Clinical trial NCT02285062
Conditions: Lymphoma, Large B-Cell, Diffuse
Keywords: R-CHOP chemotherapy DLBCL front line therapy gene expression profiling (GEP) activated B-cell (ABC) type DLBCL biomarkers Activated B-Cell (ABC) type Diffuse Large B-Cell Lymphoma, not otherwise specified Diffuse Large B-Cell Lymphoma, associated with chronic inflammation Diffuse Large B-Cell Lymphoma, Epstein-Barr virus positive (EBS+) of the elderly Diffuse Large B-Cell Lymphoma, T-cell / histiocyte-rich
Sponsor: Celgene
Start date: 2015-02-17; Completion date: 2022-07-28
Enrollment: 570 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy and safety of lenalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R2-CHOP) chemotherapy versus placebo, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (placebo-R-CHOP) chemotherapy in patients who have previously untreated ABC type DLBCL.

Detailed description:
This research study is for patients with newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL) of the activated B-cell (ABC) type who have not yet been treated. DLBCL is a cancer of a type of blood cell called B-lymphocytes. B lymphocytes are part of the body's immune system. There are different types of DLBCL. About a third of newly diagnosed DLBCL cancers are the ABC type. It has been observed that treatment does not work as well for patients with the ABC type compared to patients with other DLBCL types who receive standard treatment. However, at this time both ABC type and other DLBCL type patients receive the same standard treatments.

Patients with DLBCL who are otherwise healthy are usually treated first with the chemotherapy drug combination called R-CHOP. The drugs in this combination are "R" for rituximab, "C" for cyclophosphamide, "H" for doxorubicin which has a chemical name of hydroxydaunomycin, "O" for vincristine which has a trade name of oncovin, and "P" for prednisone. Depending on the local practice where you are treated, R-CHOP may be given for 6 or 8 cycles. A cycle could lasts for 14 or 21 days. The R-CHOP drug combination is approved for the treatment of DLBCL of all types, including ABC type. R-CHOP is standard care.

This study will test the standard R-CHOP21 against R-CHOP21 plus lenalidomide. The purpose is to see whether adding lenalidomide works better and is as safe as R-CHOP by itself. This study is only for patients with ABC type DLBCL who have not yet been treated. Lenalidomide is not approved for use in DLBCL. Its use in this disease is experimental. In this study, the experimental treatment is lenalidomide + R-CHOP21 x 6.

This study will use a gene expression profile (GEP) test to see if a patient has the ABC type. The results of this GEP test affect whether you may be treated on this study. Because the performance of this test has not been proven, it is for investigational use only, and is still under development. This means the GEP test is an experimental test.

Arms: arm 1: Lenalidomide plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) arm 2: Placebo plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
Interventions: intervention 1: lenalidomide intervention 2: Placebo intervention 3: Rituximab intervention 4: Cyclophosphamide intervention 5: Doxorubicin intervention 6: prednisone intervention 7: vincristine
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None

