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    Summary
    EudraCT Number:2017-000129-12
    Sponsor's Protocol Code Number:PCYC-1143-CA
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-08-04
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2017-000129-12
    A.3Full title of the trial
    Phase 3 Study of Ibrutinib in Combination with Venetoclax in Subjects with Mantle Cell Lymphoma
    Klinické hodnocení fáze 3 hodnotící Ibrutinib v kombinaci s Venetoclaxem u subjektů s lymfomem z plášťových buněk
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Research study of Ibrutinib in Combination with Venetoclax in patients with Mantle Cell Lymphoma
    A.4.1Sponsor's protocol code numberPCYC-1143-CA
    A.5.4Other Identifiers
    Name:IND NUMBERNumber:102,688
    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, CA
    B.5.3.3Post code94085-4521
    B.5.3.4CountryUnited States
    B.5.4Telephone number+14087740330
    B.5.5Fax number+14087740340
    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/3/13/1115
    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.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 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 nameVenetoclax - 100 mg
    D.3.2Product code ABT-199
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNVENETOCLAX
    D.3.9.2Current sponsor codeA-1195425.0
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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: 3
    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 nameVenetoclax - 10 mg
    D.3.2Product code ABT-199
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNVENETOCLAX
    D.3.9.2Current sponsor codeA-1195425.0
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 4
    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 nameVenetoclax - 50 mg
    D.3.2Product code ABT-199
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNVENETOCLAX
    D.3.9.2Current sponsor codeA-1195425.0
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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: 5
    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/3/13/1115
    D.3 Description of the IMP
    D.3.1Product nameIbrutinib
    D.3.2Product code PCI-32765
    D.3.4Pharmaceutical form Tablet
    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 number560
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    Mantle Cell Lymphoma
    E.1.1.1Medical condition in easily understood language
    Mantle Cell Lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061275
    E.1.2Term Mantle cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Safety Run-in Period:
    To evaluate the occurrence of tumor lysis syndrome (TLS) and dose-limiting toxicities (DLTs) with the concurrent administration of ibrutinib and venetoclax.

    Randomization Phase:
    To evaluate whether the combination of ibrutinib and venetoclax will result in prolongation of PFS compared to ibrutinib and placebo in subjects with relapsed or refractory MCL.

    Treatment-naive Open-label Arm:
    To evaluate the complete response (CR) rate with the combination of
    ibrutinib and venetoclax in subjects with treatment-naive MCL
    E.2.2Secondary objectives of the trial
    Safety Run-in Period: To evaluate response (partial and complete
    response), progression-free survival (PFS), duration of response (DOR),
    and overall survival (OS).
    Randomization Phase:
    • To evaluate whether the combination of ibrutinib and venetoclax will
    increase the complete response rate, the overall response rate (ORR),
    the minimal residual disease (MRD) negative remission rate in subjects
    who were MRD positive at screening and achieve CR, OS, DOR, and timeto-
    next treatment (TTNT) compared to ibrutinib and placebo.
    • To evaluate the frequency, severity, and relatedness of AEs; frequency,
    severity and management of TLS; AEs requiring dose reductions and/or
    discontinuation of study drug, or leading to death.
    • To determine the pharmacokinetics of ibrutinib and venetoclax.
    • (one more)
    TN Open-label Arm: Section 2.3.2 of the Protocol
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For SRI and Randomization Phase
    Disease-Related
    • Pathologically confirmed MCL (in tumor tissue), with documentation of
    either overexpression of cyclin D1 in association with other relevant
    markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14) as
    assessed by cytogenetics, fluorescent in situ hybridization (FISH), or
    polymerase chain reaction (PCR).
    • At least 1 measurable site of disease that is ≥2.0 cm in the longest
    diameter and measurable in 2 perpendicular dimensions per CT
    • At least 1, but no more than 5, prior treatment regimens for MCL
    including at least 1 prior rituximab/anti-CD20 containing regimen
    • Failure to achieve at least partial response (PR) with, or documented
    disease progression after, the most recent treatment regimen
    • Subjects must have adequate fresh or paraffin embedded tissue.
    Laboratory
    • Adequate hematologic function
    • Adequate hepatic and renal function
    Demographic
    • Men and women ≥ 18 years of age
    • Eastern Cooperative Oncology Group (ECOG) performance status (PS)
    of 0 or 1

    For Treatment-naive Open-label Arm:
    1. Pathologically confirmed treatment-naive MCL (tumor tissue), with
    documentation of either overexpression of cyclin D1 in association with
    other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of
    t(11;14), as assessed by cytogenetics, fluorescent in situ hybridization
    (FISH), or polymerase chain reaction (PCR)
    • A report from the local laboratory is acceptable if available; however, it
    must be reviewed and approved by the central pathology laboratory to
    verify the above criteria prior to enrollment
    • If the report from the local laboratory is not available, a tumor block or
    slides must be sent to the central pathology laboratory for confirmation
    of the MCL diagnosis prior to enrollment.
    2. Men and women ≥18 years of age with a TP53 mutation
    3. At least 1 measurable site of disease that is ≥2.0 cm in the longest
    diameter and measurable in 2 perpendicular dimensions per CT
    4. Subjects must have adequate fresh or paraffin-embedded tissue
    5. Eastern Cooperative Oncology Group (ECOG) performance status (PS)
    of ≤ 2
    6. Adequate hematologic function independent of transfusion and growth
    factor support for at least 7 days prior to first dose, with the exception of
    pegylated G CSF (pegfilgrastim) and darbepoeitin which require at least
    14 days prior to the first dose defined as:
    • Absolute neutrophil count (ANC) >1000 cells/mm3 (1.0 x 109/L)
    • Platelet count >50,000 cells/mm3 (50 x 109/L)
    • Hemoglobin >8.0 g/dL
    7. Adequate hepatic and renal function defined as:
    • Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤
    3.0 x upper limit of normal (ULN)
    • Estimated Creatinine Clearance (CrCl) ≥30 mL/min (Cockcroft-Gault)
    • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome
    or of non hepatic origin)
    8. Prothrombin time (PT) or International normal ratio (INR) <1.5 x
    upper limit of normal (ULN) and PTT (activated partial thromboplastin
    time [aPTT]) <1.5 x ULN (unless abnormalities are unrelated to
    coagulopathy or bleeding disorder). When treated with warfarin or other
    vitamin K antagonists, then INR ≤3.0
    9. Male and female subjects of reproductive potential who agree to use
    both a highly effective method 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 after the last dose of study drug
    E.4Principal exclusion criteria
    For SRI and Randomization Phase
    Disease-Related
    • History or current evidence of central nervous system lymphoma
    Concurrent Conditions
    • Concurrent enrollment in another therapeutic investigational study or
    prior therapy with ibrutinib or other BTK inhibitors
    • Prior treatment with venetoclax or other BCL2 inhibitors
    • Anticancer therapy including chemotherapy, radiotherapy, small
    molecule and investigational agents ≤21 days prior to receiving the first
    dose of study drug
    • Treatment with any of the following within 7 days prior to the first
    dose of study drug:
    o moderate or strong cytochrome P450 3A (CYP3A) inhibitors
    o moderate or strong CYP3A inducers

    For Treatment-naive Open-label Arm:
    1. Blastoid variant of MCL
    2. History or current evidence of central nervous system lymphoma
    3. Concurrent enrollment in another therapeutic investigational study or
    prior therapy, including ibrutinib or other BTK inhibitors
    4. Prior treatment with venetoclax or other BCL2 inhibitors
    5. History of other malignancies, except:
    • Malignancy treated with curative intent and with no known active
    disease present for ≥3 years before the first dose of study drug and felt
    to be at low risk for recurrence by treating physician
    • Adequately treated non-melanoma skin cancer or lentigo maligna
    without evidence of disease.
    • Adequately treated carcinoma in situ without evidence of disease.
    6. Vaccinated with live, attenuated vaccines within 4 weeks of the first
    dose of study drug
    7. Clinically significant infection requiring IV systemic treatment that
    was completed ≤14 days before the first dose of study drug
    8. Any uncontrolled active systemic infection
    9. Known bleeding disorders (eg, von Willebrand's disease or
    hemophilia)
    10. History of stroke or intracranial hemorrhage within 6 months prior to
    enrollment
    11. Known history of human immunodeficiency virus (HIV) or active with
    hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are
    positive for hepatitis B core antibody, or hepatitis C antibody must have
    a negative polymerase chain reaction (PCR) result before enrollment.
    Those who are hepatitis B surface antigen (HBsAg) or PCR positive will
    be excluded.
    12. Major surgery within 4 weeks of the first dose of study drug.
    13. 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
    14. 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
    15. Unable to swallow capsules or tablets, 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
    16. Treatment with any of the following within 7 days prior to the first
    dose of study drug:
    • Moderate or strong cytochrome P450 3A (CYP3A) inhibitors
    • Moderate or strong CYP3A inducers
    17. Administration or consumption of any of the following within 3 days
    prior to the first dose of study drug:
    • grapefruit or grapefruit products
    • Seville oranges (including marmalade containing Seville oranges)
    • star fruit
    18. Known allergy to xanthine oxidase inhibitors and/or rasburicase for
    subjects with known risk factors (as defined by high tumor burden
    and/or diminished renal function, as detailed in "Study Design" section
    above) for TLS
    19. Subjects with chronic liver disease with hepatic impairment Child-
    Pugh class B or C
    20. Female subject who is pregnant, breastfeeding or is considering
    becoming pregnant during the study or for approximately 90 days after
    the last dose of study drug
    21. Male subject who is considering fathering a child or donating sperm
    during the study or for approximately 90 days after the last dose of
    study drug
    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)
    24. Known hypersensitivity to the active ingredient or other components
    of one or more study drugs
    E.5 End points
    E.5.1Primary end point(s)
    Safety Run-in Period (including timepoints)
    • Frequency of TLS and DLTs- weekly for the 1st 5 weeks
    • Frequency, severity, and relatedness of AEs- weekly for the 1st 6 weeks, then bi-weekly until week 13, then every 4 weeks for the 1st year, every 2 months for year 2 and 3, then every 3 months thereafter until PD
    • Frequency of AEs causing study drug discontinuation, or dose reductions or leading to death- weekly for the 1st 6 weeks, then bi-weekly until week 13, then every 4 weeks for the 1st year, every 2 months for year 2 and 3, then every 3 months until discontinuation of treatment and 30 days after the last dose
    • Response (CR, PR), DOR, and PFS - every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD
    • OS - after progression every 12 weeks until death

