Clinical trial NCT02354313: Phase III, Randomized Trial: Lenalidomide vs Observation After Induction With Rituximab Followed by Cht and ASCT in MCL Adult Patients
Official title: A Phase III Multicenter, Randomized Study With Lenalidomide Maintenance vs Observation After Induction Regimen Containing Rituximab Followed by High Dose Chemotherapy and ASCT as First Line Treatment in Adult Patients With Advanced Mantle Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: MANTLE CELL LYMPHOMA
Keywords: MANTLE CELL LYMPHOMA (MCL)
Lenalidomide (Len)
Rituximab
ASCT
Revlimid
High dose chemotherapy
transplant
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
First posted: 2015-02-03
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A phase III multicenter, randomized study with Lenalidomide (Revlimid®) maintenance versus observation after intensified induction regimen containing rituximab followed by high dose chemotherapy and Autologous Stem Cell Transplantation as first line treatment in adult patients with advanced Mantle Cell Lymphoma: IIL study (MCL0208).

Detailed description: This is a Phase 3, multicenter, open-label, randomized, controlled study to determine the efficacy and safety of lenalidomide as maintenance therapy versus observation in patients with MCL in complete or partial remission after first line intensified and high-dose chemotherapy additioned with rituximab and followed by ASCT. This study will be conducted in three phases: a Screening Phase, a Treatment Phase and a Follow-up Phase

Eligibility criteria: Inclusion Criteria.

1. Any male or female adult with newly diagnosed mantle cell lymphoma according to the WHO criteria.
2. Biopsy-proven mantle cell non-Hodgkin's lymphoma, including evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32) by FISH or RT-PCR. In subjects whose tumors are negative for the cyclin D1, evidence of overexpression of cyclin D2 or D3 by immunohistochemistry will be acceptable.
3. Age ≥18 years and \< 60 with ECOG performance status 0-3, or an age from 60 to 65 years with an ECOG performance status 0-2, except when PS impairment is related to NHL.
4. Advanced stage (Stage III and IV according to Ann Arbor and stage II with bulky disease defined as a mass ≥ 5 cm or B symptoms).
5. Measurable disease (two diameters) in at least one site. Osteoblastic bone lesions, ascites and pleural effusion are not considered measurable disease.
6. Written informed consent prior to any study specific screening procedures, with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
7. Be willing and able to comply with the protocol for the duration of the study.
8. Females of childbearing potential (FCBP) must: have two negative medically supervised pregnancy test prior to starting of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the patient practices complete and continued sexual abstinence. Either commit to continued abstinence from heterosexual intercourse (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy. The following are effective methods of contraception

   * Implant
   * Levonorgestrel-releasing intrauterine system (IUS)
   * Medroxyprogesterone acetate depot
   * Tubal sterilisation
   * Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses
   * Ovulation inhibitory progesterone-only pills (i.e., desogestrel)
9. Male patients must agree to use a condom during sexual contact with a FCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after cessation of study therapy. Agree to not donate semen during study drug therapy and for a period after end of study drug therapy.
10. All patients must have an understanding that the study drug could have a potential teratogenic risk. They must agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy. They must to agree not to share study medication with another person. They must be counseled about pregnancy precautions and risks of fetal exposure.

Exclusion Criteria:

1. Non-Hodgkin's lymphoma subtypes other than MCL
2. Cytological variant with small cells with round nuclei mimicking CLL, which is frequently recognized in patients with a leukemic and splenomegaly presentation without or with minimal involvement of lymph nodes and has an indolent clinical course.
3. History of malignancy other than squamous cell carcinoma, basal cell carcinoma of the skin or carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological finding of prostate cancer (TNM stage of T1a or T1b) within the last 3 years.
4. Major surgery, other than diagnostic surgery, within the last 4 weeks.
5. Evidence of CNS involvement, patients with an history of uncontrolled seizures, central nervous system disorders or psychiatric disability considered by the Investigator to be clinically significant and adversely affecting compliance to study drugs. If clinically indicated, lumbar puncture, and MRI should be performed during the screening process.
6. Clinically significant cardiac disease (VEF \<45%) (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 6 months (New York Heart Association Class III or IV heart disease) and marked impairment of pulmonary function (pulmonary diffusing capacity \<50%).
7. Unacceptable hematologic values in the week prior to the start of study: hemoglobin \<9 g/dL, WBC \<3x109/L, platelets \<60x109/L, absolute neutrophil count (ANC)\<1.5x109/L (unless cytopenia is secondary to bone marrow involvement or autoimmune cytopenia related to lymphoma).
8. Abnormal liver function tests, within one week prior to study start above any of the values listed: serum bilirubin \> 2 mg/dL, ALT or AST \>3 times the upper normal value; alkaline phosphatase\>2.5 times the upper normal value (unless these abnormalities are due to liver involvement of lymphoma).
9. Abnormal renal function (serum creatinine \>2.0 mg/dL), unless it is disease related
10. Patients with active opportunistic infections.
11. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible. Patients with HBcAb serology, will not be excluded from the study and be given lamivudine as prophylaxis starting one week before chemotherapy. HbsAg and AST/ALT ifHBV DNA is not available, will be monitored every three weeks. If HBV DNA is available, it will be monitored along with HBsAg
12. Pregnant or lactating females

