R-CHOP + R-HAD vs R-CHOP Followed by Maintenance Lenalidomide + Rituximab vs Rituximab for Older Patients With MCL

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Mantle Cell Lymphoma
• Intervention / Treatment: Drug: R-CHOP / R-HAD; Drug: R-CHOP; Drug: Rituximab; Drug: Lenalidomide

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.

• Study Type: Interventional
• Enrollment (Actual): 623
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Bruges, Belgium, 8000
    • A. Z. Sint-Jan
  • Bruxelles, Belgium, 1000
    • Institut Jules Bordet
  • Bruxelles, Belgium, 1200
    • Université Catholique de Louvain Saint Luc
  • Charleroi, Belgium, 6000
    • Grand Hopital de Charleroi
  • Kortrijk, Belgium, 8500
    • AZ Groeninge
  • Liège, Belgium, 4000
    • CHU de Liège
  • Verviers, Belgium, 4800
    • CH de la Tourelle-Peltzer
  • Yvoir, Belgium
    • Université Catholique de Louvain Mont Godinne
• France
  • AMIENS Cedex 1, France, 80054
    • CHU d'Amiens
  • Angers, France, 49000
    • CHU d'Angers
  • Avignon Cedex 9, France, 84902
    • CH d Avignon - Hopital Henri Duffaut
  • BOULOGNE SUR MER Cedex, France, 62321
    • CH du Dr Duchenne
  • Bayonne, France, 64100
    • CH Cote Basque
  • Besancon, France, 25030
    • CHU Jean Minjoz
  • Blois, France, 41000
    • CH de Blois
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Bordeaux, France, 33300
    • Polyclinique Bordeaux Nord
  • Brest, France, 29609
    • CHU Morvan
  • CLERMONT FERRAND Cedex 2, France, 63050
    • Pôle Santé République
  • Caen, France, 14000
    • CHU caen
  • Challes les Eaux, France, 73190
    • Médipôle de Savoie
  • Chambery, France, 73011
    • CH Chambery
  • Clamart, France, 92140
    • Hôpital Antoine Béclère
  • Clermont Ferrand, France, 63000
    • CHU Estaing
  • Corbeil Essonnes, France, 91108
    • CH Sud Francilien de Corbeil
  • Creteil, France, 94010
    • Hôpital Henri Mondor
  • Dijon, France, 21034
    • CHU Le Bocage
  • Dunkerque, France, 59385
    • Ch Dunkerque
  • GRENOBLE Cedex 1, France, 38028
    • Institut Daniel Hollard
  • Grenoble, France, 38043
    • CHU de Grenoble
  • La Roche Sur Yon, France, 85925
    • CH Départemental
  • Le Chesnay, France, 78157
    • Hôpital André Mignot
  • Le Mans, France, 72000
    • CH du Mans
  • Le Mans, France, 72000
    • Clinique Victor Hugo
  • Lens, France, 62300
    • CH de Lens
  • Lille, France, 59037
    • CHU Claude Hurriez
  • Lyon Cedex 8, France, 69373
    • Centre LEON BERARD
  • MONTPELLIER Cedex 5, France, 34295
    • CHU Montpellier
  • Marseille, France, 13273
    • Institut Paoli Calmette
  • Meaux, France, 77104
    • CH de Meaux
  • Metz, France, 57038
    • Hôpital Bon Secours
  • Metz-Tessy, France, 74374
    • CH de la Région Annecy-Genevois
  • Nantes, France, 44093
    • Chu Hotel Dieu
  • ORLEANS cedex 2, France, 45067
    • CHR de la Source
  • Paris, France, 75012
    • Hopital Saint Antoine
  • Paris, France, 75743
    • Hopital Necker
  • Paris, France, 75651
    • Hopital de la Pitie Salpetriere
  • Paris cedex 10, France, 75475
    • Hôpital Saint louis
  • Perpignan, France, 66046
    • Ch Perpignan
  • Pessac, France, 33604
    • Hôpital Haut Lévêque
  • Pierre Bénite cedex, France, 69495
    • CHU Lyon Sud
  • Reims, France, 51092
    • CHU Robert Debré
  • Rennes, France, 35033
    • CHU Pontchaillou
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • Saint Quentin, France, 02321
    • CH Saint Quentin
  • St priest en jarez, France, 42271
    • Institut de Cancerologie de La Loire
  • Strasbourg, France, 67098
    • CHU de Strasbourg
  • Toulouse, France, 31059
    • CHU Purpan
  • Tours, France, 37044
    • CHU Bretonneau
  • Vandoeuvre Les Nancy, France, 54511
    • CHU Nancy Brabois
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Germany
