Clinical trial NCT01865110: R-CHOP + R-HAD vs R-CHOP Followed by Maintenance Lenalidomide + Rituximab vs Rituximab for Older Patients With MCL
Official title: Efficacy of Alternating Immunochemotherapy Consisting of R-CHOP + R-HAD vs R-CHOP Alone, Followed by Maintenance Therapy Consisting of Additional Lenalidomide + Rituximab vs Rituximab Alone for Older Patients With Mantle Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Mantle Cell Lymphoma
Keywords: Mantle Cell Lymphoma
RCHOP
RHAD
rituximab
lenalidomide
Lead sponsor: The Lymphoma Academic Research Organisation
Sponsor class: OTHER
First posted: 2013-05-30
Enrollment: 623
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study aims to evaluate whether the addition of lenalidomide to rituximab-maintenance improves progression free survival (PFS) compared to standard rituximab maintenance after induction treatment consisting of R-CHOP + R-HAD vs R-CHOP alone in older patients (≥ 60 year old) with mantle cell lymphoma.

The treatments consist of two phases: induction treatment (3 R-CHOP21 + 3 cycles of R-HAD28 alternating) vs 8 cycles of R-CHOP21) followed by maintenance treatment (13 cycles of rituximab + 26 cycles of lenalidomide vs 13 cycles of rituximab).

Detailed description: This study aims to evaluate whether the addition of lenalidomide to rituximab-maintenance improves progression free survival (PFS) compared to standard rituximab maintenance after induction treatment consisting of R-CHOP + R-HAD versus R-CHOP alone in older patients (≥ 60 year old) with mantle cell lymphoma. 643 patients will be randomized in induction phase and 433 in maintenance phase.

The treatments consist of two phases:

* induction treatment will be 3 cycles of R-CHOP21 + 3 cycles of R-HAD28(alternating) versus 8 cycles of R-CHOP21 alone
* maintenance treatment will be 13 cycles of rituximab every 8 weeks + 26 cycles of lenalidomide every 4 weeks vs 13 cycles of rituximab every 8 weeks.

Patients will be followed 2.5 years after the last patient randomized for maintenance for final analysis. All subjects who complete or discontinue the maintenance treatment for any reason will be followed for at least 3 years after his/her last study treatment administration in maintenance period for Second Primary Malignancies (SPM). A long term follow-up for progression/death will be done up to the end of period of SPM data collection.

Eligibility criteria: Inclusion Criteria:

Signed informed consent form Biopsy-proven MCL according to WHO classification

≥ 60 years of age and ineligible for autologous transplant Ann Arbor stage II-IV Previously untreated ECOG PS ≤ 2

Male subjects must:

* agree to use a condom during sexual contact with a woman of childbearing potential, even if they have had a vasectomy, throughout lenalidomide therapy
* agree to not donate semen during lenalidomide therapy.

All subjects must:

* have an understanding that the lenalidomide could have a potential teratogenic risk.
* agree to abstain from donating blood while taking lenalidomide therapy
* agree not to share study medication with another person.
* be counselled about pregnancy precautions and risks of foetal exposure.

Additional criteria for randomization in maintenance phase:

* CR, CRu or PR after induction treatment, determined as per Cheson 1999 criteria
* During the run-in period of 6 months starting from the date of the first randomization in the trial: in case of direct randomization into maintenance phase, patient must have been treated in first line by 6-8 cycles of R-CHOP.

Exclusion Criteria:

Female of childbearing potential

Any of the following laboratory abnormalities at diagnosis, if not related to lymphoma:

Absolute neutrophils count \<1,000 /mm3 Platelet count \< 75,000/mm3 AST/SGOT or ALT/SGPT \>3.0 UNL Serum total bilirubin \> 1.5 ULN (except if due to Gilbert's syndrome) Calculated creatinine clearance (Cockcroft-Gault formula or MDRD) \< 30 mL / min Central Nervous System involvement by lymphoma Contraindication for medical DVT prophylaxis for patients at high risk for DVT

Prior history of malignancies other than MCL unless the subject has been free of the disease for ≥ 5 years. Exceptions include the following:

* Basal cell carcinoma or Squamous cell carcinoma of the skin
* Carcinoma in situ of the cervix or of the breast
* Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b). Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent the patient to receive the study medication as planned.

Seropositivity for human immunodeficiency virus at study entry Seropositivity for hepatitis C virus at study entry,

Active viral infection with hepatitis B virus at study entry:

* HBsAg positive
* HBsAg negative, anti-HBs positive and anti-HBc positive

Uncontrolled illness including, but not limited to:

* Active infection requiring parenteral antibiotics.
* Uncontrolled diabetes mellitus
* Chronic symptomatic congestive heart failure (Class NYHA III or IV).
* Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months
* Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia.

Prior ≥ Grade 3 allergic hypersensitivity to thalidomide. Prior ≥ Grade 3 rash or any desquamating (blistering) rash while taking thalidomide.

Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies.

Subjects with ≥ Grade 2 neuropathy. Prior use of lenalidomide Participation in another clinical trial within three weeks before randomization in this study

Additional criteria for randomization in maintenance phase:

* SD or PD after induction treatment determined as per Cheson 1999 criteria
* Patient treated by induction immuno-chemotherapy other than 6-8 cycle of R-CHOP21 or 2-3 cycles of R-CHOP21 / 2-3 cycles of R-HAD28 (alternating)
* Patients with serious underlying medical conditions, which could impair the ability to receive maintenance treatment
* Calculated creatinine clearance of \< 30 mL / min
* ANC is \< 1,000 cells/mm³
* Platelet count is \< 50,000 cells/mm³

Primary outcomes:
measure: Progression free survival
timeFrame: 2.5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg
city: Bruges
country: Belgium
facility: A. Z. Sint-Jan
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet
city: Bruxelles
country: Belgium
facility: Université Catholique de Louvain Saint Luc
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi
city: Kortrijk
country: Belgium
facility: AZ Groeninge
city: Liège
country: Belgium
facility: CHU de Liège
city: Verviers
country: Belgium
facility: CH de la Tourelle-Peltzer
city: Yvoir
country: Belgium
facility: Université Catholique de Louvain Mont Godinne
city: AMIENS Cedex 1
country: France
facility: CHU d'Amiens
city: Angers
country: France
facility: CHU d'Angers
city: Avignon Cedex 9
country: France
facility: CH d Avignon - Hopital Henri Duffaut
city: Bayonne
country: France
facility: CH Côte Basque
city: Besancon
country: France
facility: CHU Jean Minjoz
city: Blois
country: France
facility: CH de Blois
city: Bordeaux
country: France
facility: Institut Bergonié
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord
city: BOULOGNE SUR MER Cedex
country: France
facility: CH du Dr Duchenne
city: Brest
country: France
facility: CHU Morvan
city: Caen
country: France
facility: CHU Caen
city: Challes les Eaux
country: France
facility: MEDIPOLE de SAVOIE
city: Chambery
country: France
facility: CH Chambéry
city: Châlon-sur-Sâone
country: France
facility: CHU de Châlon-sur-Sâone - William Morey
city: Clamart
country: France
facility: Hopital Antoine Beclere
city: CLERMONT FERRAND Cedex 2
country: France
facility: Pôle Santé République
city: Clermont Ferrand
country: France
facility: CHU Estaing
city: Corbeil Essonnes
country: France
facility: CH Sud Francilien de Corbeil
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Dijon
country: France
facility: CHU Le Bocage
city: Dunkerque
country: France
facility: CH Dunkerque
city: GRENOBLE Cedex 1
country: France
facility: Institut Daniel Hollard
city: Grenoble
country: France
facility: CHU de Grenoble
city: La Roche Sur Yon
country: France
facility: CH Départemental
city: La Rochelle
country: France
facility: Groupe Hospitalier La Rochelle - Ré - Aunis
city: Le Chesnay
country: France
facility: Hôpital André Mignot
city: Le Mans
country: France
facility: CH du Mans
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Lens
country: France
facility: CH de Lens
city: Lille
country: France
facility: CHU Claude Hurriez
city: Lyon Cedex 8
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Institut Paoli Calmette
city: Meaux
country: France
facility: CH de Meaux
city: Metz-Tessy
country: France
facility: CH de la Région Annecy-Genevois
city: Metz
country: France
facility: Hôpital Bon Secours
city: MONTPELLIER Cedex 5
country: France
facility: CHU Montpellier
city: Nantes
country: France
facility: CHU Hôtel Dieu
city: ORLEANS cedex 2
country: France
facility: CHR de la Source
city: Paris cedex 10
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hopital Saint Antoine
city: Paris
country: France
facility: Hôpital de la Pitié Salpêtrière
city: Paris
country: France
facility: Hôpital Necker
city: Perpignan
country: France
facility: CH Perpignan
city: Pessac
country: France
facility: Hôpital Haut Lévêque
city: Pierre Bénite cedex
country: France
facility: CHU Lyon Sud
city: Quimper
country: France
facility: CH de Quimper Cornouaille
city: Reims
country: France
facility: CHU Robert Debre
city: Rennes
country: France
facility: CHU Pontchaillou
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Quentin
country: France
facility: CH Saint Quentin
city: St priest en jarez
country: France
facility: Institut de cancérologie de la Loire
city: Strasbourg
country: France
facility: CHU de Strasbourg
city: Toulouse
country: France
facility: CHU Purpan
city: Tours
country: France
facility: CHU Bretonneau
city: Vandoeuvre Les Nancy
country: France
facility: CHU Nancy Brabois
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Amberg
country: Germany
facility: Gesundheitszentrum St. Marien GmbH
city: Berlin
country: Germany
facility: Charite´ Universitätsmedizin Berlin Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Charite´Universitätsmedizin Berlin Campus Virchow-Klinikum
city: Braunschweig
country: Germany
facility: Städt. Klinikum Braunschweig gGmbH
city: Bremen
country: Germany
facility: DIAKO Ev. Diakonie-Krankenhaus gemeinnützige GmbH
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf
city: Eschweiler
country: Germany
facility: St. Antonius Hospital
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt (Oder)
country: Germany
facility: Klinikum Frankfurt GmbH
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Hagen
country: Germany
facility: Kath. Krankenhaus Hagen gem. GmbH
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Herford
country: Germany
facility: Klinikum Herford
city: Homburg/Saar
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Karlsruhe
country: Germany
facility: Städt. Klinikum Karlsruhe
city: Kiel
country: Germany
facility: Uni-Klinikum-Schleswig-Holstein im Städt. Krankenhaus Kiel
city: Kronach
country: Germany
facility: Internistische Praxis /Hämatologie und Onkologie
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Lebach
country: Germany
facility: Onkologisches Zentrum - Lebach
city: Ludwigshafen
country: Germany
facility: Klinikum Ludwigshafen
city: Mutlangen
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf GmbH (Krankenhaus St. Franziskus)
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: München
country: Germany
facility: Klinikum der Universität München
city: Münster
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Neumarkt
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und internistische Onkologie
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg
city: Offenbach
country: Germany
facility: Gemeinschaftspraxis für Innere Medizin, Hämatologie und internistische Onkologie
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn
city: Rostock
country: Germany
facility: Universitätsklinik Rostock
city: Trier
country: Germany
facility: Mutterhaus der Borromäerinnen GmbH
city: Tübingen
country: Germany
facility: University Hospital Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Alkmaar
country: Netherlands
facility: MC Alkmaar
city: Amsterdam
country: Netherlands
facility: VUMC
city: Amsterdam
country: Netherlands
facility: OLVG
city: Amsterdam
country: Netherlands
facility: AMC
city: Breda
country: Netherlands
facility: Amphia ziekenhuis, locatie Langendijk
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch ziekenhuis
city: Den Haag
country: Netherlands
facility: Hagaziekenhuis, locatie Leyweg
city: Den Helder
country: Netherlands
facility: Gemini Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Geleen
country: Netherlands
facility: Zuyderland MC
city: Goes
country: Netherlands
facility: Admiraal De Ruyter Ziekenhuis, Goes
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: UMCG
city: Hoofddorp
country: Netherlands
facility: Spaarne ziekenhuis
city: Leeuwarden
country: Netherlands
facility: MC Leeuwarden Zuid
city: Maastricht
country: Netherlands
facility: Maastricht UMC
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Roosendaal
country: Netherlands
facility: Bravis ziekenhuis
city: Rotterdam
country: Netherlands
facility: Erasmus MC - Centrum
city: Rotterdam
country: Netherlands
facility: Erasmus MC - Daniel
city: Rotterdam
country: Netherlands
facility: Maasstadziekenhuis
city: Tilburg
country: Netherlands
facility: St.Elisabeth ZH
city: Zwolle
country: Netherlands
facility: Isala Klinieken, Sophia
city: Gdańsk
country: Poland
facility: Gdansk University School of Medicine
city: Gdynia
country: Poland
facility: Szpitale Wojewódzkie
city: Kraków
country: Poland
facility: University Hospital
city: Olsztyn
country: Poland
facility: Warminsko-Mazurskie Centrum Onkologii
city: Warszawa
country: Poland
facility: Institute of Hematology and Transfusiology
city: Warszawa
country: Poland
facility: MSCM Institute and Oncology Centre
city: Lisboa
country: Portugal
facility: Instituto Português de Oncologia de Lisboa de Francisco Gentil
city: Alcorcón
country: Spain
facility: Hospital Universitario Fundación Alcorcón
city: Badalona
country: Spain
facility: Institut Catala d'Oncologia (ICO) - Hospital Germans Trias y Pujol
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'hebron
city: Barcelona
country: Spain
facility: Hospital Clínic
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcántara
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
city: Salamanca
country: Spain
facility: Hospital Clínico de Salamanca
city: Valencia
country: Spain
facility: Hospital Clinico de Valencia
Study officials:
affiliation: MCL Network
name: Martin Dreyling, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Lymphoma Study Association
name: Vincent Ribrag, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: MCL Network
name: Johanna Cornelia Kluin-Nelemans, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: