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

Sponsor

The Lymphoma Academic Research Organisation (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01865110

Collaborator

(none)

623

Enrollment

140

Locations

Arms

141

Duration (Months)

4.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Mantle Cell Lymphoma	Drug: R-CHOP Drug: R-CHOP / R-HAD Drug: Rituximab Drug: Lenalidomide	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

623 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Nov 1, 2013

Actual Primary Completion Date :

Nov 30, 2020

Anticipated Study Completion Date :

Aug 1, 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Progression free survival [2.5 years]
2.5 years after last patient randomized in maintenance

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	ZNA Stuivenberg	Antwerpen	Belgium	2060
2	A. Z. Sint-Jan	Bruges	Belgium	8000
3	Institut Jules Bordet	Bruxelles	Belgium	1000
4	Université Catholique de Louvain Saint Luc	Bruxelles	Belgium	1200
5	Grand Hopital de Charleroi	Charleroi	Belgium	6000
6	AZ Groeninge	Kortrijk	Belgium	8500
7	CHU de Liège	Liège	Belgium	4000
8	CH de la Tourelle-Peltzer	Verviers	Belgium	4800
9	Université Catholique de Louvain Mont Godinne	Yvoir	Belgium
10	CHU d'Amiens	AMIENS Cedex 1	France	80054
11	CHU d'Angers	Angers	France	49000
12	CH d Avignon - Hopital Henri Duffaut	Avignon Cedex 9	France	84902
13	CH Côte Basque	Bayonne	France	64100
14	CHU Jean Minjoz	Besancon	France	25030
15	CH de Blois	Blois	France	41000
16	Institut Bergonié	Bordeaux	France	33076
17	Polyclinique Bordeaux Nord	Bordeaux	France	33300
18	CH du Dr Duchenne	BOULOGNE SUR MER Cedex	France	62321
19	CHU Morvan	Brest	France	29609
20	CHU Caen	Caen	France	14000
21	MEDIPOLE de SAVOIE	Challes les Eaux	France	73190
22	CH Chambéry	Chambery	France	73011
23	Hopital Antoine Beclere	Clamart	France	92140
24	Pôle Santé République	CLERMONT FERRAND Cedex 2	France	63050
25	CHU Estaing	Clermont Ferrand	France	63000
26	CH Sud Francilien de Corbeil	Corbeil Essonnes	France	91108
27	Hopital Henri Mondor	Creteil	France	94010
28	CHU Le Bocage	Dijon	France	21034
29	CH Dunkerque	Dunkerque	France	59385
30	Institut Daniel Hollard	GRENOBLE Cedex 1	France	38028
31	CHU de Grenoble	Grenoble	France	38043
32	CH Départemental	La Roche Sur Yon	France	85925
33	Hôpital André Mignot	Le Chesnay	France	78157
34	CH du Mans	Le Mans	France	72000
35	Clinique Victor Hugo	Le Mans	France	72000
36	CH de Lens	Lens	France	62300
37	CHU Claude Hurriez	Lille	France	59037
38	Centre Leon Berard	Lyon Cedex 8	France	69373
39	Institut Paoli Calmette	Marseille	France	13273
40	CH de Meaux	Meaux	France	77104
41	CH de la Région Annecy-Genevois	Metz-Tessy	France	74374
42	Hôpital Bon Secours	Metz	France	57038
43	CHU Montpellier	MONTPELLIER Cedex 5	France	34295
44	CHU Hôtel Dieu	Nantes	France	44093
45	CHR de la Source	ORLEANS cedex 2	France	45067
46	Hôpital Saint Louis	Paris cedex 10	France	75475
47	Hopital Saint Antoine	Paris	France	75012
48	Hôpital de la Pitié Salpêtrière	Paris	France	75651
49	Hôpital Necker	Paris	France	75743
50	CH Perpignan	Perpignan	France	66046
51	Hôpital Haut Lévêque	Pessac	France	33604
52	CHU Lyon Sud	Pierre Bénite cedex	France	69495
53	CHU Robert Debre	Reims	France	51092
54	CHU Pontchaillou	Rennes	France	35033
55	Centre Henri Becquerel	Rouen	France	76038
56	CH Saint Quentin	Saint Quentin	France	02321
57	Institut de cancérologie de la Loire	St priest en jarez	France	42271
58	CHU de Strasbourg	Strasbourg	France	67098
59	CHU Purpan	Toulouse	France	31059
60	CHU Bretonneau	Tours	France	37044
61	CHU Nancy Brabois	Vandoeuvre Les Nancy	France	54511
62	Institut Gustave Roussy	Villejuif	France	94805
63	Gesundheitszentrum St. Marien GmbH	Amberg	Germany	92224
64	Charite´ Universitätsmedizin Berlin Campus Benjamin Franklin	Berlin	Germany	12200
65	Charite´Universitätsmedizin Berlin Campus Virchow-Klinikum	Berlin	Germany	13353
66	Städt. Klinikum Braunschweig gGmbH	Braunschweig	Germany	38114
67	DIAKO Ev. Diakonie-Krankenhaus gemeinnützige GmbH	Bremen	Germany	28239
68	Klinikum Chemnitz gGmbH	Chemnitz	Germany	9116
69	Marien Hospital Düsseldorf	Düsseldorf	Germany	40479