  • Amberg, Germany, 92224
    • Gesundheitszentrum St. Marien GmbH
  • Berlin, Germany, 12200
    • Charite´ Universitätsmedizin Berlin Campus Benjamin Franklin
  • Berlin, Germany, 13353
    • Charite´Universitätsmedizin Berlin Campus Virchow-Klinikum
  • Braunschweig, Germany, 38114
    • Städt. Klinikum Braunschweig gGmbH
  • Bremen, Germany, 28239
    • DIAKO Ev. Diakonie-Krankenhaus gemeinnützige GmbH
  • Chemnitz, Germany, 9116
    • Klinikum Chemnitz gGmbH
  • Düsseldorf, Germany, 40479
    • Marien Hospital Dusseldorf
  • Eschweiler, Germany, 52249
    • St. Antonius Hospital
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Frankfurt (Oder), Germany
    • Klinikum Frankfurt GmbH
  • Greifswald, Germany, 17475
    • Universitätsmedizin Greifswald
  • Hagen, Germany, 58095
    • Kath. Krankenhaus Hagen gem. GmbH
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf
  • Herford, Germany, 32049
    • Klinikum Herford
  • Homburg/Saar, Germany, 66421
    • Universitätsklinikum des Saarlandes
  • Karlsruhe, Germany, 76133
    • Städt. Klinikum Karlsruhe
  • Kiel, Germany, 24116
    • Uni-Klinikum-Schleswig-Holstein im Städt. Krankenhaus Kiel
  • Kronach, Germany, 96317
    • Internistische Praxis /Hämatologie und Onkologie
  • Köln, Germany, 50937
    • Universitätsklinikum Köln
  • Lebach, Germany, 66822
    • Onkologisches Zentrum - Lebach
  • Ludwigshafen, Germany, 67063
    • Klinikum Ludwigshafen
  • Mutlangen, Germany, 73557
    • Stauferklinikum Schwäbisch Gmünd
  • Mönchengladbach, Germany, 41063
    • Kliniken Maria Hilf GmbH (Krankenhaus St. Franziskus)
  • München, Germany, 81675
    • Klinikum rechts der Isar der TU Munchen
  • München, Germany, 83177
    • Klinikum der Universität München
  • Münster, Germany, 48149
    • Universitatsklinikum Munster
  • Münster, Germany, 48149
    • Gemeinschaftspraxis für Hämatologie und Onkologie
  • Neumarkt, Germany, 92318
    • Gemeinschaftspraxis für Hämatologie und internistische Onkologie
  • Nürnberg, Germany, 90419
    • Klinikum Nürnberg
  • Offenbach, Germany, 63065
    • Gemeinschaftspraxis für Innere Medizin, Hämatologie und internistische Onkologie
  • Paderborn, Germany, 33098
    • Brüderkrankenhaus St. Josef Paderborn
  • Rostock, Germany, 18057
    • Universitätsklinik Rostock
  • Trier, Germany, 54219
    • Mutterhaus der Borromäerinnen GmbH
  • Tübingen, Germany, 72076
    • University Hospital Tübingen
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
• Netherlands
  • Alkmaar, Netherlands, 1800AM
    • MC Alkmaar
  • Amsterdam, Netherlands, 1007 MB
    • VUMC
  • Amsterdam, Netherlands, 1090 HM
    • OLVG
  • Amsterdam, Netherlands, 1100 DD
    • AMC
  • Breda, Netherlands, 4800 RL
    • Amphia ziekenhuis, locatie langendijk
  • Delft, Netherlands, 2600 GA
    • Reinier de Graaf Gasthuis
  • Den Bosch, Netherlands, 5200 ME
    • Jeroen Bosch ziekenhuis
  • Den Haag, Netherlands, 2504 LN
    • Hagaziekenhuis, locatie Leyweg
  • Den Helder, Netherlands, 1780 AT
    • Gemini Ziekenhuis
  • Enschede, Netherlands, 7500 KA
    • Medisch Spectrum Twente
  • Geleen, Netherlands, 6130 MB
    • Zuyderland MC
  • Goes, Netherlands, 4460 BB
    • Admiraal De Ruyter Ziekenhuis, Goes
  • Gouda, Netherlands, 2800 BB
    • Groene Hart Ziekenhuis
  • Groningen, Netherlands, 9700 RB
    • UMCG
  • Hoofddorp, Netherlands, 2130 AT
    • Spaarne Ziekenhuis
  • Leeuwarden, Netherlands, 8901 BR
    • MC Leeuwarden Zuid
  • Maastricht, Netherlands, 6202 AZ
    • Maastricht UMC
  • Nieuwegein, Netherlands, 3430 EM
    • Sint Antonius Ziekenhuis
  • Nijmegen, Netherlands, 6525 GA
    • Radboudumc
  • Roosendaal, Netherlands, 4700 AZ
    • Bravis Ziekenhuis
  • Rotterdam, Netherlands, 3000 CA
    • Erasmus MC - Centrum
  • Rotterdam, Netherlands, 3008 AE
    • Erasmus MC - Daniel
  • Rotterdam, Netherlands, 3079 DZ
