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    Summary
    EudraCT Number:2010-024132-41
    Sponsor's Protocol Code Number:BO21223
    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:2012-01-17
    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 number2010-024132-41
    A.3Full title of the trial
    A MULTICENTER, PHASE III, OPEN-LABEL,
    RANDOMIZED STUDY IN PREVIOUSLY
    UNTREATED PATIENTS WITH ADVANCED
    INDOLENT NON-HODGKIN'S LYMPHOMA
    EVALUATING THE BENEFIT OF GA101
    (RO5072759) PLUS CHEMOTHERAPY
    COMPARED WITH RITUXIMAB PLUS
    CHEMOTHERAPY FOLLOWED BY GA101 OR
    RITUXIMAB MAINTENANCE THERAPY IN
    RESPONDERS
    STUDIO DI FASE III, MULTICENTRICO, IN APERTO, RANDOMIZZATO, IN PAZIENTI AFFETTI DA LINFOMA NON-HODGKIN INDOLENTE AVANZATO NON TRATTATO IN PRECEDENZA, PER VALUTARE L`™EFFICACIA DI GA101 (RO5072759) PIU' CHEMIOTERAPIA, RISPETTO A RITUXIMAB PIU' CHEMIOTERAPIA, E SUCCESSIVA TERAPIA DI MANTENIMENTO CON GA101 O RITUXIMAB NEI PAZIENTI IN RISPOSTA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A MULTICENTER, PHASE III, OPEN-LABEL,
    RANDOMIZED STUDY IN PREVIOUSLY
    UNTREATED PATIENTS WITH ADVANCED
    INDOLENT NON-HODGKIN'S LYMPHOMA
    EVALUATING THE BENEFIT OF GA101
    (RO5072759) PLUS CHEMOTHERAPY
    COMPARED WITH RITUXIMAB PLUS
    CHEMOTHERAPY FOLLOWED BY GA101 OR
    RITUXIMAB MAINTENANCE THERAPY IN
    RESPONDERS
    STUDIO DI FASE III, MULTICENTRICO, IN APERTO, RANDOMIZZATO, IN PAZIENTI AFFETTI DA LINFOMA NON-HODGKIN INDOLENTE AVANZATO NON TRATTATO IN PRECEDENZA, PER VALUTARE L’EFFICACIA DI GA101 (RO5072759) PIÚ CHEMIOTERAPIA, RISPETTO A RITUXIMAB PIÚ CHEMIOTERAPIA, E SUCCESSIVA TERAPIA DI MANTENIMENTO CON GA101 O RITUXIMAB NEI PAZIENTI IN RISPOSTA
    A.4.1Sponsor's protocol code numberBO21223
    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 SponsorROCHE
    B.1.3.4CountryItaly
    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 supportF. Hoffman - La Roche Ltd.
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportGenentech Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoche S.p.A.
    B.5.2Functional name of contact pointEthics & Administrative Trial Unit
    B.5.3 Address:
    B.5.3.1Street AddressViale G.B. Stucchi 110
    B.5.3.2Town/ cityMonza (MB)
    B.5.3.3Post code20900
    B.5.3.4CountryItaly
    B.5.5Fax number+39 039 247 5085
    B.5.6E-mailITALY.INFO_CTA@ROCHE.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 nameGA101
    D.3.2Product code RO5072759
    D.3.4Pharmaceutical form 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.3.9.1CAS number 949142-50-1
    D.3.9.2Current sponsor codeRO5072759/F06
    D.3.9.3Other descriptive nameGA101
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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 Yes
    D.3.11.13.1Other medicinal product typeanticorpo monoclonale umanizzato e glicoingegnerizzato
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Mabthera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeRo 045-2294/V01
    D.3.9.3Other descriptive nameMabThera
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Yes
    D.3.11.13.1Other medicinal product typeanticorpo monoclonale murino/umano
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Mabthera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeRo 045-2294/V01
    D.3.9.3Other descriptive nameMabThera
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 Yes
    D.3.11.13.1Other medicinal product typeanticorpo monoclonale murino/umano
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Bendamustina
    D.2.1.1.2Name of the Marketing Authorisation holderMudipharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Powder 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 INNBENDAMUSTINE HYDROCHLORIDE
    D.3.9.1CAS number 3543757
    D.3.9.3Other descriptive nameRibomustin
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Yes
    D.3.11.13.1Other medicinal product typeagente antineoplastico alchilante
    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
    PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED INDOLENT NON-HODGKIN'S LYMPHOMA
    PAZIENTI AFFETTI DA LINFOMA NON-HODGKIN INDOLENTE AVANZATO NON TRATTATO IN PRECEDENZA
    E.1.1.1Medical condition in easily understood language
    PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED INDOLENT NON-HODGKIN'S LYMPHOMA
    PAZIENTI AFFETTI DA LINFOMA NON-HODGKIN INDOLENTE AVANZATO NON TRATTATO IN PRECEDENZA
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10029547
    E.1.2Term Non-Hodgkin's 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
    To evaluate the efficacy of GA101 plus chemotherapy followed by GA101 maintenance therapy compared with rituximab plus chemotherapy followed by rituximab maintenance therapy in
    patients with previously untreated advanced follicular lymphoma, as measured b investigator-assessed progression-free survival (PFS).
    valutare l’efficacia del trattamento di induzione con GA101 più chemioterapia, seguito da terapia di mantenimento con GA101, rispetto al trattamento con rituximab più chemioterapia, seguito da terapia di mantenimento con rituximab, misurata in termini di sopravvivenza libera da progressione (progression-free survival, PFS) sulla base della valutazione dello sperimentatore, in pazienti affetti da linfoma follicolare avanzato non trattato in precedenza.
    E.2.2Secondary objectives of the trial
    overall population:
    • To evaluate and compare investigator-assessed PFS between the two arms
    For overall population and follicular population, to evaluate and compare:
    • Independent Review Committee (IRC)–assessed PFS between thetwo arms
    • overall response and complete response (CR) after the end of induction treatment, as assessed by the investigator, between the two arms
    • overall response and CR after the end of induction treatment, as assessed by the IRC, between the two arms
    • overall survival, event-free survival (EFS), disease-free survival (DFS), duration of response, and time to next anti-lymphoma treatment between the two arms; EFS, DFS and duration of response will be based on investigator assessment.
    • the safety profiles between the two arms during induction and maintenance
    • To assess patient-reported outcomes
    • To evaluate medical resource utilization
    Per pop. globale:
    • valutare e confrontare PFS tra i 2 bracci in base alla valut. dello sperim.
    Per pop.globale e pop.con linfoma follicolare, valutare e confrontare:
    • PFS tra i 2 bracci in base alla valut.dal Comitato Indipendente di Revisione (IRC);
    • risposta globale e risposta completa (CR) tra i 2 bracci dopo la fine del tratt.di induzione, in base alla valut.dello sperim.;
    • risp.globale e risp.completa (CR) tra i 2 bracci dopo la fine del tratt.di induzione, in base alla valut. dell’IRC;
    • sopravv.globale, sopravv.libera da eventi (EFS), sopravv.libera da malattia (DFS), durata della risp. e tempo al successivo tratt.anti-linfoma tra i 2 bracci ;EFS, DFS e durata della risp. saranno determinate sulla base della valut. dello sperim.;
    • profilo di sicur. tra i 2 bracci durante fase di induz. e di manten.
