Clinical trial NCT02858258: ASCT After a Rituximab/Ibrutinib/Ara-c Containing iNduction in Generalized Mantle Cell Lymphoma
Official title: Autologous Transplantation After a Rituximab/Ibrutinib/Ara-c Containing iNduction in Generalized Mantle Cell Lymphoma - a Randomized European Mcl Network Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Mantle Cell Lymphoma
Keywords: MCL
Lead sponsor: European Mantle Cell Lymphoma Network
Sponsor class: OTHER
Collaborators: name: LMU Klinikum
First posted: 2016-08-08
Enrollment: 870
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

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 immuno-chemotherapy

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 immuno-chemotherapy 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 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.

Eligibility criteria: 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 \[Gilbert-Meulengracht-Syndrome\])
  * 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
* 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)
* 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.

Primary outcomes:
measure: Failure Free Survival
timeFrame: 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 outcomes:
measure: Overall Survival
timeFrame: From start of treatment until the date of first documented progression, assessed up to 120 months.
measure: Number of participants with treatment-related adverse events as assessed by CTC Version 4.03
timeFrame: 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.
measure: Progression-free survival (PFS)
timeFrame: PFS is the time to progression or death from any cause. Assed up to 120 months.
measure: Number of Secondary Primary Malignancies
timeFrame: From start of treatment through the study conduction, up to 120 months.
measure: Number of Adverse Events by CTC grade (Version 4.03)
timeFrame: From start of treatment through the study conduction, up to 120 months.
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg University Hospital, Dept of Hematology
city: Aarhus C
country: Denmark
facility: Aarhus University Hospital, Dept of Hematology
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Clinic of Hematology
city: Herlev
country: Denmark
facility: Herlev Hospital, Department of Hematology L121
city: Odense C
country: Denmark
facility: Odense University Hospital, Dept of Hematology X
city: Roskilde
country: Denmark
facility: Sjaelland University Hospital, Dept of Hematology
city: Augsburg
country: Germany
facility: Zentralklinik Augsburg, II. Med. Klinik, Hämatologie int. Onkologie
city: Aurich
country: Germany
facility: Onkologische Gemeinschaftspraxis Dr. Janssen/Dr. Reichert in der Ubbo-Emmius-Klinik
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth, Klinik f. Onkologie und Hämatologie
city: Berlin
country: Germany
facility: Vivantes Klinikum Am Urban, Klinik f. Innere Medizin, Hämatologie und Onkologie
city: Berlin
country: Germany
facility: Charité Univ.-Medizin Berlin, Med. Klinik - Hämatologie, Onkologie und Tumorimmunologie
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch, Hämatologie, Onkologie und Tumorimmunologie
city: Bochum
country: Germany
facility: Knappschaftskrankenhaus Bochum-Langendreer
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Bremen
country: Germany
facility: Diako ev. Diakonie-KH gGmbH, Med. Klinik II, Hämatologie und Onkologie
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH, Klinik f. Innere Medizin II
city: Deggendorf
country: Germany
facility: DONAUISAR Klinikum Deggendorf, Innere Medizin II
city: Dortmund
country: Germany
facility: St.-Johannes-Hospital
city: Dresden
country: Germany
facility: Gemeinschaftspraxis Dr. Mohm und Prange-Krex - Fachärzte für Innere Medizin und Hämatologie und Onkologie
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf, Klinik f. Hämatologie, Onkologie und klinische Immunologie
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt GmbH, Zentrum f. Innere Medizin u. internistische Onkologie, Hämostaseologie
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Med. Klinik 5, Hämatologie und internistische Onkologie
city: Eschweiler
country: Germany
facility: St.-Antonius-Hospital Eschweiler, Klinik für Hämatologie und Onkologie
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Klinik f. Hämatologie
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg, Klinik f. Innere Medizin, Hämatologie, Onkologie u. Stammzelltransplantation
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald, Klinik u. Poliklinik f. Innere Medizin C, Hämatologie u. Onkologie-, Transplantationszentrum
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen, Zentrum f. Innere Medizin, Klinik f. Hämatologie und Medizinische Onkologie
city: Hagen
country: Germany
facility: Katholisches Krankenhaus Hagen gGmbH, St.-Marien-Hospital, Klinik f. Hämatologie und Onkologie
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf (UKE), II. Med. Klinik u. Poliklinik, Onkologie, Hämatologie, KMT
city: Hamburg
country: Germany
facility: Asklepios Klinik Altona, II. Med.Abt. f. Hämatologie und internistische Onkologie, Stammzelltransplantation
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg, Med. Klinik - Innere Medizin V - Hämatologie, Onkologie und Rheumatologie
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes, Klinik f. Innere Medizin I Hämatologie & Onkologie
city: Idar-Oberstein
country: Germany
facility: Klinikum Idar-Oberstein GmbH, Medizinische Klinik I
city: Jena
country: Germany
facility: Universitätsmedizin Jena, Klinik f. Innere Medizin II, Abteilung Hämatologie u. Internistische Onkologie
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe, Med. Klinik III, Hämatologie und Onkologie
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik f. Innere Medizin II - Hämatologie und Onkologie
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Mittelrhein gGmbH, Ev. Stift St. Martin, Klinik f. Innere Medizin
city: Koblenz
country: Germany
facility: Praxisklinik f. Hämatologie und Onkologie Koblenz
city: Köln
country: Germany
facility: Uniklinik Köln, Klinik I für Innere Medizin
city: Landshut
country: Germany
facility: Onkologisch-Hämatologische Praxis Dr. Vehling-Kaiser
city: Landshut
country: Germany
facility: Klinikum Landshut gGmbH, Med. Klinik III, Hämatologie/Internistische Onkologie
city: Lebach
country: Germany
facility: Caritas-KHLebach, Gemeinschaftspraxis f. Hämatologie und Onkologie, Onkologisches Zentrum Lebach
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig AöR, selbständige Abteilung f. Hämatologie und Internistische Onkologie, Hämostaseologische Ambulanz
city: Lemgo
country: Germany
facility: Klinikum Lippe GmbH, Onkologie und Hämatologie
city: Ludwigshafen
country: Germany
facility: Klinikum der Stadt Ludwigshafen am Rhein gGmbH, Med. Klinik A
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg AöR, Klinik f. Hämatologie und Onkologie
city: Mainz
country: Germany
facility: Universitätsmedizin der Univ. Mainz, III. Med. Klinik u. Poliklinik
city: Minden
country: Germany
facility: Johannes Wiesling Klinikum Minden, Klinik f. Hämatologie/Onkologie, Hämostaseologie und Palliativmedizin
city: München
country: Germany
facility: Klinikum der Universität München, Med. Klinik und Poliklinik III
city: München
country: Germany
facility: Klinikum Rechts der Isar, III. Med. Klinik - Hämatologie und Onkologie
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Med. Klinik A, Translationale Onkologie / Lymphome
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg,5. Medizinische Klinik, Onkologie / Hämatologie
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg gGmbH, Med. Klinik II
city: Potsdam
country: Germany
facility: Klinikum Ernst von Bergmann Potsdam gGmbH, Zentrum f. Innere Medizin, Klinik f. Hämatologie und Onkologie
city: Regensburg
country: Germany
facility: KH Barmherzige Brüder, Klinik f. Onkologie und Hämatologie
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock, Abt. f. Hämatologie und Onkologie, Klinik und Poliklinik für Innere Medizin
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart - Katharinenhospital, Klinik f. Hämatologie und Onkologie
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus, Abt.f. Hämatologie und Onkologie
city: Traunstein
country: Germany
facility: Klinikum Traunstein, Hämatologie - Onkologie- Palliativmedizin
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen gGmbH, Okologisches Zentrum
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen, Med Klinik I, Innere Medizin II
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Klinik für Innere Medizin III
city: Wolfsburg
country: Germany
facility: Klinikum Wolfsburg, Med. Klinik II
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg, Med. Klinik u. Poliklinik II /ZIM
city: Alessandria
country: Italy