70	St. Antonius Hospital	Eschweiler	Germany	52249
71	Universitätsklinikum Essen	Essen	Germany	45147
72	Klinikum Frankfurt GmbH	Frankfurt (Oder)	Germany
73	Universitätsmedizin Greifswald	Greifswald	Germany	17475
74	Kath. Krankenhaus Hagen gem. GmbH	Hagen	Germany	58095
75	Universitätsklinikum Hamburg-Eppendorf	Hamburg	Germany	20246
76	Klinikum Herford	Herford	Germany	32049
77	Universitätsklinikum des Saarlandes	Homburg/Saar	Germany	66421
78	Städt. Klinikum Karlsruhe	Karlsruhe	Germany	76133
79	Uni-Klinikum-Schleswig-Holstein im Städt. Krankenhaus Kiel	Kiel	Germany	24116
80	Internistische Praxis /Hämatologie und Onkologie	Kronach	Germany	96317
81	Universitätsklinikum Köln	Köln	Germany	50937
82	Onkologisches Zentrum - Lebach	Lebach	Germany	66822
83	Klinikum Ludwigshafen	Ludwigshafen	Germany	67063
84	Stauferklinikum Schwäbisch Gmünd	Mutlangen	Germany	73557
85	Kliniken Maria Hilf GmbH (Krankenhaus St. Franziskus)	Mönchengladbach	Germany	41063
86	Klinikum rechts der Isar der TU München	München	Germany	81675
87	Klinikum der Universität München	München	Germany	83177
88	Gemeinschaftspraxis für Hämatologie und Onkologie	Münster	Germany	48149
89	Universitätsklinikum Münster	Münster	Germany	48149
90	Gemeinschaftspraxis für Hämatologie und internistische Onkologie	Neumarkt	Germany	92318
91	Klinikum Nürnberg	Nürnberg	Germany	90419
92	Gemeinschaftspraxis für Innere Medizin, Hämatologie und internistische Onkologie	Offenbach	Germany	63065
93	Brüderkrankenhaus St. Josef Paderborn	Paderborn	Germany	33098
94	Universitätsklinik Rostock	Rostock	Germany	18057
95	Mutterhaus der Borromäerinnen GmbH	Trier	Germany	54219
96	University Hospital Tübingen	Tübingen	Germany	72076
97	Universitätsklinikum Ulm	Ulm	Germany	89081
98	MC Alkmaar	Alkmaar	Netherlands	1800AM
99	VUMC	Amsterdam	Netherlands	1007 MB
100	OLVG	Amsterdam	Netherlands	1090 HM
101	AMC	Amsterdam	Netherlands	1100 DD
102	Amphia ziekenhuis, locatie Langendijk	Breda	Netherlands	4800 RL
103	Reinier de Graaf Gasthuis	Delft	Netherlands	2600 GA
104	Jeroen Bosch ziekenhuis	Den Bosch	Netherlands	5200 ME
105	Hagaziekenhuis, locatie Leyweg	Den Haag	Netherlands	2504 LN
106	Gemini Ziekenhuis	Den Helder	Netherlands	1780 AT
107	Medisch Spectrum Twente	Enschede	Netherlands	7500 KA
108	Zuyderland MC	Geleen	Netherlands	6130 MB
109	Admiraal De Ruyter Ziekenhuis, Goes	Goes	Netherlands	4460 BB
110	Groene Hart Ziekenhuis	Gouda	Netherlands	2800 BB
111	UMCG	Groningen	Netherlands	9700 RB
112	Spaarne ziekenhuis	Hoofddorp	Netherlands	2130 AT
113	MC Leeuwarden Zuid	Leeuwarden	Netherlands	8901 BR
114	Maastricht UMC	Maastricht	Netherlands	6202 AZ
115	Sint Antonius Ziekenhuis	Nieuwegein	Netherlands	3430 EM
116	Radboudumc	Nijmegen	Netherlands	6525 GA
117	Bravis ziekenhuis	Roosendaal	Netherlands	4700 AZ
118	Erasmus MC - Centrum	Rotterdam	Netherlands	3000 CA
119	Erasmus MC - Daniel	Rotterdam	Netherlands	3008 AE
120	Maasstadziekenhuis	Rotterdam	Netherlands	3079 DZ
121	St.Elisabeth ZH	Tilburg	Netherlands	5000 LC
122	Isala Klinieken, Sophia	Zwolle	Netherlands	8000 GK
123	Gdansk University School of Medicine	Gdańsk	Poland	80-211
124	Szpitale Wojewódzkie	Gdynia	Poland	81-519
125	University Hospital	Kraków	Poland	31-501
126	Warminsko-Mazurskie Centrum Onkologii	Olsztyn	Poland	10-228
127	Institute of Hematology and Transfusiology	Warszawa	Poland	02-776
128	MSCM Institute and Oncology Centre	Warszawa	Poland	02-781
129	Instituto Português de Oncologia de Lisboa de Francisco Gentil	Lisboa	Portugal	1099-023
130	Hospital Universitario Fundación Alcorcón	Alcorcón	Spain	28922
131	Institut Catala d'Oncologia (ICO) - Hospital Germans Trias y Pujol	Badalona	Spain	8916
132	Hospital Universitario Vall d'hebron	Barcelona	Spain	8035
133	Hospital Clínic	Barcelona	Spain	8036
134	Hospital San Pedro de Alcántara	Cáceres	Spain	10003
135	Hospital Ramón y Cajal	Madrid	Spain	28034
136	Hospital Universitario 12 de Octubre	Madrid	Spain	28041
137	Hospital Universitario Central de Asturias	Oviedo	Spain	33011
138	Clínica Universidad de Navarra	Pamplona	Spain	31008
139	Hospital Clínico de Salamanca	Salamanca	Spain	37007
140	Hospital Clinico de Valencia	Valencia	Spain	46010