    • valutare outcome riferiti dai pt
    • valutare utilizzo risorse mediche
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    PHARMACOGENETIC:
    Vers:1
    Date:2011/01/14
    Title:SAMPLE STORAGE FOR ROCHE CLINICAL REPOSITORY (RCR)
    Objectives:To learn more about:
    •How rituximab or GA101 works in the body
    •How to find the best dose of GA101 for a pt
    •Why some pt respond to rituximab or GA101 and others do not
    •Why some pt have side effects
    •The factors that may link to a disease or how a pt is affected
    •How best to develop tests for NHL and its treatment with rituximab or GA101
    •The course of NHL with or without treatment with rituximab or GA101

    FARMACOGENETICA:
    Vers:1
    Data:2011/01/14
    Titolo:RACCOLTA DI CAMPIONI PER L’ARCHIVIO CLINICO DI ROCHE (ROCHE CLINICAL REPOSITORY, RCR)
    Obiettivi:Capire meglio:
    •come agiscono rituximab/GA101 nel corpo
    •come determ. dose ottimale di GA101 per ogni pt
    •perché alcuni pt rispondono a rituximab o GA101 e altri no
    •perché alcuni pt sviluppano effetti indesiderati
    •fattori potenzialm.correlati alla comparsa della malattia e al modo in cui si manifesta in un pt
    •strategie migliori per svilupp.nuovi test per diagnosticare LNH e per valutare risp.al trattam.con rituximab o GA101
    •decorso del LNH con o senza trattam. con rituximab o GA101

    E.3Principal inclusion criteria
    • Histologically documented,CD20-positive, indolent B-cell NHL consisting of one of the following: follicular lymphoma (Grades 1−3a), splenic MZL, nodal MZL, or extranodal MZL
    • Stage III or IV disease, or Stage II bulky disease
    • For patients with follicular lymphoma: requirement for treatment, defined as
    meeting at least one of the following criteria:
    - Bulky disease, defined as a nodal or extranodal (except spleen) mass
    ≥7 cm in the greatest diameter
    Local symptoms or compromise of normal organ function due to progressive nodal disease or extranodal tumor mass
    Presence of B symptoms (fever, drenching night sweats, or unintentional
    weight loss of > 10% of normal body weight over a period of 6 months or less)
    - Presence of symptomatic extranodal disease (e.g., pleural effusions,
    peritoneal ascites)
    - Cytopenias due to underlying lymphoma (i.e., absolute neutrophil count
    < 1.0 × 109/L, hemoglobin < 10 g/dL, and/or platelet count < 100 × 109/L)
    Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm Symptomatic splenic enlargement
    • For patients with symptomatic splenic, nodal, or non-gastric extranodal MZL: disease that is de novo or has relapsed following local therapy (i.e., surgery or radiotherapy) and requires therapy, as assessed by the investigator
    For patients with symptomatic gastric extranodal MZL:
    Helicobacter pylori-negative disease that is de novo or has relapsed following
    local therapy (i.e., surgery or radiotherapy) and requires therapy,
    as assessed by the investigator, or H. pylori–positive disease that has
    remained stable, progressed, or relapsed following antibiotic therapy and
    requires therapy, as assessed by the investigator (see Appendix G for
    additional details regarding gastric extranodal MZL)
    • At least one bi-dimensionally measurable lesion (> 2 cm in its largest
    dimension by CT scan or MRI)
    In patients with splenic MZL, an enlarged spleen on CT scan or extending
    at least 2 cm below the costal margin by physical examination will
    constitute measurable disease providing that no explanation other than
    lymphomatous involvement is likely. For an enlarged liver to constitute the
    only measurable disease parameter, a liver biopsy showing proof of NHL
    in the liver is required.
    • Able and willing to provide written informed consent and to comply with the
    study protocol
    • Age ≥18 years
    • ECOG Performance status of 0, 1, or 2 (see Appendix H)
    • Adequate hematologic function (unless abnormalities are related to NHL),
    defined as follows:
    Hemoglobin ≥9.0 g/dL
    Absolute neutrophil count ≥1.5 x 109/L
    Platelet count ≥75 x 109/L
    • For men who are not surgically sterile: agreement to use a barrier method of contraception during the treatment phase and for at least 3 months after the last dose of GA101, rituximab, or bendamustine, or according to institutional guidelines for CHOP or CVP chemotherapy, whichever is longer,and agreement to request that their partners use an additional method ofcontraception, such as oral contraceptives, intrauterine device, barrier method of contraception, or spermicidal jelly
    • For women of reproductive potential who are not surgically sterile: agreement to use two adequate methods of contraception, such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly during the treatment period and for at least 12 months after the last dose of GA101 or rituximab, for at least 3 months after the last dose of bendamustine, or according to institutional guidelines for CHOP or CVP chemotherapy, whichever is longer.
    • Linfoma non-Hodgkin a cellule B indolente, CD-20 positivo, con diagnosi istologica documentata di: linfoma follicolare (gradi da 1 a 3a), linfoma della zona marginale di tipo splenico, nodale o extranodale
    • Stadio di malattia III o IV, o stadio II con malattia bulky.
    • Per i pt con linfoma follicolare: necessità di tratt. se almeno uno dei seguenti criteri sarà soddisfatto:
    - Malattia bulky definita come una massa nodale o extranodale (esclusa la milza) ≥ 7 cm nel diametro maggiore.
    - Sintomi locali o compromissione della normale funzionalità d’organo dovuta a malattia nodale progressiva o a massa tumorale extranodale.
    - Presenza di sintomi B (febbre, profuse sudorazioni notturne, perdita di peso non intenzionale superiore al 10% del peso corporeo in un periodo di 6 mesi o inferiore).
    - Presenza di malattia extranodale sintomatica (es.: effusione pleurica, ascite peritoneale).
    - Citopenia legata al linfoma (ovvero: conta totale dei neutrofili &lt;1.0 x 109/L, emoglobina &lt; 10 g/dL, e/o conta piastrinica &lt; 100 x 109/L).
    - Coinvolgimento di ≥3 siti nodali ognuno con un diametro ≥ 3cm
    - Ingrossamento sintomatico della milza.
    • Per i pt con linfoma sintomatico della zona marginale di tipo splenico, nodale o extranodale non gastrico: malattia “de novo” o recidiva in seguito ad una terapia localizzata (ovvero chirurgia o radioterapia) che richiede un tratt., in base alla valut. dello sperim.
    • Per i pt con linfoma sintomatico della zona marginale di tipo extranodale gastrico: malattia negativa per Helicobacter Pylori, che è “de novo” o recidiva in seguito ad una terapia localizzata (ovvero chirurgia o radioterapia) e che richiede un tratt., in base alla valut. dello sperim.; o malattia positiva per Helicobacter Pylori, che in seguito ad una terapia antibiotica è rimasta stabile, è progredita o è recidiva e che richiede un tratt., in base alla valut. dello sperim.
    • Almeno 1 lesione misurabile in due dimensioni ( &gt; 2 cm nel suo diametro maggiore valutato tramite TAC o RMN). Nei pt con linfoma della zona marginale di tipo splenico, una milza ingrossata alla TAC o che si estende per almeno 2 cm sotto il margine costale all’esame obiettivo, può essere considerata come una malattia misurabile purché non sia verosimile una spiegazione diversa da un coinvolgimento linfomatoso. Nei casi in cui un fegato ingrossato sia l’unico parametro di malattia misurabile, è richiesta una biopsia epatica per la conferma di linfoma non-Hodgkin.
    • Pt in grado e disposto a fornire un consenso informato scritto e di rispettare il protocollo di studio
    • Età ≥18 anni.
    • ECOG performance status di 0, 1 o 2.
    • Profilo ematologico adeguato definito come segue (a meno che le anormalità non siano correlate al linfoma non-Hodgkin):
    - emoglobina ≥9 g/dL
    - conta assoluta dei neutrofili ≥1.5 x 109/L
    - conta delle piastrine ≥75 x 109/L
    • Uomini non chirurgicamente sterili disposti ad utilizzare un metodo contraccettivo di barriera durante il periodo di tratt. in studio e per almeno 3 mesi dopo l’ultima dose di GA101, rituximab, o bendamustina o in accordo alle linee guida istituzionali per la chemioterapia CHOP o CVP, a seconda di quale periodo sia più lungo e in accordo alla richiesta che la partner utilizzi un metodo contraccettivo addizionale come ad es. contraccettivi orali, dispositivi intrauterini, metodo di barriera o gel spermicida.
