A PHASE 2/3 MULTICENTER, RANDOMIZED OPEN-LABEL STUDY TO COMPARE THE EFFICACY AND SAFETY OF LENALIDOMIDE (REVLIMID®) VERSUS INVESTIGATOR’S CHOICE IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

INTERVENTION: Trade Name: Revlimid 5mg, hard capsules Pharmaceutical Form: Capsule, hard INN or Proposed INN: LENALIDOMIDE CAS Number: 191732‐72‐6 Current Sponsor code: CC‐5013 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ Trade Name: Revlimid 10mg, hard capsules Pharmaceutical Form: Capsule, hard INN or Proposed INN: LENALIDOMIDE CAS Number: 191732‐72‐6 Current Sponsor code: CC‐5013 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐ Trade Name: Revlimid 15mg, hard capsules Pharmaceutical Form: Capsule, hard INN or Proposed INN: LENALIDOMIDE CAS Number: 191732‐72‐6 Current Sponsor code: CC‐5013 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 15‐ Product Name: Lenalidomide Product Code: CC‐5014 Pharmaceutical Form: Capsule, hard INN or Proposed INN: Lenalidomide CAS Number: 191732‐72‐6 Current Sponsor code: CC‐5013 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 20‐ Trade Name: Revlimid 25mg, hard capsules Pharmaceutical Form: Capsule, hard INN or Proposed INN: LENALIDOMIDE CAS Number: 191732‐72‐6 Current Sponsor code: CC‐5013 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐ Trade Name: GEMZAR 1g powder for solution for infusion. Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: GEMCITABINE CAS Number: 95058‐81‐4 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1000‐ Trade Name: MabThera 500mg (10mg/ml) concentrate for solution for infusion Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: RITUXIMAB CAS Number: 174722‐31‐7 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 500‐ Trade Name: Eto‐GRY® 20 mg/ml concentrate for manufacturing of an infusion solution Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: ETOPOSIDE CAS Number: 33 CONDITION: RELAPSED OR REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA ; MedDRA version: 12.1 Level: LLT Classification code 10012821 Term: Diffuse large B‐cell lymphoma recurrent PRIMARY OUTCOME: Main Objective: Stage 1; • To select adequate (e.g., p‐value <0.15 in favor of lenalidomide) subtype(s) for Stage 2. Germinal center B‐cell (GCB), non‐GCB, both subtypes, or neither subtype will be selected based on the overall response rate (ORR) in the individual subtype to lenalidomide monotherapy versus single agent of Investigator’s choice. ; Stage 2; • To compare the progression free survival (PFS) of lenalidomide monotherapy versus single agent of Investigator’s choice in the subtype(s) selected in Stage 1.; Primary end point(s): Stage 1: Overall response rate (CR+CRu+PR) to select adequate subtypes for Stage 2 testing; Stage 2: Progression‐free survival based on 1999 IWRC Secondary Objective: Evaluate concordance between IHC assays for stratification of GCB and non‐GCB to gene expression profiles ; Investigate potential predictive biomarkers of clinical response or resistance to lenalidomide; Investigate mechanistic biology parameters; Determine efficacy using the 2007 Revised Response Criteria for Malignant Lymphoma with FDG‐PET (Cheson 2007); For full secondary objectives, please see protocol. INCLUSION CRITERIA: 1.Histologically proven DLBCL by central pathology review specifically the following WHO subcategories of DLBCL a.Not otherwise specified(common morphologic variants,rare morphologic variants, molecular subgroups,and IHC subgroups[CD5+,GCB,non‐GCB]) b.Tcell/histiocyte rich c.EBV+of the elderly d.Associated with chronic inflammation e.Submission of an FFPE tumor block or appropriately stained slides from a fresh biopsy is required.If a fresh specimen cannot be obtained without putting the patient at unjustifiable risk,then slides prepared from the archival specimen supporting a prior DLBCL diagnosis may be submitted to fulfill this inclusion criterion with medical monitor approval 2.Ability to provide a tumor or lymph node biopsy specimen is required during the Screening Phase for gene expression and IHC assays.In the event that the tumor or disease bearing node is not accessible for biopsy,recruitment into the study must be approved by the Celg