    • To compare the safety profile of blinatumomab to that of ICC
    • To compare the quality of life reported by subjects treated with blinatumomab or ICC
    Phases 2 and 3
    • To characterize the pharmacokinetic parameters of blinatumomab administered to subjects with R/R aggressive B-NHL
    • Progression-free survival
    Fase 2: Valutare altri parametri di efficacia in seguito al trattamento con blinatumomab, tra cui:
    - Durata della risposta
    - Sopravvivenza libera da progressione (PFS)
    - Tasso di mobilizzazione di cellule staminali emopoietiche (HSC) avvenuta con successo
    Valutare la sicurezza di blinatumomab nel contesto S2
    Fase 3:
    Confrontare l’efficacia di blinatumomab con quella della chemioterapia scelta dallo sperimentatore in termini di:
    - Sopravvivenza globale (OS)
    - Durata della risposta
    - Tasso di successo di mobilitazione HSCs
    - Capacità di mobilizzazione delle HSC
    - Tassi di capacità a procedere al trapianto di cellule staminali emopoietiche (HSCT) (sia autologo sia allogenico) nei soggetti
    responder (CMR) o in quelli con risposta metabolica parziale (PMR) prolungata
    - Tasso di risposta obiettiva (ORR; CMR + PMR)
    - PFS
    Confrontare il profilo di sicurezza di blinatumomab con quello della chemioterapia scelta dallo sperimentatore
    Confrontare la qualità di vita riportata dai so
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    studyspecific
    activities/procedures OR subject's legally acceptable
    representative has provided informed consent prior to any study-specific
    activities/procedures being initiated when the subject has any kind of
    condition that, in the opinion of the investigator, may compromise the
    ability of the subject to give written informed consent.
    2. Age ≥ 18 at the time of informed consent
    3. Biopsy proven aggressive B-NHL, including DLBCL NOS, follicular
    lymphoma Grade 3B, Primary Mediastinal B-Cell Lymphoma, T-cell rich
    B-cell lymphoma, or DLBCL that represents transformation of indolent
    NHL, (including follicular, marginal zone, and lymphoplasmacytoid
    lymphoma) excluding chronic lymphocytic leukemia or Hodgkin
    Lymphoma. Subjects with prior indolent lymphoma must have received
    therapy after a diagnosis of transformation that is appropriate for
    aggressive histology as described in 4. The following histologies are not
    eligible:
    • Lymphoblastic lymphoma
    • Burkitt lymphoma
    • Mantle cell lymphoma
    Any histologies not specifically mentioned must be discussed with the
    medical monitor. For subjects enrolled in the phase 3 portion of study,
    pathologic samples will be submitted for central confirmation of disease
    histology.
    4. Refractory (no prior CMR) or relapsed (prior CMR) following front line
    treatment of standard multiagent chemotherapy containing an
    anthracycline AND an approved anti-CD20 agent. Examples of
    appropriate therapy include but are not limited to R-CHOP (14 or 21), RCHOEP,
    and DA-R-EOCH. For subjects with refractory disease and who
    have received radiotherapy, PET positivity should be demonstrated no
    less than 6 weeks after the last dose of radiotherapy
    5. Biopsy-proven confirmation of relapsed disease. For subjects with de
    novo aggressive B-cell lymphoma and primary refractory disease (ie
    never achieving CMR), biopsy of persistent disease is preferred but
    persistent PET positivity (ie Deauville ≥ 4) is acceptable at a minimum.
    For all subjects that have received radiotherapy for DLBCL, PET should
    be performed no less than 42 days (6 weeks) after the last dose of
    radiotherapy. For subjects with transformed disease that has been
    characterized as refractory, rebiopsy (core or excisional biopsy) with
    demonstration of persistent aggressive B-NHL is required
    6. Received a minimum of 2 cycles of standard of care platinum-based
    chemotherapy in the S1 setting and had a response of PMD, NMR, PMR as
    centrally assessed by PET-CT scan or received at least 1 cycle of S1
    chemotherapy and had evidence of PD as centrally assessed. A presalvage
    scan is required to be submitted to the central reader if a
    subject had only 1 cycle of pre-salvage chemotherapy.