    • Donne potenzialmente fertili che non sono chirurgicamente sterili disposte ad utilizzare 2 metodi contraccettivi adeguati, come ad es. contraccettivi orali, dispositivi intrauterini, o metodo di barriera in associazione a gel spermicida durante il periodo di tratt. in studio e per almeno 12 mesi dopo l’ultima dose di GA101 o rituximab, per almeno 3 mesi dopo l’ultima dose di bendamustina o in accordo alle linee guida istituzionali per la chemioterapia CHOP o CVP, a seconda di quale periodo sia più lungo.
    E.4Principal exclusion criteria
    • History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (e.g., pts in whom dosing with rituximab would be contraindicated for safety reasons)
    • Known hypersensitivity to any of the study drugs
    • Known sensitivity to murine products
    • History of sensitivity to mannitol
    • Central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation to a high-grade or diffuse large B-cell lymphoma
    • Grade 3b follicular lymphoma, SLL, or WM
    • Ann Arbor Stage I disease
    • For patients with follicular lymphoma: prior treatment for NHL by chemotherapy, immunotherapy, or radiotherapy
    • For patients with non-follicular lymphoma: prior treatment with chemotherapy or immunotherapy
    • Regular treatment with corticosteroids during the 4 weeks prior to the start of Cycle 1, unless administered for indications other than NHL at a dose equivalent to ≤ 30 mg/day prednisone
    • History of prior malignancy with the exception of curatively treated basal or squamous cell carcinoma of the skin and low-grade in situ carcinoma of the cervix
    • Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
    • For pts who will be receiving CHOP: left ventricular ejection fraction < 50% by MUGA scan or echocardiogram
    • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 w. prior to the start of Cycle 1
    • Vaccination with a live vaccine within 28 days prior to randomization
    • Recent major surgery (within 4 w. prior to the start of Cycle 1), other than for diagnosis
    • Any of the following abnormal laboratory values (unless these abnormalities are due to underlying lymphoma):
    - Creatinine > 1.5 times the upper limit of normal (ULN) (unless creatinine clearance normal), or calculated creatinine clearance < 40 mL/min (using Cockcroft–Gault formula)
    - AST or ALT > 2.5 × ULN
    - Total bilirubin > 1.5× ULN (or > 3 × ULN for pts with documented Gilbert’s syndrome)
    - INR > 1.5 × ULN in the absence of therapeutic anticoagulation
    - PTT > 1.5 × ULN in the absence of a lupus anticoagulant
    • Positive test results for chronic hepatitis B infection (defined as positive HBsAg serology). Pts with occult or prior hepatitis B infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. This population will be limited to 50 pts.
    • Positive test results for hepatitis C (hepatitis C virus antibody serology testing). Pts positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
    • Known history of HIV seropositive status
    • Positive test results for human T-lymphotropic 1 (HTLV 1) virus
    • Pregnant or lactating
    • Life expectancy < 12 months
    •Anamnesi di reaz.allergiche severe o reaz.anafilattiche alle terapie con antic. monoclonali
    •Nota sensibilità ad uno qualsiasi dei farmaci in studio
    •Nota sensibilità ai prodotti murini
    •Anamnesi di sensibilità al mannitolo
    •Linfoma del SNC, linfoma leptomeningeo, o evidenza istologica di trasformazione in linfoma ad alto grado o linfoma diffuso a grandi cellule B
    •Linfoma follicolare di grado 3b, linfoma linfocitico a piccole cellule, o malattia di Waldestrom
    •Ann Arbor Stage I
    •Per i pt con linfoma follicolare: precedente tratt. per linfoma non-Hodgkin con chemioterapia, immunoterapia o radioterapia
    •Per i pt con linfoma non follicolare: precedente tratt.con chemioterapia o immunoterapia
    •Uso costante di corticosteroidi durante le 4 sett, prima dell’inizio del Ciclo 1, a meno che somministrati per indicaz. diverse da linfoma non-Hodgkin ad un dose equivalente a 30 mg/die di prednisone
    •Anamnesi di precedente neoplasia maligna ad eccezione di carcinoma cutaneo basocellulare o squamocellulare e carcinoma in situ della cervice di basso grado trattati con intento curativo
    •Evidenza di patologie concomitanti significative e non controllate, che potrebbero compromettere aderenza al protocollo o interpretazione dei risultati, tra cui malattie cardiovascolari significative (cardiopatia di classe III o IV secondo la New York Heart Association, grave aritmia, infarto del miocardio negli ultimi 6 mesi, aritmie o angina instabili) oppure malattie polmonari (tra cui malattie polmonari ostruttive e anamnesi di broncospasmo sintomatico).
