Phase III, Randomized Trial: Lenalidomide vs Observation After Induction With Rituximab Followed by Cht and ASCT in MCL Adult Patients

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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MANTLE CELL LYMPHOMA

Intervention / Treatment
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* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria. Any male or female adult with newly diagnosed mantle cell lymphoma according to the WHO criteria. 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. 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. 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). Measurable disease (two diameters) in at least one site. Osteoblastic bone lesions, ascites and pleural effusion are not considered measurable disease. 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. Be willing and able to comply with the protocol for the duration of the study. 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) 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. 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: Non-Hodgkin's lymphoma subtypes other than MCL 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. 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. Major surgery, other than diagnostic surgery, within the last 4 weeks. 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. 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%). 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). 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). Abnormal renal function (serum creatinine >2.0 mg/dL), unless it is disease related Patients with active opportunistic infections. 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 Pregnant or lactating females

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenalidomide<br>lenalidomide 10-15 mg once daily on days 1-21, every 28 day, for two years | Drug: Lenalidomide<br>* Treatment Phase: consisting in an induction phase (3 cycles of RCHOP, given every 21 days); consolidation phase: (high-dose cyclophosphamide (CTX), 2 cycles of high dose Ara-C, BEAM and ASCT). Randomization and maintenance phase: Patients who have achieved complete or partial response will be randomized between maintenance with lenalidomide or observation.<br>* Other names: Revlimid;|
| No Intervention: Observation<br>no therapy is planned but only observation | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS will be defined as the time between the date of randomization and the date of disease progression, relapse or death from any cause.therapy to prolong progression-free survival (PFS) after completion of first-line high-dose chemotherapy additioned with rituximab and followed by ASCT in adult patients with MCL who have achieved complete response (CR) or partial response (PR). PFS is defined according to Cheson et al (JCO, 2007) as the time from randomisation until lymphoma progression or death as a result of any cause. | 30 months from randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS will be defined as the time between the date of randomization and the date of death from any cause | 36 months from randomisation (42 months from accrual) | 
| Progression Free Survival (PFS) | PFS will be defined as the time between the date of enrolment and the date of disease progression, relapse or death from any cause. | 36 months from accrual | 
| Disease-free survival (DFS) | DFS will be defined in CR patients as the time between the date of randomization and the date of relapse or death as a result of lymphoma or acute toxicity of treatment according to the Cheson 2007 | 30 months from randomisation (36 months from accrual) | 
| Event-free survival (EFS) | EFS will be defined in CR patients as the time between the date of randomization and the date of failure of treatment or death as a result of any cause according to the Cheson 2007 | 30 months from randomisation (36 months from accrual) | 
| Complete Response (CR) Rate | Proportion of CR according to the Cheson 2007 response criteria | up to 3 months from accrual | 
| Overall Response Rate (ORR) | ORR is defined as Complete Response (CR) or Partial Response (PR) according to the Cheson 2007 response criteria | up to 3 months from accrual | 
| Incidence of grade 3 or higher Toxicity measured by CTCAE v.4 at any time during therapy and follow-up. | Toxicity amount of grade 3 or more as CTCAE | 30 months from accrual | 
| Quality of life | EORTC QLQC30 questionnaire | baseline, 6-12-18-24 months from randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MANTLE CELL LYMPHOMA (MCL), Lenalidomide (Len), Rituximab, ASCT, Revlimid, High dose chemotherapy, transplant