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    Summary
    EudraCT Number:2015-004936-36
    Sponsor's Protocol Code Number:CLL13
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-10-20
    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 ConcernedGermany - BfArM
    A.2EudraCT number2015-004936-36
    A.3Full title of the trial
    A phase 3 multicenter, randomized, prospective, open-label trial of standard chemoimmunotherapy (FCR/BR) versus rituximab plus ve-netoclax (RVe) versus obinutuzumab (GA101) plus venetoclax (GVe) versus obinutuzumab plus ibrutinib plus venetoclax (GIVe) in fit pa-tients with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation
    Eine prospektive, offene, multizentrische Phase-III-Studie zur Behandlung von körperlich fitten, nicht vorbehandelten CLL Patienten ohne del(17p) oder TP53 Mutationen, die eine von vier Kombinationstherapien erhalten: Standardchemoimmuntherapie (FCR/BR) , Rituximimab und Venetoclax (RVe), Obinutuzumab und Venetoclax (GVe) oder Obinutuzumab, Ibrutinib und Venetoclax (GIVe)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Untreated patients with blood cancer (chronic lymphocytic leukemia) are randomized into four treatment arms. One treatment arm is standard-of-care. The other treatment arms are experimental, combining inhibitors with monoclonal antibodies.
    unbehandelte Patienten mit Blutkrebs (chronisch lymphatische Leukämie) werden in einen von vier Behandlungsarmen randomisiert. Ein Behandlungsarm ist die Standardbehandlung. Die anderen Behandlungsarme sind experimentell und kombinieren Antikörper und Hemmstoffe.
    A.3.2Name or abbreviated title of the trial where available
    CLL13
    CLL13
    A.4.1Sponsor's protocol code numberCLL13
    A.5.4Other Identifiers
    Name:ClinicalTrials.govNumber:NCT02950051
    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 SponsorUniversity of Cologne
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportJanssen Pharmaceutica NV
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportAbbVie Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGerman CLL Study Group
    B.5.2Functional name of contact pointInformation Desk
    B.5.3 Address:
    B.5.3.1Street AddressGleuelerstr. 176-178
    B.5.3.2Town/ cityCologne
    B.5.3.3Post code50935
    B.5.3.4CountryGermany
    B.5.4Telephone number492214788820
    B.5.5Fax number4922147886886
    B.5.6E-mailcllstudie@uk-koeln.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Gazyvaro®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche/Genentech
    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.3.1Product nameObinutuzumab/GA101
    D.3.2Product code RO5072759
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNObinutuzumab
    D.3.9.1CAS number 949142-50-1
    D.3.9.2Current sponsor codeRO5072759
    D.3.9.3Other descriptive nameOBINUTUZUMAB
    D.3.9.4EV Substance CodeSUB32751
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeRO5072759 is a humanized and glycoenginieered monoclonal antibody (mAB)
    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 nameVenetoclax
    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 INNVenetoclax
    D.3.9.2Current sponsor codeRO5537382
    D.3.9.3Other descriptive nameABT-199 (GDC-0199)
    D.3.9.4EV Substance CodeSUB130380
    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: 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 nameVenetoclax
    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 INNVenetoclax
    D.3.9.2Current sponsor codeRO5537382
    D.3.9.3Other descriptive nameABT-199 (GDC-0199)
    D.3.9.4EV Substance CodeSUB130380
    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: 4
    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 nameVenetoclax
    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 INNVenetoclax
    D.3.9.2Current sponsor codeRO5537382
    D.3.9.3Other descriptive nameABT-199 (GDC-0199)
    D.3.9.4EV Substance CodeSUB130380
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    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 nameIbrutinib
    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 INNIbrutinib
    D.3.9.1CAS number 936563-96-1
    D.3.9.3Other descriptive nameIBRUTINIB
    D.3.9.4EV Substance CodeSUB120863
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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.2.1.2Country 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.3.1Product nameBendamustine
    D.3.4Pharmaceutical form Concentrate and solvent for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBENDAMUSTINE HYDROCHLORIDE
    D.3.9.1CAS number 3543-75-7
    D.3.9.4EV Substance CodeSUB00696MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MabThera®
    D.2.1.1.2Name of the Marketing Authorisation holderRoche
    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 Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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.2.1.2Country 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.3.1Product nameFludarabine
    D.3.4Pharmaceutical form Concentrate and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFLUDARABINE
    D.3.9.1CAS number 21679-14-1
    D.3.9.4EV Substance CodeSUB07678MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.2.1.2Country 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.3.1Product nameCyclophosphamide
    D.3.2Product code 1001995601
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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
    fit patients with previously untreated CLL without del(17p) or TP53 mutation
    fit patients with previously untreated CLL without del(17p) or TP53 mutation
    E.1.1.1Medical condition in easily understood language
    patients with a special kind of blood cancer and without specified genetic risk factors
    patients with a special kind of blood cancer and without specified genetic risk factors
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10008976
    E.1.2Term Chronic lymphocytic leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate the efficacy of obinutuzumab (GA101) plus venetoclax (GVe) versus standard chemoimmunotherapy (BR/FCR) [concerning MRD negativity measured by flow cytometry in peripheral blood (PB) at month 15] and obinutuzumab plus ibrutinib plus venetoclax (GIVe) versus standard chemoimmunotherapy (BR/FCR) [concerning progression free survival (PFS)] in previously untreated, fit CLL patients without del(17p) or TP53 mutation.
    Das primäre Ziel der Studie ist, die Wirksamkeit der Kombinationsthe-rapie mit Obinutuzumab (GA101) und Venetoclax (GVe) im Vergleich zu der Standardchemoimmuntherapie (BR/FCR) [bezüglich der Nega-tivität der Minimalen Resterkrankung (MRD Negativität) im peripheren Blut (PB) ermittelt in der Durchflusszytometrie bei Monat 15] , sowie die Wirksamkeit der Kombinationstherapie mit Obinutuzumab, Ibruti-nib und Venetoclax (GIVe) im Vergleich zu der Standard Chemoim-muntherapie (BR/FCR) [bezüglich des progressionsfreien Überlebens (PFS)] bei nicht-vorbehandelten, fitten CLL Patienten ohne Del(17p) oder TP53 Mutation, zu untersuchen.
    E.2.2Secondary objectives of the trial
    Measurement of MRD-Level
    Secondary objectives of the study are the evaluation of the efficacy of rituximab plus venetoclax (RVe) versus standard chemoimmunotherapy (BR/FCR), GVe and GIVe [concerning MRD negativity measured by flow cytometry in PB at month 15 and PFS].
    Sekundäre Ziele der Studie sind die Effektivität einer Kombinations-therapie mit Rituximab und Venetoclax (RVe) im Vergleich zur Stan-dardchemoimmuntherapie (BR/FCR), GVe und GIVe [bezüglich MRD Negativität im PB ermittelt in der Durchflusszytometrie bei Monat 15 und PFS] zu untersuchen.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. 1. Documented CLL requiring treatment according to iwCLL criteria12.
    2. Age at least 18 years.
    3. Life expectancy ≥ 6 months.
    4. Ability and willingness to provide written informed consent and to ad-here to the study visit schedule and other protocol requirements.
    5. Adequate bone marrow function indicated by a platelet count >30 x10^9/l (unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy)
    6. Creatinine clearance ≥70ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight) / (72 x creatinine), for women x 0, 85). For Patients with creatinine values within the normal range the calculation of the clearance is not necessary.
    Dehydrated patients with an estimated creatinine clearance less than 70 ml/min may be eligible if a repeat estimate after adequate hydration is > 70 ml/min.
    7. Adequate liver function as indicated by a total bilirubin≤ 2 x, AST/ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
    8. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration.
    9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.
    1. Behandlungsbedürftige CLL nach den iwCLL Kriterien.
    2. Mindestalter von 18 Jahren.
    3. Lebenserwartung ≥ 6 Monate.
    4. Fähigkeit und Bereitschaft zur schriftlichen Einwilligung zur Studienteilnahme und zur Durchführung der erforder-lichen Studienvisiten und anderer Protokollanforderungen.
