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    Summary
    EudraCT Number:2014-001363-12
    Sponsor's Protocol Code Number:TRIANGLE
    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:2015-10-21
    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 number2014-001363-12
    A.3Full title of the trial
    autologous Transplantation after a Rituximab/Ibrutinib/Ara-c containing iNduction in Generalized mantle cell Lymphoma – a randomized European MCL Network trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    autologous Transplantation after a Rituximab/Ibrutinib/Ara-c containing iNduction in Generalized mantle cell Lymphoma – a randomized European MCL Network trial
    A.3.2Name or abbreviated title of the trial where available
    TRIANGLE
    A.4.1Sponsor's protocol code numberTRIANGLE
    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 SponsorKlinikum der Universität München, Medizinische Klinik und Poliklinik III
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Pharmaceutica NV
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinikum der Universität München, Medizinische Klinik und Poliklinik III
    B.5.2Functional name of contact pointHead of Study Center for Hematology
    B.5.3 Address:
    B.5.3.1Street AddressMarchioninistr. 15
    B.5.3.2Town/ cityMunich
    B.5.3.3Post code81377
    B.5.3.4CountryGermany
    B.5.4Telephone number+4989440074900
    B.5.5Fax number+4989440077900
    B.5.6E-mailstudyce@med.uni-muenchen.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 Imbruvica
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen Research & Development, LCC and Pharmacyclics, LCC
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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/3/12/984 and EU/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.3.9.3Other 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
    Generalized mantle cell Lymphoma
    E.1.1.1Medical condition in easily understood language
    Generalized mantle cell Lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10026805
    E.1.2Term Mantle cell lymphoma stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10026804
    E.1.2Term Mantle cell lymphoma stage III
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10026803
    E.1.2Term Mantle cell lymphoma stage II
    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
    To establish one of three study arms, R-CHOP/R-DHAP followed by ASCT (control arm A), R-CHOP+ibrutinib /R-DHAP followed by ASCT and ibrutinib maintenance (experimental armA+I), and R-CHOP+ibrutinib /R-DHAP followed by ibrutinib maintenance (experimental arm I) as future standard based on the comparison of the investigator-assessed failure-free survival (FFS).
    E.2.2Secondary objectives of the trial
    To compare the efficacy of the three treatment arms in terms of secondary efficacy endpoints.
    To determine the safety and tolerability of ibrutinib during induction immuno-chemotherapy and during maintenance and to compare the safety profile of the three treatment arms in terms of secondary toxicity endpoints.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically confirmed diagnosis of MCL according to WHO classification
    2. suitable for high-dose treatment including high-dose AraC
    3. Stage II-IV (Ann Arbor)
    4. Age >= 18 years and <= 65 years
    5. Previously untreated MCL
    6. At least 1 measurable lesion; in case of bone marrow infiltration only, bone marrow aspiration and biopsy is mandatory for all staging evaluations.
    7. ECOG/WHO performance status <= 2
    8. The following laboratory values at screening (unless related to MCL):
    - Absolute neutrophil count (ANC) >=1000 cells/uL
    - Platelets >=100,000 cells/uL
    - Transaminases (AST and ALT) <= 3 x upper limit of normal (ULN)
    - Total bilirubin <= 2 x ULN unless due to known Morbus Meulengracht [Gilbert-Meulengracht-Syndrome])
    - Creatinine <=2 mg/dL or calculated creatinine clearance >= 50 mL/min
    9. Written informed consent form according to ICH/EU GCP and national regulations
    10. Sexually active men and women of child-bearing potential must agree to use one of the highly effective contraceptive methods (combined oral contraceptives using two hormones, contraceptive implants, injectables, intrauterine devices, sterilized partner) together with one of the barrier methods (latex condoms, diaphragms, contraceptive caps) while on study; this should be maintained for 90 days after the last dose of study drug and 12 months after the last dose of rituximab.
    E.4Principal exclusion criteria
    1. Major surgery within 4 weeks prior to randomization.
    2. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon).
    3. History of stroke or intracranial hemorrhage within 6 months prior to randomization.
    4. Requires treatment with strong CYP3A4/5 inhibitors.
    5. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
    6. Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization.
    7. Known CNS involvement of MCL.
    8. Clinically significant hypersensitivity (e.g., anaphylactic or anaphylactoid reactions to the compound of ibrutinib itself or to the excipients in its formulation).
    9. Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies.
    10. Previous lymphoma therapy with radiation, cytostatic drugs, anti-CD20 antibody or interferon except prephase therapy according to trial protocol.
    11. Serious concomitant disease interfering with a regular therapy according to the study protocol:
    - Cardiac (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 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification or LVEF below LLN),
    - Pulmonary (e.g. chronic lung disease with hypoxemia),
    - Endocrinological (e.g. severe, not sufficiently controlled diabetes mellitus),
    - Renal insufficiency (unless caused by the lymphoma): creatinine > 2x normal value and/or creatinin clearance < 50 ml/min),
    - Impairment of liver function (unless caused by the lymphoma): transaminases > 3x normal or bilirubin > 2,0 mg/dl unless due to Morbus Meulengracht (Gilbert-Meulengracht-Syndrome).
    12. Positive test results for chronic HBV infection (defined as positive HBsAg serology) (mandatory testing)
    Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of hepatitis B surface antibody (HBSAb) after vaccination are eligible.
    13. Positive test results for hepatitis C (mandatory hepatitis C virus [HCV] antibody serology testing). Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
    14. Patients with known HIV positive infection (mandatory test).
    15.Prior organ, bone marrow or peripheral blood stem cell transplantation.
    16. Concomitant or previous malignancies within the last 3 years other than basal cell skin cancer or in situ uterine cervix cancer.
    17.Pregnancy or lactation.
    18. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule.
    19. Subjects not able to give consent.
    20. Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial.
    21. Participation in another clinical trial within 30 days before randomization in this study.
    E.5 End points
    E.5.1Primary end point(s)
    FFS defined as time from randomization to stable disease at end of immuno-chemotherapy, progressive disease, or death from any cause.
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of immuno-chemotherapy, progressive disease, or death from any cause
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints:
    1. Overall survival (OS).
    2. Progression-free survival (PFS) from randomization, from end of induction immuno-chemotherapy in patients with CR or PR at end of induction immuno-chemotherapy, and from the staging 6 weeks after end of induction assessment (at month 6).
    3. Overall response and complete remission rates at midterm, at end of induction, 3 months after end of induction immunochemotherapy (at month 6).
    4. PR to CR conversion rate during follow-up after end of induction immuno-chemotherapy.
    Secondary Toxicity Endpoints:
    1. Rates of AEs, SAEs, and SUSARs by CTC grade (Version 4.03) during induction immuno-chemotherapy and during periods of follow-up after response to immune-chemotherapy.
    2. Cumulative incidence rates of SPMs.
    E.5.2.1Timepoint(s) of evaluation of this end point
    See 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 Yes
    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) 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 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 Yes
    E.8.2.3.1Comparator description
    Six alternating courses of R-CHOP/RDHAP followed by ASCT
    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 concerned60
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA230
    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
    Croatia
    Czech Republic
    Denmark
    Finland
    Germany
    Israel
    Italy
    Netherlands
    Norway
    Poland
    Portugal
    Spain
    Sweden
    Switzerland
    United Kingdom
    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 years10
    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 years10
    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: 870
    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 state250
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 800
    F.4.2.2In the whole clinical trial 870
    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)
    Patients will be treated according to the local standard care.
    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 Deutsche Studiengruppe Niedrig Maligne Lymphome e.V. (GLSG), Klinikum Großhadern, Medizinische Klinik
    G.4.3.4Network Country Germany
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation Phase I/II platform e.V. of the European Mantle Cell Lymphoma Network, Klinikum der Universität München, Med. Klinik III
    G.4.3.4Network Country European Union
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-01-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-24
    P. End of Trial
    P.End of Trial StatusOngoing
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