    7. Radiographically measurable disease with a clearly demarcated nodal
    lesion at least 1.5 cm in its largest dimension or a target extranodal
    lesion at least 1.0 cm in its largest dimension
    8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
    9. Intention to proceed to HDT and autologous HSCT per institutional
    standards
    10. Laboratory parameters (completed within 14 days prior to
    enrollment and after the last cycle of S1 chemotherapy):
    Hematology:
    • Absolute neutrophil count (ANC) ≥ 1.0 x 1000000000/L
    • Platelets ≥ 75 x 1000000000/L
    Chemistry:
    • Creatinine clearance ≥ 50 mL/min (calculated using Cockcroft Gault
    equation)
    •Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) <
    3X upper limit of normal (ULN)
    •Total bilirubin (TBL) < 2x ULN (unless Gilbert's disease or if liver
    involvement with lymphoma)
    1. Il soggetto ha fornito il consenso informato prima di iniziare qualsiasi attività / procedura dello studio O il rappresentante
    legalmente riconosciuto del soggetto ha fornito il consenso informato prima che venga iniziata qualsiasi specifica attività/
    procedura per lo studio quando il soggetto ha qualsiasi tipo di condizione che, secondo il parere del medico, può compromettere la
    capacità del soggetto di dare un consenso informato scritto.
    2. Età ≥ 18 anni al momento del consenso informato
    3. B-NHL aggressivo da biopsia, tra cui DLBCL NOS, linfoma follicolare di grado 3 B, B-Cell linfoma primario del mediastino, linfoma
    a cellule B ricco di cellule T, o DLBCL che rappresenta la trasformazione di NHL indolente, (tra cui follicolari, zona marginale, e
    linfoma linfoplasmacitoide) escluso leucemia linfatica cronica o linfoma di Hodgkin. I soggetti con precedente linfoma indolente
    devono aver ricevuto la terapia dopo una diagnosi di trasformazione che è appropriata per l'istologia aggressiva come descritto in
    4.
    I seguenti istotipi non sono ammissibili:
    • linfoma linfoblastica
    • linfoma di Burkitt
    • linfoma a cellule mantellari
    Eventuali istotipi non espressamente menzionati devono essere discussi con il medical monitor. Per I soggetti iscritti alla fase 3 di studio, i campioni patologici saranno presentati per la conferma centralizzata dell’istologia della malattia.
    4. Refrattario (senza precedente CMR) o recidivato (con precedente CMR) dopo il trattamento di prima linea di chemioterapia con
    multiagente standard contenente un'antraciclina e un agente anti-CD20 approvato. Esempi di terapia appropriata includono ma
    non sono limitati a R-CHOP (14 o 21), RCHOEP e DA-R-EOCH. Per soggetti con malattia refrattaria, e che sono stati sottoposti a radioterapia, la positività PET deve essere dimostrata
    non meno di 6 settimane dopo la radioterapia
    5. Dimostrata evidenza di malattia recidivante confermata dalla biopsia. Per i soggetti con linfoma a cellule B de novo aggressivo e malattia refrattaria primario
    (CMR mai raggiunta) è preferita la biopsia di malattia persistente ma è accettabile al minimo la positività PET persistente (cioè
    Deauville ≥ 4). Per tutti i soggetti che hanno ricevuto la radioterapia per il DLBCL, la PET deve essere eseguita non meno di 42
    giorni (6 settimane) dopo l'ultima dose di radioterapia. Per i soggetti con malattia trasformata che è stato caratterizzata come
    refrattaria, è necessaria la ripetizione di biopsia (core o biopsia escissionale) con dimostrazione della persistente aggressivo BNHL.
