PLEASE NOTE: This study has been imported from ClinicalTrials.gov without additional data checks.

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1 PLEASE NOTE: This study has been imported from ClinicalTrials.gov without additional data checks. Trial Description Title Autologous Transplantation After a Rituximab/Ibrutinib/Ara-c Containing induction in Generalized Mantle Cell Lymphoma - a Randomized European Mcl Network Trial Trial Acronym [---]* URL of the trial [---]* Brief Summary in Lay Language The primary objective of the the trial is to establish one of three study arms, as future standard based on the comparison of the investigator-assessed failure-free survival. Brief Summary in Scientific Language Objectives and Endpoints Primary Objective: 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 arm A+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). Secondary Objectives: - 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 Page 1 of 11

2 Primary Endpoint: FFS defined as time from start of treatment to stable disease at end of immuno-chemotherapy, progressive disease, or death from any cause. Secondary Efficacy Endpoints: - Overall survival (OS) - 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) - Overall response and complete remission rates at midterm, at end of induction, 3 months after end of induction immunochemotherapy (at month 6) - PR to CR conversion rate during follow-up after end of induction immunochemotherapy Secondary Toxicity Endpoints: - 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 - Cumulative incidence rates of SPMs Exploratory Objectives: - To compare feasibility of ASCT in arm A+I vs. arm A - To compare minimal residual disease status between the three treatment groups - To determine the impact of ibrutinib during induction immunochemotherapy and during maintenance therapy on the minimal residual disease status - To determine the prognostic value of minimal residual disease status - To determine the prognostic value of positron emission tomography with fluorine 18-fluorodeoxyglucose - To determine clinical and biological prognostic and predictive factors - To determine the role of total body irradiation (TBI) in ASCT conditioning Exploratory Endpoints: - Rate of successful stem cell mobilisations (success: separation of at least Page 2 of 11

3 2x2x10(6) CD34-positive cells, including a back-up) - Rate of molecular remissions (MRD-negative patients) at midterm, at end of induction immuno-chemotherapy, and at staging time-points during follow-up in patients with remission after end of induction immuno-chemotherapy - Time to molecular remission from start of therapy - Time to molecular relapse for patients in clinical and molecular remission after end of induction immunochemotherapy - RD in FDG-PET negative or positive patients after induction and ASCT Exploratory objectives may be evaluated only in a subset of patients according to local standards and resources. Organizational Data DRKS-ID: DRKS Investigator Sponsored/Initiated Trial (IST/IIT): yes Ethics Approval/Approval of the Ethics Committee: [---]* (leading) Ethics Committee Nr.: [---]* Secondary IDs EudraCT-No. (for studies acc. to Drug Law): Primary Registry-ID: NCT (ClinicalTrials.gov) Sponsor-ID: TRIANGLE (Prof. Dr. M. Dreyling (co-chairman)) Health condition or Problem studied Free text: Mantle Cell Lymphoma ICD10: C Mantle cell lymphoma Interventions/Observational Groups Page 3 of 11

4 Arm 1: Drug: R-CHOP/R-DHAP Arm 2: Drug: Ibrutinib (Induction) Arm 3: Drug: ASCT conditioning Arm 4: Drug: Ibrutinib (Maintenance) Characteristics Study Type: Interventional Study Type Non-Interventional: [---]* Allocation: Randomized controlled trial Blinding: [---]* Who is blinded: [---]* Control: Active control (effective treament of control group) Purpose: Treatment Assignment: Parallel Phase: III Off-label use (Zulassungsüberschreitende Anwendung eines Arzneimittels): [---]* Primary Outcome - Failure Free Survival; time frame: From start of treatment until stable disease at end of immuno-chemotherapy, progressive disease, or death from any cause, whichever comes first, assessed up to 120 months. Secondary Outcome - Overall Survival; time frame: From start of treatment until the date of first documented progression, assessed up to 120 months. - Number of participants with treatment-related adverse events as assessed by CTC Version 4.03; time frame: From start of Ibrutinib treatment during induction immuno-chemotherapy and during maintenance and to compare the safety profile of the three treatment arms in terms of secondary toxicity endpoints. Through study conduction, an average of up to 30 months.; Safety and tolerability - Progression-free survival (PFS); time frame: PFS is the time to progression or death from any cause. Assed up to 120 months. - Number of Secondary Primary Malignancies; time frame: From start of treatment through the study conduction, up to 120 months.; Toxicity Endpoints - Number of Adverse Events by CTC grade (Version 4.03); time frame: From start of treatment through the study conduction, up to 120 months.; Toxicity Endpoints Countries of recruitment Page 4 of 11

5 DE Germany Locations of Recruitment Zentralklinik Augsburg, II. Med. Klinik, Hämatologie int. Onkologie, Augsburg Onkologische Gemeinschaftspraxis Dr. Janssen/Dr. Reichert in der Ubbo- Emmius-Klinik, Aurich Klinikum Bayreuth, Klinik f. Onkologie und Hämatologie, Bayreuth Vivantes Klinikum Am Urban, Klinik f. Innere Medizin, Hämatologie und Onkologie, Berlin Charité Univ.-Medizin Berlin, Med. Klinik - Hämatologie, Onkologie und Tumorimmunologie, Berlin Helios Klinikum Berlin-Buch, Hämatologie, Onkologie und Tumorimmunologie, Berlin Diako ev. Diakonie-KH ggmbh, Med. Klinik II, Hämatologie und Onkologie, Bremen Klinikum Chemnitz ggmbh, Klinik f. Innere Medizin II, Chemnitz DONAUISAR Klinikum Deggendorf, Innere Medizin II, Deggendorf Gemeinschaftspraxis Dr. Mohm und Prange-Krex - Fachärzte für Innere Medizin und Hämatologie und Onkologie, Dresden Universitätsklinikum Düsseldorf, Klinik f. Hämatologie, Onkologie und klinische Immunologie, Düsseldorf Helios Klinikum Erfurt GmbH, Zentrum f. Innere Medizin u. internistische Onkologie, Hämostaseologie, Erfurt Universitätsklinikum Erlangen, Med. Klinik 5, Hämatologie und internistische Onkologie, Erlangen Universitätsklinikum Essen, Klinik f. Hämatologie, Essen Universitätsklinikum Freiburg, Klinik f. Innere Medizin, Hämatologie, Onkologie u. Stammzelltransplantation, Freiburg Universitätsmedizin Greifswald, Klinik u. Poliklinik f. Innere Medizin C, Hämatologie u. Onkologie-, Transplantationszentrum, Greifswald Universitätsmedizin Göttingen, Zentrum f. Innere Medizin, Klinik f. Hämatologie und Medizinische Onkologie, Göttingen Katholisches Krankenhaus Hagen ggmbh, St.-Marien-Hospital, Klinik f. Hämatologie und Onkologie, Hagen Asklepios Klinik St. Georg, Hämatologie, Onkologie und Stammzelltransplantation, Hamburg Universitätsklinikum Hamburg-Eppendorf (UKE), II. Med. Klinik u. Poliklinik, Onkologie, Hämatologie, KMT, Hamburg Asklepios Klinik Altona, II. Med.Abt. f. Hämatologie und internistische Onkologie, Stammzelltransplantation, Hamburg Universitätsklinikum Heidelberg, Med. Klinik - Innere Medizin V - Hämatologie, Onkologie und Rheumatologie, Heidelberg <style fontname='dejavu Sans' isbold='true'>universitätsklinikum des Saarlandes, Klinik f. Innere Medizin I Hämatologie & Onkologie, Homburg / Saar</style> Page 5 of 11

6 Klinikum Idar-Oberstein GmbH, Medizinische Klinik I, Idar-Oberstein Universitätsmedizin Jena, Klinik f. Innere Medizin II, Abteilung Hämatologie u. Internistische Onkologie, Jena Städtisches Klinikum Karlsruhe, Med. Klinik III, Hämatologie und Onkologie, Karlsruhe Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik f. Innere Medizin II - Hämatologie und Onkologie, Kiel Gemeinschaftsklinikum Mittelrhein ggmbh, Ev. Stift St. Martin, Klinik f. Innere Medizin, Koblenz Praxisklinik f. Hämatologie und Onkologie Koblenz, Koblenz Uniklinik Köln, Klinik I für Innere Medizin, Köln Onkologisch-Hämatologische Praxis Dr. Vehling-Kaiser, Landshut Klinikum Landshut ggmbh, Med. Klinik III, Hämatologie/Internistische Onkologie, Landshut Caritas-KHLebach, Gemeinschaftspraxis f. Hämatologie und Onkologie, Onkologisches Zentrum Lebach, Lebach Universitätsklinikum Leipzig AöR, selbständige Abteilung f. Hämatologie und Internistische Onkologie, Hämostaseologische Ambulanz, Leipzig Klinikum der Stadt Ludwigshafen am Rhein ggmbh, Med. Klinik A, Ludwigshafen Universitätsklinikum Magdeburg AöR, Klinik f. Hämatologie und Onkologie, Magdeburg Universitätsmedizin der Univ. Mainz, III. Med. Klinik u. Poliklinik, Mainz Johannes Wiesling Klinikum Minden, Klinik f. Hämatologie/Onkologie, Hämostaseologie und Palliativmedizin, Minden Klinikum der Universität München, Med. Klinik und Poliklinik III, München Klinikum Rechts der Isar, III. Med. Klinik - Hämatologie und Onkologie, München Universitätsklinikum Münster, Med. Klinik A, Translationale Onkologie / Lymphome, Münster Klinikum Nürnberg,5. Medizinische Klinik, Onkologie / Hämatologie, Nürnberg Klinikum Oldenburg ggmbh, Med. Klinik II, Oldenburg Klinikum Ernst von Bergmann Potsdam ggmbh, Zentrum f. Innere Medizin, Klinik f. Hämatologie und Onkologie, Potsdam KH Barmherzige Brüder, Klinik f. Onkologie und Hämatologie, Regensburg Universitätsmedizin Rostock, Abt. f. Hämatologie und Onkologie, Klinik und Poliklinik für Innere Medizin, Rostock Klinikum Stuttgart - Katharinenhospital, Klinik f. Hämatologie und Onkologie, Stuttgart Robert-Bosch-Krankenhaus, Abt.f. Hämatologie und Onkologie, Stuttgart Klinikum Traunstein, Hämatologie - Onkologie- Palliativmedizin, Traunstein Page 6 of 11

