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    Summary
    EudraCT Number:2014-002714-23
    Sponsor's Protocol Code Number:LLC1114
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-11-21
    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 number2014-002714-23
    A.3Full title of the trial
    A phase 2 multicenter study to assess the activity and the safety
    of front-line Ibrutinib plus Rituximab (IR) in unfit patients
    with Chronic Lymphocytic Leukemia (CLL).
    Studio multicentrico di fase 2 per valutare attività e sicurezza di Ibrutinib associato a Rituximab in prima linea nei pazienti unfit affetti da Leucemia Linfocitica Cronica (LLC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to assess the efficacy and the safety
    of front-line therapy (Ibrutinib plus Rituximab )
    in patients who aren't able to undergo intensive chemotherapy or replacement of the cells from which they originate those of the blood
    with Chronic Lymphocytic Leukemia (CLL)
    Studio condotto in più centri per valutare la capacità di un farmaco denominato Ibrutinib associato ad un altro farmaco denominato Rituximab di produrre sull’organismo umano gli effetti curativi desiderati e quelli collaterali in pazienti ai quali viene diagnosticata la leucemia linfocitica cronica, che non possono essere trattati con farmaci forti e/o non possono sottoporsi alla sostituzione delle cellule da cui originano quelle del sangue.
    A.4.1Sponsor's protocol code numberLLC1114
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02232386
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorFondazione G.I.M.EM.A. Onlus Gruppo Italiano Malattie Ematologiche dell'Adulto
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportA.I.L. Associazione Italiana contro le Leucemie
    B.4.2CountryItaly
    B.4.1Name of organisation providing supportJanssen-Cilag
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFondazione GIMEMA
    B.5.2Functional name of contact pointCentro Dati GIMEMA
    B.5.3 Address:
    B.5.3.1Street Addressvia Casilina, 5
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00182
    B.5.3.4CountryItaly
    B.5.4Telephone number+390670390521
    B.5.5Fax number+390670390540
    B.5.6E-mailgimema@gimema.it
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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.3.2Product code 936563-96-1
    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 INNNA
    D.3.9.1CAS number 936563-96-1
    D.3.9.2Current sponsor codeIBRUTINIB
    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: 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 MabThera
    D.2.1.1.2Name of the Marketing Authorisation holderMabThera
    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.3.1Product nameMabThera
    D.3.2Product code rituximab
    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.3.11 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 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
    Chronic Lymphocytic Leukemia
    Leucemia linfocitica cronica
    E.1.1.1Medical condition in easily understood language
    Cancer of the white blood cells (leukocytes) which grow out of control
    and accumulate in the bone marrow and blood, where they crowd out
    healthy blood cells.
    Proliferazione abnorme di un particolare tipo di cellule presenti nel
    sangue(Linfociti),con conseguente accumulo in varie parti del corpo.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10024340
    E.1.2Term Leukemia lymphocytic chronic
    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
    To evaluate the activity of a front-line treatment with the Ibrutinib plus Rituximab (IR) combination in unfit patients with CLL in terms of Progression Free Survival (PFS) at 12 months.
    Valutare l’attività del trattamento di prima linea con Ibrutinib associato a Rituximab nei pazienti unfit affetti da LLC in termini di Progression Free Survival (PFS) a dodici mesi.
    E.2.2Secondary objectives of the trial
    Overall Responses rate (ORR).
    • Complete Responses (CRs) rate.
    • Minimal Residual Disease (MRD)
    • Time To Next Treatment (TTNT).
    • Event-Free Survival (EFS).
    • Overall Survival (OS).
    • Hematological improvement measured by hemoglobin, granulocyte and platelet counts.
    • Changes in the serum immunoglobulin levels.
    • Safety and tolerability of the IR treatment.
    • Medical resource utilization (MRU) associated with therapy, including the number of hospitalizations, emergency department visits, blood product transfusions, and use of hematopoietic growth factors.
    • Responses rate (ORR, CR), PFS, OS, EFS and TTNT according to clinical and biologic features of CLL.
    • Trafficking of lymphocytes at week +2 of treatment.
    • The role of FDG-PET/CT in discriminating Richter’s Syndrome and Secondary Malignancy.
    • Overall Responses Rate (ORR);
    • Complete Responses (CRs) Rate;
    • Minimal Residual Disease (MRD);
    • Time To Next Treatment (TTNT);
    • Event-Free Survival (EFS);
    • Overall Survival (OS);
    • Miglioramento ematologico misurato tramite emoglobina, granulociti e conta piastrinica;
    • Variazioni nei livelli di immunoglobuline sieriche;
    • Sicurezza e tollerabilità del trattamento con Ibrutinib e Rituximab;
    • Utilizzo delle risorse mediche (Medical resource utilization, MRU) associate con la terapia, compreso il numero di ospedalizzazioni, visite al pronto soccorso, trasfusioni di emoderivati ed uso di fattori di crescita ematopoietici;
    • Percentuali di risposta (ORR, CR), PFS, OS, EFS e TTNT secondo le caratteristiche cliniche e biologiche della LLC;
    • Circolazione dei linfociti durante le prima due settimane di trattamento;
    • Ruolo della FDG-PET/CT nella valutazione della Sindrome di Richter e di malignità secondari.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Ibrutinib as single agent or in combination with Rituximab has been associated with a high response rate and PFS in trials that included treatment naïve and previously treated CLL patients (Byrd 2013; Burger, 2014; O’Brien 2014). The response appeared to be independent from the clinical and biologic characteristics of the disease. However, patients with poor prognosis genetic features such as deletion 11 and deletion 17 showed a lower response duration. The current study is designed to evaluate whether first-line treatment with Ibrutinib and Rituximab results in a significant improvement in PFS at 12 months. The aims of the translational research included in this study will be to evaluate if and what extent biologic features, including the genetic abnormalities recently identified in CLL, could influence the outcome of patients treated with an Ibrutinib-based treatment. The results deriving from translational research could identify the clinical and biological profile of patients who could have a better response to the study drugs in terms of response, response duration and survival. An additional objective of the study will be to define the clinical and biologic characteristics of patients who are refractory to the treatment or will progress on treatment. The results deriving from this study could improve the individualized health care, by better understanding the study efficacy, the safety mode of action and progression of the disease. Samples will be sent and stored at the Laboratorio Centralizzazione, Ematologia, Azienda Policlinico “Umberto I”, Dipartimento Biotecnologie Cellulari ed Ematologia, Università “Sapienza”, Via Benevento 6 - 00161 Roma. Samples will be collected at defined time points of the study, at baseline, at response evaluation and at any time of failure or disease progression.
    The sampling is subject to patients’ signature on the informed consent.

    Morphology
    Smears of peripheral blood will be analyzed centrally with the standard May-Grünwald and Giemsa stain.
    Immunophenotype
    The baseline immunophenotype will be performed centrally. The immunophenotypic evaluation will be done through cell suspension of peripheral blood samples according to the 2008 IWCLL guidelines and will include the prognostic markers CD38, CD49d, ZAP-70.
    Cytogenetics
    Cytogenetic analysis will be performed in 4 different cytogenetic laboratories as follows:
    FERRARA (Prof. A. Cuneo, Azienda Ospedaliera-Universitaria, Ferrara)
    MILANO (Prof. A. Neri, Università degli Studi di Milano)
    ROMA (Dott.ssa A. Guarini, Università Sapienza, Roma)
    BARI (Prof.ssa G. Specchia, Università di Bari)

    Interphase FISH will be performed on peripheral blood samples obtained at baseline with probes for the following regions: 13q14, 12q13, 11q22/ATM and 17p13/TP53.

    Mutational analysis
    The mutational statues of the IGHV genes will be defined according to standard methods; the cutoff of 98% homology to the germline sequence will discriminate between mutated (<98% homology) and unmutated (≥98% homology) cases.
    The mutation hot spots of the TP53 (exons 4-9, including splicing sites;bRefSeq NM_000546.5), NOTCH1 (exon 34; including splicing sites; cRefSeq NM_017617.2), SF3B1 (exons 14, 15, 16, including splice sites; cRefSeq NM_012433.2) and BIRC3 (exons 6-9, including splicing sites; cRefSeq NM_001165.4) genes will be analyzed by PCR amplification and DNA direct sequencing of high-molecular-weight genomic DNA.

    Trafficking
    Cell trafficking will be evaluated by flow cytometry the expression of a panel of antigens (CD38, CD49d, CD62L, CD11a, CD18, CD69, CD80, CD86, CD200, CD40, CD154, CD44, CD27, CD184, CD185, CD43, CD81) on leukemic cells and immunocompetent populations (B and T lymphocytes), in order to characterize the modifications of chemokine receptors/adhesion molecules involved in tissue homing and retention at baseline and after administration of therapy (at week +2).
    L’obiettivo della ricerca traslazionale è quello di valutare se e in che misura le caratteristiche biologiche, comprese le anomalie genetiche recentemente identificate nella LLC, potrebbero influenzare l'esito della patologia nei pazienti trattati con Ibrutinib. I risultati derivanti dalla ricerca traslazionale identificherebbero il profilo clinico e biologico dei pazienti con migliore responsività ai farmaci in studio in termini di risposta, durata della risposta e sopravvivenza. Un ulteriore obiettivo dello studio sarà quello di definire le caratteristiche cliniche e biologiche dei pazienti che sono refrattari al trattamento o che presentano progressione della malattia durante il trattamento. I risultati derivanti da questo studio potrebbero migliorare l'assistenza sanitaria individualizzata, attraverso una migliore comprensione dell'efficacia e della sicurezza del farmaco in studio e della progressione della malattia.
    E.3Principal inclusion criteria
    18 years of age or older.
    2. Diagnosis of CLL meeting IWCLL criteria.
    3. The diagnosis of CLL requires a history of lymphocytosis with a B-lymphocyte count ≥5,000/L. Prolymphocytes may comprise no more than 55% of blood lymphocytes.
    4. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment:
    a) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia or thrombocytopenia.
    b) Massive (ie, at least 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
    c) Massive nodes (ie, at least 10 cm in longest diameter), progressive, or symptomatic lymphadenopathy.
    d) Progressive lymphocytosis with an increase of more than 50% over a 2-month period or a lymphocyte doubling time (LDT) of less than 6 months (which may be extrapolated). Lymphocyte doubling time can be obtained by linear regression extrapolation of ALCs obtained at intervals of 2 weeks over an observation period of 2 to 3 months. For patients with initial blood lymphocyte counts of less than 30 x 109/L (30,000/L), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded.
    e) Constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs:
    - Unintentional weight loss >10% within the previous 6 months prior to screening
    - Significant fatigue (inability to work or perform usual activities)
    - Fevers higher than 38.0°C for 2 or more weeks without evidence of infection; or
    - Night sweats for more than 1 month without evidence of infection
    - Measurable nodal disease by computed tomography (CT). Measurable nodal disease is defined as at least one lymph node >1.5 cm in longest diameter in a site that has not been previously irradiated. An irradiated lesion may be assessed for measurable disease only if there has been documented progression in that lesion since radiotherapy has ended.
    5. No prior treatment.
    6. Total CIRS >6 and/or creatinine clearance <70 ml/min [Cockcroft-Gault]).
    7. Hematology values within the following limits: Absolute neutrophil count (ANC) 1 x 109/L (ie, 1000/L) independent of growth factor support. Platelets 50,000/mm3 if bone marrow involvement independent of transfusion support
    8. Biochemical values within the following limits:
    a) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN)
    b) Total bilirubin ≤1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
    c) Serum creatinine ≤2 x ULN or estimated Glomerular Filtration Rate (Cockroft Gault) ≥40 mL/min
    9. Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree not to donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of ibrutinib and 12 months after the last dose of rituximab. For males, these restrictions apply for 3 months after the last dose of ibrutinib.