    • Maasstadziekenhuis
  • Tilburg, Netherlands, 5000 LC
    • St.Elisabeth ZH
  • Zwolle, Netherlands, 8000 GK
    • Isala Klinieken, Sophia
• Poland
  • Gdańsk, Poland, 80-211
    • Gdansk University School of Medicine
  • Gdynia, Poland, 81-519
    • Szpitale Wojewódzkie
  • Kraków, Poland, 31-501
    • University Hospital
  • Olsztyn, Poland, 10-228
    • Warminsko-Mazurskie Centrum Onkologii
  • Warszawa, Poland, 02-776
    • Institute of Hematology and Transfusiology
  • Warszawa, Poland, 02-781
    • MSCM Institute and Oncology Centre
• Portugal
  • Lisboa, Portugal, 1099-023
    • Instituto Português de Oncologia de Lisboa de Francisco Gentil
• Spain
  • Alcorcón, Spain, 28922
    • Hospital Universitario Fundacion Alcorcon
  • Badalona, Spain, 8916
    • Institut Catala d'Oncologia (ICO) - Hospital Germans Trias y Pujol
  • Barcelona, Spain, 8036
    • Hospital Clínic
  • Barcelona, Spain, 8035
    • Hospital Universitario Vall d'Hebron
  • Cáceres, Spain, 10003
    • Hospital San Pedro de Alcántara
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de octubre
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Oviedo, Spain, 33011
    • Hospital Universitario Central de Asturias
  • Pamplona, Spain, 31008
    • Clinica Universidad de Navarra
  • Salamanca, Spain, 37007
    • Hospital Clinico De Salamanca
  • Valencia, Spain, 46010
    • Hospital Clinico de Valencia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Induction experimental arm; R-CHOP / R-HAD : Alternating 3 cycles of R-CHOP administered in 3 week cycles + 3 cycles of R-HAD administered in 4 week cycles.	Drug: R-CHOP / R-HAD; R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) administered in 3 week cycles for 3 cycles R-HAD (rituximab, cytarabine, dexamethasone) administered in 3 week cycles for 4 cycles alternating; Other Names: rituximab, CHOP; rituximab HD AraC
Active Comparator: Standart induction arm; 8 cycles of R-CHOP administered in 3 week cycles	Drug: R-CHOP; R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) administered in 3 week cycles for 8 cycles; Other Names: rituximab, CHOP
Experimental: Maintenance experimental arm; lenalidomide + rituximab : 13 cycles of rituximab SC 1400 mg administered in 8 week cycles + 26 cycles Lenalidomide 15 mg 3 weeks every 4 weeks for 24 months	Drug: Rituximab; Rituximab SC 1400 mg every 8 weeks for 24 months; Other Names: Mabthera; Drug: Lenalidomide; Lenalidomide 15 mg 3 weeks every 4 weeks for 24 months; Other Names: Revlimid
Active Comparator: Maintenance standart arm; 13 cycles of rituximab SC 1400 mg administered in 8 week cycles for 24 months	Drug: Rituximab; Rituximab SC 1400 mg every 8 weeks for 24 months; Other Names: Mabthera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	2.5 years after last patient randomized in maintenance	2.5 years

Collaborators and Investigators

• Sponsor: The Lymphoma Academic Research Organisation
• Investigators: Principal Investigator: Martin Dreyling, Prof. Dr., MCL Network; Principal Investigator: Vincent Ribrag, Dr, Lymphoma Study Association; Principal Investigator: Johanna Cornelia Kluin-Nelemans, Prof. Dr., MCL Network

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2013
• Primary Completion (Actual): November 30, 2020
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: May 24, 2013
• First Submitted That Met QC Criteria: May 29, 2013
• First Posted (Estimated): May 30, 2013

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: lenalidomide; rituximab; Mantle Cell Lymphoma; RCHOP; RHAD
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Mantle-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Lenalidomide; Rituximab; Prednisone; Doxorubicin; Vincristine
• Other Study ID Numbers: MCL R2 Elderly

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO