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    Summary
    EudraCT Number:2019-003854-99
    Sponsor's Protocol Code Number:CLL17
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-003854-99
    A.3Full title of the trial
    A phase 3 multicentre, randomized, prospective, open-label trial of Ibrutinib monotherapy versus fixedduration Venetoclax plus Obinutuzumab versus fixed-duration Venetoclax plus Ibrutinib in patients with previously untreated chronic lymphocytic leukaemia (CLL).
    Studio di fase 3, multicentrico, randomizzato, prospettico, in aperto con ibrutinib in monoterapia rispetto a venetoclax in associazione a obinutuzumab rispetto a ibrutinib a durata fissa in associazione a venetoclax in pazienti con leucemia linfocitica cronica (Chronic Lymphocytic Leukaemia – CLL) non trattata precedentemente.
    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 three treatment arms. In one treatment arm an inhibitor is continuously taken. The other treatment arms are fixed in time, combining an inhibitor with another inhibitor or a monoclonal antibody.
    I pazienti con tumore del sangue (leucemia linfocitica cronica) non trattato sono randomizzati in tre bracci di trattamento. In un braccio di trattamento viene assunto un inibitore in modo continuo. Gli altri bracci di trattamento hanno durata fissa, combinando un inibitore con un altro inibitore o un anticorpo monoclonale.
    A.3.2Name or abbreviated title of the trial where available
    -
    -
    A.4.1Sponsor's protocol code numberCLL17
    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 AddressGleueler Str. 176-178
    B.5.3.2Town/ cityCologne
    B.5.3.3Post code50935
    B.5.3.4CountryGermany
    B.5.4Telephone number004902214788820
    B.5.5Fax number0049022147886886
    B.5.6E-mailcll-17@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 Venclyxto (AIC: 045198)
    D.2.1.1.2Name of the Marketing Authorisation holderABBVIE DEUTSCHLAND GMBH & CO. KG
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameABT-199 (GDC-0199), Venetoclax
    D.3.2Product code [-]
    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 code-
    D.3.9.3Other descriptive nameABT-199
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    D.2.1.1.1Trade name Venclyxto (AIC: 045198)
    D.2.1.1.2Name of the Marketing Authorisation holderABBVIE DEUTSCHLAND GMBH & CO. KG
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameABT-199 (GDC-0199), Venetoclax
    D.3.2Product code [-]
    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 code-
    D.3.9.3Other descriptive nameABT-199
    D.3.9.4EV Substance CodeSUB176260
    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 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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    D.2.1.1.1Trade name Imbruvica
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameIbrutinib
    D.3.2Product code [-]
    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.3.9.2Current sponsor code-
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    D.2.1.1.1Trade name GAZYVARO - 1000 MG - CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONCINO - 1000MG/40ML - 1 FLACONCINO
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE REGISTRATION LIMITED
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameObinutuzumab/GA101
    D.3.2Product code [RO5072759]
    D.3.4Pharmaceutical form Concentrate for solution for injection/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 code-
    D.3.9.3Other descriptive nameObinutuzumab
    D.3.9.4EV Substance CodeSUB32751
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    D.2.1.1.1Trade name Venclyxto (AIC: 045198)
    D.2.1.1.2Name of the Marketing Authorisation holderABBVIE DEUTSCHLAND GMBH & CO. KG
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameABT-199 (GDC-0199), Venetoclax
    D.3.2Product code [-]
    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 code-
    D.3.9.3Other descriptive nameABT-199
    D.3.9.4EV Substance CodeSUB176260
    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 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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Patients with previously untreated CLL requiring treatment.
    Pazienti con LLC non trattata in precedenza che richiedono un trattamento.
    E.1.1.1Medical condition in easily understood language
    Patients with previously untreated chronic lymphocytic leukaemia (blood cancer) in need of treatment.
    Pazienti con leucemia linfocitica cronica non trattata in precedenza (tumore del sangue) che necessitano di trattamento.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10008958
    E.1.2Term Chronic lymphocytic leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration ibrutinib plus venetoclax by measuring progression-free survival (PFS) in patients with previously untreated CLL.
    L’obiettivo primario dello studio è di confrontare l’efficacia di ibrutinib in monoterapia continua rispetto a venetoclax in associazione a obinutuzumab a durata fissa e rispetto a ibrutinib a durata fissa in associazione a venetoclax attraverso la misurazione della sopravvivenza libera da progressione (Progression-Free Survival-PFS) in pazienti con CLL non trattata precedentemente.
    E.2.2Secondary objectives of the trial
    Secondary objectives of the study are the evaluation of the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and with fixed-duration ibrutinib plus venetoclax by measuring for example MRD negativity in patients with previously untreated CLL.
    Obiettivi secondari dello studio sono la valutazione dell'efficacia della monoterapia continua con ibrutinib rispetto a venetoclax a durata fissa in associazione a obinutuzumab e rispetto a ibrutinib in associazione a venetoclax a durata fissa, misurando ad esempio la negatività della MRD in pazienti con LLC non trattata in precedenza.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Documented CLL requiring treatment according to iwCLL criteria [23].
    2. Age at least 18 years.
    3. Life expectancy = 6 months.
    4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
    5. Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL:
    a. Absolute neutrophil count = 1.0 × 109/L
    b. Platelet counts = 30 × 109/L; in cases of thrombocytopenia clearly due to CLL (per the discretion of the investigator), platelet count should be = 10 × 109/L
    c. Total haemoglobin = 9 g/dL (without transfusion support, unless anaemia is due to CLL)
    6. GFR >30ml/min directly measured with 24hr urine collection, 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) or an equally accurate method.
    a. 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 30 ml/min may be eligible if a repeat estimate after adequate hydration is > 30 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 for study screening (i.e. PCR only required when serology was positive).
    9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.
    1. CLL documentata che necessita di trattamento in accordo ai criteri iwCLL.
    2. Età di almeno 18 anni.
    3. Aspettativa di vita = 6 mesi.
    4. Capacità e volontà di fornire il proprio consenso informato scritto e di rispettare il programma delle visite dello studio e altri requisiti del protocollo.
    5. Adeguata funzionalità del midollo osseo indipendentemente dal supporto con fattore di crescita o trasfusionale nelle 2 settimane precedenti l’inizio dello screening, a meno che la citopenia sia dovuta alla CLL:
    a. Conta assoluta dei neutrofili = 1.0 × 109/L
    b. Conta piastrinica = 30 × 109/L; nei casi di trombocitopenia chiaramente dovuta a CLL (a discrezione dello sperimentatore), la conta piastrinica deve essere = 10 × 109/L
    c. Emoglobina totale = 9 g/dL (senza supporto trasfusionale, a meno che l’anemia non sia dovuta a CLL)
    6. GFR >30ml/min misurata direttamente con la raccolta delle urine nelle 24 ore, in base alla formula di Cockroft e Gault modificata (per gli uomini : GFR ˜ ((140 – età) x peso corporeo)/ (72 x creatinina), per le donne x 0, 85) oppure un metodo ugualmente accurato.
    a. Per i pazienti con valori di creatinina entro i limiti di normalità il calcolo della clearance non è necessario. I pazienti disidratati con una clearance della creatinina stimata inferiore a 30 ml/min possono essere eleggibili se una stima ripetuta dopo adeguata idratazione è > 30 ml/min.
    7. Adeguata funzionalità epatica indicata da bilirubina totale = 2 x, AST/ ALT = 2.5 x del valore ULN istituzionale, a meno che non direttamente attribuibile alla CLL del paziente o a sindrome di Gilbert.
    8. Test sierologico negativo per epatite B (HbsAg negativo e anti-HBc negativo; i pazienti positivi per anti-HBc possono essere inclusi se la PCR per HBV DNA è negativa e la PCR per HBV-DNA viene effettuata ogni mese fino a 12 mesi dopo l’ultimo ciclo di trattamento), test negativo per RNA dell’epatite C entro 6 settimane prima della registrazione per lo screening di studio (ovvero la PCR è richiesta solo quando la sierologia è positiva).
    9. ECOG performance status 0-2.
    E.4Principal exclusion criteria
    1. Any prior CLL-specific therapies (except corticosteroid treatment administered 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). When Richter transformation is suspected, PET-CT and/or biopsy should be performed to rule out transformation.
