ASCT After a Rituximab/Ibrutinib/Ara-c Containing iNduction in Generalized Mantle Cell Lymphoma

Mantle Cell Lymphoma Clinical Trial

Official title:

Autologous Transplantation After a Rituximab/Ibrutinib/Ara-c Containing iNduction in Generalized Mantle Cell Lymphoma - a Randomized European Mcl Network Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02858258
• Other study ID #: TRIANGLE
• Status: Recruiting
• Phase: Phase 3
• First received: July 14, 2016
• Last updated: December 17, 2017
• Start date: July 2016
• Est. completion date: May 2026

Study information

• Verified date: December 2017
• Source: European Mantle Cell Lymphoma Network
• Contact: Döndü Gözel
• Phone: +49 89 4400
• Email: Doendue.Goezel[@]med.uni-muenchen.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 870
• Est. completion date: May 2026
• Est. primary completion date: May 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma

Intervention

Drug:
• R-CHOP/R-DHAP
Drug: R-CHOP/DHAP Alternating 3x R-CHOP (Rituximab , Cyclophosphamide ,Doxorubicine ,Vincristine , Prednisone) / 3x R-DHAP (Rituximab , Dexamethasone, Ara-C, Cisplatine, G-CSF)
• Ibrutinib (Induction)
Ibrutinib: only in cycle 1,3,5 on Day 1-19
• ASCT conditioning
ASCT conditioning THAM or BEAM, stratified per site before trial activation at site THAM (TBI (total body irradiation), Ara-C, Melphalan) or BEAM (BCNU, Etoposide, Cytarabine, Melphalan)
• Ibrutinib (Maintenance)
Ibrutinib (Maintenance), daily 560 mg for 2 years;

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Prof. Dr. M. Dreyling (co-chairman)	Klinikum der Universitaet Muenchen

Countries where clinical trial is conducted

Denmark,  Germany,  Italy,  Norway,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Failure Free Survival		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	Overall Survival		From start of treatment until the date of first documented progression, assessed up to 120 months.
Secondary	Number of participants with treatment-related adverse events as assessed by CTC Version 4.03	Safety and tolerability	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.
Secondary	Progression-free survival (PFS)		PFS is the time to progression or death from any cause. Assed up to 120 months.
Secondary	Number of Secondary Primary Malignancies	Toxicity Endpoints	From start of treatment through the study conduction, up to 120 months.
Secondary	Number of Adverse Events by CTC grade (Version 4.03)	Toxicity Endpoints	From start of treatment through the study conduction, up to 120 months.