    Randomization Phase Primary Endpoint:
    The primary efficacy endpoint of the Phase 3 portion of this study is PFS, defined as the duration from the date of randomization to the date of investigator-assessed disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause,
    whichever occurs first- every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD
    Treatment-naive Open-label Arm Primary Endpoint
    The primary efficacy endpoint of the treatment-naive open-label arm is
    the complete response (CR) rate based on the best overall response
    according to the Revised Response Criteria for Malignant Lymphoma
    (Cheson 2014) - every 3 months for the first year starting with week 13;
    every 4 months during the second and third years, and every 6 months
    thereafter until PD
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please refer to section E.5.1
    E.5.2Secondary end point(s)
    Randomization Phase Secondary Endpoints (including timepoints):
    Efficacy:
    • Complete response rate (CR) based on the best overall response according to the revised criteria- every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD
    • Objective response rate (ORR), defined as CR or PR according to the revised criteria- every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD
    • MRD-negative remission rate in subjects who achieve CR. A MRD-negative remission is defined as undetectable MRD as assessed by flow cytometry in both bone marrow and peripheral blood collected at the time of CR, with requirement of confirmation of MRD negativity in the subsequent peripheral blood 12 weeks later-every 3 months for the first year starting with week 13; every 4 months during the second and third years, and every 6 months thereafter until PD
    Treatment-Naive Open-Label Arm Secondary Endpoints
    • Overall response rate (ORR), defined as CR or PR according to the
    Revised Response Criteria for Malignant Lymphoma (Cheson 2014) -
    every 3 months for the first year starting with week 13; every 4 months
    during the second and third years, and every 6 months thereafter until
    PD
    • Duration of Response (DOR), defined for subjects who achieve an
    overall response as the time from the first occurrence of response (CR or
    PR) to disease progression or death, whichever occurs first - every 3
    months for the first year starting with week 13; every 4 months during
    the second and third years, and every 6 months thereafter until PD
    • Duration of CR, defined for subjects who achieve CR as the time from
    the first occurrence of CR to disease progression or death, whichever
    occurs first - every 3 months for the first year starting with week 13;
    every 4 months during the second and third years, and every 6 months
    thereafter until PD
    • MRD-negative remission rate in subjects who achieve CR. MRDnegative
    remission is defined the same as described in Section 10.2.3 of
    the Protocol - every 3 months for the first year starting with week 13;
    every 4 months during the second and third years, and every 6 months
    thereafter until PD
    • PFS, defined as the time from the date of the first dose of study
    treatment to the date of disease progression using the Revised Response
    Criteria for Malignant Lymphoma (Cheson 2014), or death from any
    cause, whichever occurs first - every 3 months for the first year starting
    with week 13; every 4 months during the second and third years, and
    every 6 months thereafter until PD
    • OS, defined as the time from the date of the first dose of study
    treatment to death from any cause - after progression every 12 weeks
    until death
    • TTNT, defined as the duration from the date of the first dose of study
    treatment to the start date of any anti-lymphoma treatment subsequent
    to study treatment - after progression every 12 weeks until death
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to section E.5.2
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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) 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 Yes
    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 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA85
    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
    Belgium
    Canada
    Czechia
    France
    Germany
    Greece
    Hungary
    Italy
    Korea, Republic of
    Netherlands
    Poland
    Spain
    Turkey
    Ukraine
    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 years6
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months3
    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: 134
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 228
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 328
    F.4.2.2In the whole clinical trial 362
    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)
    Once a subject has completed the End-of-Treatment Visit, they will enter the Follow-up Phase.Subjects in Long-term Follow-up will be contacted approximately every 12 weeks (±14 days) by clinic visit or telephone to assess survival and the use of alternative anticancer therapy. Subjects will be contacted until death, subject withdrawal, or
    study termination by the Sponsor, whichever occurs first.At the end of
    study, subjects may continue to receive ibrutinib, or a different drug or
    treatment.
    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 Decision2017-10-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-02
    P. End of Trial
    P.End of Trial StatusOngoing
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