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    Summary
    EudraCT Number:2015-003429-32
    Sponsor's Protocol Code Number:ImbruVeRCHOP-Trial
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-08-19
    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 ConcernedGermany - BfArM
    A.2EudraCT number2015-003429-32
    A.3Full title of the trial
    “Ibrutinib (Imbruvica®), Bortezomib (Velcade®) s.c., Rituximab, CHOP for the treatment of elderly patients (age 61-80 years) with CD20+ diffuse large B-cell lymphoma, IPI ≥ 2”
    „Eine Phase-I/II-Studie zur Untersuchung von Ibru-tinib (Imbruvica®), Bortezomib (Velcade®) s.c., Rituximab, CHOP in der Behandlung von älteren Patienten (Alter 61-80 Jahre) mit CD20+ diffus großzelligem Lymphom (DLBCL) und IPI ≥ 2“
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    “Ibrutinib (Imbruvica®), Bortezomib (Velcade®) s.c., Rituximab, CHOP for the treatment of elderly patients (age 61-80 years) with CD20+ diffuse large B-cell lymphoma, IPI ≥ 2”
    „Eine Phase-I/II-Studie zur Untersuchung von Ibru-tinib (Imbruvica®), Bortezomib (Velcade®) s.c., Rituximab, CHOP in der Behandlung von älteren Patienten (Alter 61-80 Jahre) mit CD20+ diffus großzelligem Lymphom (DLBCL) und IPI ≥ 2“
    A.3.2Name or abbreviated title of the trial where available
    ImbruVeRCHOP-Trial
    A.4.1Sponsor's protocol code numberImbruVeRCHOP-Trial
    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 SponsorCharité - Universitätsmedizin Berlin
    B.1.3.4CountryGermany
    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 supportJanssen-Cilag GmbH
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportDeutsches Konsortium für translationale Krebsforschung (DKTK)
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportPreclinical Comprehensive Cancer Center (PCCC)
    B.4.2CountryGermany
    B.4.1Name of organisation providing supportBerlin Institute of Health (BIH)
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCharité - Universitätsmedizin Berlin
    B.5.2Functional name of contact pointCVK, Hematology, Oncology and Tumor
    B.5.3 Address:
    B.5.3.1Street AddressAugustenburger Platz 1
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13353
    B.5.3.4CountryGermany
    B.5.4Telephone number+4930450 553 896
    B.5.5Fax number+4930450 553 986
    B.5.6E-mailclemens.schmitt@charite.de
    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 Yes
    D.2.1.1.1Trade name Velcade
    D.2.1.1.2Name of the Marketing Authorisation holderJANSSEN-CILAG INTERNATIONAL NV
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 nameVelcade
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBORTEZOMIB
    D.3.9.1CAS number 179324-69-7
    D.3.9.3Other descriptive nameVELCADE
    D.3.9.4EV Substance CodeSUB20020
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number3,5
    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 Yes
    D.2.1.1.1Trade name IMBRUVICA
    D.2.1.1.2Name of the Marketing Authorisation holderJANSSEN-CILAG INTERNATIONAL NV
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 nameIMBRUVICA
    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 INNIMBRUVICA
    D.3.9.1CAS number 936563-96-1
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    untreated CD20-positive DLBCL-like aggressive Non-Hodgkin’s lymphoma, 61-80 years of age with unfavorable risk profile (IPI ≥ 2)
    E.1.1.1Medical condition in easily understood language
    CD20-positive diffuse large B-cell lymphoma, IPI ≥ 2
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of this clinical trial is to assess the efficacy of the treatment determined as the 2-year PFS for patients with DLBCL. The regimen will be considered unacceptable if ≤ 60 % of patients (i.e. ≤ 36 patients in a cohort of 60 patients) are progression-free at 2 years. With this decision rule, the regimen will be correctly rejected with at least 95% power if true 2-year PFS rate falls below 50%. If true 2-year PFS rate is 75%, the treatment will be rejected erroneously with a 0.007 probability. “Responders” (i.e. patients achieving a CR or a PR) vs. “Non-Responders” are based on the Revised Response Criteria for Malignant Lymphoma.