    3. Patients with a history of PML.
    4. An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the study treatment or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could compromise the patients’ safety or interfere with the absorption or metabolism of the study drugs (e.g. inability to swallow tablets or impaired resorption in the gastrointestinal tract).
    5. Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent 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.
    6. Uncontrolled or active infection.
    7. Patients with known infection with human immunodeficiency virus (HIV).
    8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers (incl. up to 7 days prior to study treatment start).
    9. Anticoagulant therapy with warfarin or phenprocoumon, (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed about the potential risk of bleeding under treatment with ibrutinib).
    10. History of stroke or intracranial hemorrhage within 6 months prior to registration for study screening.
    11. Known bleeding disorders
    12. Child B / C liver cirrhosis
    13. Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
    14. Vaccination with live vaccines 28 days prior to registration for study screening.
    15. Major surgery less than 30 days before start of study treatment.
    16. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
    17. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
    18. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly).
    19. 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.
    20. Legal incapacity.
    21. Prisoners or subjects who are institutionalized by regulatory or court order.
    22. Persons who are in dependence to the sponsor or an investigator.
    1. Qualsiasi terapia pregressa specifica per CLL (ad eccezione del trattamento con corticosteroidi somministrato a causa della necessità di un intervento immediato; nei 10 giorni precedenti l’inizio dello studio, sono consentite solo dosi equivalenti fino a 20 mg di prednisolone).
    2. Trasformazione di CLL (trasformazione di Richter) Quando si sospetta la trasformazione di Richter, devono essere effettuate PET-TAC e/o biopsia per escludere la trasformazione.
    3. Pazienti con anamnesi di PML.
    4. Un punteggio di 4 relativo al deterioramento di un singolo organo/sistema valutato tramite definizione CIRS che limita la capacità di ricevere il trattamento in studio o altra patologia che mette in pericolo di vita, condizione medica o disfunzione di sistema d’organo che, a giudizio dello sperimentare, potrebbe compromettere la sicurezza del paziente o interferire con l’assorbimento o il metabolismo dei farmaci in studio (ad es. incapacità di deglutire le compresse o compromissione del riassorbimento nel tratto gastrointestinale).
    5. Patologie maligne diverse dalla CLL che attualmente richiedono terapie sistemiche, non trattate in precedenza con intento curativo (a meno che la patologia maligna non sia in remissione stabile a discrezione del medico curante o mostri segni di progressione dopo il trattamento curativo).
    6. Infezione non controllata o attiva.
    7. Pazienti con infezione nota da virus dell’immunodeficienza umana (H IV).
    8. Necessità di terapia con forti inibitori/induttori di CYP3A4 e CYP3A5.
    9. Terapia anticoagulante con warfarin o fenprocumone (una terapia anticoagulante (ad es. con DOAC) è consentita, ma i pazienti devono essere adeguatamente informati sui rischi potenziali di sanguinamento durante il trattamento con ibrutinib).
    10. Anamnesi di ictus o emorragia intracranica nei 6 mesi precedenti la registrazione per lo screening dello studio.
    11. Disturbi della coagulazione noti.
    12. Cirrosi epatica Child B/C.
    13. Utilizzo di agenti sperimentali che possono interferire con il farmaco in studio nei 28 giorni precedenti la registrazione per lo screening dello studio.
    14. Vaccinazione con vaccini vivi nei 28 giorni precedenti la registrazione per lo screening dello studio.
    15. Intervento chirurgico maggiore meno di 30 giorni prima dell’inizio del trattamento in studio.
    16. Anamnesi di reazioni allergiche severe o reazioni anafilattiche ad anticorpi monoclonali murini o umanizzati, sensibilità o allergia nota a prodotti murini.
    17. Nota ipersensibilità a qualsiasi sostanza attiva o a qualsiasi eccipiente di uno dei farmaci utilizzati nello studio.
    18. Donne in gravidanza o allattamento (si richiede un test di gravidanza per tutte le donne potenzialmente fertili entro i 7 giorni precedenti l’inizio del trattamento in studio; ulteriori test di gravidanza saranno effettuati con cadenza mensile).
    19. Uomini fertili o donne potenzialmente fertili se non si applica uno dei seguenti:
    a. Chirurgicamente sterile o = 2 anni dall’inizio della menopausa
    b. Disposto a utilizzare due metodi contraccettivi affidabili compreso un metodo contraccettivo altamente efficace (indice di Pearl < 1) e un metodo efficace aggiuntivo (di barriera) durante il trattamento in studio e per 18 mesi dopo la fine del trattamento in studio.
    20. Incapacità legale.
    21. Detenuti o soggetti che sono istituzionalizzati a seguito di ordine regolatorio o del tribunale.
    22. Persone dipendenti dello Sponsor o dello sperimentatore.
    E.5 End points
    E.5.1Primary end point(s)
    Investigator-assessed PFS, defined as the time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines), or death from any cause, whichever occurs first.
    PFS valutata dall'investigatore, definita come il tempo che intercorre tra la randomizzazione e il primo evento di progressione o ricaduta (determinato utilizzando le linee guida standard IWCLL), o la morte per qualsiasi causa, a seconda di quale delle due si verifichi per prima.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The first analysis will be the interim PFS analysis and will take place after 65% of the total 212 events have been observed, i.e. 138 PFS events and a follow-up of at least 24 months after lasst patient enrolled will trigger the interim analysis.
    La prima analisi sarà l'analisi PFS provvisoria e avrà luogo dopo che il 65% dei 212 eventi totali sono stati osservati, vale a dire 138 eventi PFS e un follow-up di almeno 24 mesi dopo l'ultimo paziente arruolato farà scattare l'analisi provvisoria.
    E.5.2Secondary end point(s)
    • Rates of undetectable MRD (uMRD, i.e. <10-4) in peripheral blood (PB) and bone marrow (BM) at final restaging (RE), which will be at cycle 18 after start of treatment, and additional BM assessment approx. 12 months after RE
    • MRD levels in PB at different time points (cycle 1 before start of therapy, start of cycle 7, start of cycle 13 [end of VG treatment], start of cycle 16 [ end of VI treatment], final restaging [cycle 18], after-wards every 6 months to end of study)
    • Duration of undetectable MRD (uMRD)
    • Overall response rate (ORR; defined as rate of a response of CR, CRi, or PR) as per iwCLL guidelines at final restaging
    • Complete response rate (CRR; defined as rate of a response of CR or CRi) at final restaging as per iwCLL guidelines
    • Overall survival (OS)
    • Event-free survival (EFS) (I vs VG and I vs VI)
    • Time to next treatment (TTNT)
    • PFS2 (i.e. PFS after second-line treatment)
    Safety parameters:
    • Type, frequency, and severity of
    - adverse events (AEs) and
    - adverse events of special interest (AESI)
    - adverse events of particular interest (AEPI)
    and their relationship to study treatment
    • Tumour lysis syndrome (TLS) risk category after G or I lead-in (before venetoclax ramp up)
    Exploratory analyses:
    • Evaluation of relationship between various baseline markers and clini-cal outcome parameters (e.g. PFS, OS, ORR relative to del17p/TP53, IGHV, fitness, etc)
    • MRD by methods other than flow cytometry
    • Correlation between MRD in BM and PB
    • Correlation between MRD in BM and PFS/ EFS/ OS
    • Correlation between MRD in PB and PFS/ EFS/ OS
    • Health-related quality of life by EORTC QLQC30 and QLQ-CLL17 questionnaires
    • Medical Resource Utilization
    • Tassi di MRD non rilevabile (undetectable MRD – uMRD, ovvero <10-4) nel sangue periferico (Peripheral Blood – PB) e midollo osseo (Bone Marrow – BM) alla ristadiazione finale (restaging – RE), che sarà effettuata al ciclo 18 dopo l’inizio del trattamento, e con una valutazione aggiuntiva del BM circa 12 mesi dopo RE
    • Livelli di MRD in PB a differenti momenti nel tempo (ciclo 1 prima dell’inizio della terapia, inizio del ciclo 7, inizio del ciclo 13 [¿ fine del trattamento VG], inizio del ciclo 16 [¿ fine del trattamento VI], ristadiazione finale [ciclo 18], successivamente ogni 6 mesi fino alla fine dello studio
    • Durata della MRD non rilevabile (uMRD)
    • Tasso di risposta globale (Overall Response Rate – ORR; definita come la data di una risposta di CR, CRi o PR) in base alle linee guida iwCLL alla ristadiazione finale
    • Tasso di risposta completa (Complete Response Rate – CRR; definito come tasso di una risposta di CR o CRi) alla ristadiazione finale in base alle linee guida iwCLL
    • Sopravvivenza globale (Overall Survival - OS)
    • Sopravvivenza libera da eventi (Event-Free Survival – EFS) (I rispetto a VG e I rispetto a VI)
    • Tempo al successivo trattamento (Time to Next Treatment – TTNT)
    • PFS2 (ovvero, PFS dopo il trattamento di seconda linea)
    Parametri di sicurezza:
    • Tipo, frequenza e severità di
    - Eventi avversi (Adverse Events – AE) e
    - Eventi avversi di speciale interesse (Adverse Events of Special Interest – AESI)
    - Eventi avversi di particolare interesse (Adverse Events of Particular Interest – AEPI)
    e loro correlazione con il trattamento in studio.
    • Categoria di rischio per sindrome da lisi tumorale (Tumor Lysis Syndrome – TLS) dopo induzione con G o I (prima del passaggio a venetoclax)
    Analisi esplorative:
    • Valutazione della relazione tra vari indicatori basali e parametri di esito clinico (ad es. PFS, OS, ORR rispetto a del17p/TP53, IGHV, condizione fisica, ecc.)
    • MRD con metodi diversi dalla citometria di flusso
    • Correlazione tra MRD in BM e PB
    • Correlazione tra MRD in BM e PFS/EFS/OS
    • Correlazione tra MRD in PB e PFS/EFS/OS
    • Qualità della vita correlata alla salute valutata tramite in questionari EORTC QLQC30 e QLQ-CLL17
    • Utilizzo delle risorse sanitarie
    E.5.2.1Timepoint(s) of evaluation of this end point
    In terms of timely completion, the final PFS analysis will be conducted as soon as 212 events have occurred. This will trigger the time point of the analysis of secondary endpoints. Safety analyses are independent from primary and secondary efficacy analyses.
    In termini di completamento tempestivo, l'analisi finale PFS sarà condotta non appena si saranno verificati 212 eventi. Questo farà scattare il time point dell'analisi degli endpoint secondari. Le analisi di sicurezza sono indipendenti dalle analisi di efficacia primaria e secondaria.
    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 trial3
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA152
    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 Information not present in EudraCT
    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
    Italy
    Netherlands
    Norway
    Spain
    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
    The end of the clinical trial is defined as the time point 213 PFS events have been reached. This will take place approximately 80 months after first patient has been randomized (FPI).
    La fine dello studio clinico è definita come il time point in cui sono stati raggiunti 213 eventi PFS. Questo avverrà circa 80 mesi dopo che il primo paziente è stato randomizzato (FPI).
    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: 897
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 897
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 747
    F.4.2.2In the whole clinical trial 897
    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)
    For patients randomized to the I arm: In countries where local legislation and regulations permit, patients who remain on treatment with ibrutinib at closure of study, but who cannot access ibrutinib in routine clinical practice, may access ibrutinib via the manufacturer.
    For patients randomized to the VG and VI arm, treatment is administered over a fixed-duration (see treatment schedules) and therefore no continuation of treatment is required post study.
    Per i pazienti randomizzati al braccio I: nei paesi in cui la legislazione e i regolamenti locali lo consentono, i pazienti che rimangono in trattamento con ibrutinib alla chiusura dello studio, ma che non possono accedere a ibrutinib nella pratica clinica di routine, possono accedervi tramite il produttore. Per i pazienti randomizzati al braccio VG e VI, il trattamento viene somministrato su una durata fissa (vedere gli orari), quindi non è richiesta la sua continuazione dopo lo studio.
    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 Decision2021-02-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-14
    P. End of Trial
    P.End of Trial StatusOngoing
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