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    Summary
    EudraCT Number:2011-005468-10
    Sponsor's Protocol Code Number:C16011
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-10-01
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2011-005468-10
    A.3Full title of the trial
    A Phase 3 Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of Dexamethasone Plus MLN9708 or Physician's Choice of Treatment Administered to Patients With Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
    Estudio de fase 3, aleatorizado, controlado, abierto, multicéntrico para evaluar la seguridad y la eficacia de Dexametasona más MLN9708 en comparación con el tratamiento elegido por el médico administrado a pacientes con amiloidosis sistémica de cadenas ligeras recidivante o refractaria
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess the safety and efficacy of dexamethasone plus MLN9708 or physician choice of treatment in patients with relapsed or refractory amyloidosis.
    Un estudio para evaluar la seguridad y eficacia de Dexametasona más MLN9708 o el tratamiento elegido por el médico en pacientes con amiloidosis recidivante o refractaria.
    A.4.1Sponsor's protocol code numberC16011
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01659658
    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 pointDrug Information Call Center
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne St
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post code02139
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1510740 2412
    B.5.5Fax number+1800881 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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMLN9708 Capsules, 4.0mg
    D.3.2Product code MLN9708
    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.3.9.3Other descriptive nameMLN9708
    D.3.9.4EV Substance CodeSUB31688
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.0
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMLN9708 Capsules, 3.0mg
    D.3.2Product code MLN9708
    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.3.9.3Other descriptive nameMLN9708
    D.3.9.4EV Substance CodeSUB31688
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.0
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMLN9708 Capsules, 2.3mg
    D.3.2Product code MLN9708
    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.3.9.3Other descriptive nameMLN9708
    D.3.9.4EV Substance CodeSUB31688
    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: 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 Dexamethasone 8 mg GALEN® tablets
    D.2.1.1.2Name of the Marketing Authorisation holderGALENpharma 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 Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDexamethasone
    D.3.9.1CAS number 50-02-2
    D.3.9.3Other descriptive nameDEXAMETHASONE
    D.3.9.4EV Substance CodeSUB07017MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    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: 5
    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 Dexamethasone 4 mg GALEN® tablets
    D.2.1.1.2Name of the Marketing Authorisation holderGALENpharma 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 Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDexamethasone
    D.3.9.1CAS number 50-02-2
    D.3.9.3Other descriptive nameDEXAMETHASONE
    D.3.9.4EV Substance CodeSUB07017MIG
    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.IMP: 6
    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 Alkeran 2 mg Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderLaboratoires GENOPHARM
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMELPHALAN
    D.3.9.1CAS number 148-82-3
    D.3.9.3Other descriptive nameMelphalan
    D.3.9.4EV Substance CodeSUB08728MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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: 7
    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 Cyclophosphamide Tablets 50 mg
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter Healthcare 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 Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.3Other descriptive nameCyclophosphamide
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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: 8
    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 Thalidomide Celgene 50 mg hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 Capsule, hard
    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 INNTHALIDOMIDE
    D.3.9.1CAS number 50-35-1
    D.3.9.4EV Substance CodeSUB10958MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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: 9
    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 Revlimid 15 mg hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 Capsule, hard
    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 INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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: 10
    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 Revlimid 10 mg hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 Capsule, hard
    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 INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 11
    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 Revlimid 5 mg hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 Capsule, hard
    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 INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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: 12
    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 Alkeran 2 mg Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderAspen Pharma Trading Limited
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMELPHALAN
    D.3.9.1CAS number 148-82-3
    D.3.9.3Other descriptive nameMelphalan
    D.3.9.4EV Substance CodeSUB08728MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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
    Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
    Amiloidosis sistémica de cadenas ligeras recidivante o refractaria
    E.1.1.1Medical condition in easily understood language
    Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
    Amiloidosis sistémica de cadenas ligeras recidivante o refractaria
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To determine whether dexamethasone plus MLN9708 improves hematologic response (PR + VGPR + CR) versus a physician?s choice of a chemotherapy regimen as selected from the list of offered treatment options in patients diagnosed with relapsed or refractory AL amyloidosis.