Protocol documents:
Prot_000.pdf: 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
1
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
TITLE PAGE
PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO 
CONTROLLED, MULTICENTER STUDY TO COMPARE 
THE EFFICACY AND SAFETY OF LENALIDOMIDE 
(CC-5013) PLUS R-CHOP CHEMOTHERAPY (R2-CHOP)
VERSUS PLACEBO PLUS R-CHOP CHEMOTHERAPY
IN SUBJECTS WITH PREVIOUSLY UNTREATED
ACTIVATED B-CELL TYPE DIFFUSE LARGE B-CELL 
LYMPHOMA
The “ROBUST” Study
INVESTIGATIONAL PRODUCT (IP):
Lenalidomide (CC-5013)
PROTOCOL NUMBER:
CC-5013-DLC-002
ORIGINAL DATE:
16 May 2014
AMENDMENT No. 1 DATE:
25 Aug 2015
AMENDMENT No. 2 DATE:
24 Jan 2017
AMENDMENT No. 3 DATE:
04 Feb 2019
AMENDMENT No. 4 DATE:
12 Jun 2019
EudraCT NUMBER:
2013-004054-21
IND NUMBER:
60,100
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
USA
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
2
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address: Celgene Corporation, 86 Morris Ave, Summit, NJ 07901
Phone:
E-mail:
Note: The back-up 24 hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls
Back-up 24 Hour Global Emergency Contact Call Center: 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
3
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
(See Appended Electronic Signature Page)
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
4
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
5
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
6
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
PROTOCOL SUMMARY
Study Title
Phase 3 Randomized, Double-Blind, Placebo Controlled, Multicenter Study to Compare the 
Efficacy and Safety of Lenalidomide (CC-5013) Plus R-CHOP Chemotherapy (R2-CHOP)
Versus Placebo Plus R-CHOP Chemotherapy in Subjects with Previously Untreated Activated 
B-cell Type Diffuse Large B-cell Lymphoma
Indication 
Previously untreated, activated B-cell (ABC) type diffuse large B-cell lymphoma (DLBCL).
Objectives
To evaluate the efficacy and safety of lenalidomide, rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone (R2-CHOP) chemotherapy versus placebo, rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (placebo-R-CHOP) chemotherapy 
in subjects who have previously untreated ABC type DLBCL.
Study Design
This randomized, placebo controlled study is designed to evaluate the efficacy and safety of R2-
CHOP chemotherapy versus placebo-R-CHOP chemotherapy in previously untreated ABC type 
DLBCL.  The study is divided into the Screening Period, Treatment Period, and Follow-up 
Period.  Approximately 560 subjects will be randomized over approximately a 34-month accrual 
period.
The Screening Period for eligibility determination may begin after the subject signs the informed 
consent form.  During the Screening Period subjects will undergo safety and other assessments, 
including central pathology confirmation of DLBCL diagnosis and determination of ABC type.  
Following confirmation of eligibility, subjects will undergo randomization to either the 
experimental or control arm in a 1:1 ratio.  
The Treatment Period begins with Cycle 1 Day 1 dosing.  Subjects will receive protocol-
specified treatments for 6 cycles.  Treatment will continue to completion; or until the outcome of 
the computed tomography (CT) scan at Midcycle (between Weeks 9 – 12 which is after Cycle 3 
but before Cycle 4) indicates a treatment change based on response assessment; disease 
progression; unacceptable toxicity; death; or withdrawal of consent, whichever occurs first. End 
of Treatment is defined as the later date of either End of Lenalidomide/Placebo or End of R-
CHOP.
The Follow-up Period for each subject begins immediately after their End of Treatment date.  
Subjects will be followed for first and second progressions, subsequent antilymphoma therapy, 
development of any second primary malignancies (SPMs), and overall survival (OS) according 
to the schedule described in Table 5. After the 12 Apr 2019 primary analysis, subjects will only 
be followed for SPM and OS data collection.
The pharmacokinetic (PK) substudy is designed to evaluate the PK of lenalidomide when co-
administered with and without R-CHOP.  It will be conducted at selected sites and will be 
optional for subjects at those sites.  Approximately 20 subjects will be included in the PK 
substudy.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
7
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Study Population
Subjects must have a diagnosis of ABC type DLBCL, be previously untreated, have at least one 
measurable lesion by CT scan, and have adequate liver, renal, cardiac, and bone marrow 
function. 
Length of Study
The primary analysis will occur when the required 192 progression free survival (PFS) events 
(progressions/deaths) in the intent-to-treat (ITT) population have occurred, which is 
approximately 42 months from the start of enrollment.  After the primary analysis, those subjects 
who are alive will still be followed exclusively for second primary malignancies and overall 
survival for up to 5 years from the date the last subject is randomized. The total study duration is 
approximately 8 years (34 months accrual period + 5 years SPM follow-up).  
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary 
 analysis, as pre-specified in the protocol and/or the 
Statistical Analysis Plan, whichever is the later date.
Study Treatments
Study treatments in a 21-day cycle are: lenalidomide / placebo Days 1 – 14; rituximab, 
cyclophosphamide, doxorubicin, and vincristine Day 1; prednisone Days 1 – 5. Refer to Table 7
for complete details.
Overview of Efficacy Assessments
The International Working Group (IWG) Response Criteria for non-Hodgkin’s lymphoma 
(NHL) (Cheson, 2014), and the Deauville Criteria for scan interpretation (Itti, 2013; Meignan,
2013), will be used for efficacy assessments.  The local investigator will perform real time 
efficacy review to guide subject management, with the exception of the assessment performed 3 
– 4 weeks after Cycle 6 which will be reviewed in real time by the Independent Response 
Adjudication Committee (IRAC).  The IRAC will also perform a subsequent batched review of 
all assessments. Additional efficacy evaluation includes a CT scan to support disease restaging
at Midcycle (once between Weeks 9 – 12 which is after Cycle 3 but before Cycle 4).  
Overview of Safety Assessments
Safety will be monitored throughout the study.  Safety evaluations will include adverse event 
(AE), SPM, and concomitant medication assessment, physical examinations, vital sign 
measurements, and clinical laboratory safety tests.  
Second primary malignancies will be monitored as events of interest and should be included as 
part of the assessment of AEs throughout the course of the study. Investigators are to report any 
SPMs as serious adverse events (SAEs), regardless of causal relationship to investigational 
product (IP) (lenalidomide, placebo, rituximab, cyclophosphamide, doxorubicin, vincristine, or 
prednisone), occurring at any time for the duration of the study, from the time of signing the 
Informed Consent Document (ICD) for up to 5 years from the date the last subject is 
randomized.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
8
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................15
1.1.
Diffuse Large B-cell Lymphoma ............................................................................15
1.2.
Biological and Clinical Significance of DLBCL Typing .........................................15
1.2.1.
GCB versus ABC Gene Expression Profiling Assay Used in This Protocol.............16
1.3.
Biomarkers in DLBCL............................................................................................16
1.3.1.
Biomarkers in DLBCL Pathogenesis ......................................................................16
1.3.3.
Mechanistic Biomarkers .........................................................................................17
1.4.
Preclinical Data on Lenalidomide in DLBCL..........................................................17
1.5.
Clinical Efficacy Data on Lenalidomide in DLBCL................................................18
1.5.1.
Relapsed / Refractory DLBCL................................................................................18
1.5.2.
Front Line DLBCL.................................................................................................20
1.5.2.1.
Mayo Clinic R2-CHOP Data ..................................................................................20
1.5.2.2.
FIL R2-CHOP Data................................................................................................23
1.5.3.
Clinical Efficacy Data Conclusion ..........................................................................26
1.6.
Clinical Safety Events of Interest for Lenalidomide ................................................26
1.6.1.
Deep Vein Thrombosis ...........................................................................................26
1.6.1.1.
Deep Vein Thrombosis in Multiple Myeloma .........................................................26
1.6.1.2.
Deep Vein Thrombosis in Non-Hodgkin’s Lymphoma ...........................................27
1.6.2.
Tumor Flare Reaction.............................................................................................28
1.6.3.
Tumor Lysis Syndrome ..........................................................................................29
2.
STUDY OBJECTIVES...........................................................................................31
2.1.
Primary Objective...................................................................................................31
2.2.
Secondary Objective...............................................................................................31
3.
STUDY ENDPOINTS............................................................................................32
3.1.
Primary Endpoint....................................................................................................32
3.2.
Secondary Endpoints ..............................................................................................32
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
9
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
4.
OVERALL STUDY DESIGN ................................................................................33
4.1.
Study Design ..........................................................................................................33
4.1.2.
Screening Period.....................................................................................................33
4.1.3.
Treatment Period ....................................................................................................34
4.1.4.
Treatment Decisions Based on Midcycle CT Scan..................................................34
4.1.5.
Treatment Decisions Based on End of Treatment CT and PET Scans......................34
4.1.6.
End of Treatment Date............................................................................................35
4.1.7.
Follow-up Period....................................................................................................35
4.1.9.
Independent and Central Assessment Committees...................................................36
4.2.
Study Design Rationale ..........................................................................................36
4.3.
Study Duration .......................................................................................................39
5.
TABLE OF EVENTS.............................................................................................40
6.
PROCEDURES......................................................................................................44
7.
STUDY POPULATION.........................................................................................54
7.1.
Number of Subjects and Sites .................................................................................54
7.2.
Inclusion Criteria....................................................................................................54
7.3.
Exclusion Criteria...................................................................................................56
8.
DESCRIPTION OF STUDY TREATMENTS........................................................59
8.1.
Description of Investigational Products...................................................................59
8.2.
Treatment Schedule and Administration .................................................................59
8.2.1.
Optional Prephase Treatment..................................................................................59
8.2.2.
Optional Consolidation Treatment (Pre-Specified)..................................................60
8.2.3.
Mandatory Primary Neutropenia Prophylaxis .........................................................60
8.2.4.
Lenalidomide/Placebo-R-CHOP Regimen ..............................................................60
8.2.5.
Lenalidomide / Placebo ..........................................................................................61
8.2.6.
Rituximab...............................................................................................................61
8.2.7.
Cyclophosphamide .................................................................................................62
8.2.8.
Doxorubicin............................................................................................................62
8.2.9.
Vincristine..............................................................................................................62
8.2.10.
Prednisone..............................................................................................................62
8.2.11.
Lenalidomide/Placebo-R-CHOP Regimen Modifications........................................63
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8.2.12.
Requalification Criteria For Subsequent Treatment Cycles .....................................63
8.2.13.
Overdose ................................................................................................................68
8.2.14.
Discontinuation ......................................................................................................68
8.5.
Method of Treatment Assignment...........................................................................71
8.6.
Packaging and Labeling..........................................................................................71
8.7.
Investigational Product Accountability and Disposal ..............................................72
8.8.
Investigational Product Compliance........................................................................72
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................73
9.1.
Prohibited Concomitant Medications ......................................................................73
9.2.
Permitted Concomitant Medications .......................................................................73
9.2.1.
Hematopoietic Growth Factors and Transfusions....................................................73
9.2.2.
Pneumocystis Pneumonia Prophylaxis....................................................................73
9.3.
Recommended Concomitant Medications ...............................................................73
9.3.1.
CNS Lymphoma Prophylaxis .................................................................................73
9.3.2.
Nausea Prophylaxis ................................................................................................73
9.3.3.
Rituximab Infusion Reaction Prophylaxis...............................................................73
9.3.4.
HBV Reactivation Prophylaxis ...............................................................................74
9.3.5.
TLS Prophylaxis.....................................................................................................74
9.3.6.
Venous Thromboembolism Prophylaxis .................................................................74
9.4.
Mandatory Concomitant Medication.......................................................................74
9.4.1.
Primary Neutropenia Prophylaxis ...........................................................................74
10.
STATISTICAL ANALYSES..................................................................................75
10.1.
Overview................................................................................................................75
10.2.
Study Population Definitions ..................................................................................75
10.3.
Sample Size and Power Considerations...................................................................76
10.4.
Background and Demographic Characteristics........................................................77
10.5.
Subject Disposition.................................................................................................77
10.6.
Efficacy Analysis....................................................................................................77
10.6.1.
Primary Efficacy Endpoint Definition.....................................................................77
10.6.2.
Secondary Efficacy Endpoint Definitions ...............................................................78
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10.6.4.
Analysis Method.....................................................................................................80
10.7.
Safety Analysis.......................................................................................................81
10.8.
Interim Analysis .....................................................................................................82
11.
ADVERSE EVENTS..............................................................................................83
11.1.
Monitoring, Recording, and Reporting of Adverse Events ......................................83
11.2.
Evaluation of Adverse Events.................................................................................83
11.2.1.
Seriousness.............................................................................................................83
11.2.2.
Severity / Intensity..................................................................................................85
11.2.3.
Causality ................................................................................................................86
11.2.4.
Duration .................................................................................................................86
11.2.5.
Action Taken..........................................................................................................86
11.2.6.
Outcome.................................................................................................................86
11.3.
Abnormal Laboratory Values..................................................................................86
11.4.
Pregnancy...............................................................................................................87
11.4.1.
Females of Childbearing Potential: .........................................................................87
11.4.2.
Male Subjects.........................................................................................................87
11.5.
Reporting of Serious Adverse Events......................................................................88
11.5.1.
Safety Queries ........................................................................................................88
11.6.
Expedited Reporting of Adverse Events..................................................................88
12.
DISCONTINUATIONS .........................................................................................90
12.1.
Discontinuation of Investigational Product..............................................................90
12.2.
Discontinuation from the Study ..............................................................................90
13.
EMERGENCY PROCEDURES.............................................................................91
13.1.
Emergency Contact.................................................................................................91
13.2.
Emergency Identification of Investigational Products .............................................91
14.
REGULATORY CONSIDERATIONS...................................................................92
14.1.
Good Clinical Practice............................................................................................92
14.2.
Investigator Responsibilities ...................................................................................92
14.3.
Subject Information and Informed Consent.............................................................92
14.4.
Confidentiality........................................................................................................93
14.5.
Protocol Amendments.............................................................................................93
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................93
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14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................94
14.8.
Closure of the Study ...............................................................................................94
15.
DATA HANDLING AND RECORDKEEPING.....................................................95
15.1.
Data/Documents.....................................................................................................95
15.2.
Data Management...................................................................................................95
15.3.
Record Retention....................................................................................................95
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................97
16.1.
Study Monitoring and Source Data Verification......................................................97
16.2.
Audits and Inspections............................................................................................97
17.
PUBLICATIONS ...................................................................................................98
18.
REFERENCES.......................................................................................................99
19.
APPENDICES......................................................................................................108
19.1.
Ann Arbor Staging System ...................................................................................108
19.2.
Modified Cumulative Illness Rating Scale (Salvi, 2008a)......................................109
19.3.
Deauville Criteria for PET Scan Interpretation (Meignan, 2009)...........................119
19.4.
IWG Response Criteria for NHL (Cheson, 2014)..................................................120
19.5.
Cairo-Bishop Definitions of Tumor Lysis Syndrome ............................................122
19.6.
EQ-5D..................................................................................................................123
19.7.
FACT-LYM .........................................................................................................126
19.8.
Pregnancy Prevention Risk Management Plan ......................................................129
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LIST OF TABLES
Table 1:
Mayo Clinic Study MC078E Baseline Characteristics.............................................21
Table 2:
Mayo Clinic Study MC078E Efficacy Results ........................................................22
Table 3:
FIL Study REAL07 Baseline Characteristics ..........................................................24
Table 4:
FIL Study REAL07 Efficacy Results ......................................................................25
Table 5:
Table of Events.......................................................................................................40
Table 6:
Performance Status by Eastern Cooperative Oncology Group Scale........................49
Table 7:
Lenalidomide/Placebo-R-CHOP Regimen ..............................................................61
Table 8:
Dose Modification Rules – Lenalidomide / Placebo................................................64
Table 9:
Dose Reduction Levels – Lenalidomide..................................................................66
Table 10:
Recommended Dose Modification Rules – Cyclophosphamide and/or 
Doxorubicin............................................................................................................66
Table 11:
Recommended Dose Modification Rules – Vincristine ...........................................67
Table 12:
Recommended Dose Modification Rules – Lenalidomide/Placebo R-CHOP 
Regimen .................................................................................................................67
Table 16:
IWG Response Criteria for NHL (Cheson, 2014)..................................................120
Table 17:
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS) ...............122
Table 18:
Cairo-Bishop Definition of Clinical TLS ..............................................................122
Table 19:
Cairo-Bishop Grading System for TLS .................................................................122
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LIST OF FIGURES
Figure 1:
Mayo Clinic Study MC078E PFS by Subtype.........................................................23
Figure 2:
FIL Study REAL07 PFS and OS by Subtype ..........................................................25
Figure 3:
Overall Study Design..............................................................................................38
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1.
INTRODUCTION 
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and AE profile of lenalidomide.
1.1.
Diffuse Large B-cell Lymphoma
Diffuse large B-cell Lymphoma is a distinct histological type within mature B-cell NHL that is 
characterized by large tumor cells and aggressive clinical behavior.  This type accounts for 
approximately 31% of all newly diagnosed malignant lymphomas (Armitage, 1998).
CHOP chemotherapy in combination with the anti-CD20 monoclonal antibody rituximab on a 
21-day schedule is a standard of care in newly diagnosed cases in most countries worldwide 
(Feugier, 2005; Ketterer, 2013). In the GELA study of R-CHOP versus CHOP front line therapy 
in elderly subjects, following R-CHOP treatment the 5-year event-free survival (EFS) was 47%, 
the 5-year progression free survival (PFS) was 54%, and the 5-year overall survival (OS) was 
58% (Feugier, 2005).  While approximately 50% to 60% of patients are cured (Feugier, 2005; 
Micallef, 2011), for those patients who are refractory or who progress following R-CHOP, 
treatment options are limited and outlook is poor; most die within the next two years.  Since 
roughly 40% to 50% of patients are not cured on initial therapy, evaluating other front line 
treatment options is warranted.  Other attempts to improve cure rate, including R-ACVBD, 
CHOEP, dose dense regimens (R-CHOP14), and high dose regimens (DA-EPOCH), have not 
replaced R-CHOP21 as a standard of care (Ketterer, 2013; Micallef, 2011; Recher, 2011).  
1.2.
Biological and Clinical Significance of DLBCL Typing
As initially described by Staudt and colleagues, DLBCL is composed primarily of two 
biologically distinct pathophysiologic entities (Alizadeh, 2000).  The authors classified DLBCL 
by gene expression profiling (GEP) into the germinal center B-cell (GCB) and the activated B-
cell (ABC) types, derived from different cells of origin.  Subsequently, an additional type was 
noted by GEP called type III, (Rosenwald, 2002), which has since been renamed as unclassifiable 
type. Although GEP is now capable of discerning all three types, GCB, ABC, and unclassifiable; 
immunohistochemistry (IHC) is capable of discerning only two, GCB and non-GCB.  The less 
precise IHC method groups ABC and unclassifiable together as the non-GCB type.  The 
Lymphoma/Leukemia Molecular Profiling Project reported approximately 60% GCB and 40% 
non-GCB (including ABC and unclassifiable) in 240 newly diagnosed DLBCL subject biopsy 
samples examined by GEP (Fu, 2008; Lossos, 2004; Rosenwald, 2002).  
The different DLBCL types have been reported to have different clinical outcomes with CHOP 
(Rosenwald, 2002) and R-CHOP (Fu, 2008) therapy, supporting the concept that these are 
distinct clinical and molecular subtypes.  In the first line setting the 5-year OS rates for the GCB, 
unclassifiable, and ABC types were 60%, 39%, and 35%, respectively, with CHOP treatment 
(Rosenwald, 2002).  With R-CHOP, the 3-year EFS for GCB and non-GCB subtypes was 67% 
and 52% respectively, and the 3-year OS was 85% and 69%, respectively (Fu, 2008). With R-
CHOP and predominantly higher risk patients (IPI 0/1 = 21%, IPI 2/3 = 63%, and IPI 4/5 = 15%) 
the median PFS for the ABC type was 1.5 years (Lenz, 2008).  In the relapsed setting, the 
prognosis appears to be approximately the same for both the GCB and non-GCB subtypes
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(Costa, 2008; Wilson, 2008), which may possibly reflect the selection of GCB subjects with 
poorer prognosis not cured initially by R-CHOP.
1.2.1.
GCB versus ABC Gene Expression Profiling Assay Used in This Protocol
The cell of origin (COO) as characterized by GEP and performed on fresh tissue biopsy samples 
is considered a gold standard.  However defining COO is not currently the routine diagnostic 
work-up in clinical practice.  Moreover, it is not a practical method for subject selection in 
clinical trials due to the fresh biopsy sample requirement as well as the substantial time and 
technological expertise required to perform the assay.
This protocol will use a validated GEP based assay performed on 
 
 with formalin-fixed paraffin-embedded (FFPE) biopsy material to identify 
eligible subjects with the required ABC type. The 
 was validated 
against the original COO model defined by Lenz (Lenz, 2008) using an independent cohort of 68 
FFPE biopsies.  In the validation cohort the assay was accurate, as only one case with definitive 
COO was incorrectly assigned by 
 and robust, with >95% concordance of COO 
assignment between two independent laboratories (Scott, 2014). Although the assay is 
technically verified, it has not received marketing approval by a health authority beyond being 
Conformité Européenne (CE) marked in the European Union (EU).  The assay is being 
developed as a companion diagnostic to lenalidomide in conjunction with the assay 
manufacturer, 
.  Analytical assay validation is not a part of this CC-
5013-DLC-002 protocol.
1.3.
Biomarkers in DLBCL
1.3.1.
Biomarkers in DLBCL Pathogenesis
In recent years a number of chromosomal rearrangements, acquired mutations, or aberrant 
expression of genes coding for proteins as well as for micro ribonucleic acid (miRNA) have been 
identified in DLBCL.  Many are associated with a particular DLBCL subtype or yield prognostic 
information.  For example, BCL2 is a commonly affected gene in the GCB subtype, and EZH2 is 
also mutated in the GCB subtype (Morin, 2010; Schuetz, 2012).  Activation of NF-κB and 
mutation of MYD88 are more common in the ABC type (Compagno, 2009; Ngo, 2011).  Co-
expression of MYC/BCL2 is associated with a very aggressive clinical course in both subtypes, 
although it has been reported to be more common in the ABC type (Green, 2012; Hu, 2013; 
Johnson, 2012).  Additionally, mutations in MYC, CDKN2A, SOCS1, MYD88, CARD11, 
TP53, and other genes have demonstrated prognostic information in patients with DLBCL 
receiving front line treatment (Gisselbrecht, 2012; Horn, 2013; Jardin, 2008; Schif, 2013).  
Single nucleotide polymorphisms (SNPs) are also reported to be associated with prognosis
(Ding, 2013; Li, 2013).
 
 
 
 
 
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1.3.3.
Mechanistic Biomarkers
Recent research on the mechanism of action of lenalidomide, pomalidomide, and thalidomide 
suggest that in tumor cells and T cells, cereblon, a component of E3 ubiquitin ligase complexes, 
is a target for binding by these compounds. These studies showed that the loss of cereblon or a 
binding partner, such as DDB1, decreases or eliminates the antitumor and immunomodulatory 
activity of lenalidomide and pomalidomide (Ito, 2010; Zhu, 2011; Lopez-Girona, 2012).  A 
number of recent studies have reported correlation between pre-treatment levels of cereblon 
measured by GEP or by IHC methods to clinical outcomes in subjects treated with regimens 
containing lenalidomide, pomalidomide or thalidomide. Very recently multiple groups have 
described Aiolos (IKZF3) and Ikaros (IKZF1) as two direct substrates of the CRL4 CRBN E3 
ligase complex. These proteins act as transcriptional repressors in T-cells and are also drivers of 
proliferation in multiple myeloma (MM) cells (Lu, 2013; Gandhi, 2013; Krönke, 2013).
 
 
 
 
 
