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    Summary
    EudraCT Number:2013-005129-22
    Sponsor's Protocol Code Number:FIL_BRB
    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:2014-03-17
    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 number2013-005129-22
    A.3Full title of the trial
    FASE II STUDY WITH BORTEZOMIB, RITUXIMAB AND BENDAMUSTIN –BRB- FOR NON-HODGKIN LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA’S PATIENTS AT FIRST RELAPSE
    STUDIO DI FASE II CON BORTEZOMIB, RITUXIMAB E BENDAMUSTINA -BRB- IN PAZIENTI AFFETTI DA LINFOMA NON HODGKIN LINFOPLASMOCITICO/MORBO DI WALDENSTROM ALLA PRIMA RECIDIVA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    FASE II STUDY WITH BORTEZOMIB, RITUXIMAB AND BENDAMUSTIN –BRB- FOR NON-HODGKIN LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA’S PATIENTS AT FIRST RELAPSE
    STUDIO DI FASE II CON BORTEZOMIB, RITUXIMAB E BENDAMUSTINA -BRB- IN PAZIENTI AFFETTI DA LINFOMA NON HODGKIN LINFOPLASMOCITICO/MORBO DI WALDENSTROM ALLA PRIMA RECIDIVA
    A.4.1Sponsor's protocol code numberFIL_BRB
    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 SponsorFondazione Italiana Linfomi
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen and Cilag
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSegreteria Fondazione Italiana Linfomi Onlus
    B.5.2Functional name of contact pointSegreteria FIL
    B.5.3 Address:
    B.5.3.1Street AddressVia Venezia 16
    B.5.3.2Town/ cityAlessandria
    B.5.3.3Post code15121
    B.5.3.4CountryItaly
    B.5.4Telephone number00390131206129
    B.5.5Fax number00390131263455
    B.5.6E-mailsegreteria@filinf.it
    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 Velcade
    D.2.1.1.2Name of the Marketing Authorisation holderJANSSEN-CILAG SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameBortezomib
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous 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.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number375
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBENDAMUSTINE
    D.3.9.1CAS number 16506-27-7
    D.3.9.4EV Substance CodeSUB05707MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    NON-HODGKIN LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA’S PATIENTS
    Pazienti affetti da linfoma non-hodgkin linfoplasmocitico, morbo di Waldenstrom
    E.1.1.1Medical condition in easily understood language
    NON-HODGKIN LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA’S PATIENTS
    Pazienti affetti da linfoma non-hodgkin linfoplasmocitico, morbo di Waldenstrom
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10047801
    E.1.2Term Waldenstrom's macroglobulinaemia
    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
    This is a prospective, multicenter phase II trial designed to determine efficacy and safety of Bortezomib plus Rituximab plus Bendamustine in patients with relapsed/refractory Waldenstrom's Macroglobulinemia.
    Primary Objective is to assess whether the experimental treatment achieves an absolute increase of PFS rate from 50 to 65% at 18 months with respect to the standard treatment.

    Valutare l’efficacia e la sicurezza della chemioimmunoterapia in combinazione con Bortezomib, Rituximab e Bendamustina (BRB).
    Obiettivo principale: -determinare se il trattamento sperimentale BRB ottiene un aumento del tasso di PFS a 18 mesi dal 50 al 65% rispetto al trattamento standard.
    E.2.2Secondary objectives of the trial
    Secondary Objectives are to asses:
    -Overall Response Rate (ORR)
    -Overall Survival (OS)
    -Toxicity
    Obiettivi secondari:
    - tasso di risposta globale (ORR)
    - la sopravvivenza globale (OS)
    - il profilo di tossicità
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Histological proven diagnosis of Lymphoplasmacytic/citoid lymphoma/Waldenstrom macroglobulinemia according to REAL/WHO Classification
    -Relapsed/refractory disease after receiving one line chemotherapy
    -Age >= 18
    -Presence of at least one of the following criteria for the definition of active disease: Systemic symptoms or Hemoglobin less than 10 g/dL (due to lymphoma) or Platelets less than 100 x 109/L (due to lymphoma) or symptomatic splenomegaly or Bulky disease (>7 cm) or Hyperviscosity syndrome, peripheral neuropathy up to grade 1 (Waldenstrom's disease-related) , hemolytic anemia, and immune complex vasculitis
    -Life expectancy >6 months
    -ECOG performance status 0- 2
    -LVEF ≥45% or FS ≥37%
    -Creatinine up to 1.5 x ULN
    -Conjugated bilirubin up to 2 x ULN
    -Alkaline phosphatase and transaminases up to 2 x ULN
    -Written informed content
    - Esame istologico (midollo osseo o biopsia linfonodale) comprovante la diagnosi di linfoma NHL indolente CD20 positivo sulla base della classificazione REAL/WHO: lymphoplasmacytic/citoid lymphoma/ Waldenstrom macroglobulinemia
    - Pazienti con malattia in recidiva/progressione dopo una iniziale risposta ad una prima linea di chemioterapia o con malattia resistente ad una linea chemioterapica
    - Età >= 18 anni
    - Presenza di almeno uno dei seguenti criteri per la definizione di malattia attiva: sintomi costituzionali e/o citopenia e/o organomegalia e/o sindrome da iperviscosità e/o malattia bulky
    - Aspettativa di vita > 6 mesi
    - ECOG performance status 0-2
    - PMN >1 x109/l
    - Piastrine >50 x 109/l
    - Frazione d’eiezione cardiaca ≥37%
    - Creatinina non superiore a 1.5 volte i valori normali
    - Bilirubina non superiore a 2 volte i valori normali
    - Fosfatasi alcalina e transaminasi non superiori a 2 volte i valori normali
    -Comprensione e firma volontaria del consenso informato
    E.4Principal exclusion criteria
    -Patients not agreeing to take adequate contraceptive precautions during and for at least 6 months after cessation of therapy
    -History of other malignancies within 3 years prior to study entry except for: adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage, localized prostate cancer treated surgically with curative intent; good prognosis DCIS of the breast treated with lumpectomy alone with curative intent
    -Medical condition requiring long term use (>1 months) of systemic corticosteroids
    -Active bacterial, viral, or fungal infection requiring systemic therapy
    -Peripheral neuropathy of any grade >=2
    -Concurrent medical condition which might exclude administration of therapy
    -Cardiac insufficiency (NYHA grade III/IV)
    -Myocardial infarction within 6 months of entry on study
    -Severe chronic obstructive pulmonary disease with hypoxemia
    -Severe diabetes mellitus difficult to control with adequate insulin therapy
    -Hypertension that is difficult to control
    -Impaired renal function with creatinine clearance <30 ml/min
    -HIV positivity
    -HBV positivity with the exception of patients HbsAg and HBV-DNA negative and Ab anti-HBcore positive (these patients need to receive prophylaxis with Lamivudine)
    -HCV positivity with the exception of patients with HCV RNA negative
    -Participation at the same time in another study in with investiogational drugs are used
    -Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins
    -Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent.
    -Women in pregnancy or breastfeeding
    - Uomini e donne in età fertile o donne potenzialmente in gravidanza, a meno di sterilità determinatachirurgicamente o che utilizzino adeguati metodi contraccettivi
    - Storia di altre neoplasie nei 3 anni precedenti all’arruolamento, ad eccezione del carcinoma in situ della cervice uterina adeguatamente trattato, carcinoma squamoso della pelle; carcinoma prostatico a basso grado, stadio iniziale, localizzato, trattato chirurgicamente a scopo eradicante; carcinoma duttale in situ della mammella a buona prognosi trattato con quadrantectomia a scopo eradicante
    - Condizioni mediche che richiedano terapia cronica con steroide (>1 mese)
    - Malattia attiva di HCV, HBV (nei pazienti con HbsAg e HBV-DNA negativi ma Ab anti-HBcore positivo obbligatoria la profilassi con Lamivudina)
    - HIV positività
    - Malattie attive batteriche virali o fungine che richiedano terapia sistemica
    - Neuropatia periferca di ogni grado > =2
    - Altra condizione medica che potrebbe escludere la somministrazione della terapia
    - Insufficienza cardiaca (NYHA classi III/IV)
    - Infarto miocardico acuto entro 6 mesi dall’arruolamento nello studio
    - Severa malattia cronica ostruttiva polmonare con ipossiemia
    - Diabete mellito severo con difficoltà ad ottenere un adeguato controllo con insulina
    -Ipertensione difficile da controllare
    -Insufficienza renale con clearance della creatinina <30 ml/min
    -HIV positività
    -HBV positività con l'eccezione dei pazienti HbsAg e HBV-DNA negative e Ab anti-HBcore positivo (questi pazienti devono ricevere la profilassi con lamivudina)
    -HCV positività ad eccezione dei pazienti con HCV RNA negativi
    -Concomitante partecipazione ad un altro studio in cui sono utilizzati farmaci sperimentali
    -Nota ipersensibilità o reazioni anafilattiche ad anticorpi murini o proteici
    -Qualsiasi altra condizione medica o psicologica che possa compromettere la possibilità di fornire adeguato consenso informato
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is the asses progression free survival (PFS).
    PFS is measured from the beginning of therapy to the date of disease progression, relapse or death from any cause.
    Patients without any relapse at the end of the follow-up will be censored at their last assessment date.
    L'endpoint primario è la sopravvivenza libera da progressione (PFS).
    PFS è misurata dall'inizio della terapia alla data di progressione della malattia, recidiva o morte per qualsiasi causa.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Minimum follow up time required for all patients will be 2 years.
    Tempo minimo di follow-up richiesto per tutti i pazienti sarà di 2 anni.
    E.5.2Secondary end point(s)
    Overall response rate (ORR): a patient is defined as a responder if he has a complete or very good partial or partial response.
    Overall survival (OS): measured from the beginning of therapy to the date of death from any cause. Patients alive at the time of the final analysis will be censored at the date of the last contact.
    Toxicity: severe, life- threatening, fatal (grade 3, 4 and 5) and/or serious adverse events are defined according to “Common Terminology Criteria for Adverse Events” (CTCAE)
    Tasso di risposta globale (ORR): un paziente viene definito come responder se ha una risposta parziale o completa o parziale molto buona.
    La sopravvivenza globale (OS): misurata dall'inizio della terapia alla data di morte per qualsiasi causa. Pazienti vivi al momento dell'analisi finale saranno censurati alla data dell'ultimo contatto.
    Tossicità: grave, pericolosa per la vita, fatale (grado 3, 4 e 5) e / o eventi avversi gravi sono definite in base a "criteri terminologia comune per gli Eventi Avversi" (CTCAE)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Minimum follow up time required for all patients will be 2 years; 5 years for the toxicity.
    Tempo minimo di follow-up richiesto per tutti i pazienti sarà di 2 anni; 5 anni per la tossicità.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 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 concerned40
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    xx
    xx
    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 months
    E.8.9.1In the Member State concerned days
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 31
    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 state61
    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)
    At the end of participation in the study patients will be followed as required by standard practice.
    Al termine della partecipazione allo studio i pazienti verranno seguiti secondo quanto previsto dalla comune pratica clinica.
    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 Decision2014-05-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-09
    P. End of Trial
    P.End of Trial StatusOngoing
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