    -To determine whether dexamethasone plus MLN9708 improves 2-year vital organ (that is, heart or kidney) deterioration and mortality rate versus a physician?s choice of a chemotherapy regimen as selected from the list of offered treatment options in
    patients diagnosed with relapsed or refractory AL amyloidosis. Kidney deterioration is defined as progression to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal transplantation.
    -Determinar si la administración de dexametasona y MLN9708 mejora la respuesta hematológica (RP+RPMB+RC) en comparación con el tratamiento quimioterápico seleccionado por el médico (a partir de una lista de opciones terapéuticas disponibles), en pacientes diagnosticados con amiloidosis sistémica de cadenas ligeras recidivante o refractaria. -Determinar si la administración de dexametasona y MLN9708 mejora el deterioro de los órganos vitales (corazón o riñón) y la tasa de mortalidad al cabo de 2 años en comparación con el tratamiento quimioterápico seleccionado por el médico (a partir de una lista de opciones terapéuticas disponibles), en pacientes diagnosticados con amiloidosis sistémica de cadenas ligeras recidivante o refractaria. El deterioro cardiaco se define como la necesidad de hospitalización por la presencia de insuficiencia cardiaca. El deterioro renal definido como la progresión a enfermedad renal terminal (ERT) que precise diálisis de mantenimiento o un trasplante renal.
    E.2.2Secondary objectives of the trial
    Key secondary objectives:
    -To determine OS
    -To determine the complete hematologic response rate

    The protocol provides details of further secondary objectives.
    Los principales objetivos secundarios son:
    -Determinar la supervivencia global (SG).
    -Determinar la tasa de respuesta hematológica completa (RC).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patients 18 years or older.

    2. Biopsy-proven diagnosis of AL amyloidosis according to the following standard criteria:
    a. Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo
    red staining with exhibition of an apple-green birefringence
    b. If clinical and laboratory parameters insufficient to establish AL amyloidosis or in
    cases of doubt, amyloid typing may be necessary (see Section 15.1)

    3. Measurable disease as defined by serum differential free light chain concentration
    (dFLC, difference between amyloid forming [involved] and nonamyloid forming
    [uninvolved] free light chain [FLC]) ? 50 mg/L).

    4. Objective, measurable major (cardiac or renal ) organ amyloid involvement as defined as follows (amyloid involvement of at least 1 required):
    a. Cardiac involvement is defined as the presence of a mean left ventricular wall
    thickness on echocardiogram greater than 12 mm in the absence of a history of
    hypertension or valvular heart disease, or in the presence of unexplained low voltage
    (< 0.5 mV) on the electrocardiogram
    b. Renal involvement is defined as proteinuria (predominantly albumin) > 0.5 g/day in
    a 24- hour urine collection
    Note: Amyloid involvement of other organ systems is allowed, but not required.

    5. Must be relapsed or refractory after 1 or 2 prior therapies.
    For this protocol, relapsed is defined as PD documented more than 60 days after last
    dose; refractory is defined as documented absence of hematologic response or
    hematologic progression on or within 60 days after last dose of prior therapy.
    a. Patient may not be refractory to proteasome inhibitor therapy
    b. Given that the physician may select from an offered list of regimens to treat a
    specific patient, the patient may be refractory to an agent/s listed within the list of offered treatment choices
    c. Must have recovered (ie, ? Grade 1 toxicity or patient?s baseline status) from the reversible effects of prior therapy
    d. If a patient has received a transplant as his/her first-line therapy, he/she must be
    at least 3 months posttransplantation and recovered from the side effects of the
    stem cell transplant6. Patient must meet criteria for 1 of the following AL Amyloidosis Risk Stages (as defined
    by NT-proBNP cut off of < 332 pg/mL and troponin T cut-off of 0.035 ng/mL as
    thresholds):
    a. Stage 1: both NT-proBNP and troponin T under threshold
    b. Stage 2: either NT-proBNP or troponin T [but not both] over threshold;
    c. Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP
    < 8000 pg/mL)