    •Per i pt che ricevono CHOP: LVEF &lt; 50% misurata con MUGA o ecocardiogramma
    •Infez.attive di origine batterica, virale, fungina, micobatterica, parassitica o altre infez. (ad esclusione delle infez.fungine del letto ungueale) o qualsiasi episodio maggiore di infez. che richiede tratt. con antibiotici per via e.v. o ospedalizzazione (correlata al completamento del tratt. antibiotico) entro 4 sett. dall’inizio del ciclo 1.
    •Vaccinaz. con vaccini vivi meno di 28 gg. prima della random.
    •Recente intervento chirurgico importante (nelle 4 sett. precedenti l’inizio del Ciclo 1), ad esclusione di intervento necessario per la diagnosi.
    •Presenza di una qualsiasi delle seguenti anomalie dei parametri di lab (a meno che siano dovute al linfoma):
    - Creatinina &gt; 1.5 volte il limite superiore di normalità (a meno che la clearance della creatinina sia normale), oppure clearance renale della creatinina calcolata con la formula di Cockcroft-Gault &lt; 40 ml/min.
    - Aspartato aminotransferasi (AST) o alanina aminotransferasi (ALT) &gt; 2,5 volte il limite superiore di normalità.
    - Bilirubina totale ≥ 1.5 volte il limite superiore di normalità (UNL) (oppure &gt; 3 volte UNL nei pt con documentata malattia di Gilbert )
    -INR (International Normalized Ratio) &gt; 1.5 volte UNL in assenza di terapia anticoagulante.
    -Tempo di tromboplastina parziale (PTT) &gt; 1.5 volte UNL in assenza di lupus anticoagulante.
    •Risultati positivi ai test per l’infez. cronica da epatite B (definita come positività all'antigene di superficie dell'epatite B. Potranno essere inclusi massimo 50 pt con infez. da epatite B occulta o precedente (definita come positività all'anticorpo del core dell'epatite B e negatività HBsAg) se il DNA virale dell'epatite B non è rilevabile. Questi pt dovranno essere disposti ad effettuare controlli mensili del test HBV DNA.
    •Risultati positivi ai test per l’epatite C (positività all’ anticorpo del virus dell’epatite C). Pt positivi per l’antic. HCV saranno eleggibili solo se l’HCV RNA è negativo.
    •Infezione nota da HIV
    •Risultati positivi al Virus Umano T-Linfotrofico 1.
    •Donne in gravidanza o allattamento
    •Aspettativa di vita&lt;12 mesi
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint, PFS in patients with follicular lymphoma, is defined as the time from randomization to the first occurrence of progression or relapse as assessed by the investigator according to the Revised Response Criteria for Malignant Lymphoma, or death from any cause. PFS for patients without disease progression, relapse, or death will be censored at the time of the last tumor assessment, or if no tumor assessments were performed after the baseline visit, at the time of randomization.
    L’endpoint primario di efficacia è la PFS nei pazienti con linfoma follicolare, definita come il tempo dalla randomizzazione al verificarsi del primo evento di progressione o di recidiva, valutato dallo sperimentatore in conformità ai Revised Response Criteria for Malignant Lymphoma, o al decesso per qualsiasi causa. Nei pazienti che non sono progrediti, ricaduti o deceduti, la PFS sarà censita il giorno dell’ultima valutazione del tumore, oppure il giorno della randomizzazione se non sono disponibili valutazioni del tumore dopo la visita basale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS in patients with follicular lymphoma, is defined as the time from randomization to the first occurrence of progression or relapse as assessed by the investigator according to the Revised Response
    Criteria for Malignant Lymphoma, or death from any cause. PFS for patients without disease progression, relapse, or death will be censored at the time of the last tumor assessment, or if no tumor assessments were performed after the baseline visit, at the time of randomization.
    PFS nei pazienti con linfoma follicolare, definita come il tempo dalla randomizzazione al verificarsi del primo evento di progressione o di recidiva, valutato dallo sperimentatore in conformità ai Revised Response Criteria for Malignant Lymphoma, o al decesso per qualsiasi causa.
    Nei pazienti che non sono progrediti, ricaduti o deceduti, la PFS sarà censita il giorno dell’ultima valutazione del tumore, oppure il giorno della randomizzazione se non sono disponibili valutazioni del tumore dopo la visita basale.
    E.5.2Secondary end point(s)
    overall population:
    • Investigator-assessed PFS
    overall population and follicular population:
    • IRC-assessed PFS
    • CR and overall response (CR or PR) at the end of induction, as assessed by the investigator
    • CR and overall response (CR or PR) at the end of induction, as assessed by the IRC
    • Overall survival, defined as the time from randomization to death from any cause
    • EFS, defined as the time from randomization to disease progression/relapse as assessed by the investigator, death from any cause, or start of a new anti-lymphoma therapy a documented CR to disease progression as assessed by the investigator or death from any cause
    • Duration of response, defined for patients with a best overall response of CR or PR as the time from first occurrence of a documented CR or PR to disease progression/relapse as assessed by the investigator or death from any cause
    • Time to next anti-lymphoma treatment, defined as the time from random. to start of new non-protocol anti-lymphoma therapy or death from any cause
    • Change from baseline to the end of study in PROs based on the FACT-Lym instrument, as outlined below.
    - Change from baseline in all domains of the FACT-G
    - Change from baseline in the total outcome index (ranges from 0 to 116): sum of physical well-being (7 items), functional well-being (7 items), and Lym subscale (15 items) scores
    - Change from baseline in the FACT-Lym subscale score (ranges from 0 to 60): 15 lymphoma-specific items
    - Change from baseline in the FACT-Lym total score (ranges from 0 to 168): sum of physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and Lym subscale (15 items) scores
    • EQ-5D summary scores at baseline, during treatment, after treatment, at the last assessment prior to progression, and at the first assessment after progression
    • Medical resource utilization, including number of hospitalizations, length of hospital stay, types of subsequent drug therapies, and types of medical and surgical procedures (i.e., blood transfusions, bone marrow transplantation, or stem-cell transplantation)
    pop. globale:
    • PFS valutata dallo sperimentatore.
    popolazione globale e popolazione con linfoma follicolare:
    • PFS valutata dell’IRC
    • CR e risposta globale (CR o PR) alla fine della terapia di induzione, secondo la valutazione dello sperimentatore
    • CR e risposta globale (CR o PR) alla fine della terapia di induzione, secondo la valutazione dell’IRC
    • sopravvivenza globale, definita come il tempo dalla random. al decesso per qualsiasi causa
    • EFS, definita come il tempo dalla random. alla progressione/recidiva di malattia valutata dallo sperim., al decesso per qualsiasi causa o all’inizio di una nuova terapia anti-linfoma
    • DFS, definita, per i pazienti con una CR come migliore risposta globale, come il tempo dal primo evento documentato di CR alla progressione della malattia, in base alla valutazione dello sperimentatore, o al decesso per qualsiasi causa
    • Durata della risposta, definita, per i pazienti con una CR o PR come migliore risposta globale, come il tempo dal primo evento di CR o PR documentata alla progressione/recidiva di malattia, valutata dallo sperimentatore, o al decesso per qualsiasi causa
    • Tempo al successivo tratt. anti-linfoma, definito come il tempo dalla random. all’inizio di una nuova terapia anti-linfoma non prevista dal protocollo o al decesso per qualsiasi causa
    • Variazione dei PROs tra il basale e la fine dello studio in base al questionario FACT-Lym, come specificato di seguito.