7 Klinikum Mutterhaus der Borromäerinnen ggmbh, Okologisches Zentrum, Trier Universitätsklinikum Tübingen, Med Klinik I, Innere Medizin II, Tübingen Universitätsklinikum Ulm, Klinik für Innere Medizin III, Ulm Klinikum Wolfsburg, Med. Klinik II, Wolfsburg Universitätsklinikum Würzburg, Med. Klinik u. Poliklinik II /ZIM, Würzburg Recruitment Planned/Actual: [---]* (Anticipated or Actual) Date of First Enrollment: 2016/07/31 Target Sample Size: 870 Monocenter/Multicenter trial: Multicenter trial National/International: [---]* Inclusion Criteria Gender: Both, male and female Minimum Age: 18 Years Maximum Age: 65 Years Additional Inclusion Criteria All patients must meet the following criteria: - Histologically confirmed diagnosis of MCL according to WHO classification - suitable for high-dose treatment including high-dose Ara-C - Stage II-IV (Ann Arbor) - Age 18 years and 65 years - Previously untreated MCL - At least 1 measurable lesion; in case of bone marrow infiltration only, bone marrow aspiration and biopsy is mandatory for all staging evaluations. - ECOG/WHO performance status 2 - The following laboratory values at screening (unless related to MCL): - Absolute neutrophil count (ANC) 1000 cells/µl - Platelets 100,000 cells/µl - Transaminases (AST and ALT) 3 x upper limit of normal (ULN) - Total bilirubin 2 x ULN unless due to known Morbus Meulengracht Page 7 of 11

8 [Gilbert-Meulengracht-Syndrome]) - Creatinine 2 mg/dl or calculated creatinine clearance 50 ml/min - Written informed consent form according to ICH/EU GCP and national regulations - Sexually active men and women of child-bearing potential must agree to use highly effective contraceptives (eg, condoms, implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or sterilized partner) while on study; this should be maintained for 90 days after the last dose of study drug. Exclusion criteria Any potential subject who meets any of the following criteria will be excluded from participating in the study. - Major surgery within 4 weeks prior to randomization. - Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg phenprocoumon). - History of stroke or intracranial hemorrhage within 6 months prior to randomization. - Requires treatment with strong CYP3A4/5 inhibitors. - 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. - Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization. - Known CNS involvement of MCL - Clinically significant hypersensitivity (eg, anaphylactic or anaphylactoid reactions to the compound of ibrutinib itself or to the excipients in its formulation) - Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies - Previous lymphoma therapy with radiation, cytostatic drugs, anti-cd20 antibody or interferon except prephase therapy according to trial protocol Page 8 of 11

9 - 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) normal - Renal insufficiency (unless caused by the lymphoma): creatinine > 2x 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) - Patients with unresolved hepatitis B or C infection or known HIV positive infection (mandatory test) - Prior organ, bone marrow or peripheral blood stem cell transplantation - Concomitant or previous malignancies within the last 3 years other than basal cell skin cancer or in situ uterine cervix cancer - Pregnancy or lactation - Any psychological, familiar, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule - Subjects not able to give consent - Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial - Participation in another clinical trial within 30 days before randomization in this study. Addresses Page 9 of 11

10 Primary Sponsor Prof. Dr. M. Dreyling (co-chairman) Telephone: [---]* Fax: [---]* [---]* URL: [---]* Contact for Scientific Queries Klinikum der Universität München Martin Dreyling, Prof. Telephone: [---]* Fax: [---]* [---]* URL: [---]* Contact for Public Queries Döndü Gözel Telephone: Fax: [---]* doendue.goezel at med.uni-muenchen.de URL: [---]* Collaborator, Other Address Klinikum der Universitaet Muenchen Telephone: [---]* Fax: [---]* [---]* URL: [---]* Sources of Monetary or Material Support [---]* Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor Telephone: [---]* Fax: [---]* [---]* URL: [---]* Status Recruitment Status: Recruiting ongoing Page 10 of 11

11 Study Closing (LPLV): [---]* Trial Publications, Results and other documents The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs. - Translation on version: 1 - Last processed date by ClinicalTrials.gov: 2016/09/11 * This entry means the parameter is not applicable or has not been set. *** This entry means that data is not displayed due to insufficient data privacy clearing.