    6. Chi ha ricevuto minimo 2 cicli di chemioterapia standard di cura a base di platino in ambito S1 ed ha avuto una risposta di PMD, NMR,
    PMR valutata centralmente da scansione PET-TC o ricevuto almeno 1 ciclo di chemioterapia e S1 avuto evidenza di PD come
    valutato centralmente.- Una scansione di pre-savage deve essere inviata alla lettura centralizzata se un soggetto ha avuto solo un ciclo di chemioterapia pre-salvavita.
    7. Malattia radiograficamente misurabile con una lesione nodale chiaramente delimitata ad almeno 1,5 cm nella sua dimensione
    maggiore o una lesione target extranodale di almeno 1,0 cm nella sua dimensione più grande
    8. Performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2
    9. Intenzionati a procedere e potenzialmente eleggibili per HDT e trapianto autologo per gli standard istituzionali
    10. Parametri di laboratorio (completati entro 14 giorni prima dell'arruolamento e dopo l'ultimo ciclo di chemioterapia S1):
    Ematologia: Conta assoluta dei neutrofili (ANC) ≥ 1,0 x 1000000000 / L; Le piastrine ≥ 75 x 1000000000 / L - Chimica: • clearance
    della creatinina ≥ 50 ml / min (calcolato utilizzandol’equazione di Cockcrift Gault); aspartato aminotransferasi (AST) / alanina aminotransferasi (ALT) <limite superiore 3X
     del normale (ULN); bilirubina totale (TBL) <2x ULN (a meno di malattia di Gilbert o di coinvolgimento del fegato con linfoma)
    E.4Principal exclusion criteria
    1. CMR following S1 chemotherapy
    2. Treatment within 30 days prior to randomization with another investigational device or drug study (ies). Other investigational procedures while participating in this study are excluded
    3. Prior anti-CD19-directed therapies
    4. Prior HDT with autologous HSCT
    5. Prior allogeneic HSCT
    6. Presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis
    7. Evidence of CNS involvement by NHL
    8. Known infection with human immunodeficiency virus or chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (anti-hepatitis C virus positive)
    9. History of malignancy other than B-NHL within the past 3 years with the exception of:
    • Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    • Adequately treated cervical carcinoma in situ without evidence of disease
    • Adequately treated breast ductal carcinoma in situ without evidence of disease
    • Prostatic intraepithelial neoplasia without evidence of prostate cancer
    • Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ
    10. Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing.
    11. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge.
    12. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
    13. Female subjects who are pregnant or breastfeeding or planning to become pregnant or breastfeed while receiving blinatumomab and for an additional 48 hours after the last dose of blinatumomab. (Females of child bearing potential should only be included after a confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test.)
    14. Female subjects of childbearing potential unwilling to use an effective method of contraception while receiving blinatumomab and for an additional 48 hours after the last dose of blinatumomab.
    Note: The pregnancy, breastfeeding and contraceptive requirements are specific for blinatumomab. The investigator is responsible for providing the subject (male and female) with pregnancy and breastfeeding (female only) avoidance requirements for other medications given during the study.