    - Variazione dal basale di tutte le aree FACT-G.
    - Variazione dal basale dell’indice totale di outcome (range da 0 a 116): somma dei punteggi del benessere fisico (7 domande), del benessere funzionale (7 domande) e della sottoscala per i linfomi (15 domande).
    - Variazione dal basale del punteggio della sottoscala FACT-Lym (range da 0 a 60): 15 domande specifiche per i linfomi.
    - Variazione dal basale del punteggio totale FACT-Lym (range da 0 a 168): somma dei punteggi del benessere fisico (7 domande), del benessere sociale/familiare (7 domande), del benessere emotivo (6 domande), del benessere funzionale (7 domande) e della sottoscala per i linfomi (15 domande).
    • Punteggi riassuntivi EQ-5D al basale, durante il tratt., dopo il tratt., all’ultima valutaz. prima della progressione e alla prima valutaz. dopo la progressione.
    • Utilizzo di risorse mediche, inclusi il numero e la durata delle ospedalizzazioni, i tipi di terapie farmacologiche assunte dopo l’interruzione del tratt. in studio e i tipi di procedure mediche e chirurgiche effettuate (ossia emotrasfusioni, trapianto di midollo osseo o trapianto di cellule staminali).
    E.5.2.1Timepoint(s) of evaluation of this end point
    • OS=the time from randomization to death from any cause
    • EFS=the time from randomization to disease progression/relapse as assessed by the investigator, death from any cause, or start of a new anti-lymphoma therapy
    a documented CR to disease progression as assessed by the investigator or death from any cause
    • Duration of response, defined for patients with a best overall response of CR or PR as the time from first occurrence of a documented CR or PR to disease progression/relapse as assessed by the investigator or death from any cause
    • Time to next anti-lymphoma treatment, defined as the time from randomization to start of new non-protocol anti-lymphoma therapy or death from any cause
    • sopravv.globale=tempo da random. a decesso per qualsiasi causa
    • EFS=tempo da random. a progressione/recidiva di malattia valutata dallo sperim., a decesso per qualsiasi causa o a inizio di una nuova terapia anti-linfoma
    • DFS per i pt con una CR come migliore risp.globale=tempo da primo evento documentato di CR a progr. della malattia, in base alla valut. dello sperim., o a decesso per qualsiasi causa
    • Durata della risposta per i pt con una CR o PR come migliore risposta globale=tempo da primo evento di CR o PR documentata a progr./recidiva di malattia, valutata dallo sperim., o a decesso per qualsiasi causa
    • Tempo al successivo tratt. anti-linfoma=tempo da randomizz. a inizio di una nuova terapia anti-linfoma non prevista dal protocollo o a decesso per qualsiasi causa
    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 Yes
    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) No
    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 Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA160
    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
    Argentina
    Australia
    Bosnia and Herzegovina
    Brazil
    Canada
    Chile
    China
    Colombia
    El Salvador
    Guatemala
    Japan
    Mexico
    Panama
    Peru
    South Africa
    Taiwan
    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
    The date of the last follow-up visit (to occur 5 years after the last study treatment) of the last patient entered, or sooner, if all patients have progressed, died, or withdrawn from the study.
    Ultima visita di follow-up dell’ultimo pt arruolato (prevista 5 anni dopo l’ultima dose di trattame. dello studio) oppure prima se tutti i pt saranno in progressione di malattia, saranno deceduti oppure usciti prematuramente dallo studio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months128
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months128
    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.1.1Number of subjects for this age range: 0
    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: 900
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 500
    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 state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 746
    F.4.2.2In the whole clinical trial 1400
    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)
    Up to today there is no plan for treatment or care after a subject has ended his/her participation in the trial.
    Ad oggi non è previsto alcun programma per il trattamento o l'assistenza dei soggetti al termine della loro partecipazione allo studio.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation GLSG Study Group - Studienzentrale der Medizinischen Klinik III
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation NCRI Study Group
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-04-08
    P. End of Trial
    P.End of Trial StatusOngoing
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