    10. Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [-hCG]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study.
    11. A signed informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
    1. 1. 18 o più anni di età;
    2. Diagnosi di LLC secondo i criteri IWCLL del 2008;
    3. La diagnosi di LLC richiede una storia di linfocitosi con conta B-linfocitica ≥5,000/L. I prolinfociti possono comprendere non più del 55% dei linfociti del sangue;
    4. Malattia attiva che sia in accordo con almeno uno dei seguenti criteri IWCLL 2008 che richiedano trattamento:
    a) Evidenza di deficit progressivo midollare che si manifesta con lo sviluppo o il peggioramento di anemia o trombocitopenia;
    b) Grave splenomegalia (es: almeno 6 cm al di sotto del margine costale sinistro) progressiva o sintomatica;
    c) Grandezza dei linfonodi (es:, almeno 10 cm nel diametro maggiore), linfoadenopatia progressiva o sintomatica;
    d) Linfocitosi progressiva con un aumento di più del 50% in un periodo di due mesi o lymphocyte doubling time (LDT) di meno di sei mesi (dato che può essere estrapolato). L’LDT può essere ottenuto tramite linear regression extrapolation of ALCs ottenuta ad intervalli di due settimane per un periodo di osservazione di 2-3 mesi. Per i pazienti con conta iniziale dei linfociti del sangue inferiore a 30 x 109/L (30,000/L), l’LDT non dovrebbe essere usato come unico parametro per definire l’indicazione al trattamento. Inoltre i fattori che contribuiscono alla linfocitosi o alla linfadenopatia, a parte la LLC (es: infezioni) dovrebbero essere esclusi;
    e) Sintomi di costituzione, definiti come uno o più dei seguenti sintomi o segni correlati alla malattia:
    - Perdita non intenzionale di peso >10% nei sei mesi precedenti lo screening;
    - Significativo affaticamento (impossibilità di lavorare o effettuare le normali attività);
    - Febbri più elevate di 38.0°C per due o più settimane senza evidenza di infezioni; oppure
    - Sudorazioni notturne per più di un mese senza evidenza di infezione;
    - Patologia linfonodale misurabile tramite computed tomography (CT). La patologia linfonodale misurabile è definita come almeno un linfonodo >1.5 cm nel diametro più lungo in un sito che non sia stato precedentemente irradiato. Una lesione irradiata può essere valutata per la patologia misurabile solo se ci sia stata una progressione documentata in quella lesione dopo il termine della radioterapia;
    5. Nessun precedente trattamento;
    6. CIRS totale > 6 e/o clearance della creatinina < 70 ml/min [Cockcroft-Gault]);
    7. Valori ematologici entro i seguenti limiti: Conta assoluta dei neutrofili (Absolute neutrophil count, ANC) 1 x 109/L (es: 1000/L) indipendente dal supporto dei fattori di crescita; Piastrine 50.000/mm3 se il coinvolgimento del midollo osseo è indipendente dal supporto trasfusionale;
    8. Valori biochimici entro i seguenti limiti:
    a. Alanina aminotransferasi (ALT) e aspartato aminotransferasi (AST) ≤3 x limite superiore alla norma (upper limit of normal, ULN);
    b. Bilirubina totale ≤1.5 x ULN a meno che l’aumento della bilirubina sia dovuta alla sindrome di Gilbert o ad un’origine non epatica;
    c. Creatinina sierica ≤ 2 x ULN o Tasso di filtrazione glomerulare stimato (Cockroft Gault) ≥ 40 mL/min;
    9. Le donne potenzialmente fertili e gli uomini sessualmente attivi devono praticare un metodo di controllo delle nascite altamente efficace durante e dopo lo studio in accordo con le normative locali in merito all’uso di metodi per il controllo delle nascite per soggetti partecipanti alle sperimentazioni cliniche. Gli uomini devono essere d’accordo a non donare lo sperma durante e dopo lo studio. Per le donne, queste restrizioni si applicano per un mese dopo all’ultima dose di ibrutinib e 12 mesi dopo l’ultima dose di rituximab. Per i maschi queste restrizioni si applicano per i tre mesi successivi all’ultima dose di ibrutinib;
    10. Le donne potenzialmente fertili devono avere un test di gravidanza negativo del sangue (gonadotropina beta corionica umana [-hCG]) o delle urine allo screening. Le donne che siano in gravidanza o in allattamento sono non eleggibili per questo studio;
    11. Firma (o firma del relativo rappresentante legale) del consenso informato che indichi la comprensione di scopo e procedure dello studio, inclusi i biomarcatori, e la disponibilità a partecipare allo studio.
    E.4Principal exclusion criteria
    1. Any significant concurrent, uncontrolled medical condition or organ system dysfunction and/or laboratory abnormality or psychiatric disease which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk or prevent the subject from signing the informed consent form.
    2. Pregnant or lactating females
    3. Known presence of alcohol and/or drug abuse.
    4. Any potential subject who meets any of the following criteria will be excluded from participating in the study.
    5. Major surgery within 4 weeks of randomization.
    6. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
    7. Known central nervous system lymphoma.
    8. History of stroke or intracranial hemorrhage within 6 months prior to randomization, or of a significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.
    9. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) in any moment of the study.
    10. Requires treatment with strong CYP3A inhibitors.
    11. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association
    12. Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
    13. Known history of human immunodeficiency virus (HIV) positive serology for HIV; active Hepatitis B Virus infection or positive serology for Hepatitis B (HBV) defined as a positive test for HBsAg and HBV-DNA; active Hepatitis C or HCV-RNA positive; any uncontrolled active systemic infection requiring intravenous (IV) antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection; history of tuberculosis within the last five years or recent exposure to tuberculosis equal to or less than 6 months.
    14. Richter’s syndrome (RS), concomitant or past malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
    1. Qualsiasi condizione medica significativa, concomitante e non controllabile o disfunzione organo-sistemica e/o anormalità di laboratorio o patologia psichiatrica che, a giudizio dello sperimentatore, possa compromettere la sicurezza del paziente, interferire con l’assorbimento o il metabolismo delle capsule di Ibrutinib o esporre gli outcome dello studio ad un rischio non dovuto o impedire al soggetto di firmare il consenso informato;
    2. Donne in gravidanza o in allattamento;
    3. Noto abuso di alcol o farmaci;
    4. Qualsiasi potenziale soggetto che incontri qualsiasi dei seguenti criteri sarà escluso dalla partecipazione allo studio;
    5. Chirurgia maggiore nelle quattro settimane precedenti la randomizzazione;
    6. Anemia emolitica autoimmune non controllata o trombocitopenia;
    7. Linfoma del Sistema Nervoso Centrale noto;
    8. Storia di ictus o emorragia intracranica nei sei mesi precedenti la randomizzazione o patologia cerebrovascolare significativa negli ultimi sei mesi o evento in corso con sintomi attivi o sequelae;
    9. Necessità di terapia anticoagulante con warfarin o antagonisti della vitamina K equivalenti (es: phenprocoumon) in qualsiasi momento dello studio;
    10. Necessità di trattamento con potenti inibitori del CYP3A;
    11. Patologia cardiovascolare clinicamente significativa come aritmie non controllate o sintomatiche, scompenso cardiaco congestizio o infarto del miocardio entro sei mesi dallo screening o qualsiasi patologia cardiaca di grado 3 (moderato) o grado 4 (grave) come definita dalla New York Heart Association;
    12. Vaccinazione con vaccini vivi o attenuati entro quattro settimane dalla randomizzazione;
    13. Storia nota di positività sierologica per il virus HIV (human immunodeficiency virus); infezione attiva da virus dell’epatite B o positività sierologica per virus dell’epatite B definita come positività al per HBsAg e HBV-DNA; epatite C attiva o HCV-RNA positivo; qualsiasi infezione sistemica attiva non controllata che richieda un trattamento antibiotico, antifungino o antivirale endovena, come, ma non limitata a, infezione renale cronica, infezione toracica cronica; storia di tubercolosi nei cinque anni precedenti o recente esposizione alla tubercolosi uguale o inferiore a sei mesi;
    14. Sindrome di Richter, malignità concomitante o passata. I soggetti che non abbiano avuto malignità per almeno cinque anni o che abbiano una storia di cancro della pelle (non melanoma) completamente asportato o un carcinoma in situ trattato con successo sono eleggibili.
    E.5 End points
    E.5.1Primary end point(s)
    Progression Free Survival (PFS)
    Progression Free Survival (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 12 months
    Dopo 12 mesi
    E.5.2Secondary end point(s)
    •Rate of Overall Response Rate (ORR) measured in terms of number of patients in CR/PR at the end of induction therapy.
    • Rate of Complete Responses (CR) measured in terms of number of patients in CR at the end of induction therapy.
    • Minimal Residual Disease (MRD) in terms of rate of MRD-negative CRs at the end of induction therapy.
    • Time To Next Treatment (TTNT) after treatment discontinuation.
    • Event-Free Survival (EFS) at 36 months.
    • Overall Survival (OS) at 36 months.
    • Rate of hematological improvement in patients with baseline anemia, neutropenia and thrombocytopenia defined by hemoglobin >11 g/dL or increase ≥50% over baseline, granulocyte >1500 mm3 or platelet count >100,000/mm3, respectively.
    • Rate of patients with improvement in the immunoglobulin levels.
    • Incidence of adverse events (AEs) and severe adverse events (SAEs).
    • Rate of patients requiring hospitalization, emergency department visits, blood product transfusions and use of hematopoietic growth factors.
    • Rate of ORR, CR, PFS, EFS, TTNT and OS according to clinical and biologic variables: age, size of nodes, CIRS score, stage, ß2-microglobulin, lymphocyte count, stage, CD38, CD49d, ZAP-70, IGVH mutation status, FISH profile (11q del; 17p del; trisomy 12; 13q del; no aberrations) and mutations of TP53, NOTCH1, SF3B1 and BIRC3.
    • Proportion of leukemic and of normal lymphocyte subpopulations, including evaluation of cytokine receptors/adhesion molecules on peripheral blood lymphocytes at week +2 from the start of treatment.
    • Rate of cases of patients with RS or SM identified by FDG-PET/CT.
    Overall Responses Rate (ORR);
    • Complete Responses (CRs) Rate;
    • Minimal Residual Disease (MRD);
    • Time To Next Treatment (TTNT);
    • Event-Free Survival (EFS);
    • Overall Survival (OS);
    • Miglioramento ematologico misurato tramite emoglobina, granulociti e conta piastrinica;
    • Variazioni nei livelli di immunoglobuline sieriche;
    • Sicurezza e tollerabilità del trattamento con Ibrutinib e Rituximab;
    • Utilizzo delle risorse mediche (Medical resource utilization, MRU) associate con la terapia, compreso il numero di ospedalizzazioni, visite al pronto soccorso, trasfusioni di emoderivati ed uso di fattori di crescita ematopoietici;
    • Percentuali di risposta (ORR, CR), PFS, OS, EFS e TTNT secondo le caratteristiche cliniche e biologiche della LLC;
    • Circolazione dei linfociti durante le prima due settimane di trattamento;
    • Ruolo della FDG-PET/CT nella valutazione della Sindrome di Richter e di malignità secondari.
    E.5.2.1Timepoint(s) of evaluation of this end point
    During and at the end of the study
    Durante ed al termine dello studio
    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 Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned37
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee 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
    LVLS
    Ultima visita ultimo paziente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 56
    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 No
    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 state156
    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)
    Not applicable
    Non applicabile
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation G.I.M.EM.A. Gruppo Italiano Malattie Ematologiche dell'Adulto
    G.4.3.4Network Country Italy
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-01-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-11-27
    P. End of Trial
    P.End of Trial StatusOngoing
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