facility: Azienda Ospedaliera SS. Antonio e Biagio e C. Arrigo, SC Ematologia
city: Bologna
country: Italy
facility: Policlinico S. Orsola Malpighi, Istituto di Ematologia e Oncologia Medica Seragnoli
city: Bolzano
country: Italy
facility: Comprensorio Sanitario di Bolzano, Ematologia e trapianto di midollo osseo
city: Brescia
country: Italy
facility: Spedali Civili, Struttura Complessa di Ematologia
city: Cagliari
country: Italy
facility: Ospedale Businco, UO Ematologia - CTMO
city: Cuneo
country: Italy
facility: ASO S. Croce e Carle, S.C. di Ematologia e Trapianto di Midollo Osseo
city: Firenze
country: Italy
facility: AOU Policlinico Careggi, Unità Funzionale di Ematologia
city: Genova
country: Italy
facility: IRCCS AOU S. Martino - IST, Clinica Ematologia
city: Genova
country: Italy
facility: IRCCS AOU S. Martino - IST, Ematologia
city: Meldola (FC)
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Ematologia
city: Milano
country: Italy
facility: Istituto Scientifico San Raffaele, Unità Ricerca Clinica Linfomi
city: Milano
country: Italy
facility: Ospedale Niguarda, Struttura Complessa di Ematologia
city: Modena
country: Italy
facility: Università di Modena e Reggio Emilia Policlinico - COM Centro Oncologico Modenese, Dipartimento di Oncologia ed Ematologia
city: Monza
country: Italy
facility: Ospedale S. Gerardo, Divisione di Ematologia
city: Napoli
country: Italy
facility: "IRCCS Istituto Nazionale dei Tumori di Napoli - Pascale", Ematologia Oncologica
city: Novara
country: Italy
facility: AOU Maggiore della Carità - Università del Piemonte Orientale, S.C.D.U Ematologia
city: Palermo
country: Italy
facility: AO Ospedali Riuniti Villa Sofia-Cervello, Divisione di Ematologia
city: Pavia
country: Italy
facility: IRCCS Fondazione Policlinico San Matteo, Clinica Ematologia
city: Pisa
country: Italy
facility: Azienda Ospedaliera Pisana Ospedale "S.Chiara", Dipartimento di Oncologia Divisione di Ematologia
city: Ravenna
country: Italy
facility: Ospedale S. Maria delle Croci, U.O di Ematologia
city: Reggio Calabria
country: Italy
facility: Azienda Ospedaliera Bianchi, Melacrino, Morelli, Divisione di Ematologia
city: Reggio Emilia
country: Italy
facility: Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS, Ematologia
city: Rimini
country: Italy
facility: Ospedale degli Infermi, U.O. Ematologia
city: Roma
country: Italy
facility: Policlinico Tor Vergata, UOC Oncoematologia
city: Roma
country: Italy
facility: Università La Sapienza, Ematologia
city: San Giovanni Rotondo
country: Italy
facility: Casa Sollievo della Sofferenza, U.O. Ematologia
city: Torino
country: Italy
facility: A.O. Città della Salute e della Scienza, SC Ematologia
city: Torino
country: Italy
facility: A.O. U. Città della Salute e della Scienza, S C Ematologia U
city: Treviso
country: Italy
facility: Ospedale Cà Foncello, U.O.C. Ematologia
city: Tricase
country: Italy
facility: Ospedale Cardinale Panico, Divisione di Ematologia
city: Udine
country: Italy
facility: ASUI Integrata di Udine, Clinica Ematologia
city: Verona
country: Italy
facility: Ospedale Policlinico G.B. Rossi, "Centro trapianto midollo osseo Ematologia"
city: Vicenza
country: Italy
facility: Ospedale S. Bortolo, Ematologia
city: Bergen
country: Norway
facility: Haukeland University Hospital , Dept. of Oncology and Medical Physics
city: Oslo
country: Norway
facility: Oslo University Hospital, Dept of Oncology
city: Stavanger
country: Norway
facility: Stavanger University Hospital, Division for Hematology&Oncology
city: Tromsø
country: Norway
facility: UNN Tromsø, Oncology Dep
city: Trondheim
country: Norway
facility: St. Olavs Hospital, Department of Oncology
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital, Section of Hematology and Coagulation, Dept of internal medicine
city: Linköping
country: Sweden
facility: University Hospital, Dept of Hematolgy
city: Lulea
country: Sweden
facility: Sunderbyn Hospital, Dept of Medicine
city: Lund
country: Sweden
facility: Skane University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Center of Hematology
city: Umea
country: Sweden
facility: Norrland University Hospital, Dept of Oncology
city: Uppsala
country: Sweden
facility: Academic Hospital, Dept of Oncology
city: Örebro
country: Sweden
facility: Örebro University Hospital, Dept of Oncology
Study officials:
affiliation: Klinikum der Universität München
name: Martin Dreyling, Prof.
role: PRINCIPAL_INVESTIGATOR
References: