Study of Lenalidomide Maintenance Versus Placebo in Responding Elderly Patients With DLBCL and Treated With R-CHOP

Study Overview
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Brief Summary
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This study is designed as a phase III, randomized, double-blind, placebo-controlled trial to explore the effect of maintenance therapy with lenalidomide versus placebo on progression-free survival (PFS) in patients treated with R-CHOP responding to induction therapy For the primary efficacy variable, PFS, an improvement in median PFS from 38.6 months for Treatment Arm B to 54 months for Treatment Arm A (corresponding to a 2-year PFS of 65% vs 73.6%), is considered clinically relevant.

Detailed Description
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Patients should have received at least 6 and up to 8 cycles of the R-CHOP 14 or R-CHOP 21 regimen or 6 R-CHOP-14 or -21 completed by 2 Rituximab alone in accordance to local preferences. Patients can be registered to participate in the study at two time points: At time of initial diagnosis and study enrolment (signature of informed consent) before the first cycle of treatment with R-CHOP. At randomization (signature of informed consent) after treatment in first line with R-CHOP and have reached at least PR or CR. Evaluation of the response to R-CHOP must be in accordance with Revised Response Criteria for Malignant Lymphoma(2007). Stratification: Before randomization, the patients will be stratified according to the country and the response to R-CHOP (PR vs CR). Randomization: Patients in CR/PR after R-CHOP will be randomized to maintenance therapy with lenalidomide or placebo.

Official Title
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Double Blind Randomized Phase III Study of Lenalidomide Maintenance Versus Placebo in Responding Elderly Patients With DLBCL and Treated With R-CHOP in First Line

Conditions
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Lymphoma, Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Ages Eligible for Study: Between 60 and 80 years old Genders Eligible for Study: Both Accepts Healthy Volunteers: No Inclusion Criteria: For patients registered at the time of initial diagnosis Patient with histologically proven CD20+ diffuse large B cel LYMPHOMA (DLBCL) 5WHO classification 2008) including clinical subtypes (primitive mediastinal, intravascular, etc.). Patients with De Novo Transformed DLBCL from low grade lymphoma (Follicular, other..) may also be included. Patients with DLBCL associated with some small cell infiltration in bone marrow may also be included Or CD20+ B-cell lymphoma with intermediate features between DLBCL and Burkitt or with intermediate features between DLBCL and classical Hodgkin lymphoma Or CD20+ Follicular lymphoma grade 3B Or CD20+ Aggressive B-cell lymphoma unclassifiable previous untreated with chemo- or radiotherapy For patients registered after response evaluation to first line treatment with R-CHOP: Patient with histologically proven CD20+ diffuse large B cell LYMPHOMA (DLBCL) 5WHO classification 2008) including clinical subtypes (primitive mediastinal, intravascular, etc.). Patients with De Novo Transformed DLBCL from low grade lymphoma (Follicular, other..) may also be included. Patients with DLBCL associated with some small cell infiltration in bone marrow may also be included Or CD20+ B-cell lymphoma with intermediate features between DLBCL and Burkitt or with intermediate features between DLBCL and classical Hodgkin lymphoma Or CD20+ Follicular lymphoma grade 3B Or CD20+ Aggressive B-cell lymphoma unclassifiable Have reached a CR or PR after first line treatment with at least 6 cycles of R-CHOP 14 regimens and up to 8 cycles of R-CHOP21 Previously untreated with Radiotherapy For all patients: aged from 60 to 80 years at time of registration Ann Arbor stages II-IV at time of initial diagnosis aaIPI> 1 at time of initial diagnosis ECOG performance status 0-2 Minimum life expectancy of 3 months Following laboratory values at screening: ANC≥ 1000.10^6/L and Platelets≥60000.10^6/L AST<5*ULN, ALT<5*ULN, Total Bilirubin<1,5*ULN Creatinine clearance>30mL/min Women are are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and after end of study. Men agree not to father a child during participation in the trial and during the 12 months thereafter. Having previously signed a written informed consent form Exclusion Criteria: Any other histological type of Lymphoma, Burkitt included. Any history of treated or non treated small B-cell lymphoma Central nervous system or meningeal involvement by lymphoma Contraindication to any drug contained in the chemotherapy regimen Myocardial infarction during last 3 months or unstable coronary disease or uncontrolled chronic symptomatic congestive heart insufficiency NYHA III-IV Uncontrolled hypertension Uncontrolled diabetes mellitus as defined by the investigator Active systemic infection requiring treatment previously known HIV positive serology Active hepatitis B or C Prior history of malignancies other than lymphoma within 3 years Serious medical or psychiatric illness

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenalidomide<br>Lenalidomide daily for 3 weeks every 4 weeks for 24 months | Drug: Lenalidomide<br>* Daily for 3 weeks every 4 weeks for 24 months<br>* Other names: Revlimid;|
| Placebo Comparator: Placebo<br>Placebo daily for 3 weeks every 4 weeks for 24 months | Drug: Placebo<br>* Daily for 3 weeks every 4 weeks for 24 months<br>|

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 measured from the date of randomization to the date of first documented disease progression or death. Progression data will be assigned to the earliest time when any progression is observed without prior missing assessments during the study up to the end of the follow up phase. | Final PFS analysis will be realized when the number of events (160) has been reached or at the latest when the last patient into the study will finish follow up. The approximate schedule will be 75 months after the first patient randomized. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | From the date of randomization to the date of death from any cause Interim analysis of OS will be performed at the time of the PFS final analysis; it is projected to have 97 deaths at this time. Final analysis of OS at the end of the study, defined by the last visit of follow-up for the last patient randomized, 5 years after its randomization | 5 years | 
| Event-Free Survival (EFS) | From the date of randomization to the date of first documented disease progression, relapse, initiation of new anti-lymphoma therapy or death from any cause Interim analysis of EFS will be performed at the time of the PFS final analysis. Final analysis of OS at the end of the study, defined by the last visit of follow-up for the last patient randomized, 5 years after its randomization | 5 years | 
| Response rate at the end of maintenance treatment |  | 24 months | 
| Percentage of patients who convert from PR (partial response) to CR (complete response) |  | 24 months | 
| Safety of lenalidomide in maintenance | Toxicities occured during maintenance phase will be measured and reported from grade 2 for infection and neurological toxicities and from grade 3 for other toxicities according to CTCAE v3 | 5 years | 
| PFS2 | From randomization to objective tumor progression on next-line treatment or death from any cause | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lenalidomide (Revlimid), diffuse large B-cell lymphoma, phase III study, after R-CHOP, Maintenance treatment, Maintenance