    7. ECOG Performance Status ? 2

    8. Clinical laboratory values:
    a. Absolute neutrophil count ? 1000/?L
    b. Platelet count ?75,000/?L
    c. Total bilirubin ? 1.5 x ULN
    d. Alkaline phosphatase ? 5 x ULN,
    e. ALT or AST ?3 x ULN
    f. Calculated creatinine clearance ? 30 mL/min

    9. Female patients who:
    a. If they are of childbearing potential, agree to practice 2 effective methods of
    contraception, at the same time, from the time of signing the informed consent
    through 30 days after the last dose of study treatment, AND
    b. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
    c. Agree to completely abstain from heterosexual intercourse
    Male patients, even if surgically sterilized (ie, status post vasectomy), who:
    a. Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, AND
    b. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
    c. Agree to completely abstain from heterosexual intercourse

    10. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
    1.Pacientes ambos sexos ?18. 2.Diagnóstico amiloidosis de cadenas laterales (confirmado por biopsia), de acuerdo con los siguientes criterios estándar: a.Diagnóstico histoquímico de amiloidosis, determinado en especímenes de tejido teñidos con rojo Congo (presencia de birrefringencia verde-manzana). b. Si número insuficiente de parámetros clínicos y analíticos para determinar el diagnóstico de amiloidosis AL, o si dudas, quizá sea preciso realizar estudio de tipado de amiloidosis (apartado 15.1).3.Presencia de enfermedad mensurable, definida como concentración diferencial de cadenas ligeras libres [CLL] en suero (dCLL,diferencia entre CLL implicadas que forman depósitos amiloides, y no implicadas que no forman depósitos amiloides ?50mg/l).4.Presencia de afectación de órganos importantes (corazón o riñón) por amiloidosis, objetiva y medible, según se define a continuación (al menos se requiere la afectación por amiloidosis de 1 de los 2): a.Se considera que existe afectación cardiaca cuando en el ecocardiograma se determina que el grosor medio de la pared del ventrículo izquierdo es >12mm, sin que el paciente tenga antecedentes de hipertensión o valvulopatía cardiaca, o en presencia de un voltaje inexplicablemente bajo (<0,5mV) en electrocardiograma. b.Se considera que existe afectación renal cuando paciente presenta proteinuira (predominantemente albúmina) > 0,5g/día, en orina de 24 horas. Nota: Se permite afectación por amiloidosis de otros sistemas orgánicos, aunque ello no constituye un requisito.5.Presentar enfermedad recidivante o refractaria tras haber recibido 1 o 2 tratamientos previos. En este protocolo ?recidivante? se define como la progresión de la enfermedad, documentada más de 60 días después de la última dosis; ?refractaria? se define como la ausencia de respuesta hematológica o la progresión hematológica (de forma documentada) en el transcurso de los 60 días posteriores a la última dosis del tratamiento previo a.El paciente no debe presentar resistencia a los tratamientos con inhibidores del proteasoma.b.Dado que el médico puede seleccionar el tratamiento para un paciente en particular de una lista de tratamientos disponibles, el paciente puede presentar resistencia a uno de los fármacos incluidos en la lista de opciones terapéuticas disponibles. c.Los pacientes deben haberse recuperado de los efectos reversibles de los tratamientos previos (deben presentar toxicidad de grado ?1 o haber retornado a su situación basal).d.Si un paciente ha recibido trasplante como tratamiento de primera línea, deberán trancurrir al menos 3 meses desde el trasplante, y el paciente deberá haberse recuperado de los efectos secundarios asociados con el trasplante de células madre. 6.El paciente deberá satisfacer los criterios de 1 de las siguientes fases de riesgo de la amiloidosis de cadena ligera (de acuerdo con los siguientes valores liminares: NT-proBNP: <332pg/ml; troponina T:0,035ng/ml):a.Fase 1: tanto la concentración de NT-proBNP como la concentración de troponina T se sitúan por debajo de los valores liminares.b.Fase 2: Bien la concentración de troponina o la concentración de NT-proBNP [aunque no ambas] están por encima del valor liminar. c.Fase 3: tanto la concentración de NT-proBNP como la concentración de troponina T están por encima del valor liminar (aunque la concentración de NT-proBNP es < 8000pg/ml). 7.Categoría funcional ECOG ?2 8.Valores de análisis clínicos: a.Recuento absoluto de neutrófilos ?1000/µl. b.Recuento plaquetario ?75.000/µl c.Bilirrubina total ?1,5xLSN d.Fosfatasa alcalina ?5xLSN e.ALT o AST >3xLSN f.Aclaramiento calculado de creatinina ?30 ml/min 9.Pacientes femeninas: a.Si están en edad fértil, deberán estar de acuerdo en utilizar 2 métodos anticonceptivos eficaces (de forma simultánea), desde el momento en el que se firme el consentimiento informado, hasta el 30º día posterior a la última dosis del tratamiento del estudio, Y b.También deberán seguir las directrices de cualquier programa anticonceptivo específico del tratamiento, si corresponde, O c.Deberán abstenerse completamente de mantener relaciones heterosexuales. Pacientes varones, incluso aquellos sometidos a esterilización quirúrgica (que se hayan sometido a una vasectomía): a.Deberán comprometerse a utilizar métodos anticonceptivos de barrera eficaces, tanto durante el período de tratamiento del estudio como durante los 4 meses posteriores a la última dosis del fármaco del estudio, Y b.También deberán seguir las directrices de cualquier programa anticonceptivo específico del tratamiento, si corresponde, O c.Deberán abstenerse completamente de mantener relaciones heterosexuales. 10.Proporcionar por escrito su consentimiento voluntario, antes de realizar cualquier procedimiento relacionado con el estudio que no forme parte de la atención sanitaria habitual. Se hará saber al paciente que podrá retirar dicho consentimiento en cualquier momento, sin perjuicio de la atención médica que pueda recibir posteriormente.
    E.4Principal exclusion criteria
    Prospective patients will be excluded from this study if they meet ANY of the following
    criteria:

    1. Amyloidosis due to mutations of the transthyretin gene or presence of other
    non-AL amyloidosis.

    2. Female patients who are lactating, breastfeeding, or pregnant.

    3. Medically documented cardiac syncope, uncompensated NYHA Class 3 or 4 congestive heart failure (Section 15.6), myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically important autonomic disease.

    4. Clinically overt multiple myeloma, including monoclonal BM plasma cells ?10%
    to ? 30%, and at least 1 of the following:
    a. Bone lesions
    b. Hypercalcemia, defined as a calcium of > 11 g/dL

    5. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or GI procedure that could interfere with the oral
    absorption or tolerance of treatment.

    6. Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational or which would be considered as a treatment of AL amyloidosis. However, patients may be on chronic steroids (maximum dose 20 mg/day prednisone or equivalent [Section 15.7]) if they are being given for
    disorders other than amyloidosis (eg, adrenal insufficiency, rheumatoid arthritis, etc.).

    7. 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.

    8. Ongoing or active infection, known HIV positive, known to be hepatitis B surface
    antigen-positive or has known or suspected active hepatitis C infection.

    9. Psychiatric illness/social situations that would limit compliance with study requirements.

    10. Known allergy to boron, MLN9708, any of the study treatments, their analogues, or
    excipients.

    11. 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 the first dose of study treatment.
    1.Presencia de amiloidosis debida a mutaciones del gen de la transtiretina o presencia de otro tipo de amiloidosis distinta a la amiloidosis AL.2.Mujeres que estén embarazadas o se encuentren en etapa de lactancia.3.Presencia médicamente documentada de síncope cardiaco, insuficiencia cardiaca congestiva descompensada (de clase 3 o 4 [NYHA]) ?apartado 15.6?, infarto de miocardio en el transcurso de los 6 meses previos, angina de pecho inestable, arritmias ventriculares repetitivas clínicamente significativas (a pesar de recibir tratamiento antiarrítmico) o hipotensión ortostática intensa o enfermedad neurovegetativa clínicamente importante.4.Presencia de mieloma múltiple clínicamente manifiesto, esto es, una concentración de células plasmáticas monoclonales en la médula ósea ? 10% y ? 30%, y al menos 1 de los siguientes criterios:a. Lesiones óseas.b. Hipercalcemia (concentración de calcio > 11 g/dl).5.Incapacidad para ingerir medicaciones orales, incapacidad o negativa a cumplir los requisitos relativos a la administración del fármaco, o procedimiento gastrointestinal que pueda interferir con la absorción oral o la tolerancia al tratamiento.6.Requerir la administración concomitante de otro tratamiento quimioterápico, inmunoterápico, radioterápico o cualquier otro tratamiento complementario en fase de investigación o para el tratamiento de la amiloidosis AL. Sin embargo, los pacientes pueden recibir tratamiento prolongado con esteroides (dosis máxima de 20 mg/día de prednisona o equivalente [apartado 15.7]), si estos se administran para trastornos distintos a la amiloidosis (por ejemplo, insuficiencia suprarrenal, artritis reumatoide, etc.).7.Presencia de comorbilidades sistémicas u otras enfermedades concomitantes intensas que, en opinión del investigador, hagan que no sea apropiado incluir al paciente en el estudio o interfieran significativamente con la correcta evaluación de la seguridad y toxicidad de los tratamientos prescritos.8.Infección en curso o activa, infección conocida por VIH, resultados positivos para el antígeno de superficie de la hepatitis B o infección activa por hepatitis C (conocida o sospechada).9.Presencia de enfermedad psiquiátrica o situación social que pueda limitar el cumplimiento de los requisitos del estudio.10.Alergia conocida al boro, MLN9708, cualquier de los tratamientos del estudio, sus análogos o excipientes. 