 
1.4.
Preclinical Data on Lenalidomide in DLBCL
There is biological plausibility and also preclinical data that provide strong support for why 
lenalidomide should be expected to significantly enhance the efficacy of the current standard of 
care R-CHOP in the treatment of the ABC type of DLBCL.   
In DLBCL cell line models, lenalidomide preferentially suppresses the proliferation of ABC
cells in vitro and delays tumor growth in a human tumor xenograft model, with minimal effect 
on GCB cells. This tumoricidal effect was associated with down-regulation of interferon 
regulatory factor 4 (IRF4, also known as MUM1), a hallmark of ABC cells (Zhang, 2013).  IRF4 
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inhibition by lenalidomide induced down-regulation of B-cell receptor (BCR)-dependent NF-κB, 
and this effect was reported to require co-expression of cereblon, a molecular target of 
lenalidomide (Zhang, 2013).  It has also been reported that NF-κB mediates resistance to 
chemotherapy and that decreased NF-κB expression may restore sensitivity to chemotherapy 
agents (Bottero, 2001; Luo, 2005).  Independently, Yang also reported on the activity of 
lenalidomide in ABC type DLBCL cell lines (Yang, 2012).  Lenalidomide killed ABC cells by 
augmenting autocrine interferon beta (IFN-ß) production, which was dependent on oncogenic 
MYD88 mutations in these lymphomas.  In a cereblon-dependent fashion, lenalidomide down-
regulated IRF4 and SPIB transcription factors which repress IFN-ß production. 
In addition to the direct antitumor effects on the ABC tumor cells, lenalidomide exerts potent 
immunomodulatory activity.  Preclinical studies have shown an enhancement of antibody 
dependent cell mediated cytotoxicity (Wu, 2008) and antitumor effects in vivo (Hernandez-
Ilizaliturri, 2005; Zhang, 2009) when lenalidomide was combined with rituximab.  In a murine 
NHL model, lenalidomide induced significant increase in the recruitment of NK cells to tumor 
sites, resulting in enhanced antitumor activity of rituximab (Reddy, 2007). When combined with
rituximab, lenalidomide improved survival in a mouse NHL model and the antitumor activity 
was shown to be NK cell-mediated (Hernandez-Ilizaliturri, 2005).
Preclinical studies suggest that lenalidomide may promote restoration of antitumor 
immunological effects in patients with certain hematological malignancies.  Impaired T-cell 
immunological synapse formation has been reported in chronic lymphocytic leukemia (CLL), 
follicular lymphoma (FL) and DLBCL patients and is thought to be a mechanism of cancer 
immune evasion (Ramsay, 2008; Ramsay, 2009). Lenalidomide treatment of the T-cells and the 
tumor cells collected from these patients repaired the immune synapse defects by enhancement 
of the F-actin synapse. In vitro studies have shown that lenalidomide induced actin cytoskeleton 
reorganization and polarization of NHL cells as early as 30 minutes, a process termed “capping,” 
which is considered an important subcellular component of the immune synapse formation 
(Gaidarova, 2009).  Additionally it has been shown that the combined use of lenalidomide and 
rituximab enhances NK cell-mediated immune synapse formation and the resultant cytotoxicity, 
versus using each agent alone.  Lenalidomide induces CD20-localization within the “cap,” and 
the addition of rituximab can enhance immune synapse formation (Gaidarova, 2009).  The 
capping of CD20 is accompanied by redistribution of other proteins that become part of the 
immune synapse complex.  Therefore, the capping process induced by lenalidomide appears 
integral to immune synapse formation and may coordinately enhance the clustering of both the 
CD20 antigen and the attached rituximab, potentially further enhancing its activity, which would 
support the clinical combination of these agents.
1.5.
Clinical Efficacy Data on Lenalidomide in DLBCL
1.5.1.
Relapsed / Refractory DLBCL
Single agent lenalidomide activity in relapsed or refractory DLBCL subjects has been noted in 
two Celgene-sponsored single arm clinical trials in aggressive NHL: study CC-5013-NHL-002 
(Wiernik, 2008) and study CC-5013-NHL-003 (Witzig, 2011).  Data from both studies were 
combined for a revised analysis of 134 DLBCL subjects as study design was nearly identical and 
subject baseline characteristics were similar.  Results showed an overall response rate (ORR) of 
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26.1% (35/134), a median PFS of 2.7 months, and a median response duration of 6.0 months 
(Czuczman, 2010).  In these clinical trials, COO typing was not conducted.  
Hernandez-Ilizaliturri et al reported in a retrospective analysis of 40 relapsed/refractory 
aggressive NHL subjects (34 DLBCL, 6 composite/transformed DLBCL) treated with single 
agent lenalidomide at Roswell Park Cancer Institute, Mayo Clinic, University of Bologna, and 
Hackensack University that there was a preferential clinical activity of lenalidomide in patients 
with the non-GCB subtype DLBCL (Hernandez-Ilizaliturri, 2011).  The tumor response rate was 
52.9% (5 CR, 4 PR) in the non-GCB subtype (n=17) compared to 8.7% (1 CR, 1 PR) in the GCB 
subtype (n=23).  Median PFS for lenalidomide was 6.2 months for the non-GCB and 1.7 months 
for the GCB subtype (p=0.004).  There were no differences in age, disease stage at time of 
treatment, international prognostic index (IPI) scores, or number of prior therapies between the 
GCB and non-GCB groups.
These observations led to the CC-5013-DLC-001 Phase 2/3 randomized clinical trial of single 
agent lenalidomide versus investigator’s choice in subjects with relapsed/refractory DLBCL in 
GCB and non-GCB subtypes.  In this trial, subjects with relapsed DLBCL underwent GCB 
versus non-GCB typing during the screening phase, and the typing information was used to 
assign subjects to two different cohorts defined by the subtype.  The subjects were then 
randomized to receive lenalidomide or single agent of investigator choice.  This study is still 
ongoing.    
At the time of planned final analysis (N=102 mITT; 54 non-GCB, 48 GCB), the CC-5013-DLC-
001 study showed a statistically significant improvement of median PFS for lenalidomide versus 
investigator’s choice treatment in the non-GCB subtype as assessed by the IRAC (control 7.1 
weeks versus lenalidomide 15.2 weeks; p = 0.021, HR [95% CI] = 0.50 [0.27, 0.92]).  There was 
a favorable trend in ORR as assessed by IRAC (control 11.5% versus lenalidomide 28.6%, 
p=0.179) and dORR (control 3.8% versus lenalidomide 21.4%, p = 0.102).  There was also a 
favorable trend in median OS in the non-GCB subtype (control 20.4 weeks versus lenalidomide 
32.3 weeks; p = 0.253, HR [95% CI] = 0.70 [0.38, 1.30]).  Of note, 16/26 (61.5%) of non-GCB 
subjects in the control arm crossed over to lenalidomide upon radiological evidence of disease 
progression on the comparator treatment (Czuczman, 2014).  
The CC-5013-DLC-001 study also included exploratory objectives related to gene expression 
profiling. If medically feasible, subjects were required to provide a fresh frozen lymph node or 
tumor biopsy at study enrollment; biopsies for 65 subjects were provided.  Samples were then 
typed as ABC, GCB, or unclassifiable using Affymetrix U133 Plus 2.0 GeneChip microarrays.  
At the time of planned final analysis (N= 65 mITT, 27 ABC type, 8 unclassifiable type, 30 GCB
type) the study showed a favorable trend in median PFS for lenalidomide versus investigator’s
choice treatment in the ABC type as assessed by IRAC (control 6.3 weeks versus lenalidomide 
82.0 weeks; p = 0.105, HR [95% CI] = 0.44 [0.15 – 1.23]).  There was also a favorable trend in 
median OS in the ABC type (control 18.6 weeks versus lenalidomide 108.4 weeks; p = 0.144, 
HR [95% CI] = 0.47 [0.17, 1.33]).
Taken together, these data of lenalidomide single agent in subjects with relapsed DLBCL suggest 
that lenalidomide has preferential activity in non-GCB and ABC types of DLBCL.  Further 
evidence supporting this preferential activity in the non-GCB subtype is observed in preclinical 
models (Section 1.4).
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1.5.2.
Front Line DLBCL
The chemo-immunotherapeutic regimen of R-CHOP is a standard of care worldwide for the 
treatment of patients with newly diagnosed DLBCL.  Two academic clinical research groups 
have developed the combination regimen of lenalidomide + rituximab + CHOP (R2-CHOP) in 
patients with newly diagnosed DLBCL: the Mayo Clinic Cancer Center in the US and the Italian 
cooperative group, Fondazione Italiana Linfomi (FIL).  
1.5.2.1.
Mayo Clinic R2-CHOP Data
Protocol MC078E is an investigator initiated Phase 1/2 study of R2-CHOP in subjects with 
newly diagnosed, previously untreated DLBCL and follicular grade IIIA/B B-cell lymphoma, 
sponsored by the Mayo Clinic. 
The objective of the Phase 1 cohort of this study was to establish the maximum tolerated dose 
(MTD) of lenalidomide that could be combined with R-CHOP.  A total of 24 subjects with 
newly diagnosed, untreated CD20-positive DLBCL or follicular grade III NHL were enrolled.
Twenty of these 24 subjects had DLBCL.  Subjects received oral lenalidomide on Days 1-10 
with standard dose R-CHOP every 21 days. The lenalidomide dose levels tested were 15, 20,
and 25 mg. The median age was 65 (35-82) years and 54% were over 60 years. Three subjects
received 15 mg, 3 received 20 mg, and 18 received 25 mg of lenalidomide. No dose-limiting 
toxicity was found, and 25 mg on Days 1-10 was the recommended dose for the Phase 2 portion 
of this study. The incidence of Grade 4 neutropenia and thrombocytopenia was 67% and 21%, 
respectively. Febrile neutropenia was rare (4%) and there were no deaths due to toxicity. The 
ORR was 100% with a CR rate of 77%. It was concluded that lenalidomide at the dose of 25 
mg/day administered on Days 1 to 10 of 21-day cycle can be safely combined with R-CHOP in 
the initial chemotherapy of aggressive B-cell lymphoma (Nowakowski, 2011). 
Based on these phase 1 results, the phase 2 cohort of the study was conducted to assess the 
efficacy of this combination.  Response was evaluated using positron emission tomography or 
computed tomography (PET/CT) by standard criteria (Cheson, 2007). The study is still ongoing; 
data from this study were presented at ASH 2012 and at the International Conference on 
Malignant Lymphoma (ICML) 2013 (Nowakowski, 2012, Nowakowski 2013).  Sixty-seven
subjects were accrued to the Phase 2 cohort with median follow up of 2.1 years; 55 (88%) 
subjects had previously untreated DLBCL.  All subjects received R-CHOP21 for 6 cycles plus 
lenalidomide 25 mg (R2-CHOP) on Days 1 – 10 of each cycle.  Although not prospectively 
planned, subjects were retrospectively subtyped by IHC using the Hans algorithm (Hans, 2004).  
Furthermore, 87 consecutive subjects with DLBCL and similar clinical characteristics 
participating in the Mayo Clinic Lymphoma Database and treated with standard R-CHOP alone 
served as a contemporaneously matched control. Table 1 below describes the baseline 
characteristics of the 55 DLBCL subjects treated with R2-CHOP in the Mayo Clinic phase 2 trial 
and the 87 subjects treated with R-CHOP as matched control.  Subjects treated with R2-CHOP
had fewer subjects with low IPI score and were also older as compared to the R-CHOP cohort.
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Table 1:
Mayo Clinic Study MC078E Baseline Characteristics
Characteristic
R2-CHOP
(N=55)
R-CHOP
(N=87)
P value
Age
Median (range)
68 years (22-87)
61 years (41-86)
0.0077
Sex
Male
38 (69.1%)
50 (57.5%)
0.1647
ECOG PS
0
1
2
3
24 (43.6%)
25 (45.5%)
6 (10.9%)
0
32 (36.8%)
41 (47.1%)
11 (12.6%)
  3 (3.4%)
0.6093
Stage (Ann Arbor)
II
III
IV 
8 (14.5%)
16 (29.1%)
31 (56.4%)
20 (23.0%)
14 (16.1%)
53 (60.9%)
0.3213
IPI
Low
Low-intermediate
High-intermediate
High 
  3 (5.5%)
22 (40.0%)
22 (40.0%)
8 (14.5%)
18 (20.7%)
16 (18.4%)
38 (43.7%)
15 (17.2%)
0.0096
DLBCL Subtype (Hans)
GCB
Non-GCB
34 (62%)
21 (38%)
59 (68%)
28 (32%)
n/a
DLBCL = diffuse large B-cell lymphoma; ECOG PS = Eastern Cooperative Oncology Group Performance Status; 
GCB = germinal center B-cell; IPI = international prognostic index (Nowakowski, 2013). 
Safety data of the R2-CHOP regimen showed the most common Grade 3 and 4 toxicities with
R2-CHOP were neutropenia (12% Grade 3, 74% Grade 4), thrombocytopenia (30% Grade 3, 
16% Grade 4), anemia (20% Grade 3, 0% Grade 4), febrile neutropenia (12% Grade 3, 0% Grade 
4), pneumonia (2% Grade 3, 0% Grade 4), sepsis (0% Grade 3, 2% Grade 4), venous thrombosis 
(0% Grade 3, 2% Grade 4), fatigue (2% Grade 3, 0% Grade 4) and dehydration (2% Grade 3, 0% 
Grade 4). Overall, R2-CHOP is considered well tolerated (Nowakowski, 2013).
Efficacy data from 51 evaluable subjects treated with R2-CHOP showed CR 73%, PR 27%,
ORR 100% (Table 2), and 3-year PFS 65% overall.  The ORR, CR, and PFS compare favorably 
with the matched control cohort Figure 1.
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Although not prospectively planned, subjects were retrospectively subtyped as GCB or non-GCB 
by IHC using the Hans algorithm (Hans, 2004). Table 2 summarizes the phase 2 efficacy data 
for the overall population and also by GCB vs. non-GCB subtype reported thus far 
(Nowakowski, 2012, Nowakowski 2013).  In non-GCB subjects, the ORR and CR were better in 
subjects treated with R2-CHOP when compared with the subjects treated with R-CHOP (ORR 
100% vs 69%; CR 80% vs 50%).  This level of difference was not observed in the GCB subtype.
An updated manuscript was recently published (Nowakowski, 2015).
Table 2:
Mayo Clinic Study MC078E Efficacy Results
R2CHOP1
N=55
R-CHOP “control”2
N=87
ORR
51/51 (100%)
68/83 (82%)
CR
37/51 (73%)
56/83 (67%)3
PR
14/51 (27%)
12/83 (14%)
GCB
N=31
Non-GCB
N=20
GCB
N=57
Non-GCB
N=26
ORR
31 (100%)
20 (100%)
50 (88%)
18  (69%)
CR
23 (74%)
16 (80%)
43 (75%)
13 (50%)
PR
8 (26%)
4 (20%)
7 (12%)
5 (19%)
NR/PD
0 (0%)
0 (0%)
7 (12%)
8 (31%)
CR = complete response; GCB = germinal center B-cell; NR = no response; ORR = objective response rate; PD = 
progressive disease; PR = partial response (Nowakowski, 2013). 
1 Assessment by Cheson 2007 criteria; 4 subjects were not evaluable because of refusal (n=3) or death before 
evaluation (n=1)
2 Assessment by Cheson 1999 criteria; 4 subjects unevaluable for response assessment
3 Including CR=54, complete response unconfirmed (CRu)=2
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Figure 1:
Mayo Clinic Study MC078E PFS by Subtype 
GC = germinal center; GCB = germinal center B-cell; (Nowakowski, 2013). 
1.5.2.2.
FIL R2-CHOP Data
The Italian cooperative group FIL conducted a prospectively designed multicenter phase 1/2 
study to evaluate the toxicity and efficacy of lenalidomide plus R-CHOP21 in untreated elderly 
DLBCL subjects, the REAL07 trial. 
The objective of the Phase 1 cohort of the REAL07 trial was to determine the maximum 
tolerated dose of this combination.  Four lenalidomide doses (5, 10, 15, and 20 mg/day on Days 
1-14) using the continual reassessment method were planned in combination with each course of 
R-CHOP for a total of 6 courses. Seven subject cohorts (n=3 each) were treated (total n=21) at 
10, 20, 15, 15, 15, 10, and 10 mg of lenalidomide. Dose-limiting toxicities occurred in seven 
subjects during the first three treatment courses. The third dose-level of lenalidomide (15 
mg/day) was selected as the maximum tolerated dose, with an estimated dose-limiting toxicity
probability of 0.345 (95% credibility interval 0.164-0.553). Grade 3-4 hematologic adverse 
events were: neutropenia in 28% of the courses, thrombocytopenia in 9%, and anemia in 3%. 
Non-hematologic toxicities were moderate: grade 4 increase of creatinine phosphokinase (n=1), 
grade 3 cardiac (n=2), grade 3 neurologic (n=3), and grade 3 gastrointestinal (n=1). In this phase 
1 study, 90% of subjects achieved an overall response with 81% achieving complete remission.  
It was concluded that this combination is tolerable in elderly DLBCL subjects, and lenalidomide 
given at 15 mg on Days 1-14 of each cycle in combination with standard R-CHOP21 was the 
recommended dosing schedule for Phase 2 study (Chiappella, 2013a).  Nine subjects were 
treated at this dosing schedule in the Phase 1 cohort.
Phase 2 of the REAL07 trial was a study to investigate the efficacy of R2-CHOP in CD20+ 
elderly DLBCL or FL grade IIIB subjects.  Key inclusion criteria included age 60-80, Ann Arbor 
stage II-IV, and IPI > 2.  The primary endpoints were ORR and CR rate after 6 courses of R2-
CHOP by using Cheson, 2007 criteria and included PET negativity as a requirement for CR.  The 
secondary endpoints were 2-year OS, 2-year PFS, and relationship between response and 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
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Confidential and Proprietary
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CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
histopathological features.  Subjects were treated with lenalidomide given at 15 mg on Days 1-14 
of each cycle in combination with standard R-CHOP21 for 6 cycles.  Subjects were 
retrospectively subtyped by IHC using the Hans algorithm (Hans, 2004), although this analysis 
was not prospectively planned.  
Forty subjects were enrolled.  The phase 2 cohort data analyses included these 40 subjects plus 9 
subjects from the phase 1 cohort treated at the recommended phase 2 dose/schedule (total N=49).
Table 3 describes the subject baseline characteristics.
Table 3:
FIL Study REAL07 Baseline Characteristics
R2-CHOP, N = 49 
Median age (range)
69 (61-79)
Bone marrow 
17 (35%)
Male
29 (59%)
B symptoms
21 (43%)
Stage III/IV 
8/35 (16/71%)
LDH > normal 
22 (45%)
PS >1 
31 (63%)
IPI IH/H risk 
29 (59%)
DLBCL/FLgIIIb 
45/3 (92/8%)
β2m > normal 
34 (69%)
PS = performance status, DLBCL = diffuse large B-cell lymphoma, FL = follicular lymphoma, LDH = 
lactase dehydrogenase, IPI = international prognostic index, IH = intermediate / high risk, H = high risk, 
β2m = beta 2 microglobulin (Chiappella, 2013b). 
The most significant common hematological toxicities recorded in 277 cycles of treatment were 
neutropenia (9% grade 3, 22% grade 4), leukocytopenia (15% grade 3, 13% grade 4), febrile 
neutropenia (3% grade 3, 1%, grade 4), thrombocytopenia (5% grade 3, 7% grade 4), and anemia 
(4% grade 3, < 0.5% grade 4) (Chiappella, 2013b).
Table 4 summarizes the response data reported thus far from the REAL07 trial, for the 40 
subjects enrolled in the phase 2 cohort plus 9 subjects from the phase 1 cohort treated at the 
recommended phase 2 dose/schedule (total N=49). The overall results for all 49 subjects showed 
a CR rate of 86%, ORR 92%, 2-year PFS 73%, and 2-year OS 92%.  
Among these 49 subjects, GCB vs. non-GCB typing assignment was achieved in 34 subjects (17 
subjects with GCB, and 17 subjects with non-GCB) by Hans criteria (Table 4). The CR rate in 
subjects with non-GCB subtype appears to be better than the in GCB subtype subjects (88% vs 
76%).  In addition, as was observed in the Mayo Clinic study, among the subjects treated with 
R2-CHOP regimen, the PFS and OS curves of the subjects with the non-GCB subtype appear to 
be about the same as or better than the GCB subtype subjects, suggesting that adding 
lenalidomide to standard therapy improved treatment outcome in non-GCB subjects who have a 
poor prognosis and typically have a worse outcome to treatment (Figure 2).
An updated manuscript was recently published (Vitolo, 2014).
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Lenalidomide (CC-5013)
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Table 4:
FIL Study REAL07 Efficacy Results
Total
N=49
GCB
N=17
Non-GCB
N=17
ORR
45/49 (92%)
15/17 (88%)
15/17 (88%)
CR
42/49 (86%)
13/17 (76%)
15/17 (88%)
PR
3/49 (6%)
2/17 (12%)
0/17
NR
3/49 (6%) 
2/17 (12%)
1/17 (6%)
NA (death)
1/49 (2%)
0/17
1/17 (6%)
PFS
73%1
(95% CI: 57-84)
71%2
(95% CI: 43-87)
81%2
(95% CI: 53-94)
OS
92%1
(95% CI: 79-97)
88%2
(95% CI: 59-97)
94%2
(95% CI: 65-99)
ORR = overall response rate, CR = complete response, PR = partial response, NR = no response, NA = not 
applicable, PFS = progression free survival, OS = overall survival (Chiappella, 2013b). 
1 At 2-years
2 At 18 months
Figure 2:
FIL Study REAL07 PFS and OS by Subtype
A. PFS
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B. OS
GC = germinal center (Chiappella, 2013b). 
1.5.3.
Clinical Efficacy Data Conclusion
In summary, the R2-CHOP efficacy data from the Mayo Clinic MC078E study and the FIL 
REAL07 study compare favorably to historical R-CHOP21 data with a better CR rate at the end 
of induction therapy and better PFS.  Furthermore, promising efficacy results were also 
demonstrated in the non-GCB subtype, which generally has a poorer outcome when treated with 
R-CHOP alone.  Clinically meaningful improvements as demonstrated by higher CR rate (80% 
in Mayo study, 88% in FIL study, vs 50% in the R-CHOP historical control) and longer PFS 
(18-month PFS of 80% in Mayo study, 81% in FIL study vs 30% in 87 subjects from Mayo 
Clinic Lymphoma Database who were treated with R-CHOP as matched control) in non-GCB 
DLBCL subjects are considered significant in this difficult to treat sub-population.  The addition 
of lenalidomide could ameliorate the poor prognosis effect of the ABC phenotype and improve 
treatment outcome in this subgroup of subjects. 
From a safety perspective, this combination is tolerable, without unexpected toxicities. The 
Grade 3 and 4 toxicities are primarily hematological in nature, and manageable with supportive 
care.    
1.6.
Clinical Safety Events of Interest for Lenalidomide
1.6.1.
Deep Vein Thrombosis
1.6.1.1.
Deep Vein Thrombosis in Multiple Myeloma
Venous thromboembolic events (VTE), such as deep venous thrombosis (DVT) and pulmonary 
embolism (PE), have occurred in subjects with multiple myeloma treated with lenalidomide 
combination therapy, and in subjects with MDS or lymphoma treated with lenalidomide 
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monotherapy. A significantly increased risk of DVT and PE has been observed in subjects with 
multiple myeloma who were treated with lenalidomide and dexamethasone therapy (see 
Revlimid prescribing information).  Clinical data in multiple myeloma subjects treated with 
lenalidomide suggests that concomitant administration of gluco-corticosteroids or erythropoietin 
can increase the thrombotic risk. Male gender and smoking history have also been reported to 
increase the risk of VTE in myeloma subjects treated with lenalidomide (Leleu, 2011).
In two randomized studies (MM-009 and MM-010) a significantly increased risk of DVT and PE 
