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    Summary
    EudraCT Number:2013-005478-22
    Sponsor's Protocol Code Number:PCYC-1127-CA
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-06-19
    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 ConcernedGreece - EOF
    A.2EudraCT number2013-005478-22
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ibrutinib or Placebo in Combination With Rituximab in Subjects with Previously Treated Waldenstrom’s Macroglobulinemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Clinical Study of Rituximab with or without Ibrutinib in Subjects with Previously Treated Waldenstrom’s Macroglobulinemia
    A.4.1Sponsor's protocol code numberPCYC-1127-CA
    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, Incorporated
    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, Incorporated
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportJohnson & Johnson
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPharmacyclics, Incorporated
    B.5.2Functional name of contact pointMedical Monitor
    B.5.3 Address:
    B.5.3.1Street Address995 East Arques Avenue
    B.5.3.2Town/ citySunnyvale, CA
    B.5.3.3Post code94085-4521
    B.5.3.4CountryUnited States
    B.5.4Telephone number001408215 3770
    B.5.6E-maillstyles@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.3.9.3Other descriptive namePCI-32765
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed or refractory Waldenstrom’s Macroglobulinemia
    E.1.1.1Medical condition in easily understood language
    Leukemia or Lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10047804
    E.1.2Term Waldenstrom's macroglobulinaemia recurrent
    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
    To evaluate the effect of the addition of ibrutinib to rituximab on progression-free survival (PFS) assessed by an independent review committee (IRC) in subjects with previously treated Waldenstrom’s Macroglobulinemia WM.
    Efficacy evaluations will be based on the modified Consensus Response Criteria from the VIth International Workshop for WM (NCCN 2014).
    E.2.2Secondary objectives of the trial
    Efficacy
    To compare the treatment arms in terms of the following:
    • Overall Response Rate (ORR) assessed by IRC (≥ PR; according to the modified VIth International Workshop on Waldenstrom's Macroglobulinemia (IWWM) [NCCN 2014] criteria).
    • Hematological improvement measured by hemoglobin.
    • Time to next treatment (TTnT).Overall survival (OS).

    Safety
    • To evaluate the safety and tolerability of ibrutinib when combined with rituximab therapy compared to rituximab in combination with placebo.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    An open-label ibrutinib substudy (Arm C) is included to further investigate the safety and efficacy of ibrutinib monotherapy in subjects with WM who would otherwise be excluded from the randomized study because they are considered refractory to the last prior rituximab containing therapy.
    PFS, ORR, hematological improvement measured by hemoglobin, TTnT, FACTAn, OS and other efficacy parameters as well as safety analyses will be summarized descriptively for Arm C. No comparator analysis will be done with Arms A or B.
    E.3Principal inclusion criteria
    For the Randomized Study (Arm A and Arm B):

    - Previously treated for Waldenstrom’s macroglobulinemia and have either documented disease progression or had no response (stable disease) to the most recent treatment regimen.
    - Centrally confirmed clinicopathological diagnosis of WM in accordance with the consensus panel of the Second International Workshop on WM (Owen 2003).
    - Measurable disease defined as serum monoclonal IgM >0.5 g/dL.
    - Symptomatic disease meeting at least 1 of the recommendations from the Second International Workshop on Waldenström Macroglobulinemia for requiring treatment (Kyle 2003).
    - Adequate hematologic function.
    - Adequate hepatic and renal function.
    - PT/INR ≤1.5 x ULN and PTT (aPTT) ≤1.5 x ULN.
    - Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Ethical/Other

    For the Open-label Substudy Treatment Arm C:
    To be enrolled in the substudy, each potential subject must meet all of the inclusion criteria defined in Protocol Section 4.1.1 (Arm A & Arm B). IN ADDITION, the following criterion must be met:
    1. Disease that is refractory to the last prior rituximab-containing therapy defined as either
    • Relapse after the last rituximab-containing therapy <12 months since last dose of rituximab,
    OR
    • Failure to achieve at least a MR after the last rituximab-containing therapy.
    E.4Principal exclusion criteria
    - Known involvement of the central nervous system by WM.
    - Disease that is refractory to the last prior rituximab-containing therapy defined as either
    • Relapse after the last rituximab-containing therapy <12 months since last dose of
    rituximab,
    OR
    • Failure to achieve at least a MR after the last rituximab-containing therapy.
    If the subject meets this exclusion criterion and therefore is excluded from the main randomized study, participation in the non randomized substudy (Arm C) may be considered (Section 4.2)
    - Rituximab treatment within the last 12 months before the first dose of study drug.
    - Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of rituximab.
    - Prior exposure to ibrutinib or other BTK inhibitors.
    - Received any WM-related therapy (eg, chemotherapy, immunotherapy, investigational drug) ≤30 days prior to first administration of study treatment.
    - Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia.
    - History of stroke or intracranial hemorrhage within 12 months prior to enrollment.
    - Known history of infection with human immunodeficiency virus (HIV).
    - History of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) .
    - Any uncontrolled active systemic infection.
    - Major surgery (as defined in Section 6.2.2) within 4 weeks of first dose of study drug.
    - Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
    - Significant screening electrocardiogram (ECG) abnormalities.
    - Currently active, clinically significant cardiovascular disease.
    - Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function.
    - Concomitant use of warfarin or other Vitamin K antagonists.
    - Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor.

    The exclusion criteria for the substudy are identical to those of the main randomized study as described in Protocol Section 4.1.2, EXCEPT for criteria 2, 3, and 4, which are related to prior rituximab use and do not apply for the substudy Arm C.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS) assessed by an independent review
    committee (IRC), which is defined as duration from the date of
    randomization to the date of disease progression or death, whichever is first reported, assessed according to the modified VIth IWWM (NCCN 2014) criteria.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Refer to protocol section 10.6.1.
    E.5.2Secondary end point(s)
    Multiplicity adjustment will be made in a sequential hierarchical manner based on a closed testing procedure as outlined in protocol section 10.8 (interim analysis) to control the overall type 1 error.

    - Overall response rate (ORR) defined as the proportion of subjects who achieve Partial response (PR) or better according to the modified VIth IWWM (NCCN 2014) criteria as assessed by IRC.

    - Hematological improvement as measured by change from baseline hemoglobin level.

    - Time-to-next treatment (TTnT) as measured from the date of randomization to the start date of any subsequent WM treatment.

    - Overall survival (OS) as measured from the date of randomization to the date of the subject’s death from any cause.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Refer to protocol section 10.6.2.
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA38
    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
    Australia
    Canada
    France
    Germany
    Greece
    Italy
    Spain
    United States
    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 study will occur approximately 3 years after the last subject is randomized, or the Sponsor terminates the study, whichever comes first.

    At the time of the study closure, a survival sweep will be conducted. All subjects who are on study and not known to have died prior to the survival sweep will be contacted at that time.
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 133
    F.4.2.2In the whole clinical trial 180
    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 who have withdrawn consent or been lost to follow-up before the end of the clinical trial will be treated with standard therapy. Subjects who have completed the study and were receiving clinical benefit will have access to ibrutinib through either a commercially available source, if available, or an extension study.
    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 Decision2014-07-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-11-07
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