11.Tratamiento sistémico con inhibidores potentes del CYP1A2 (fluvoxamina, enoxacina, ciprofloxacina), inhibidores potentes del CYP3A (claritromicina, telitromicina, itraconazol, voriconazol, ketoconazol, nefazodona, posaconazol) o inductores potentes del CYP3A (rifampina, rifapentina, rifabutina, carbamazepina, fenitoína, fenobarbital) o haber recibido Ginkgo biloba o hierba de San Juan en el transcurso de los 14 días previos a la primera dosis del tratamiento del estudio
    E.5 End points
    E.5.1Primary end point(s)
    -Overall hematologic (CR + VGPR + PR) response rate based on central laboratory results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria as evaluated by an Adjudication Committee (AC)
    -2-year vital organ (that is, heart or kidney) deterioration and mortality rate. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to end-stage renal disease (ESRD) with the
    need for maintenance dialysis or renal transplantation. Vital organ deterioration will be evaluated by an AC.
    -Tasa global de respuesta hematológica (RC + RPMB + RP), basándose en los resultados del laboratorio central y en los Criterios de Consenso de la Sociedad Internacional de Amiloidosis (ISA) de 2010, de acuerdo con la evaluación de un Comité de Validación (CV).
    -Deterioro de los órganos vitales (esto es, el corazón o el riñón) y tasa de mortalidad al cabo de 2 años. El deterioro cardiaco se define como la necesidad de hospitalización por la presencia de insuficiencia cardiaca. El deterioro renal se define como la progresión a enfermedad renal terminal (ERT) que precise diálisis de mantenimiento o un trasplante renal. Un CV evaluará el deterioro de los órganos vitales.
    E.5.1.1Timepoint(s) of evaluation of this end point
    As well as the timepoints provided, all the below are assessed at screening.
    ?Haematology-D1 & D14 of C1-C3, D1 every 3 cycles (Q3C) until PD, EOT
    ?Clinical Chemistry & vital signs-D1 all cycles until PD, EOT
    ?Urinalysis-EoT
    ?24h Urine Collection (Creatinine)-D1/C1, EOT
    ?Serum Cardiac Markers-D1/C2, D1/C3, D1/QC3 until PD; every 6wks in follow-up
    ?ECG-D1/C2, EOT
    ?Echocardiogram-D1/C3, D1/QC3 until PD, EOT, every 12wks in follow-up
    ?NYHA-D1/C2, D1/C3, D1 of subsequent cycles until PD, EOT, every 12wks in follow-up
    ?Serum albumin/calculated creatinine clearance & eGFR-D1/C3, D1 QC3 until PD, EOT, every 12wks in follow-up
    ?CT/MRI/alkaline phosphate/ALT-D1/C3, QC3 until PD, EoT, every 12wks in follow-up
    A full list of procedures is presented in the Schedule of Events.
    Crit. de valoración tambien evaluados en seleccion:-Proteina M suero /CLL: D1 hasta PE, FdT., cada 6 s. durante SSP-Proteina M orina: C1D1, como clínicamente indicado, FdT, cada 12s durante SSP.-IgG/Inmunofijación PE, FdT, como clínicamente indicado-Serie de radiografías óseas: como clínicamente indicado-Médula ósea: como clínicamente indicado-Proteina total: D1/C3, D1/C3C hasta PE, FdT, cada 12s. En seguimiento (ES)-Marcadores cardiacos D1/C2, D1/C3, D1/ C3C hasta PE, FdT, cada 6 s. ES-ECG-D1/C2, FdT-Eco D1/C3, D1/ C3C hasta PE, FdT, cada 12 s. ES-NYHA: D1/C2, D1/C3, D1 ciclos posteriores hasta PE, FdT, cada 12 s. ES-Albúmina sérica, aclaramiento calculado de creatinina y TFGe-D1/C3, D1 C3C hasta PE, cada 12 s. ES-TC o RMN, fosfatasa alcalina y ALT-D1/C3, C3C hasta PE, cada 12 s. ES
    E.5.2Secondary end point(s)
    The key secondary endpoints are:
    -Complete hematologic response rate (CR) according to central laboratory results and ISA criteria as evaluated by an AC

    -OS, measured as the time from randomization to the date of death

    Other secondary endpoints are:
    -PFS, defined as the time from the date of randomization to the date of first
    documentation of disease progression (hematologic PD or major organ progression [specifically involvement of heart or kidney] whichever occurs first) according to central laboratory results and ISA criteria as evaluated by an AC, or death due to any cause, whichever occurs first

    - Hematologic disease PFS, defined as the time from the date of randomization to the
    date of first documented hematologic disease progression according to central
    laboratory results and ISA criteria, as evaluated by an AC, or death due to any cause, whichever occurs first

    -Time to vital organ (that is, heart or kidney) deterioration and mortality rate. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney
    deterioration is defined as progression to ESRD with the need for maintenance
    dialysis or renal transplantation.

    -Best response in the vital organs allowed at study entry (heart and kidney) according
    to central laboratory results and International Society of Amyloidosis criteria as evaluated by an AC.

    - Vital organ PFS, defined as the time from the date of randomization to the date of
    first documentation of progression of vital organ (that is, heart or kidney) according
    to central laboratory results and ISA criteria, as evaluated by an AC, or death due to any cause, whichever occurs first

    - Duration of hematologic response, measured as the time from the date of first
    documentation of hematologic response to the date of first documented hematologic
    disease progression, respectively according to central laboratory results and ISA
    criteria as determined by an AC

    -Adverse events (AEs), serious adverse events (SAEs), and assessments of clinical
    laboratory values

    -TTF, defined as the time from the date of randomization to the date of first
    documented treatment failure. Treatment failure is defined as : 1) death due to any
    cause; 2) hematologic progression or major organ progression according to central laboratory results and ISA criteria as evaluated by an AC; 3) clinically morbid organ disease requiring additional therapy; or 4) withdrawn for any reason

    - Time to subsequent anticancer treatment, defined as the time from the date of randomization to the start date of subsequent anticancer treatment

    -QOL from patient-reported outcomes instruments (changes from baseline in health status based on SF-36 v2 survey, the FACT/GOG-Ntx, and a symptom scale
    questionnaire

    -Collection of Health Utilization (HU) related to the disease and the therapy in both treatment arms and the EQ-5D questionnaire data.
    -Plasma concentration-time data to contribute to future population PK analysis

    - Prognostic impact of polymorphisms in the major NF-kB pathway-related genes,
    such as NFKB2 and TRAF3, on response to MLN9708
    -SSP, definida como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha en la que se documente por primera vez la progresión de la enfermedad (progresión de la enfermedad hematológica o progresión de órganos importantes [en particular, afectación del corazón o del riñón], lo que ocurra primero), de acuerdo con la evaluación del CV, basándose en los resultados del laboratorio central y los criterios de la ISA, o la muerte por cualquier causa, lo que ocurra primero.
    -La SSP de la enfermedad hematológica se define como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha en la que se documente por primera vez la progresión de la enfermedad hematológica (de acuerdo con la evaluación del CV, basándose en los resultados del laboratorio central y los criterios de la ISA), o la muerte por cualquier causa, lo que ocurra primero.
    -Tiempo transcurrido hasta el deterioro de los órganos vitales (esto es, el corazón o el riñón) y tasa de mortalidad. El deterioro cardiaco se define como la necesidad de hospitalización por la presencia de insuficiencia cardiaca. El deterioro renal se define como la progresión a enfermedad renal terminal (ERT) que precise diálisis de mantenimiento o un trasplante renal.
    -Mejor respuesta en los órganos vitales permitidos en el momento de inclusión en el estudio (corazón y riñón), de acuerdo con la evaluación del CV, basándose en los resultados del laboratorio central y los criterios de la ISA.
    -SSP (en relación con los órganos vitales), definida como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha en la que se documente por primera vez la progresión de los órganos vitales (esto es, corazón o riñón), de acuerdo con la evaluación del CV, basándose en los resultados del laboratorio central y los criterios de la ISA, o la muerte por cualquier causa, lo que ocurra primero.
    -Duración de la respuesta hematológica, es decir, el tiempo transcurrido desde la fecha en la que se documente por primera vez la respuesta hematológica hasta la fecha en la que se documente por primera vez la progresión de la enfermedad hematológica, de acuerdo con la evaluación del CV, basándose respectivamente en los resultados del laboratorio central y en los criterios de la ISA.
    -Acontecimientos adversos (AA), acontecimientos adversos graves (AAG) y evaluaciones de los valores de los análisis clínicos.
    -TFT, definido como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha en la que se documente por primera vez el fracaso del tratamiento. El fracaso del tratamiento se define como: 1) muerte por cualquier causa; 2) progresión hematológica o progresión de un órgano importante, de acuerdo con la evaluación de un CV, basada en los resultados del laboratorio central y en los criterios de la ISA; 3) enfermedad orgánica clínicamente mórbida que requiera la administración de tratamiento adicional; o 4) retirada por cualquier motivo.
    -Tiempo transcurrido hasta el posterior tratamiento antineoplásico, definido como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de inicio del posterior tratamiento antineoplásico.
    -Calidad de vida, a partir de los resultados percibidos por el paciente en distintos instrumentos (cambios respecto al estado de salud basal, de acuerdo con el cuestionario SF-36 v2, el FACT/GOG-Ntx y una escala de síntomas).
    -Obtención de datos relativos a la utilización de recursos sanitarios (URS) relacionados con la enfermedad y el tratamiento en ambos grupos de tratamiento, así como de los datos del cuestionario EQ-5D.
    -Datos relativos a la relación concentración plasmática-tiempo, que resultarán de utilidad en futuros análisis de farmacocinética poblacional.
    -Impacto pronóstico de los polimorfismos en los principales genes relacionados con la ruta del NF-kB, tales como NFKB2 y TRAF3, en respuesta a MLN9708