    1. CMR a seguito di chemioterapia S1
    2. Trattamento entro 30 giorni prima della randomizzazione con un altro dispositivo o farmaco sperimentale. Altre procedure
    sperimentali durante la partecipazione a questo studio sono esclusi
    3. terapie precedenti anti-CD19-diretti
    4. HDT precedente con autologo trapianto
    5. precedente HSCT allogenico
    6. Presenza di patologie del sistema nervoso centrale (CNS) clinicamente rilevanti come l'epilessia, paralisi, afasia, ictus, gravi
    lesioni cerebrali, demenza, morbo di Parkinson, la malattia cerebellare, sindrome cerebrale organica, o psicosi
    7. Evidenza di NHL a livello del CNS
    8. Infezione nota da virus dell'immunodeficienza umana o infezione cronica da virus dell'epatite B (superficie dell'epatite B
    positivo) o virus dell'epatite C (anti-virus dell'epatite C positivi)
    9. Storia di tumore maligno diverso da B-NHL negli ultimi 3 anni, con l'eccezione di:
    • Malignità trattate con intento curativo e senza malattia attiva conosciuta presenti per ≥ 3 anni prima dell’arruolamento e
    valutato come a basso rischio di recidiva da parte del medico
    • cancro della pelle non-melanoma o lentigo maligna o senza evidenza di malattia adeguatamente trattati
    • carcinoma cervicale in situ, senza evidenza di malattia adeguatamente trattati
    • carcinoma duttale mammario in situ senza evidenza di malattia trattato adeguatamente
    • neoplasia intraepiteliale prostatica senza evidenza di cancro alla prostata
    • carcinoma uroteliale invasivo papillare o carcinoma in situ adeguatamente trattato
    10. Il soggetto ha una nota la sensibilità alle immunoglobuline o uno qualsiasi dei prodotti o componenti da somministrare durante
    lo studio.
    11. il soggetto rischia di non essere disponibile per completare tutte le visite o le procedure dello studio, e / o di rispettare tutte le
    procedure dello studio richieste al meglio della conoscenza del ricercatore e del soggetto.
    12. Storia o evidenza di qualsiasi altro disturbo clinicamente significativo, condizione o malattia (ad eccezione di quelle descritte
    sopra) che, a giudizio dello sperimentatore o del medico dello sponsor, se consultato, porrebbe un rischio per la sicurezza del
    soggetto o potrebbe interferire con la valutazione dello studio, le procedure o il suo completamento.
    13. soggetti di sesso femminile in gravidanza o allattamento o che stanno pianificando una gravidanza o allattamento durante la
    ricezione Blinatumomab e per altre 48 ore dopo l'ultima dose di Blinatumomab. (Donne in età fertile devono essere incluse solo
    dopo un periodo mestruale confermato e devono avere un test di gravidanza negativo altamente sensibile nell'urina o nel siero.)
    14. soggetti di sesso femminile in età fertile che non vogliono usare un metodo contraccettivo efficace durante il trattamento con
    Blinatumomab e per altre 48 ore dopo l'ultima dose di Blinatumomab.
    • Nota: La gravidanza, l'allattamento al seno e la necessità di utilizzare contraccettivi sono specifici per Blinatumomab
    E.5 End points
    E.5.1Primary end point(s)
    Phases 2 and 3:
    • CMR as determined by central radiographic assessment of positron emission tomography-computed tomography (PET-CT) scans using the Lugano Classification
    Fasi 2 e 3 : CMR determinata mediante valutazione radiografica centrale delle scansioni di tomografia a emissione di positroni-tomografia computerizzata (PET-TC) usando la Lugano Classification
    E.5.1.1Timepoint(s) of evaluation of this end point
    From first subject randomised: 8, 13, 18, 23 months
    Dal primo soggetto randomizzato: 8, 13, 18, 23 mesi
    E.5.2Secondary end point(s)
    Key Secondary Endpoint:
    Phase 3:
    • OS
    Other Secondary Endpoints:
    Phase 2:
    • ORR
    • PFS
    • Duration of response (DOR)
    • Successful mobilization rate
    • HSCT (both autologous and allogeneic) rates among subjects with post-blinatumomab complete response (CMR) + partial response (PMR)
    • 100-day non-relapse mortality (NRM) after autologous HSCT
    • Blinatumomab concentration steady state, clearance, and half life
    • Incidence and severity of adverse events
    Phase 3:
    • Objective response rate (ORR; CMR+PMR)
    • PFS
    • DOR
    • Successful mobilization rate following protocol assigned therapy
    • HSCT (both autologous and allogeneic) rates among responding subjects (CMR or PMR)
    • 100-day NRM after autologous HSCT rate
