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    Summary
    EudraCT Number:2013-003561-34
    Sponsor's Protocol Code Number:PCYC-1121-CA
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-11-08
    Trial results View 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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2013-003561-34
    A.3Full title of the trial
    A Multicenter, Open-Label, Phase 2 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Subjects with Relapsed/Refractory Marginal Zone Lymphoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to assess the safety and effectiveness of Ibrutinib in subjects with relapsed/refractory marginal zone lymphoma.
    A.4.1Sponsor's protocol code numberPCYC-1121-CA
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01980628
    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 SponsorPharmacyclics LLC
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPharmacyclics LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPharmacyclics LLC
    B.5.2Functional name of contact pointClinical Trial information
    B.5.3 Address:
    B.5.3.1Street Address995 East Arques Avenue
    B.5.3.2Town/ citySunnyvale, California
    B.5.3.3Post code94085
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1408774 0330
    B.5.5Fax number+1408774 0340
    B.5.6E-mailinfo@pcyc.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product 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 codePCI-32765 (Ibrutinib)
    D.3.9.3Other descriptive nameIBRUTINIB
    D.3.9.4EV Substance CodeSUB88115
    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.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed or refractory marginal zone lymphoma
    E.1.1.1Medical condition in easily understood language
    Relapsed or refractory marginal zone lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level HLT
    E.1.2Classification code 10029621
    E.1.2Term Non-Hodgkin's lymphomas unspecified histology indolent
    E.1.2System Organ Class 100000004851
    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 efficacy of ibrutinib therapy in subjects with marginal zone lymphoma (MZL) using the overall response rate (ORR) as assessed by an Independent Review Committee (IRC)
    E.2.2Secondary objectives of the trial
    •To evaluate efficacy parameters such as the duration of response (DOR), progression-free survival (PFS), and overall survival (OS) to ibrutinib therapy in subjects with MZL
    •To evaluate the safety and tolerability of ibrutinib in subjects with MZL
    •To determine the plasma pharmacokinetics of ibrutinib and the metabolite, PCI-45227

    Exploratory Objectives:
    •To evaluate prognostic and predictive biomarkers relative to treatment outcomes

    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Tumor Tissue Biopsy.
    For subjects who meet all eligibility criteria and who consent to the optional tumor biopsy substudy, pre-treatment and post-progression tumor biopsies will be performed and samples sent to the central laboratory.
    Tumor samples may be analyzed by gene expression profiling (GEP) or other methods to define biomarkers that predict response or resistance to ibrutinib therapy.
    Exploratory Objectives:
    •To evaluate prognostic and predictive biomarkers relative to treatment outcomes
    E.3Principal inclusion criteria
    Subjects must meet all of the following criteria in order to be eligible:
    1)Histologically documented marginal zone lymphoma including splenic, nodal, and extranodal sub-types,subjects with splenic MZL must have an additional measurable lesion, nodal or extranodal, as described in inclusion criteria 5
    2)Previously received one or more lines of therapy including at least one CD20-directed regimen (either as monotherapy or as chemoimmunotherapy) with documented failure to achieve at least partial remission (PR) or documented disease progression after, the most recent systemic treatment regimen
    3)Men and women ≥18 years of age
    4)Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
    5)≥1 measurable lesion on computed tomography (CT) scan (>1.5 cm in longest dimension). Lesions in anatomical locations (such as extremities or soft tissue lesions) that are not well visualized by CT may be measured by magnetic resonance imaging (MRI) instead.(Subjects with spleen-only disease are
    considered as not having measurable disease.)
    6)Life expectancy of >3 months, in the opinion of the investigator
    7)Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for ≥2 years; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry.
    8)Male and female subjects who agree to use highly effective methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) during the period of therapy and for 30 days (females) and 90 days (males) after the last dose of study drug
    9)Documented evidence of need for treatment, including, but not limited to, threatened end-organ function, bulky disease (>5 cm), symptoms, requirement for transfusion or growth factor support, or medically significant need for intervention
    10)For subjects with presumptive evidence of transformation based on clinical assessment of factors such as, but not limited to, increasing lactate dehydrogenase (LDH), rapidly worsening disease, or frequent B-symptoms, a pre-treatment biopsy is required to rule out large cell transformation
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria are not eligible:
    1)Medically apparent central nervous system lymphoma or leptomeningeal disease
    2)History of other malignancies except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer, or other solid tumors curatively treated with no evidence of disease for ≥2 years
    3)History of allogeneic stem-cell (or other organ) transplantation
    4)Any chemotherapy, anticancer antibodies, or other systemic anticancer therapy within 21 days of the first dose of study drug
    5)Any external beam radiation therapy within 6 weeks prior to the first dose of study drug
    6)Use of radio- or toxin-immunoconjugates within 70 days of the first dose of study drug
    7)Concurrent use of warfarin or other vitamin K antagonists
    8)Concurrent use of a strong cytochrome P450 (CYP) 3A inhibitor. Subjects who have received a strong CYP3 A inhibitor prior to entering the study must have discontinued therapy for at least 5 half lives of the prohibited medication
    9)Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of >20 mg/day of prednisone) within 28 days of the first dose of study drug
    10)Significant screening electrocardiogram (ECG) abnormalities including, but not limited to, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree block, or corrected QT interval (QTc) ≥470 msec.Subjects with a cardiac pacemaker who have a QTc interval of ≥470 msec may be eligible if these findings are considered not clinically significant as documented via a cardiology evaluation.
    11)Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (New York Heart Association >Class 2), unstable angina, uncontrolled hypertension, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
    12)Recent infection requiring intravenous anti-infective treatment that was completed ≤14 days before the first dose of study drug
    13)Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), Grade 0 or 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
    14)Known bleeding diathesis (eg, von Willebrand’s disease) or hemophilia
    15)Known history of infection with human immunodeficiency virus (HIV) or history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV), or any uncontrolled active systemic infection
    16)Any of the following abnormalities:
    oAbsolute neutrophil count (ANC) <750 cells/mm3 (0.75 x 109/L), unless there is documented bone marrow involvement
    oPlatelet count <50,000 cells/mm3 (50 x 109/L) independent of transfusion support, unless there is documented bone marrow involvement
    oSerum aspartate transaminase (AST) or alanine transaminase (ALT) ≥3.0 x upper limit of normal (ULN)
    oCreatinine >2.0 x ULN or Estimated Glomerular Filtration Rate (GFR [Cockcroft Gault]) < 30 mL/min
    oHemoglobin <8.0 g/dL
    oBilirubin >1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
    oPT/INR >1.5 x ULN and PTT (aPTT) >1.5 x ULN
    17)Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction
    18)Major surgery within 4 weeks prior to the first dose of study drug
    19)Any life-threatening illness, medical condition, including uncontrolled diabetes mellitus (DM), or organ system dysfunction that, in the opinion of the investigator, could compromise the subject’s safety or put the study outcomes at undue risk
    20)Concurrent enrollment in another therapeutic investigational study or have previously taken ibrutinib
    21)Lactating or pregnant
    22)Unwilling or unable to participate in all required study evaluations and procedures
    23)Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
    E.5 End points
    E.5.1Primary end point(s)
    •Overall response rate (complete remission [CR] + partial remission [PR])
    E.5.1.1Timepoint(s) of evaluation of this end point
    at the earliest 52 weeks after the last subject is enrolled
    E.5.2Secondary end point(s)
    •Efficacy:
    oDuration of response (DOR)
    oProgression-free survival (PFS)
    oOverall survival (OS)
    •Safety:
    oFrequency, severity, and relatedness of adverse events (AEs)
    oFrequency of AEs requiring discontinuation of study drug or dose reductions
    E.5.2.1Timepoint(s) of evaluation of this end point
    at the earliest 52 weeks after the last subject is enrolled
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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
    Belgium
    France
    Germany
    United Kingdom
    United States
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months11
    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 months1
    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: 36
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 60
    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)
    Subjects may continue to receive study drug until one of the discontinuation criteria are met (as outlined in Section 9 of the protocol). Subjects with disease progression will discontinue study treatment
    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 Lymphoma Study Association (LYSA)
    G.4.3.4Network Country France
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-12-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-02
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