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 30 months from randomisation
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 36 months from randomisation (42 months from accrual)
measure: Progression Free Survival (PFS)
timeFrame: 36 months from accrual
measure: Disease-free survival (DFS)
timeFrame: 30 months from randomisation (36 months from accrual)
measure: Event-free survival (EFS)
timeFrame: 30 months from randomisation (36 months from accrual)
measure: Complete Response (CR) Rate
timeFrame: up to 3 months from accrual
measure: Overall Response Rate (ORR)
timeFrame: up to 3 months from accrual
measure: Incidence of grade 3 or higher Toxicity measured by CTCAE v.4 at any time during therapy and follow-up.
timeFrame: 30 months from accrual
measure: Quality of life
timeFrame: baseline, 6-12-18-24 months from randomisation
Other outcomes:
Locations:
city: Mestre
country: Italy
facility: UO Ematologia Ospedale Dell'Angelo
state: VE
city: Alessandria
country: Italy
facility: SC Ematologia A.O.SS. Biagio e Antonio e C. Arrigo
city: Avellino
country: Italy
facility: AORN San G.Moscati
city: Aviano (PN)
country: Italy
facility: Centro di riferimento Oncologico - Oncologia Medica A
city: Bologna
country: Italy
facility: Istituto di Ematologia ed Oncologia Medica A. Seragnoli Policlinico S. Orsola
city: Bolzano
country: Italy
facility: Divisione di Ematologia e TMO, Ospedale di Bolzano
city: Brescia
country: Italy
facility: Divisione di Ematologia Spedali Civili
city: Cagliari
country: Italy
facility: Divisione di Ematologia Osp.Businco
city: Candiolo
country: Italy
facility: IRCC Onco-Ematologia
city: Cuneo
country: Italy
facility: S.C. di Ematologia e Trapianto di Midollo Osseo ASO S. Croce e Carle
city: Firenze
country: Italy
facility: Divisione di Ematologia, Policlinico Careggi
city: Genova
country: Italy
facility: Ematologia, A.O.U. San Martino
city: Genova
country: Italy
facility: Clinica Ematologica, A.O.U. San Martino - IST
city: Lecce
country: Italy
facility: Divisione di Ematologia Ospedale Vito Fazzi
city: Meldola (FC)
country: Italy
facility: Istituto Scientifico Romagnolo per lo studio e la cura dei Tumori-IRST - Meldola / Cesena
city: Messina
country: Italy
facility: Ematologia AO Ospedali Riuniti Papardo-Piemonte
city: Milano
country: Italy
facility: Divisione di Ematologia, Ospedale Niguarda
city: Milano
country: Italy
facility: Dipartimento di Ematologia e Oncologia - Ospedale Maggiore Policlinico Mangiagalli e Regina Elena
city: Milano
country: Italy
facility: Unità Linfomi- Dipartimento Oncoematologia- Istituto Scientifico San Raffaele IRCCS
city: Mirano
country: Italy
facility: Dipartimento di Scienze Mediche UOC di Oncologia ed Ematologia Oncologica - Ospedale di Mirano
city: Modena
country: Italy
facility: Dip. di Oncologia ed Ematologia - Università di Modena e Reggio Emilia Policlinico - COM Centro Oncologico Modenese
city: Monza
country: Italy
facility: Osp.San Gerardo Divisione di Ematologia
city: Novara
country: Italy
facility: S.C.D.U Ematologia Azienda Ospedaliera Universitaria Maggiore - Università del Piemonte Orientale
city: Nuoro
country: Italy
facility: U.O.C. Ematologia e CTMO Presidio Ospedale S. Francesco
city: Pagani
country: Italy
facility: U.O. Oncoematologia Ospedale "Andrea Tortora"
city: Palermo
country: Italy
facility: Divisione di Ematologia, Azienda Ospedali Riuniti Villa Sofia Cervello
city: Palermo
country: Italy
facility: Oncoematologia e TMO Clinica "La Maddalena"
city: Parma
country: Italy
facility: Cattedra di Ematologia - Centro Trapianti Midollo Osseo - Università Parma
city: Pavia
country: Italy
facility: Fondazione Policlinico San Matteo Clinica Ematologica
city: Piacenza
country: Italy
facility: U.O. Ematologia e Centro Trapianto Midollo Osseo - Ospedale G. da Saliceto
city: Pisa
country: Italy
facility: Dipartimento di Oncologia Divisione di Ematologia, Azienda Ospedaliera Pisana Ospedale "S.Chiara"
city: Potenza
country: Italy
facility: Divisione di Ematologia con TMO - Ospedale San Carlo
city: Ravenna
country: Italy
facility: U.O di Ematologia Ospedale S. Maria delle Croci
city: Reggio Calabria
country: Italy
facility: Divisione di Ematologia - Presidio Ospedali Riuniti Bianchi, Melacrino, Morelli
city: Reggio Emilia
country: Italy
facility: S. C. Ematologia - Azienda Ospedaliera Arcispedale - "S.Maria Nuova" IRCCS
city: Rimini
country: Italy
facility: UO Ematologia - Ospedale degli Infermi
city: Roma
country: Italy
facility: Cattedra di Ematologia Università Cattolica Policlinico Gemelli
city: Roma
country: Italy
facility: Dipartimento di Biotecnologie Cellulari ed Ematologia Università "La Sapienza"
city: Roma
country: Italy
facility: Divisione di Ematologia Policlinico Università Tor-Vergata
city: Rozzano (MI)
country: Italy
facility: Divisione di Oncologia Medica ed Ematologia, Istituto Clinico Humanitas
city: San Giovanni Rotondo
country: Italy
facility: Divisione di Ematologia, Centro Trapianto di Cellule Staminali, IRCCS "Casa Sollievo della Sofferenza"
city: Sassari
country: Italy
facility: Istituto di Ematologia - Azienda Ospedaliero Universitaria di Sassari
city: Siena
country: Italy
facility: Divisione di Ematologia - Policlinico Le Scotte
city: Terni
country: Italy
facility: Struttura Complessa di Oncoematologia - Ospedale Santa Maria
city: Torino
country: Italy
facility: S.C.D.U. Ematologia Universitaria A.O. Città della Salute e della Scienza di Torino
city: Torino
country: Italy
facility: SC. Ematologia A.O. Città della Salute e della Scienza
city: Trani
country: Italy
facility: Divisione di Ematologia ASL BAT 1
city: Treviso
country: Italy
facility: U.O. Ematologia e Immunoematologia - Ospedale Cà Foncello
city: Tricase
country: Italy
facility: Divisione di Ematologia Ospedale Cardinale Panico
city: Trieste
country: Italy
facility: Ematologia Clinica Ospedale Maggiore
city: Udine
country: Italy
facility: Clinica Ematologica ASUI Integrata di Udine
city: Verona
country: Italy
facility: Ospedale Policlinico G.B. Rossi
city: Lisboa
country: Portugal
facility: Departemento de Hematologia di Instituto Português de Oncologia de Lisboa Francisco Gentil
Study officials:
affiliation: Humanitas Gavazzeni - Bergamo, Lombardia
name: Sergio Cortelazzo, MD
role: STUDY_DIRECTOR
References:
citation: Zaccaria GM, Ferrero S, Hoster E, Passera R, Evangelista A, Genuardi E, Drandi D, Ghislieri M, Barbero D, Del Giudice I, Tani M, Moia R, Volpetti S, Cabras MG, Di Renzo N, Merli F, Vallisa D, Spina M, Pascarella A, Latte G, Patti C, Fabbri A, Guarini A, Vitolo U, Hermine O, Kluin-Nelemans HC, Cortelazzo S, Dreyling M, Ladetto M. A Clinical Prognostic Model Based on Machine Learning from the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial. Cancers (Basel). 2021 Dec 31;14(1):188. doi: 10.3390/cancers14010188.
citation: Ladetto M, Cortelazzo S, Ferrero S, Evangelista A, Mian M, Tavarozzi R, Zanni M, Cavallo F, Di Rocco A, Stefoni V, Pagani C, Re A, Chiappella A, Balzarotti M, Zilioli VR, Gomes da Silva M, Arcaini L, Molinari AL, Ballerini F, Ferreri AJM, Puccini B, Benedetti F, Stefani PM, Narni F, Casaroli I, Stelitano C, Ciccone G, Vitolo U, Martelli M. Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial. Lancet Haematol. 2021 Jan;8(1):e34-e44. doi: 10.1016/S2352-3026(20)30358-6. Epub 2020 Dec 22.
citation: Zaccaria GM, Ferrero S, Rosati S, Ghislieri M, Genuardi E, Evangelista A, Sandrone R, Castagneri C, Barbero D, Lo Schirico M, Arcaini L, Molinari AL, Ballerini F, Ferreri A, Omede P, Zamo A, Balestra G, Boccadoro M, Cortelazzo S, Ladetto M. Applying Data Warehousing to a Phase III Clinical Trial From the Fondazione Italiana Linfomi Ensures Superior Data Quality and Improved Assessment of Clinical Outcomes. JCO Clin Cancer Inform. 2019 Oct;3:1-15. doi: 10.1200/CCI.19.00049.
citation: Ferrero S, Rossi D, Rinaldi A, Bruscaggin A, Spina V, Eskelund CW, Evangelista A, Moia R, Kwee I, Dahl C, Di Rocco A, Stefoni V, Diop F, Favini C, Ghione P, Mahmoud AM, Schipani M, Kolstad A, Barbero D, Novero D, Paulli M, Zamo A, Jerkeman M, da Silva MG, Santoro A, Molinari A, Ferreri A, Gronbaek K, Piccin A, Cortelazzo S, Bertoni F, Ladetto M, Gaidano G. KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study. Haematologica. 2020 Jun;105(6):1604-1612. doi: 10.3324/haematol.2018.214056. Epub 2019 Sep 19.
citation: Bomben R, Ferrero S, D'Agaro T, Dal Bo M, Re A, Evangelista A, Carella AM, Zamo A, Vitolo U, Omede P, Rusconi C, Arcaini L, Rigacci L, Luminari S, Piccin A, Liu D, Wiestner A, Gaidano G, Cortelazzo S, Ladetto M, Gattei V. A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: results from the Fondazione Italiana Linfomi MCL-0208 trial. Haematologica. 2018 May;103(5):849-856. doi: 10.3324/haematol.2017.184325. Epub 2018 Feb 22.