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    Summary
    EudraCT Number:2011-005496-17
    Sponsor's Protocol Code Number:C16010
    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:2012-09-03
    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 number2011-005496-17
    A.3Full title of the trial
    A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma.
    Studio di Fase 3, randomizzato, in doppio cieco, multicentrico per confrontare MLN9708 orale in combinazione con lenalidomide e desametasone verso placebo in combinazione con lenalidomide e desametasone in pazienti adulti affetti da mieloma multiplo recidivante e/o refrattario
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    To determine whether adding MLN9708 to the combination of lenalidomide and dexamethasone improves survival in patients with multiple myeloma whose disease is no longer responding or has not responded, to previous treatment.
    Studio per valutare se l'aggiunta di MLN9708 a lenalidomide e desametasone migliora la soprevvivenza nei pazienti con mieloma multiplo che non rispondono o non rispondono pi?recedenti trattamenti.
    A.4.1Sponsor's protocol code numberC16010
    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 SponsorMILLENNIUM PHARMACEUTICALS, 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 supportMillennium Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMillennium Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointMillennium, Drug Information Call C
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne Street
    B.5.3.2Town/ cityCambridge, MA
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 510 740 2412
    B.5.5Fax number+1 800 881 6092
    B.5.6E-mailmedical@mlnm.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/3/11/899
    D.3 Description of the IMP
    D.3.1Product nameMLN9708 2.3 mg
    D.3.2Product code NA
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIxazomib
    D.3.9.1CAS number 1239908-20-3
    D.3.9.2Current sponsor codeMLN9708
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.3
    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.IMP: 2
    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/3/11/899
    D.3 Description of the IMP
    D.3.1Product nameMLN9708 3.0 mg
    D.3.2Product code NA
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIxazomib
    D.3.9.1CAS number 1239908-20-3
    D.3.9.2Current sponsor codeMLN9708
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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.IMP: 3
    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/3/11/899
    D.3 Description of the IMP
    D.3.1Product nameMLN9708 4.0 mg
    D.3.2Product code NA
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIxazomib
    D.3.9.1CAS number 1239908-20-3
    D.3.9.2Current sponsor codeMLN9708
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed and/or Refractory Multiple Myeloma
    Mieloma multiplo refrattario e/o recidivante.
    E.1.1.1Medical condition in easily understood language
    Cancer
    Cancro
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.0
    E.1.2Level PT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    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 determine whether the addition of oral MLN9708 to the background therapy of lenalidomide and dexamethasone improves progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (RRMM)
    • Stabilire se l’aggiunta di MLN9708 orale alla terapia di background con lenalidomide e desametasone migliori la sopravvivenza libera da progressione (PFS, progression-free survival) in pazienti affetti da mieloma multiplo recidivante e/o refrattario (RRMM, relapsed and/or refractory multiple myeloma)
    E.2.2Secondary objectives of the trial
    -To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone improves overall survival (OS) - To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone improves the OS in high-risk patients carrying deletion del(17)
    • Stabilire se l’aggiunta di MLN9708 orale a lenalidomide e desametasone migliori la sopravvivenza globale (OS, overall survival) • Stabilire se l’aggiunta di MLN9708 orale a lenalidomide e desametasone migliori la OS in pazienti ad alto rischio portatori della delezione del(17)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male or female patients 18 years of age or older. 2.Multiple myeloma diagnosed according to standard criteria either currently or at the time of initial diagnosis. NOTE: The initial diagnosis must be symptomatic MM, although the relapsed disease does not need to be symptomatic. 3.Patients must have measurable disease defined by at least 1 of the following 3 measurements: •Serum M-protein ≥ 1 g/dL (≥ 10 g/L). •Urine M-protein ≥ 200 mg/24 hours. •Serum free light chain assay: involved free light chain level ≥10 mg/dL (≥ 100 mg/L), provided that the serum free light chain ratio is abnormal. 4.Patients with relapsed and/or refractory MM who have received 1 to 3 prior therapies. NOTE: This patient population includes the following 3 categories of patients: •Patients who relapsed from their previous treatment(s) but were not refractory to any previous treatment. •Patients who were refractory to all lines of previous treatment(s) (ie, patients who have never responded to any therapies received). •Patients who were relapsed from at least 1 previous treatment AND additionally were refractory to at least 1 previous treatment. For the purposes of this study, refractory disease is defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy. A line of therapy is defined as 1 or more cycles of a planned treatment program. This may consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation, followed by maintenance is considered 1 line of therapy. Autologous and allogenic transplants are permitted. 5.Patients must meet the following clinical laboratory criteria: •Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days prior to randomization. •Total bilirubin ≤ 1.5 X the upper limit of the normal range (ULN). •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN. •Calculated creatinine clearance ≥ 30 mL/min NOTE: Patients with creatinine clearance of 30 to 50 mL/min will receive lenalidomide at a reduced dose (10 mg), which may subsequently be increased if well tolerated and no response. 6.ECOG performance status of 0, 1, or 2. 7.Patients who received prior allogenic transplant must have no active graft-versus-host disease (GVHD). 8.Female patients who: •Are postmenopausal for at least 24 months before the screening visit, OR •Are surgically sterile, OR •If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from at least 28 days before starting study drug through 30 days after the last dose of study treatment, OR agree to completely abstain from heterosexual intercourse, AND •Must also adhere to the guidelines of the lenalidomide pregnancy prevention program: Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 to 14 days and again within 24 hours prior to starting Cycle 1 of lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, 1 highly effective method and 1 additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal ......
    Criteri di inclusione: Per essere idonei a questo studio, un paziente potenziale dovrà soddisfare ciascuno dei seguenti criteri principali: 1 – Pazienti di sesso maschile o femminile di età maggiore o uguale a 18 anni. 2 – Mieloma multiplo diagnosticato, secondo criteri standard, attualmente o al momento della diagnosi iniziale. NOTA: La diagnosi iniziale deve essere di MM sintomatica, sebbene la malattia recidivante non debba essere necessariamente sintomatica. 3 – I pazienti devono presentare una malattia misurabile definita da almeno una delle 3 misure seguenti: - M-proteina nel siero  1 g/dl ( 10 g/l). - M-proteina nelle urine  200 mg/24 ore. - Analisi delle catene leggere libere nel siero: livello di catene leggere libere coinvolte  10 mg/dl ( 100 mg/l) se la concentrazione di catene leggere libere nel siero è anormale. 4 – Pazienti con MM recidivante e/o refrattaria che hanno ricevuto a 1 a 3 precedenti terapie. NOTA: Questa popolazione di pazienti comprende le seguenti 3 categorie di pazienti: - Pazienti che hanno avuto una recidiva dopo il/i loro precedente/i trattamento/i ma che non sono risultati refrattari ad alcun precedente trattamento. - Pazienti che sono risultati refrattari a tutte le linee di precedenti trattamenti (ossia pazienti che non hanno mai risposto ad alcuna terapia ricevuta). - Pazienti che hanno avuto una recidiva dopo almeno 1 precedente trattamento E che inoltre sono risultati refrattari ad almeno 1 precedente trattamento. Ai fini di questo studio, la malattia refrattaria è definita come la progressione della malattia in trattamento o la progressione entro 60 giorni dopo l’ultima dose di una data terapia. Una linea di terapia è definita come 1 o più cicli di un programma di trattamento pianificato. Essa può essere costituita da 1 o più cicli programmati di terapia ad agente singolo o terapia in combinazione, nonché da una sequenza di trattamenti somministrati in modo programmato. Per esempio, un approccio di trattamento programmato di terapia di induzione seguito da un trapianto autologo di cellule staminali, seguito da mantenimento è considerato 1 linea di terapia.(41) Sono ammessi trapianti autologhi e allogenici. 5 – I pazienti devono soddisfare i seguenti criteri clinici di laboratorio: - Conta assoluta dei neutrofili (ANC)  1.000/mm3 e conta piastrinica  75.000/mm3. Trasfusioni di piastrine per aiutare i pazienti a soddisfare i criteri di idoneità non sono ammessi entro 3 giorni prima della randomizzazione. - Bilirubina totale  1,5 volte il limite superiore della norma (ULN). - Alanina aminotransferasi (AST) e aspartato aminotransferasi (ALT)  3 x ULN. - Clearance della creatinina calcolata ≥ 30 ml/min NOTA: I pazienti con clearance della creatinina da 30 a 50 ml/min riceveranno - lenalidomide a una dose ridotta (10 mg), che potrà essere successivamente incrementata se sarà ben tollerata e in caso di mancata risposta. 6 – Stato di performance ECOG pari a 0, 1 o 2. 7 – Pazienti che sono stati sottoposti a precedente trapianto allogenico non devono avere una reazione attiva da trapianto contro l’ospite (GVHD). 8 – Pazienti di sesso femminile che: - sono in post-menopausa da almeno 24 mesi prima della visita di screening, OPPURE - sono chirurgicamente sterili, OPPURE - Se sono in età fertile, accettano di utilizzare 2 metodi contraccettivi efficaci, contemporaneamente, a partire da almeno 28 giorni prima dell’inizio dell’assunzione del farmaco dello studio fino a 30 giorni dopo l’ultima dose del trattamento dello studio, OPPURE accettano di praticare la completa astinenza da rapporti eterosessuali, E - devono inoltre osservare le linee guida del programma di prevenzione della gravidanza del lenalidomide: Le donne in età fertile devono risultare negative a un test di gravidanza sul siero o sulle urine con una sensibilità di almeno 25 mIU/ml ....
    E.4Principal exclusion criteria
    1. Patient was refractory to lenalidomide or proteasome inhibitor-based therapy at any line. NOTE: Refractory disease defined as disease progression on treatment or progression within 60 days after the last dose of a given therapy. Patients who progress after 60 days from the last dose of a given therapy will be considered relapsed and are eligible for inclusion in the study. Patients who were refractory to thalidomide-based therapy are eligible. 2. Female patients who are lactating or pregnant. 3. Failure to have fully recovered (ie, < Grade 1 toxicity) from the effects of prior chemotherapy regardless of the interval since last treatment. 4. Major surgery within 14 days before randomization. 5. Radiotherapy within 14 days before randomization. 6. Central nervous system involvement. 7. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before randomization. 8. Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome. 9. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. 10. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before randomization in the study. 11. Ongoing or active systemic infection, active hepatitis B virus infect, active hepatitis C infection, or known human immunodeficiency virus (HIV) positive. 12. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. 13. Psychiatric illness/social situation that would limit compliance with study requirements. 14. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 15. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment. 16. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
    Criteri di esclusione Non devono essere randomizzati nello studio i pazienti che soddisfino uno qualsiasi dei seguenti criteri di esclusione: 1 – Il paziente era refrattario al lenalidomide o a una terapia a base di inibitori del proteasoma in qualsiasi linea. NOTA: La malattia refrattaria è definita come la progressione della malattia in trattamento o la progressione entro 60 giorni dopo l’ultima dose di una data terapia. I pazienti che hanno una progressione dopo 60 giorni dall’ultima dose di una data terapia saranno considerati recidivanti e saranno idonei all’inclusione nello studio. Sono idonei i pazienti che erano refrattari a una terapia a base di talidomide. 2 – Le pazienti in fase di allattamento o in gravidanza. 3 – Mancata completa remissione (ossia tossicità &lt; Grado 1) dagli effetti di una precedente chemioterapia a prescindere dall’intervallo trascorso dall’ultimo trattamento. 4 – Chirurgia maggiore entro 14 giorni prima della randomizzazione. 5 – Radioterapia entro 14 giorni prima della randomizzazione. 6 – Coinvolgimento del sistema nervoso centrale. 7 – Infezione che necessita di terapia antibiotica sistemica o altra infezione grave entro 14 giorni prima della randomizzazione. 8 – Diagnosi di macroglobulinemia di Waldenstrom, sindrome di POEMS (polineuropatia, organomegalia, endocrinopatia, gammopatia monoclonale e alterazioni cutanee), leucemia plasmatica, amiloidosi primaria, sindrome mielodisplastica o sindrome mieloproliferativa. 9 – Evidenza di attuali condizioni cardiovascolari incontrollate, compresi ipertensione incontrollata, aritmia cardiaca incontrollata, insufficienza cardiaca congestizia sintomatica, angina instabile o infarto miocardico entro gli ultimi 6 mesi. 10 – Trattamento sistemico con forti inibitori di CYP1A2 (fluvoxamina, enoxacina, ciprofloxacina), forti inibitori di CYP3A (claritromicina, telitromicina, itraconazolo, voriconazolo, ketoconazolo, nefazodone, posaconazolo) o forti induttori di CYP3A (rifampina, rifapentina, rifabutina, carbamazepina, fenitoina, fenobarbital), o uso di ginkgo biloba o erba di S. Giovanni entro 14 giorni prima della randomizzazione nello studio. 11 – Infezione sistemica in corso o attiva, infezione attiva da virus dell’epatite B, infezione attiva da epatite C o positività nota al virus dell’immunodeficienza umana (HIV). 12 – Malattie sistemiche co-morbide o altra grave malattia concomitante che, a giudizio dello sperimentatore, renderebbe inappropriato l’ingresso del paziente in questo studio o interferirebbe significativamente con la corretta valutazione della sicurezza e della tossicità dei regimi prescritti. 13 – Patologia psichiatrica/situazione sociale che limiterebbero il rispetto dei requisiti dello studio. 14 – Allergia nota a uno dei farmaci dello studio, ai loro analoghi o eccipienti nelle varie formulazioni di un agente. 15 – Incapacità a deglutire un farmaco orale, incapacità o non volontà di attenersi ai requisiti della somministrazione dei farmaci, o procedura gastrointestinale (GI) che potrebbe interferire con l’assorbimento orale o con la tolleranza del trattamento. 16 – Diagnosi o trattamento per un'altra neoplasia maligna entro 2 anni prima della randomizzazione o precedente diagnosi di un’altra neoplasia maligna e presenza di evidenza di malattia residua. I pazienti con carcinoma cutaneo non melanomatoso o carcinoma in situ di qualsiasi tipo non sono esclusi qualora siano stati sottoposti a resezione completa.
    E.5 End points
    E.5.1Primary end point(s)
    PFS, defined as the time from the date of randomization to the date of first documentation of disease progression based on central laboratory results and international myeloma working group (IMWG) criteria as evaluated by an independent review committee (IRC), or death due to any cause, whichever occurs first.
    - sopravvivenza libera da progressione (PFS, progression-free survival), definita come il tempo trascorso dalla data della randomizzazione fino alla data della prima documentazione di progressione di malattia in base ai risultati del laboratorio centralizzato e ai criteri dell'international myeloma working group (IMWG) valutati da un comitato di revisione indipendente (IRC, independent review committee), oppure fino al decesso per qualsiasi causa, a seconda dell'evento che si verifichi per primo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS, defined as the time from the date of randomization to the date of first documentation of disease progression based on central laboratory results and international myeloma working group (IMWG) criteria as evaluated by an independent review committee (IRC), or death due to any cause, whichever occurs first.
    - sopravvivenza libera da progressione (PFS, progression-free survival), definita come il tempo trascorso dalla data della randomizzazione fino alla data della prima documentazione di progressione di malattia in base ai risultati del laboratorio centralizzato e ai criteri dell'international myeloma working group (IMWG) valutati da un comitato di revisione indipendente (IRC, independent review committee), oppure fino al decesso per qualsiasi causa, a seconda dell'evento che si verifichi per primo.
    E.5.2Secondary end point(s)
    - OS, measured as the time from the date of randomization to the date of death - OS in high-risk patients carrying del(17).
    Gli endpoint secondari principali sono costituiti da: - sopravvivenza globale (OS, overall survival), misurata come il tempo trascorso dalla data della randomizzazione alla data del decesso - sopravvivenza globale in pazienti ad alto rischio che presentino del(17).
    E.5.2.1Timepoint(s) of evaluation of this end point
    - OS, measured as the time from the date of randomization to the date of death - OS in high-risk patients carrying del(17).
    - sopravvivenza globale (OS, overall survival), misurata come il tempo trascorso dalla data della randomizzazione alla data del decesso - sopravvivenza globale in pazienti ad alto rischio che presentino del(17).
    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 No
    E.6.12Pharmacoeconomic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA107
    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
    Brazil
    Canada
    China
    Hong Kong
    Israel
    Korea, Republic of
    Mexico
    New Zealand
    Russian Federation
    Singapore
    Taiwan
    Thailand
    Turkey
    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
    Patients will be considered to have completed the study if they are followed until death or until the sponsor terminates the study.
    Lo studio sarà completato con il follow up sino alla morte o sino a che lo sponsor né deciderà la fine.
    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 months80
    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 months81
    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: 281
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 422
    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 state23
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 470
    F.4.2.2In the whole clinical trial 703
    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)
    After participation in the trial, if applicable, patients will be treated with the current standard therapy.
    Dopo la partecipazione allo studio, se applicabile, i pazienti saranno trattati con la terapia standard.
    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 Decision2012-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-06-12
    P. End of Trial
    P.End of Trial StatusOngoing
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