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    Summary
    EudraCT Number:2016-003286-26
    Sponsor's Protocol Code Number:PCYC-1140-IM
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-02-12
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-003286-26
    A.3Full title of the trial
    A Randomized, Double-Blind Phase 3 Study of Ibrutinib in Combination With Corticosteroids versus Placebo in Combination With Corticosteroids in Subjects with New Onset Chronic Graft Versus Host Disease (cGVHD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Ibrutinib in Combination With Corticosteroids versus Placebo in Combination With Corticosteroids in Patients with New Onset Chronic Graft Versus Host Disease (cGVHD)
    A.4.1Sponsor's protocol code numberPCYC-1140-IM
    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 code94085-4521
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1780-EMA/OD/178/16
    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
    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.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
    Chronic Graft Versus Host Disease (cGVHD)
    E.1.1.1Medical condition in easily understood language
    cGVHD is immune system attack on normal tissue following transplantation of cells from a donor
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10066261
    E.1.2Term Chronic graft versus host disease
    E.1.2System Organ Class 10021428 - Immune system disorders
    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 in combination with prednisone (Arm A) versus placebo in combination with prednisone (Arm B) based on the response rate at 24 weeks as determined by NIH Consensus Development Project criteria in subjects with new onset moderate to severe cGVHD.
    E.2.2Secondary objectives of the trial
    To compare the two treatment arms in terms of the following:
    Efficacy
    - Proportion of subjects obtaining steroid dose level less than 0.15 mg/kg/d at 24 weeks
    - Withdrawal of all immunosuppressants (with the exception of ibrutinib/placebo) at 48 weeks
    - Overall survival (OS)
    - Response rate at 48 weeks
    Safety
    - Safety and tolerability
    - Differences in steroid-related morbidities (eg, hyperglycemia, hypertension)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Prior to randomization, each potential subject must satisfy all of the following inclusion criteria.

    Disease related
    1. New onset moderate or severe cGVHD as defined by the NIH Consensus Development Project Criteria (2014).
    2. History of an allogeneic hematopoietic cell transplant.
    3. Need for systemic treatment with corticosteroids for cGVHD.
    4. No previous systemic treatment for cGVHD (including extracorporeal photopheresis [ECP]).
    5. Participants may be receiving other immunosuppressants for the prophylaxis or treatment of acute GVHD but the doses of these medications must have been stable for at least 2 weeks prior to Screening. Prednisone dose must also be at or below 0.5 mg/kg/d at the time of randomization unless started within the previous 7 days for cGVHD.
    6. Participants may have received pre-transplant ibrutinib for other reasons besides cGVHD such as for the treatment of leukemia or lymphoma, but must not have received a BTK inhibitor since the time of transplant.

    Demographic
    7. Age ≥12 years old.
    8. Karnofsky or Lansky (subjects <16 years) performance score ≥60.

    Laboratory
    9. Adequate hepatic and renal function defined as:
    - AST, ALT ≤3 x ULN (unless of non-hepatic origin). If AST/ALT increase is associated with cGVHD then ≤5 x ULN
    is acceptable
    - Total bilirubin ≤1.5 x ULN (unless of non-hepatic origin or due to Gilbert’s Syndrome)
    - Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault formula)
    10. Adequate hematological function defined as:
    - Absolute neutrophil count ≥1.0 x 109/L and off growth factor support for 7 days
    - Platelets ≥30 x 109/L and no transfusion for 7 days
    11. PT/INR <1.5 x ULN and PTT (aPTT) <1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder). When treated with warfarin or other vitamin K antagonist, then INR ≤3.0.

    Ethical/Other
    12. Male and female subjects of reproductive potential who agree to use both a highly effective methods of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc) during the period of therapy and for 90 days for both females and males after the last dose of study drug.
    E.4Principal exclusion criteria
    To be enrolled in the study, potential subjects must meet NONE of the following exclusion criteria:

    Disease related
    1. Received any previous systemic treatment for cGVHD (with the exception of systemic corticosteroids started for cGVHD within 7 days of randomization).
    2. Inability to begin a prednisone dose ≥0.5 mg/kg/d for the treatment of cGVHD.

    Concurrent conditions
    3. Received any investigational agent ≤28 days before randomization.
    4. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
    5. Any uncontrolled active systemic infection or active infection requiring systemic treatment that was ongoing ≤7 days before randomization.
    6. Progressive underlying malignant disease or any post-transplant lymphoproliferative disease.
    7. History of other malignancy (not including the underlying malignancy that was the indication for transplant), with the following exceptions:
    - Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to Screening and felt to be at low risk for recurrence by treating physician
    - Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
    - Adequately treated cervical carcinoma in situ without current evidence of disease
    8. Subject has a concurrent illness which in the opinion of the investigator may interfere with the treatment and evaluation of the subject.
    9. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
    10. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
    11. Known history of human immunodeficiency virus (HIV).
    12. Subject with chronic liver disease with hepatic impairment per Child-Pugh classification Class B or C (Appendix E).
    13. Active hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before randomization. Those who are PCR positive will be excluded.
    14. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
    15. Major surgery within 4 weeks of first dose of study drug.
    16. 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.
    17. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
    18. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix D) with the exception of strong CYP3A inhibitors used for anti-fungal prophylaxis (eg, posaconazole).
    19. Female subject who is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 3 months of last dose study drug. Male subject who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug.
    20. Unwilling or unable to participate in all required study evaluations and procedures.
    21. 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)
    The primary endpoint is the response rate at 24 weeks. Response will be defined by the NIH Consensus Development Project Criteria (2014) and must occur:
    - In the absence of new therapy for cGVHD
    In the absence of relapse or return of the underlying disease that was the indication for transplant (or post transplant
    lymphoproliferative disease [PTLD]), or death
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    E.5.2Secondary end point(s)
    Secondary endpoints will assess for additional clinical benefits including corticosteroid dose reduction, withdrawal of all immunosuppressants, and overall survival (OS).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints for the secondary end points are detailed in the 'Schedule of assessments' in Appendix A of the protocol
    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 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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
    Austria
    Canada
    China
    Croatia
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    Singapore
    Spain
    Taiwan
    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
    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 months6
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days15
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 35
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 35
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 151
    F.1.3Elderly (>=65 years) No
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 54
    F.4.2.2In the whole clinical trial 186
    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)
    None
    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 Decision2017-08-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-07-12
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