was seen in subjects with multiple myeloma who were treated with REVLIMID® (lenalidomide) 
in combination with dexamethasone (see Revlimid Prescribing Information). In these pivotal 
trials for lenalidomide in subjects with multiple myeloma receiving lenalidomide plus 
dexamethasone, DVT and PE were reported as SAEs in 7.4% and 3.7% of subjects, respectively,
compared to 3.1% and 0.9% of subjects receiving placebo and dexamethasone.  The protocols
did not require systematic DVT prophylaxis. An analysis of pooled data from the MM-009 and 
MM-010 studies demonstrated that thromboembolic events were significantly higher in subjects 
treated with lenalidomide/dexamethasone in the absence of prophylactic use of an anticoagulant 
(p < 0.001) (Dimopoulos, 2009). The effect of adding erythropoietin to lenalidomide/
dexamethasone demonstrated a higher, but not statistically significant rate of thrombosis in the 
erythropoietin group 18% versus 10% for the lenalidomide/dexamethasone group without the 
addition of erythropoietin (p=0.14) (Weber, 2007). 
The Eastern Cooperative Oncology Group (ECOG) trial E4A03 evaluated lenalidomide 25 mg 
on Days 1-21 plus high-dose dexamethasone 40 mg on Days 1-4, 9-12 and 17-20 of a 28-day 
cycle (RD) versus lenalidomide plus low-dose dexamethasone 40 mg on Days 1, 8, 15, and 22 
(Rd) in subjects with newly-diagnosed multiple myeloma. Overall, VTEs including DVT and 
PE occurred in 26% of 223 subjects in the RD arm and in 12% of 220 subjects in the Rd arm 
(Rajkumar, 2010). DVT prophylaxis was to be used in both arms.
1.6.1.2.
Deep Vein Thrombosis in Non-Hodgkin’s Lymphoma
Factors known to increase thrombotic risk in cancer patients in general, not necessarily those 
receiving lenalidomide, include the underlying disease, family history, immobilization, hormonal 
therapy, central venous catheter placement, recent DVT, doxorubicin and other factors (Zhou, 
2010; Park, 2012; Lyman, 2013).
Venous thrombotic events, including DVT and PE, have been reported in patients during 
treatment for NHL, generally occurring at incidences from ~7% up to 20% (Komrokji, 2006; 
Mohren, 2005; Ottinger, 1995; Zhou, 2010).  The risk is significantly higher for females, patients 
with renal dysfunction or high hemoglobin levels, and patients receiving doxorubicin- or 
methotrexate-based regimens (Zhou, 2010). Ottinger et al analyzed incidence, risk factors, 
causes and prognostic significance of VTE in high-grade NHL in a prospective clinical trial of 
593 subjects.  They reported a 6.6% incidence of VTE, with 77% of all cases occurring before or 
within the first 3 months of chemotherapy. Vessel compression by high-grade NHL was 
identified as the leading cause of VTE (Ottinger, 1995).
In lymphoma lenalidomide clinical trials, DVT and PE were reported in 7 (2.6%) and 6 (2.2%) 
of 266 subjects with relapsed or refractory aggressive NHL receiving lenalidomide in clinical 
studies NHL-002 and NHL-003 (Wiernik, 2008; Witzig, 2011). In clinical study NHL-001, 
DVT and PE were reported in 0 (0%) and 1 (2.3%) of 43 subjects with indolent relapsed or 
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refractory NHL (Witzig, 2009). Antithrombotic prophylaxis was not suggested in NHL-001 or 
NHL-002 but was required for subjects considered to be at high risk of developing DVT in 
NHL-003. In the recent CALGB 50401 Phase 2 study evaluating lenalidomide plus rituximab 
versus lenalidomide single-agent therapy in relapsed FL subjects (N=89), thrombosis was 
reported in 2 (4%) of 44 subjects in the lenalidomide plus rituximab arm versus 7 (16%) of 45 
subjects in the lenalidomide arm (Leonard, 2012). In a study evaluating lenalidomide plus 
rituximab in relapsed / refractory mantle cell lymphoma (MCL) subjects (n=44), 3
thromboembolic events were reported (2 [5%] Grade 3; 1 [5%] Grade 4) after 379 cycles of 
lenalidomide plus rituximab (Wang, 2012).
In two front line DLBCL clinical trials evaluating lenalidomide plus R-CHOP, VTE rates were 
reported.  In REAL07 (n=49), which required LMWH heparin as VTE prophylaxis, the Grade 3 
VTE rate was 2% and the grade 4 rate was 0% (Chiappella, 2012).  In a Mayo Clinic study 
(n=47) which required 325 mg aspirin daily as VTE prophylaxis, the grade 3 VTE rate was 0% 
and the grade 4 rate was 2% (Nowakowski, 2015).
It cannot be excluded that the risk of VTE is increased in the subjects participating in this study 
treated with R-CHOP and lenalidomide. For recommendations on VTE prophylaxis in the 
present study see Section 9.3.6.
1.6.2.
Tumor Flare Reaction
Tumor flare reaction (TFR) is defined in the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) Version 3 as a constellation of signs and symptoms 
of tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other 
electrolyte disturbances in direct relation to initiation of therapy (Cancer Therapy Evaluation 
Program, 2003). 
TFR is an adverse effect of lenalidomide previously reported in subjects with CLL (Chanan-
Khan, 2008a).  In clinical studies of lenalidomide in subjects with NHL, TFR has also been 
reported, but at a lower rate than in CLL patients (Corazzelli, 2010; Eve, 2010; Witzig, 2011). 
The clinical manifestations of TFR seen in subjects treated with lenalidomide are similar for 
CLL and lymphoma subjects, and typically occur in the first cycle.  Symptoms include a sudden 
increase in the size and tenderness of the disease bearing sites, including the lymph nodes, spleen 
and/or the liver, often accompanied by pain and sometimes accompanied by low-grade fever and 
non-pruritic diffuse rash (Chanan-Khan, 2008a; Witzig, 2009). The increase in 
lymphadenopathy may be localized or generalized.  In lymphoma patients, TFR is not usually 
accompanied by lymphocytosis.  The onset of TFR has been as early as within a few hours after 
the first dose, but in the vast majority of cases is within the first 2-3 weeks of the first cycle
(Witzig, 2009).  Tumor flare reaction can recur to a lesser extent if the dose is increased (Witzig, 
2009). Based on experience in Celgene-sponsored clinical studies, TFR subsides over time and 
usually resolves in 1-2 weeks with or without intervention (Witzig, 2009).
TFR data on single-agent lenalidomide in over 400 subjects with relapsed or refractory 
aggressive or indolent NHL who received lenalidomide in four Celgene sponsored Phase 2 
clinical studies (NHL-001, NHL-002, NHL-003, and MCL-001) are now available.  These were
Phase 2 multicenter, single-arm, open-label studies that evaluated lenalidomide 25 mg/day for 21 
days of a 28-day cycle. In NHL-001 there were 43 previously treated subjects with indolent 
NHL (Witzig, 2009), in NHL-002 49 subjects with relapsed/refractory aggressive NHL 
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(Wiernik, 2008), in NHL-003 217 subjects with relapsed/refractory aggressive NHL (Witzig, 
2011), and in MCL-001 134 subjects with MCL (Goy, 2012).  Tumor flare reaction occurred in 4 
subjects (Grade 1 [n = 1] and Grade 2 [n = 3]) in the NHL-001 study; none in the NHL-002 
study; 7 of 217 subjects in the NHL-003 study (Grade 1 [n = 2], Grade 2 [n = 2] and Grade 3 [n 
= 3]); and 13 of 134 subjects in the MCL-001 study (Grade 1 [n = 7], and Grade 2 [n = 6]).  The
data from these protocols suggested that subjects experienced TFR during the first 1 to 2 weeks 
of Cycle 1 and that the TFR may be treated symptomatically with non-steroidal anti-
inflammatory drugs (NSAIDs).  
In a single-center, open-label Phase 2 investigator initiated study, Ahmadi et al evaluated the use 
of lenalidomide, dexamethasone and rituximab (cohort 1) versus lenalidomide plus rituximab 
(cohort 2) in subjects with relapsed or refractory indolent B-cell or MCL resistant to rituximab 
(Ahmadi, 2011).  Tumor flare was reported in 12 (5 in cohort 1 and 7 in cohort 2) of the 45 
subjects (MCL and FL).
It is important to note that the increased lymphadenopathy seen in TFR may mimic progressive 
disease (PD).  Therefore, careful monitoring and evaluation to differentiate TFR from PD is 
necessary for addressing treatment of individual subjects including making decisions whether to 
discontinue treatment (Chanan-Khan, 2008b). There are currently no laboratory or radiological 
tests that distinguish TFR from PD. The distinction may be made on clinical grounds, 
incorporating observations such as timing of the event relative to the start of lenalidomide, 
associated physical findings, laboratory findings, and pace of disease before and after institution 
of lenalidomide treatment. Also, in the case of TFR, inflammation and edema may be reduced or 
disappear after short-term treatment with NSAIDs and/or corticosteroids.
1.6.3.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is a well-known constellation of metabolic abnormalities resulting 
from spontaneous or treatment-related tumor necrosis or fulminant apoptosis. The metabolic 
abnormalities include: hyperkalemia, hyperuricemia and hyperphosphatemia with secondary 
hypocalcaemia with risk of renal failure. TLS has been reported in subjects receiving rituximab 
plus lenalidomide, and rituximab plus chemotherapy.
The presence of known risk factors such as bulky disease, pre-existing (moderate) renal 
insufficiency, high ALC and high uric acid levels (> 8 mg/ dL) prior to therapy are known to 
increase the likelihood of TLS.  Early identification of subjects at risk, initiation of prophylactic 
measures, as well as the careful monitoring for early signs of laboratory TLS, and prompt 
initiation of supportive care are critical to prevent potentially life-threatening metabolic 
derangements (Cairo, 2010).  
The experience with tumor lysis syndrome in Celgene-sponsored studies of single-agent
lenalidomide in NHL is summarized below.  Four Phase 2 multicenter, single-arm, open-label 
studies evaluated lenalidomide 25 mg/day for 21 days of a 28-day cycle: NHL-001 in 43 
previously treated subjects with indolent non-Hodgkin lymphoma (Witzig, 2009), NHL-002 in 
49 subjects with relapsed/refractory aggressive NHL (Wiernik, 2008), NHL-003 in 217 subjects 
with relapsed/refractory aggressive NHL (Witzig, 2011), and MCL-001 in 134 subjects with 
relapsed/refractory MCL (Goy, 2012).  All four protocols suggested that subjects receive TLS 
prophylaxis (allopurinol or equivalent) and be well hydrated during the first 7 days of 
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lenalidomide administration in the first cycle or as clinically indicated. Grade 1 TLS occurred in 
1 of the 433 (< 0.3%) subjects receiving lenalidomide. 
In an investigator initiated study, a single-center, open-label Phase 2 study, Dutia et al (Dutia, 
2010) evaluated the use of lenalidomide and rituximab in subjects with relapsed or refractory 
indolent B-cell NHL.  Two of the first 4 subjects treated using the lenalidomide dose of 25 mg 
developed TLS.  Thus, the lenalidomide dose was reduced to 20 mg and allopurinol prophylaxis 
was used in all subsequent subjects with no further TLS events recorded.  
For recommendations on TLS prophylaxis in the present study see Section 9.3.5.
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2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the study is to compare the efficacy of R2-CHOP versus placebo-R-
CHOP.
2.2.
Secondary Objective
The secondary objective of this study is to compare the safety of R2-CHOP versus placebo-R-
CHOP.  
 
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3.
STUDY ENDPOINTS
3.1.
Primary Endpoint
!
Progression-free Survival (PFS)
3.2.
Secondary Endpoints
Key secondary endpoint
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Event-free Survival (EFS)
Other secondary endpoints
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Overall Survival (OS)
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Complete Response (CR) rate 
!
Duration of CR
!
Time to next lymphoma therapy (TTNLT)
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Objective response rate (ORR)
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Health-related quality of life (HRQoL) as measured by the EuroQol 5 Dimension 
Scale (EQ-5D) and the Functional Assessment of Cancer Therapy for Patients with 
Lymphoma (FACT–Lym) standardized measures of health status
 
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4.
OVERALL STUDY DESIGN
4.1.
Study Design
This randomized, placebo-controlled study is designed to evaluate the efficacy and safety of R2-
CHOP chemotherapy versus placebo-R-CHOP chemotherapy in subjects with previously 
untreated CD20+, ABC type DLBCL. Stratification for randomization will be employed to 
reduce bias related to subject IPI score, presence of bulky disease, and age. Randomization in 
this parallel treatment design is in a 1:1 ratio to either R2-CHOP or placebo-R-CHOP.  Celgene, 
as well as the investigator and subject, will be blinded to treatment assignment.  
This study is divided into Screening (4.1.2), Treatment (4.1.3) and Follow-up Periods (4.1.7).  
Details of the study treatments are described in Section 8.
Approximately 560 subjects will be randomized.  Subjects who discontinue or withdraw from the 
study will not be replaced. There is one planned interim analysis for futility at 50% information
level and one planned final analysis for superiority.  See Section 10 for a detailed description of 
Statistical Analyses.
The study will be conducted in compliance with Good Clinical Practice (GCP).
 
 
 
  
 
 
 
4.1.2.
Screening Period
Screening for eligibility determination may begin after the subject signs the informed consent
form.  All screening assessments must be completed within 28 days prior to Cycle 1 Day 1.  The 
only exceptions to the 28-day time period are for the lymph node/tumor biopsy and the bone 
marrow biopsy/optional aspirate, which may occur up to 8 weeks prior to C1D1; and the PET 
and CT scans, which may occur up to 6 weeks prior to C1D1.
During the Screening Period, subjects will undergo safety and other assessments to determine 
eligibility for the study as shown in Section 5 Table of Events and as described in detail in 
Section 6 Procedures.  If subject eligibility is confirmed, then randomization via the interactive 
voice response system (IVRS) is the final part of the Screening Period.  Pre-specification of
optional therapies such as the extra two doses of single agent rituximab or consolidation 
radiotherapy will also be registered in IVRS prior to randomization.
Key aspects of screening include Central Pathology assessment of disease diagnosis, typing by 
GEP, and CD20+ status; local assessment of bone marrow involvement by lymphoma; 
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documentation of measurable disease by CT scan; collection of a PET scan; and verification of 
adequate liver, renal, cardiac, and bone marrow function.  
4.1.3.
Treatment Period
The Treatment Period begins with the first dose of lenalidomide/placebo or of the chemotherapy 
drugs as described in Section 8.  Subjects will receive protocol-specified treatments for 6 cycles, 
and if standard of care per local practice, may also receive two additional doses of single agent 
rituximab if pre-specified in IVRS prior to randomization.  Treatment will continue to 
completion, or until the outcome of the Midcycle CT scan (once between Weeks 9 – 12 which is 
after Cycle 3 but before Cycle 4) indicates a treatment change; disease progression; unacceptable 
toxicity; death; or withdrawal of consent, whichever occurs first. 
In order to manage toxicity and allow subjects to complete 6 cycles of treatment, dose delay and 
modification rules will be followed (Section 8).  Key aspects of ongoing safety monitoring 
include physical exam, AE assessment, and hematology/chemistry laboratory testing prior to the 
initiation of every cycle, and at additional time points as shown in the Table of Events, Table 5.
Key aspects of ongoing efficacy assessment include: CT scans at Screening, Midcycle (once 
between Weeks 9 – 12 which is after Cycle 3 but before Cycle 4), once between 3 – 4 weeks 
after completing Cycle 6, and in follow-up at specified time points; and PET scans at Screening 
and once 3 – 4 weeks after completing Cycle 6.  A subject’s withdrawal from study treatment 
due to the outcome of the Midcycle CT scan or for disease progression will be based upon 
investigator assessment. However, the response evaluation 3 – 4 weeks after completing cycle 6 
will be based on real time IRAC review per Section 4.1.5.
4.1.4.
Treatment Decisions Based on Midcycle CT Scan
Following the Midcycle CT scan, it is acceptable to change therapies if the CT shows evidence 
of lack of response or progression.
Only a CT scan is required for the Midcycle assessment.  If a combined PET-CT is performed, 
measurements, response assessment, and treatment decisions should be based on the diagnostic 
quality CT portion of the PET-CT scan.  If a combined PET-CT without contrast is performed, 
then progression may not be scored on PET positivity alone, but must be confirmed by CT with 
contrast or a biopsy of the PET positive lesion.  As noted by the ICML Imaging Working Group, 
the positive predictive value of an interim PET in DLBCL is variable; therefore, the decision to 
change therapies solely on the basis of Midcycle PET is not recommended, unless there is clear 
evidence of progression (Barrington, 2014).
4.1.5.
Treatment Decisions Based on End of Treatment CT and PET Scans
After Cycle 6, response will be evaluated in real time by Central Radiology and this evaluation 
should guide immediate decisions regarding the subject’s next treatment.  The radiological 
assessment schedule is the same for all subjects, regardless of whether the optional two doses of 
single agent rituximab are administered.  Therefore, the CT and PET scans required at 3 – 4 
weeks after completing Cycle 6 must be completed before the optional Cycle 7 dose of rituximab 
is administered.  The scans acquired 3 – 4 weeks after Cycle 6 should be forwarded immediately 
to Central Radiology.  All prior scans should be sent to Central Radiology at that time if for 
some reason they were not forwarded already.
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If a combined PET-CT is performed, measurements, response assessment, and treatment 
decisions should be based on the diagnostic quality CT portion of the PET-CT scan. If a 
combined PET-CT without contrast is performed, then progression may not be scored on PET
positivity alone, but must be confirmed by CT with contrast or a biopsy of the PET positive
lesion.  The same modality should be used throughout all post-baseline assessment time-points
for a given subject if possible.
4.1.6.
End of Treatment Date
The End of Lenalidomide/Placebo Date is defined as the date of Cycle 6 Day 21 for subjects who 
complete 6 full cycles of lenalidomide/placebo treatment per protocol; or it is the date either the 
investigator or subject decided to permanently discontinue lenalidomide/placebo treatment. The 
End of R-CHOP Date is defined as the date of Cycle 6 Day 21 for subjects who complete 6 full 
cycles of R-CHOP treatment per protocol; or it is the date either the investigator or subject 
decided to permanently discontinue R-CHOP treatment. The optional, extra 2 doses of rituximab 
do not extend the End of R-CHOP Date.  Study treatment includes both lenalidomide/placebo 
and R-CHOP, and these may be completed or discontinued at different times.  Therefore, the End 
of Treatment Date is defined as the later date of either End of Lenalidomide/Placebo or End of 
R-CHOP.  
4.1.7.
Follow-up Period  
The Follow-up Period for each subject begins immediately after their End of Treatment Date; 
this rule applies to all subjects.  This includes subjects who complete the full course of treatment,
who complete the full course of treatment plus the 2 extra dose of rituximab, who discontinue 
treatment due to progression or toxicity, as well as those who discontinue before progression to 
pursue a new antilymphoma/salvage therapy (chemotherapy, SCT, radiotherapy, etc.).  Note that 
a subject receiving the 2 extra doses of rituximab would be in the Follow-up period during 
receipt of the last 2 rituximab doses.  Subjects will be followed for first and second progressions,
subsequent antilymphoma therapies, development of SPMs, and overall survival according to the 
schedule described in Table 5. CT scans continue at the protocol specified time points until first 
progression and must be submitted to Central Radiology.  
If a combined PET-CT is performed, measurements, response assessment, and treatment 
decisions should be based on the diagnostic quality CT portion of the combined PET-CT scan.  If 
a combined PET-CT without contrast is performed, then progression may not be scored on PET
positivity alone, but must be confirmed by CT with contrast or a biopsy of the PET positive
lesion.  
After the 12 Apr 2019 primary analysis, subjects will only be followed for SPM and OS data 
collection.
 