    5. Ausreichende Knochenmarksfunktion mit Thrombozyten >30.000/mm³ (wenn nicht auf direkte CLL Infilitration zu-rückzuführen, ermittelt durch Knochenmarksbiopsie)
    6. Kreatinine Clearance ≥70ml/min errechnet nach der modi-fizierten Cockcroft-Gault-Formel oder direkt gemessen im 24-Stunden Sammelurin. Für Patienten mit einem Kreatininwert im Normbereich ist eine Berechnung der Kreatinin Clearance nicht notwendig.
    7. Ausreichende Leberfunktionen mit einem Gesamtbilirubin ≤ 2 x, AST/ALT ≤ 2.5 x Wert des lokalen Normalwertes, sofern nicht direkt auf die CLL oder auf das Gilbert’s Syndrome zurückzuführen.
    8. Serologischer Ausschluss einer aktiven Hepatitis-B (d.h. HBsAg negativ und Anti-HBc negativ; Patienten mit posi-tivem Anti-HBc dürfen an der Studie teilnehmen, wenn die PCR für HBV-DNA negativ ist und monatlich nach der letzten Obinutuzumab Verabreichung für ein Jahr), nega-tive Testuntersuchung für Hepatites-C-RNA innerhalb von 6 Wochen vor der Registrierung
    9. Eastern Cooperative Oncology Group Performance Sta-tus (ECOG) performance Status 0-2.
    E.4Principal exclusion criteria
    1. Any prior CLL-specific therapies (except corticosteroid treatment ad-ministered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted).
    2. Transformation of CLL (Richter transformation).
    3. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of prednisolone or intravenous immunoglobulins (IVIG) being administered for he-molysis
    4. Detected del(17p) or TP53 mutation.
    5. Patients with a history of PML.
    6. Any comorbidity or organ system impairment rated with a single CIRS (cumulative illness rating scale) score of 4 (excluding the eyes/ears/nose/throat/larynx organ system), a total CIRS score of more than 6 or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could comprise the patients safety or interfere with the absorption or me-tabolism of the study drugs (e.g, inability to swallow tablets or im-paired resorption in the gastrointestinal tract).
    7. Urinary outflow obstruction.
    8. Malignancies other than CLL currently requiring systemic therapies, not being treated in curative intention before (unless the malignant disease is in a stable remission due to the discretion of the treating physician) or showing signs of progression after curative treatment.
    9. Uncontrolled or active infection.
    10. Patients with known infection with human immunodeficiency virus (HIV).
    11. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibi-tors/inducers.
    12. Anticoagulant therapy with warfarin or phenoprocoumon,
    (rotation to alternative anticoagulation is allowed, but note that patients being treated with NOAKs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib).
    13. History of stroke or intracranial hemorrhage within 6 months prior to registration.
    14. Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
    15. Vaccination with live vaccines 28 days prior to registration.
    16. Major surgery less than 30 days before start of treatment.
    17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
    18. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
    19. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly).
    20. Fertile men or women of childbearing potential unless:
    a. surgically sterile or ≥ 2 years after the onset of menopause
    b. willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment.
    21. Legal incapacity.
    22. Prisoners or subjects who are institutionalized by regulatory or court order.
    23. Persons who are in dependence to the sponsor or an investigator.
    1. Vorherige Behandlung der CLL (mit Ausnahme von Stero-idgaben bei unverzüglichem Therapiebedarf; innerhalb der letzten10 Tage vor Start der Studientherapie ist jedoch nur die Behandlung mit einem Dosisäquivalent bis zu 20 mg Prednisolon gestattet).
    2. Transformation der CLL (Richtertransformation).
    3. Dekompensierte Hämolyse, definiert als anhaltender Hä-moglobin-Abfall trotz drei oder mehr vorangegangener Behandlungen der Hämolyse mit Prednisolon oder intravenös verabreichten Immunglobulinen (IVIG).
    4. Nachgewiesene del(17p) oder TP53 Mutation.
    5. Bekannte PML.
    6. Schwere Begleiterkrankungen oder Einschränkungen ei-nes Organsystems, die mit einem CIRS (cumulative ill-ness rating scale) Score von 4 bewertet wurden (ausge-nommen des Bereichs von Au-gen/Ohren/Nase/Hals/Kehlkopf), ein Gesamt-CIRS-Score von über 6 oder eine andere lebensbedrohliche Erkran-kung, ein medizinischer Zustand oder eine Organdysfunk-tion, die – nach Einschätzung des Prüfarztes- die Sicher-heit des Patienten im Rahmen der Studie beeinträchtigen oder mit der Aufnahme oder Verstoffwechslung der Studienmedikation interagieren könnten (z.B. Unfähigkeit, Tabletten zu schlucken oder eingeschränkte Resorption im Gastrointestinaltrakt).
    7. Verschluss der ableitenden Harnwege
    8. Andere maligne Erkrankungen, die aktuell einer systemi-schen Therapie bedürfen oder nicht kurativ behandelt werden können (außer das Malignom ist in einer stabilen Remission nach Maßgabe des behandelnden Arztes), oder die nach einer abgeschlossenen Behandlung in ku-rativer Absicht Zeichen eines Progress vorweisen.
    9. Unkontrollierte oder aktive Infektionen
    10. Patienten mit einer bekannten HIV-Infektion
    11. Notwendigkeit der Einnahme von starken CYP3A4 und CYP3A5 Inhibitoren/Induktoren
    12. Antikoagulation mit Warfarin oder Phenoprocoumon.
    Die Umstellung auf andere Antikoagulantien ist erlaubt, aber bitte beachten Sie, dass Patienten, die mit NOAKs behandelt werden, ausreichend über die Gefahr von Blutungen bei der gleichzeitigen Einnahme von Ibrutinib informiert werden müs-sen.
    13. Schlaganfall oder intrakranielle Blutung innerhalb der letz-ten 6 Monate vor Studieneinschluss.
    14. Innerhalb der letzten 28 Tage vor Studieneinschluss The-rapie mit anderen Studienmedikamenten, die mit dieser Studientherapie interagieren könnten.
    15. Impfung mit einem Lebendimpfstoff innerhalb der letzten 28 Tage vor Registration
    16. Größerer chirurgischer Eingriff weniger als 30 Tage vor Behandlungsstart
    17. Schwere allergische oder anaphylaktische Reaktionen auf humanisierte oder murine monoklonale Antikörper in der Vergangenheit sowie bekannte Sensitivität oder Allergie auf murine Produkte
    18. Überempfindlichkeit gegen einen Wirkstoff oder einen der weiteren Bestandteile der verwendeten Studienmedika-mente.
    19. Schwangere Frauen und stillende Mütter (ein Schwanger-schaftstest wird vor Beginn der Studie sowie monatlich während der Therapie durchgeführt).
    20. Zeugungsfähige Männer und Frauen, es sei denn:
    - chirurgisch sterilisiert oder ≥ 2 Jahre nach Einsetzen der Menopause
    - fähig und bereit, zwei Verhütungsmethoden während und bis 18 Monate nach Ende der Studientherapie anzu-wenden, darunter ein hocheffektives Verhütungsmittel (Pearl Index <1) und zusätzlich eine Barrieremethode
    21. Geschäftsunfähigkeit
    22. Gefangene oder Personen, die gemäß einer behördlichen oder richterlichen Anordnung institutionalisiert sind
    23. Personen, die in Abhängigkeit zum Sponsor bzw. einem Prüfer stehen
    E.5 End points
    E.5.1Primary end point(s)
    • Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by flow cytometry at month (MO) 15 for the comparison [GVe versus standard chemoimmunotherapy (SCIT)].
    • Progression free survival (PFS) for the comparison [GIVe versus SCIT]
    • Negativität der minimalen Resterkrankung (MRD) im peripheren Blut (PB) ermittelt in der Durchflusszytometrie bei Monat (MO) 15 [GVe im Vergleich zur Standard Chemoimmuntherapie (SCIT)].
    • Progressionsfreies Überleben (PFS) [GIVe im Vergleich zu SCIT]
    E.5.1.1Timepoint(s) of evaluation of this end point
    Q3 2022
    Q3 2022
    E.5.2Secondary end point(s)
    • MRD levels in PB at MO 15 (all other comparisons except for [GVe ver-sus SCIT])
    • MRD levels in PB at different time points (MO 2, 9 and 13; MRD at later time points might be evaluated according to the discretion of the treating physician at local laboratories)
    • MRD levels measured in bone marrow (BM) at final restaging (RE, 2 month after the end of last treatment cycle)
    • PFS (all other comparisons except for [GIVe versus SCIT])
    • Overall response rate (ORR) [MO 3, 9, 13, 15]
    • (Clinical) CR / CRi rate [Interim staging [IST], cycle 9 day 1 (or final re-staging (RE) for patients in the SCIT arm), IR (or three month after RE for patients in the SCIT arm respectively) and MO 15] (with regard to best response achieved)
    • Event-free survival (EFS)
    • Overall survival (OS)
    • Duration of response in patients with:
    o complete response (CR) or CR with incomplete recovery of the bone marrow (CRi),
    o partial response (PR)
    • Time to next CLL treatment
    • Safety parameters:
    Type, frequency, and severity of
    o adverse events (AEs) and
    o adverse events of special interest (AESI)
    and their relationship to study treatment
    • Health-related quality of life by MARS and EORTC QLQ-C30 and QLQ-CLL16 questionnaires
    • Exploratory evaluations of potential associations between biomarkers and subject characteristics or outcome measures
    - MRD Niveau im PB bei MO 15 [alle Vergleiche bis auf [GVe versus SCIT]]
    - MRD Niveau im PB bei verschiedenen Zeitpunkten (MO 2, 9 und 13)
    - MRD Niveau im Knochenmark (BM) bei Final Restaging (RE) (2 Monate nach dem letzten Behandlungszyklus)
    - PFS [alle Vergleiche außer [GIVe versus SCIT]]
    - Gesamtansprechrate (ORR) [MO 3, 9, 13, 15]
    - (klinische) CR / CRi Rate [Interim Staging [IST], Zyklus 9 Tag 1 (oder RE für Patienten im SCIT Arm), IR (oder 3 Monate nach RE entsprechend für Patienten im SCIT Arm) und MO 15] [hinsichtlich des besten erzielten Ansprechens]
    - Ereignisfreies Überleben (EFS)
    - Gesamtüberleben (OS)
    - Dauer des Ansprechens bei Patienten mit:
    - Kompletter Remission (CR) oder CR mit inkompletter Regeneration des Knochenmarks (CRi),
    - Partieller Remission (PR)
    - Behandlungsfreie Zeit und Dauer bis zur nächsten CLL Be-handlung
    - Sicherheitsanalysen:
    Typ, Häufigkeit und Schweregrad von
    - Unerwünschten Ereignissen (AEs) und
    - Unerwünschten Ereignissen mit besonderem Interesse (AESI)
    sowie ihre Beziehung zu der Studienbehandlung
    - Lebensqualität gemäß EORTC QLQ-C30 und QLQ-CLL16 Fragebögen
    - Explorative Analysen von PFS und MRD für mehrere prog-nostische Subgruppen
    E.5.2.1Timepoint(s) of evaluation of this end point
    Q3 2022
    Q3 2022
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned60
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA130
    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
    Austria
    Belgium
    Denmark
    Finland
    Germany
    Ireland
    Israel
    Netherlands
    Norway
    Sweden
    Switzerland
    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
    Q3 2022
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    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: 600
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 320
    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 state540
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 820
    F.4.2.2In the whole clinical trial 920
    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)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-11-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-27
    P. End of Trial
    P.End of Trial StatusOngoing
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