    • Patient-reported clinical outcome assessments quality of life (QOLCOA) using the EQ-5D and FACT-Lymphoma tools
    • Blinatumomab steady state concentration and clearance
    • Safety:
    - Overall incidence and severity of treatment-emergent adverse events
    Exploratory Endpoints (Phase 2 and 3):
    • Pharmacodynamics, including descriptive analysis of quantitative and qualitative features of lymphocyte populations and serum or plasma concentrations of cytokines
    • Response rates and duration according to COO designation and c-myc
    and bcl-2 rearrangement and overexpression, R-IPI, Secondary IPI,
    NCCN IPI, as determined from pretreatment specimens
    • Quantitative analysis of CF CT-DNA as determined by analysis of
    tumor-associated mutations in CF CT-DNA from plasma collected at
    various timepoints before, during, and after treatment
    Fase 3:
    OS
    Altri endpoint secondari:
    Fase II:
    ORR
    PFS
    Durata della risposta (DOR)
    Tasso di mobilizzazione avvenuta con successo
    Tassi di HSCT (sia autologo sia allogenico) nei soggetti con risposta completa (CMR) + risposta parziale (PMR) dopo il trattamento
    con blinatumomab
    Mortalità senza recidiva (NRM) a 100 giorni dall’HSCT autologo
    Concentrazione allo stato stazionario, clearance ed emivita di blinatumomab
    Incidenza e gravità degli effetti avversi
    Fase 3:
    Tasso di risposta obiettiva (ORR; CMR + PMR)
    PFS
    DOR
    Tasso di mobilizzazione avvenuta con successo in seguito alla terapia prevista dal protocollo
    Tassi di HSCT (sia autologo sia allogenico) nei soggetti responder (CMR o PMR)
    Tasso di NRM a 100 giorni dall’HSCT autologo
    Valutazioni dell’outcome clinico qualità della vita (QOLCOA) riportate dai pazienti usando gli strumenti EQ-5D e FACT-Lymphoma
    Concentrazione allo stato stazionario e clearance di blinatumomab
    Sicurezza:
    - Incidenza e gravità complessiva degli eventi avversi al trattamento
    Endpoint esplorativi (fase 2 e 3):
    • Farmacodinamica, compresa un’analisi descrittiva di quantitativi e identificatore file XML: LPyOso7bbeXsM6wJ4ZhwQ5oTWWM=
    Pag 14/26
    Caratteristiche qualitative delle popolazioni linfocitarie e del siero o del plasma
    concentrazioni di citochine
    • Tassi di risposta e durata in base alla designazione COO e c-myc e riorganizzazione e sovraespressione bcl-2, R-IPI, IPI secondario, NCCN IPI, come determinato dai campioni di pretrattamento
    • Analisi quantitative di CF CT-DNA come determinata dall’analisi di mutazioni associate al tumore in CF CT-DNA dal plasma raccolto a diversi timepoints prima, durante e dopo il trattamento
    - Incidenza complessiva e gravità degli eventi avversi emersi durante il trattamento
    E.5.2.1Timepoint(s) of evaluation of this end point
    From first subject randomised: 18, 26 months
    Dal primo soggetto randomizzato: 18, 26 mesi
    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 No
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    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 Yes
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.4Number of treatment arms in the trial2
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA119
    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
    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
    Study completion will occur once 236 death events for phase 3 subjects have occurred or 12 months after the last subject in phase 3 is randomized if 236th death in phase 3 subjects is not observed
    Il completamento dello studio avverrà dopo che eventi di decesso si saranno verificati nella fase 3 o dopo 12 mesi dalla randomizzazione dell'ultimo soggetto se il 236° decesso non viene osservato nella fase 3
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months4
    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: 166
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 166
    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 state27
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 195
    F.4.2.2In the whole clinical trial 332
    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)
    in accordo al protocollo
    in accordo al protocollo
    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 Decision2016-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-10
    P. End of Trial
    P.End of Trial StatusCompleted
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