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    Summary
    EudraCT Number:2017-001099-49
    Sponsor's Protocol Code Number:CLOSE(PS-CLL-001)
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-06-01
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-001099-49
    A.3Full title of the trial
    Clonal evolution in progressive CLL patients harboring subclonal TP53 aberrations treated with ibrutinib first-line
    Evoluzione clonale in pazienti con leucemia linfatica cronica in progressione portatori di alterazioni subclonali di TP53 trattati con ibrutinib come terapia di prima linea
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    therapy with ibrutinib for patients with Chronic lymphocytic leukemia with subclonal TP53 aberrations
    terapia con Ibrutinib per pazienti affetti da leucemia linfatica cronica che presentano alterazioni subclonali di TP53
    A.3.2Name or abbreviated title of the trial where available
    CLOSE (PS-CLL-001)
    CLOSE (PS-CLL-001)
    A.4.1Sponsor's protocol code numberCLOSE(PS-CLL-001)
    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 SponsorOSPEDALE SAN RAFFAELE
    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 supportJanssen-Cilag International N.V., Belgium
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOspedale San Raffaele
    B.5.2Functional name of contact pointUfficio Data Management
    B.5.3 Address:
    B.5.3.1Street Addressvia Olgettina 60
    B.5.3.2Town/ cityMilano
    B.5.3.3Post code20132
    B.5.3.4CountryItaly
    B.5.4Telephone number00390226433919
    B.5.5Fax number00390226436119
    B.5.6E-mailscarano.eloise@hsr.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/12/984-EMA/OD/156/11
    D.3 Description of the IMP
    D.3.1Product nameibrutinib
    D.3.2Product code [PCI-32765]
    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 codeNA
    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.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 (CLL)
    leucemia linfatica cronica (LLC)
    E.1.1.1Medical condition in easily understood language
    Chronic Lymphocytic Leukemia never treated
    leucemia linfatica cronica mai trattata
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10008956
    E.1.2Term Chronic lymphatic leukaemia
    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 characterize the dynamics of the clonal composition in progressive CLL patients harboring TP53 mutations detected by NGS, at different time points (Baseline, Weeks 2,4, 12,24,48,72, 96 and then every year until the end of study, at disease progression)
    ¿ Caratterizzare le dinamiche della composizione clonale in pazienti con CLL in progressione con mutazioni di TP53 rilevate tramite NGS, a tempi diversi (Baseline, settimane 2,4, 12,24,48,72, 96 e poi ogni anno fino alla fine dello studio, a progressione della malattia)
    E.2.2Secondary objectives of the trial
    To assess response to treatment in terms of overall response rate, progression-free survival and overall survival.
    Definire la risposta al trattamento in termini di risposta complessiva, sopravvivenza libera da progressione e globale
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. =18 years old
    2. Documented diagnosis of CLL according to International workshop on CLL (IwCLL) 2008 criteria
    3. Previously untreated (steroid treatment previously administered to control autoimmune complications is allowed)
    4. Negative HBsAg and negative HBcAb or positive HBcAb and negative for HBV DNA by quantitative PCR, HCV antibody negative or, in case of HCV antibody positive, HCV RNA negative
    5. Progressive disease requiring treatment according to IwCLL 2008 criteria
    6. Cohort 2 only: Evidence of a small (<20%) subclone carrying TP53 deletion by FISH
    1. =18 anni
    2. Diagnosi documentata di CLL in base ai criteri dell’International Workshop on CLL (IwCLL) 2008
    3. Non trattati in precedenza (È consentito un trattamento steroideo precedentemente somministrato per controllare complicazioni autoimmuni)
    4. HBsAg e HBcAb negativi o HBcAb positivo e HBV DNA negativo mediante PCR quantitativa, anticorpi anti-HCV negativa o, in caso di anticorpi anti-HCV positivi, HCV RNA negativo
    5. Malattia progressiva che richiede un trattamento secondo i criteri IwCLL 2008
    6. Solo per la coorte 2: evidenza di un piccolo subclone (<20%) portatore di delezione TP53 mediante FISH
    E.4Principal exclusion criteria
    1. Histologically documented transformation from CLL to aggressive lymphoma (Richter transformation)
    2. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
    3. Concomitant use of warfarin or other Vitamin K antagonists
    4. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor
    5. Evidence of clonal TP53 mutations detected by Sanger sequencing and/or del17p in =20% of the nuclei by FISH
    1. Trasformazione istologicamente documentata da CLL a linfoma aggressivo (trasformazione di Richter)
    2. Storia di ictus o emorragia intracranica nei 6 mesi precedenti l'arruolamento
    3. Uso concomitante di warfarin o altri antagonisti della vitamina K
    4. Necessità di trattamento con un forte inibitore del citocromo P450 (CYP) 3A
    5. Evidenza di mutazioni TP53 clonali rilevato tramite sequenziamento Sanger e/o del17p in =20% dei nuclei alla FISH
    E.5 End points
    E.5.1Primary end point(s)
    • TP53 mutated subclone size at WEEK 2,4,12,24,48,72,96 and yearly thereafter compared to baseline [i.e. (TP53 mutated alleles at WEEK 2,4,12,24,48,72,96 and yearly thereafter)/(TP53 mutated alleles at baseline)]
    • Dimensione del subclone TP53 mutato alle SETTIMANE 2,4,12,24,48,72,96 e poi annualmente rispetto al basale [i.e. (allele TP53 mutato alle SETTIMANE 2,4,12,24,48,72,96 e poi annualmente)/(allele TP53 mutato al basale)]
    E.5.1.1Timepoint(s) of evaluation of this end point
    during treatment period
    durante periodo di trattamento
    E.5.2Secondary end point(s)
    • Overall response rate (ORR); Progression-free survival (PFS); Overall survival (OS)
    Risposta complessiva (ORR); Sopravvivenza libera da progressione (PFS); Sopravvivenza globale (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    during treatment and follow up period; during treatment and follow up period; during treatment and follow up period
    durante periodo di trattamento e di follow up; durante periodo di trattamento e di follow up; durante periodo di trattamento e di follow up
    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) 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.8.2.4Number of treatment arms in the trial1
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Switzerland
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months0
    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: 5
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 170
    F.4.2.2In the whole clinical trial 185
    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
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-12
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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