    E.2.2Secondary objectives of the trial
    • Feasibility & assessment of toxicity
    • 1-year PFS & 2-year PFS for patients substratified by their different cell-of-origin (c-o-o) subtypes (i.e. GCB vs
    ABC by GEP)
    • CRR, ORR, DFS, OS in all patients & the GCB vs. ABC subgroups
    • Frequency of secondary CNS involvement
    • Protocol adherence
    • Predictive value of an IHC-based prediction score compared to a GEP-based c-o-o signature (GCB DLBCL, ABC/non-GCB DLBCL )
    • Predictive value of MRD (minimal residual disease) Levels or MRD reduction after two cycles
    • Correlation of response & outcome with GEP-based gene subsets under therapy (cycle 1 and 3) & with
    specific mutations identified by sequencing analysis of candidate loci
    • Targeted re-sequencing of primary lymphoma material & whole-exome or whole-genome sequencing in a subset of
    the patients
    • Establishment of patient-derived xenograft (PDX) mouse models
    • Proteome and metabolome analyses of patient primary (or PDX) lymphoma material & serum
    • Analyses of relapses
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Written informed consent indicating that they understand the purpose of and procedures required for the study, including biomarkers and are willing to participate in the study
    • Age ≥ 61 years and ≤ 80 years
    • CD20-positive diffuse large B-cell lymphoma (DLBCL); including T-cell-rich large B-cell lymphoma, anaplastic large B-cell lymphoma; follicular lymphoma grade 3b or primary transformed follicular lymphoma at initial diagnosis
    • Lymphoma biopsy native, fresh-frozen for genome-wide transcriptome array or RNA-Seq analyses (gene expression profiling [GEP]) for molecular subtype diagnosis
    • Willingness to consent to a re-biopsy in C1/day d2, and – in case of a residual lesion by interim CT – in C3/d2 if it can be obtained without inadequate risk
    • Unfavorable risk profile according to the IPI score (IPI ≥ 2)
    • Performance status (ECOG) 0-2
    • Bi-dimensionally measurable disease (measurable by CT scan or MRI)
    • Cardiac ejection fraction ≥ 50 % without clinically significant abnormalities
    • Adequate hematological function: hemoglobin ≥ 9 g/dL absolute neutrophil count ≥ 1,00/μL independent of growth factor support and platelet count ≥ 100,000/μL or ≥50,000/μL if bone marrow involvement independent of transfusion support in either situation
    • Adequate renal function as documented by serum creatinine level < 2 x ULN or estimated GFR ≥ 40ml/min/1,73m²
    • Adequate hepatic function (total bilirubin ≤ 1,5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of nonhepatic
    origin, alanine aminotransferase ALT and aspartate aminotransferase AST ≤ 3 x ULN)
    • Life expectancy > 6 months
    • Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [ß-hCG]) or
    urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study.
    • Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth
    control during and after the study consistent with local regulations regarding the use of birth control methods for
    subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females,
    these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 month
    after the last dose of study drug
    E.4Principal exclusion criteria
    • Unable to sign informed consent
    • Secondary transformed B-NHL or types of NHL other than DLBCL and its subtypes according to WHO classification
    • Prior therapy for DLBCL
    • Known central nervous system lymphoma
    • CNS involvement by lymphoma or any evidence of spinal cord compression. Brain CT/MRI is only mandatory (within 4 weeks prior to study entrance) in case of clinical suspicion of CNS involvement by lymphoma
    • Major surgery within 4 weeks of study entrance
    • History of stroke or intracranial hemorrhage within 6 months prior to study entrance
    • Anticoagulation with Warfarin or equivalent vitamin K antagonists (e.g, Phenprocoumon)
    • Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure or myocardial infarction within 6 months of Screening or any class 3 or 4 cardiac disease as defined by NYHA
    • Treatment with strong CYP3A inhibitors
    • Known history of human immunodeficiency virus HIV or active Hepatitis C virus or active Hepatitis B virus infection
    or any uncontrolled active systemic infection requiring intravenous iv antibiotics
    • Vaccination with live, attenuated vaccines within 3 weeks of study entrance
    • History of solid organ transplantation
    • Pregnant or nursing females
    • Prior malignancy (except adequately treated basal cell carcinoma and squamous cell carcinoma of the skin, cervical cancer in situ, or any other cancer for which the patient has been in remission for at least 5 years)
    • Known hypersensitivity or contraindication to any of the study drugs, its ingredients or recombinant human
    antibodies and contrast agents
    • Pre-existing polyneuropathy of any kind > grade I
    • Severe chronic obstructive pulmonary disease with hypoxemia
    • Current or recent (within the last 30 days prior to enrollment) treatment with another investigational drug or participation in another clinical trial
    • Evidence of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or patient at high risk from treatment complications
    • Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigators opinion, could compromise the subjects safety, interfere with the absorption or metabolism of ibrutinib capsules or put the study outcomes at undue risk
    • Any co-existing medical or psychological condition that would compromise the ability to give informed consent
    • Subjects who are legally detained in an official institution
    • Subjects who may be dependent on the sponsor, the investigator or the trial sites, have to be exclude from the trial
    • Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is the 2-year progression-free survival (PFS) for all patients.
    E.5.1.1Timepoint(s) of evaluation of this end point
    A first analysis (after enrollment of approximately 40 patients) is planned for publication and/or congress presentation in 2019
    E.5.2Secondary end point(s)
    Secondary endpoints are feasibility and assessment of toxicity, the 1-year PFS and 2-year PFS stratified by DLBCL c-o-o subtypes (GCB vs. ABC by GEP), calculated from d1 of C1. CR, ORR, DFS, OS of ABC and GCB DLBCL and correlation with GEP or other molecular signatures, PET results (given a PET amendment), MRD levels and the frequency of secondary CNS Manifestation at different time points
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    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 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 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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years7
    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 years3
    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.1.3Elderly (>=65 years) Yes
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    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)
    After termination of this study patients will be treated with standard care or standard followup
    assessments will be done.
    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 Decision2017-01-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-09
    P. End of Trial
    P.End of Trial StatusOngoing
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