    E.5.2.1Timepoint(s) of evaluation of this end point
    -OS-every 12wks in follow-up
    -PFS-every 6wks in follow-up
    -AEs-first dose until 30 days after last dose
    -SAEs-informed consent until 30 days after last dose
    -PK-C1/D1 (1h & 4h post dose), C1/D14, C2/pre-dose, C2/D14; C3 to C10 (predose)
    As well as the timepoints provided, all the below are assessed at screening.
    -ECOG-D1 all cycles, EOT, every 6wks in follow-up
    -SF36v2-D1/C1, D1 QC3 until PD, EOT, every 6wks in follow-up
    -FACT/GOG-Ntx/Symptom Scale-D1 all cycles, EOT, every 6wks in follow-up
    -EQ5D-D1 all cycles, EOT, every 6wks in follow-up
    -Serum free light chains-D1/C2, D1/C3, D1 subsequent cycles until PD, EOT, every 6wks in follow-up
    -AL Amyloidosis Symptoms-D1 all cycles, EOT, every 6wks in follow-up
    A full list of procedures is presented in the Schedule of Events.
    SG- cada 12 s. en seguimiento.-SSP cada 6 s. en seguimiento.-AA- primera dosis hasta 30 días después de la ultima dosis.-AAG- consentimiento informado hasta 30 días después de la ultima dosis.-FC C/D (1h &4 h tras la dosis) C/D14, C2/ pre-dosis, C2/D14; C3 hasta C10 (pre-dosis).- ECOG D1 todos los ciclos, fin de tratamiento (FT), cada 6 s. en seguimiento.-SF-36 v2- D1/C1, D1 C3C hasta PE, FT, cada 6 s. en seguimiento.-FACT/GOG-Ntx/ Escala de síntomas D1 de cada ciclo, FT, cada 6 s. en seguimiento.-EQ5D- D1 todos los ciclos, FT, cada 6 s. en tratamiento.-Cadenas ligeras libres en suero D1/C2, D1/C3, D1 ciclos posteriores hasta PE, cada 6 s. en seguimiento.-Síntomas de la amiloidosis sistémica de cadenas ligeras D1 todos los ciclos, FT, cada 6 s. en seguimiento
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic 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) 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 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) 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    Australia
    Brazil
    Canada
    Denmark
    France
    Germany
    Greece
    Israel
    Italy
    Korea, Republic of
    Netherlands
    Norway
    Sweden
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Study will have 2 IAs:
    1.FA for hematologic response. If test is significant, study will continue; otherwise, it will be terminated.
    2.FA for 2yr vital organ deterioration & mortality rate. If test is not significant, the study will be terminated; otherwise, OS will be tested. If OS is significant, complete hematologic response rate will be tested & study stopped for evidence of efficacy; if test is not significant, study will continue to the FA.
    See Protocol Section 8 for further detail
    Tendrá 2 AP: 1 AF para respuesta hematológica. Si test significativo, estudio continuará, sino terminará. 2. AF para deterioro de órganos vitales y tasa de mortalidad tras 2 a.
    Si test no significativo, el estudio será terminado, sino, se evaluara SG. Si SG es significativa, se evaluará tasa de respuesta hematológica completa , y el estudio podrá detenerse si hay indicios de eficacia, si test no significativo, el estudio continuará hasta AF. Ver sección 8 del protocolo para detalles adicionales
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 124
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 124
    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 state11
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 248
    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)
    Patients have the opportunity to receive treatment until their disease progresses or until they experience unacceptable toxicity. After disease progression, patients will be followed for survival, vital organ deterioration, and subsequent therapy at least every 12 weeks.
    Los pacientes tienen la oportunidad de recibir tratamiento hasta que su enfermedad progresa, o hasta que experimentan una toxicidad inaceptable. Después de progresión de la enfermedad, los pacientes estarán en seguimiento de supervivencia, deterioro de órganos vitales, y terapia posterior al menos cada 12 semanas.
    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 Decision2012-11-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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