 
 
 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
36
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
4.1.9.
Independent and Central Assessment Committees
A Data Monitoring Committee (DMC) composed of oncologists and a biostatistician, who are all 
independent of and external to Celgene, will review ongoing safety data throughout the study
according to the DMC charter, and may review interim efficacy data for futility.  The DMC will 
make recommendations regarding the continuation of the study, potential amendments, or 
necessary safety measures.  
An IRAC will review all CT and PET scans and relevant clinical data for efficacy assessment 
using the IWG Response Criteria for NHL (Cheson, 2014).  Their retrospective, batched review 
will be the basis for efficacy endpoint calculations.  Additionally, the IRAC will perform a real 
time review of scans collected 3 – 4 weeks after Cycle 6.  Otherwise, eligibility assessment for 
inclusion criterion number 4 for measurable disease and response assessment will also be 
performed locally by the investigator and will guide enrollment and treatment decisions.  
A Central Pathology laboratory will perform screening testing of lymph node / tumor biopsy 
samples to determine disease diagnosis, ABC versus GCB type, and CD20+ status.  Their review 
will serve as the basis for determining eligibility for inclusion criterion number 1 and exclusion 
criterion number 2.
A Central Laboratory will perform hematology and chemistry testing of screening and on-study 
subject blood samples.  Their results will be the basis for safety endpoint calculations.  Central 
safety laboratory data will also be the primary guide for eligibility and subject management.  
However, local laboratory results may be used to guide clinical decisions and dose 
modifications, and if used, those data will also be collected.  
4.2.
Study Design Rationale
The worldwide standard of care in front line, advanced stage DLBCL is R-CHOP on a 21 day
schedule for 6 – 8 cycles; this includes such countries as the US (NCCN, 2013), Canada 
(Cheung, 2007), Japan (Ishizawa, 2007), China (Lin, 2005), and countries in Europe (Feugier, 
2005; Ghielmini, 2013; Tilly, 2012).  Therefore, R-CHOP is the control arm drug selection.
The local standard practice in some countries / investigative sites is to give a total of 8 cycles of 
rituximab.  Therefore in order to accommodate local practice in this global study, investigators 
may choose to give two additional doses of single agent rituximab at the end of the 6 cycles of 
R2-CHOP or placebo-R-CHOP induction therapy. However, to minimize bias, investigators are 
required to pre-specify this option in IVRS before randomization. 
As discussed in Section 1.5, the PFS data from the REAL07 and Mayo Clinic studies, both in 
front line DLBCL GCB and non-GCB subtypes, are the basis for evaluating R2-CHOP in the 
present study (Chiappella, 2012; Nowakowski, 2015).  The 3-year PFS rate of 65% for non-GCB 
subjects treated with R2-CHOP shown by the Mayo Clinic suggests that R2-CHOP is 
particularly active in the non-GCB subject group (Nowakowski, 2015), and is the basis for 
selecting only the ABC type of DLBCL for this study.
The REAL07 study in subjects aged 60 - 80 years tested lenalidomide at 15 mg on Days 1 – 14 
per 21-day cycle whereas the Mayo Clinic study in subjects 18 or older tested lenalidomide at 25 
mg on Days 1- 10 per 21-day cycle.  Both studies treated subjects for 6 cycles and required 
pegfilgrastim prophylaxis for neutropenia and also required DVT prophylaxis.  A comparison of 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
37
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
the most common, Grade 3 and 4 hematological toxicities of neutropenia, thrombocytopenia, 
anemia, and febrile neutropenia suggests that the 15 mg schedule is better tolerated (Chiappella,
2012; Nowakowski, 2015) and is the basis for the lenalidomide dose and schedule selected for 
this study.
Progression-free survival was selected as the study primary endpoint because it is a measure of 
clinical benefit most acceptable to regulatory authorities.  PFS in the ITT population will be
assessed by independent, centralized review.
Event free survival was selected as a key secondary endpoint because it is a measure of clinical 
benefit well accepted by clinicians in this disease setting. EFS captures information on what is 
considered failure of frontline chemotherapy (ie., R-CHOP), namely inadequate response such as 
stable disease or failure to achieve PET-negativity that often requires change in therapy and start 
of salvage therapy.  On the other hand, the PFS endpoint does not capture such change in therapy 
as a PFS event. Depending on the exact definition of PFS, a subject who has inadequate 
response to front line therapy and thus changes to salvage therapy would either be censored or be 
recorded as not having a progression, requiring continued follow-up through subsequent lines of 
therapy until an actual progression of disease (tumor enlargement) is recorded.  It is of note that 
in a recent meta-analysis of several clinical trials, both 3-year PFS and 3-year EFS were highly 
correlated with difference in 5-year OS (rs of 0.90 [95% CI 0.73 – 0.96] (Lee, 2011). 
The IWG response criteria were selected to provide an international standard for the assessment 
of lymphoma (Cheson, 2014).  The use of this established tool and an IRAC will ensure that data 
across centers are evaluated consistently and will also allow for comparison to historical data.  
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
38
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Figure 3:
Overall Study Design
Screening Period   
Treatment Period
Follow Up Period
Day -28 to -1
Informed 
Consent
Central 
Pathology 
assessment of 
disease and 
subtype; 
eligibility 
review; 
stratification 
(IPI, bulky 
disease, age); 
and
randomization
Lenalidomide + R-CHOP21
x 6 cycles*
Follow for first 
and second 
progressions, 
OS, subsequent 
antilymphoma 
therapy, and 
SPM**
Placebo + R-CHOP21
x 6 cycles*
ABC
GCB, 
unclassifiable
Ineligible
IPI= international prognostic index, ABC= activated B-cell, GCB= germinal center B-cell, OS=overall survival, SPM= second 
primary malignancy
* It is permissible to administer an additional two doses (1 dose per 21-day cycle) of single agent rituximab 
after the 6 cycles of study treatment are complete if it is considered standard of care per local practice.  
However, the decision to administer these extra two doses must be pre-specified in IVRS prior to 
randomization.   
Study treatment will continue until 6 cycles of treatment are complete; or until unacceptable toxicity; or until 
the outcome of the CT scan conducted once between weeks 9-12 (after Cycle 3 but before Cycle) indicates a 
treatment change based on response assessment; disease progression; or withdrawal of consent; whichever 
occurs first.
** All subjects who discontinue treatment and who maintain consent, will proceed directly to the Follow-up 
Period.  This includes subjects who complete the full course of treatment, who discontinue treatment due to 
progression or toxicity, as well as those who discontinue before progression to pursue a new antilymphoma 
therapy (chemotherapy, SCT, radiotherapy, etc.).  During the Follow-up Period scans continue at protocol 
specified time points until first progression and are submitted to central radiology.   
Subjects who are alive after the 12 Apr 2019 primary analysis will still be followed exclusively for second 
primary malignancies and survival for up to 5 years from the date the last subject is randomized.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
39
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
4.3.
Study Duration
The primary analysis will occur when the required 192 PFS events (progressions / deaths) in the 
ITT population have occurred, which is approximately 42 months from the start of enrollment.  
After the primary analysis, those subjects who are alive will still be followed exclusively for 
second primary malignancies and survival for up to 5 years from the date the last subject is 
randomized. Therefore, the study duration is approximately 8 years (34 month accrual period + 5 
years SPM follow-up).  See Section 10.3.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary 
 analysis, as pre-specified in the protocol and/or the 
Statistical Analysis Plan, whichever is the later date.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
40
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
5.
TABLE OF EVENTS
Table 5:
Table of Events
Screening Period
Treatment Period
Follow-up Period
Day -28 to Day -1
Cycles 1-6
Day 1
(+/- 3 days)
Cycles 1-2 
Day 8
(+/- 3 days)
End of Treatment Visit
(+/- 3 days)
Weeks 34,46, 58, 70, 82, 
94, 106, 118, 130, 142, 154 
(± 1 week);  180, 206, 258, 
310 (± 2 weeks) until first 
progression
Informed Consent
X
Complete Medical History
X
Central Nervous System (CNS) 
Lymphoma Evaluation
X
Hepatitis B Virus (HBV) Testing
X
Hepatitis C Virus (HCV) Testing
X
Creatinine Clearance (CrCl)
X
Body surface Area (BSA) 
Calculation
X
Electrocardiogram (ECG)
X
Multiple Gated-Acquisition Scan 
(MUGA) / Echocardiography
X
X
Saliva Sample
X
Lymph Node / Tumor Biopsy
Within 8 weeks
prior to C1D1
Submit Lymph Node / Tumor 
Biopsy to Central Pathology
X
Inclusion / Exclusion Criteria 
Review 
X
Detailed information for each row, if applicable, is provided in Section 6.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
41
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Table 5:
Table of Events (Continued)
Screening Period
Treatment Period
Follow-up Period
Day -28 to Day -1
Cycles 1-6
Day 1
(+/- 3 days)
Cycles 1-2 
Day 8
(+/- 3 days)
End of Treatment Visit
(+/- 3 days)
Weeks 34,46, 58, 70, 82, 94, 
106, 118, 130, 142, 154 (± 1 
week);  180, 206, 258, 310 
(± 2 weeks) until first 
progression
Pre-specify Optional 
Consolidation Radiotherapy
and/or Additional Rituximab
X
Randomization
X
Modified Cumulative Illness 
Rating Scale (subjects >80 years)
X
Physical Examination
X
X  
X
X
X
Required until the            
12 Apr 2019 primary 
analysis
Vital Signs
X
X
X
X
Complete Blood Count (CBC) 
with Differential
X
X
X
X
Lactate Dehydrogenase (LDH)
X
X
X
X
Serum Chemistry
X
X
X
X
Thyroid Stimulating Hormone 
(TSH)
X
X
Serum Immunoglobulin
X
X
Lenalidomide Counselling
X
X
Pregnancy Testing - for FCBP 
with Regular or No Menstrual 
Cycles
24 hours prior to 
lenalidomide/placebo 
dosing, and once 
during day -10 to -14
Weekly during first 28 days; 
every cycle on Day 1 thereafter
At End of Lenalidomide/Placebo
and at 28 Days after End of 
Lenalidomide/Placebo
Pregnancy Testing- for FCBP 
with Irregular Menstrual Cycles
24 hours prior to 
lenalidomide/placebo 
dosing, and once 
during day -10 to -14
Weekly during first 28 days; 
every cycle on Days 1 and 14 
thereafter
At End of Lenalidomide/Placebo 
and at both 14 and 28 days after 
End of Lenalidomide/Placebo
Detailed information for each row, if applicable, is provided in Section 6.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
42
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Table 5:
Table of Events (Continued)
Screening Period
Treatment Period
Follow-Up Period
Day -28 to Day -1
Cycles 1-6
Day 1
(+/- 3 days)
Cycles 1-2 
Day 8
(+/- 3 days)
End of Treatment Visit
(+/- 3 days)
Weeks 34,46, 58, 70, 82, 
94, 106, 118, 130, 142, 154 
(± 1 week);  180, 206, 258, 
310 (± 2 weeks) until first 
progression
Quality of Life Assessment 
X
Once between Weeks 9–12, 
(after Cycle 3 but before Cycle 
4) 
Once 3 – 4 weeks after 
completing Cycle 6
(Prior to optional Cycle 7 
rituximab)
X
Required until the 12 Apr 
2019 primary analysis
Performance Status
X
At Midcycle 
Computed Tomography (CT) 
Neck, Chest, Abdomen, Pelvis
Within 6 weeks prior 
to C1D1
Response Assessment 
(Cheson, 2014)
Positron Emission 
Tomography (PET) of Neck, 
Chest, Abdomen, Pelvis
Within 6 weeks prior 
to C1D1
Bone Marrow Biopsy
Within 8 weeks prior 
to C1D1
Procedure is dependent on the 
post Cycle 6 PET scan results and 
is required only if Bone Marrow 
Biopsy is positive at Screening, 
and there is an equivocal post 
Cycle 6 PET scan finding in the 
bone marrow
Bone Marrow Aspirate 
(optional)
Within 8 weeks prior 
to C1D1
Detailed information for each row, if applicable, is provided in Section 6.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
43
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Table 5:
Table of Events (Continued)
Screening Period
Treatment Period
Follow-Up Period
Day -28 to Day -1
Cycles 1-6
Day 1
(+/- 3 days)
Cycles 1-2 
Day 8
(+/- 3 days)
End of Treatment Visit
(+/- 3 days)
Weeks 34,46, 58, 70, 82, 
94, 106, 118, 130, 142, 154 
(± 1 week);  180, 206, 258, 
310 (± 2 weeks) until first 
progression
Administer Investigational 
Product (IP) – Start Cycle
X
(± 1 day)
IP Accountability and
Compliance
X
X
Administer Mandatory 
Primary Neutropenia 
Prophylaxis
(1-3 days after 
chemotherapy
or per local 
practice;
details in 
Section 8.2.3)
Tumor Lysis Syndrome (TLS) 
Assessment
Cycles 1 - 2
(same day as 
dosing)
X
(± 1 day)
Adverse Event
After signing the informed consent document through 28 days after last dose, which includes the 
optional two additional doses of single agent rituximab, if administered.
Concomitant Medications / 
Procedures
Subsequent Antilymphoma 
therapy and Progression 
After signing the informed consent document until the subject has died, revokes consent, or until the 12 Apr 2019 primary 
analysis, whichever occurs first.
Assessment of Second Primary 
Malignancy (SPM)
After signing the informed consent document until the subject has died, revokes consent, or for up to 5 years from the date the 
last subject is randomized, whichever occurs first.
Survival Information
Detailed information for each row, if applicable, is provided in Section 6.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
44
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
6.
PROCEDURES
Informed Consent must be obtained prior to performing any procedures specifically for this 
study that are beyond standard of care.  The subject may withdraw consent at any time for all or 
certain aspects of the study as follows:
1. Withdraw consent for study treatment, but allow Follow-up Period assessments and data 
collection on subsequent antilymphoma therapy, PFS
, SPM, and survival 
information.
2. Withdraw consent for study treatment and Follow-up Period assessments, but allow data 
collection on subsequent antilymphoma therapy, PFS
, SPM, and survival 
information.
3. Withdraw all consent.
Central Nervous System (CNS) Lymphoma Evaluation will be performed at Screening.  CNS 
involvement should be considered if paranasal sinus, testicular, epidural, or bone marrow sites 
are involved, or if there are ≥ 2 extra-nodal sites and elevated LDH.  If CNS lymphoma is 
deemed possible by the investigator, then the subject is required to have a negative cerebrospinal 
fluid (CSF) cytology examination, and a head CT or MRI during Screening.  Refer to Section 
9.3.1 for permitted, concomitant CNS prophylaxis treatment.
Hepatitis B Virus (HBV) Testing will be performed at Screening by the Central Laboratory and 
includes hepatitis B surface antigen (HBsAg), antibody to the hepatitis B surface antigen (anti-
HBs), and antibody to the hepatitis B core antigen (anti-HBc).  If a subject is anti-HBc positive 
the Central Laboratory will automatically perform a quantitative polymerase chain reaction test 
to measure viral DNA load. If Screening Central Laboratory results are not available and 
treatment needs to be urgently started, then local laboratory results may be used to confirm 
eligibility, however the Celgene medical monitor must be consulted.  Additionally, the data must 
be submitted to Celgene in the case report form (CRF) and the investigator must ensure that 
samples for the Central Laboratory are drawn before investigational product is administered and 
immediately sent to the Central Laboratory.
Hepatitis C Virus (HCV) Testing will be performed at Screening by the Central Laboratory on 
all subjects.  If Screening Central Laboratory results are not available and treatment needs to be 
urgently started, then local laboratory results may be used to confirm eligibility, however the 
Celgene medical monitor must be consulted.  Additionally, the data must be submitted to 
Celgene in the CRF and the investigator must ensure that samples for the Central Laboratory are 
drawn before investigational product is administered and immediately sent to the Central 
Laboratory.  
For those who are HCV positive, the investigator must confirm that the subject is an acceptable 
candidate for R-CHOP therapy and does not have an active HCV infection or unacceptable liver 
damage as documented by one of the following options: FibroScan® (liver ultrasound for 
fibrosis), liver biopsy, zero RNA viral load by local laboratory, or other local practice test.
Creatinine Clearance will be assessed at Screening by the Central Laboratory.  If Screening 
Central Laboratory results are not available and treatment needs to be urgently started, then local 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
45
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
laboratory results may be used to confirm eligibility, however the Celgene medical monitor must 
be consulted.  Additionally, the data must be submitted to Celgene in the CRF and the 
investigator must ensure that samples for the Central Laboratory are drawn before investigational 
product is administered and immediately sent to the Central Laboratory.  Creatinine clearance 
(CrCl) is estimated using the Cockcroft-Gault formula where CrCl (mL/min) = (140 – age) 
(weight [kg]) / 72 (serum creatinine [mg/dL]; for females, the formula is multiplied by 0.85 
(Cockcroft, 1976).
Body Surface Area (BSA) will be calculated using the subject’s height and weight according to 
local pharmacy practice.  Height will be collected only at Screening; however, weight will be 
collected at the start of every cycle.  It is up to pharmacist and investigator discretion whether 
BSA will be recalculated prior to preparing every cycle of chemotherapy from Cycle 2 onward, 
or whether the Screening / Cycle 1 BSA will be used throughout the study. If BSA is to be 
recalculated, the same calculation method should be used throughout the study per subject.  
Electrocardiogram (ECG) will be performed at Screening to assess heart electrical function.  If 
an ECG was performed as standard of care within 28 days of dosing, that data may be used to 
fulfill the eligibility requirement.  
Multiple Gated-Acquisition Scan (MUGA) / Echocardiography will be performed at 
Screening and End of Treatment Visit to assess left ventricular ejection fraction (LVEF).  If a 
MUGA/echocardiography was performed as standard of care within 28 days of dosing, that data 
may be used to fulfill the eligibility requirement.  Note that MUGA is highly preferred, but if this 
testing modality is not available or is not standard local practice, then echocardiography will be 
acceptable.
Saliva Sample is to be collected in a 2 mL ORAgene kit tube during Screening.  The sample is 
for germline mutational analysis and the results do not impact subject eligibility.
Lymph Node/Tumor Biopsy specimen preserved as a formalin-fixed paraffin-embedded block
(FFPE) or unstained slides, and acquired within 8 weeks prior to C1D1, must be available.  If 
submitting unstained slides, 15-20 are highly recommend in order to complete all testing.  If an 
archival specimen is not available or is not acceptable, a re-biopsy is required prior to 
randomization.  This procedure should be performed before initiating the optional pre-phase 
corticosteroid treatment.  Refer to Inclusion Criterion 3 for more details on specimen 
acceptability.  Refer to the laboratory manual for sample handling instructions.  
Submit Lymph Node/Tumor Biopsy to Central Pathology. The Screening biopsy sample is to
be submitted to Central Pathology during Screening with enough time planned to allow central 
confirmation of disease, subtype, and CD20 status.  Central Pathology will review and provide
biopsy results within three calendar days (includes Saturday and Sunday) of receiving a complete 
sample set, properly prepared and labeled, and accompanied by the correct paperwork.
Inclusion/Exclusion Criteria must be reviewed and cleared prior to randomization.  Celgene 
corporate policy does not allow waivers to any eligibility criteria. 
Pre-specify Optional Consolidation Radiotherapy and/or Additional Rituximab if 
applicable.  If the investigator intends to administer optional consolidation radiotherapy (Section 
8.2.2) and / or an optional two additional doses of single agent rituximab (Section 8.2.6
Rituximab), these must be pre-specified prior to randomization through the IVRS.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
46
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Randomization is accomplished through the IVRS, by a designated member of the 
investigator’s staff once all eligibility criteria have been verified.  Randomization is part of the 
Screening Period and may be completed up to 7 days prior to Cycle 1 Day 1 dosing (to allow 
pharmacy preparations) however, the Screening Period must not exceed 28 days.  
Modified Cumulative Illness Rating Scale (CIRS) is to be assessed at Screening only for 
subjects >80 years of age.  The following organ specific categories are assessed: heart; 
hypertension; vascular-hematopoietic; respiratory; eyes, ears, nose, throat, and larynx; upper 
gastrointestinal; lower gastrointestinal; liver and biliary trees; renal; genitourinary; 
musculoskeletal/integument; central and peripheral nervous system; endocrine-metabolic system 
and breast; psychiatric and behavioral diseases.  DLBCL illnesses or disease related organ 
damage should not be assessed as part of this rating scale. If there are two or more 
illnesses/impairments in one organ category, the illness/impairment with the highest severity will 
be evaluated.  Each organ category is scored separately according to Appendix 19.2 (Salvi,
2008a).
Physical Examination includes assessment of lymphadenopathy, hepatomegaly and 
splenomegaly, as clinically indicated. The exam is performed at Screening, at every cycle on 
Day 1, during Cycles 1 - 2 on Day 8, and at End of Treatment Visit.  If the most recent protocol 
scheduled or unscheduled assessment was performed within 7 days prior to End of Treatment
Visit, the assessment does not need to be repeated again at End of Treatment Visit.  If a subject
has discontinued treatment for any reason other than disease progression or death, the exam is 
required to continue during the Follow-up Period at Weeks 34, 46, 58, 70, 82, 94, 106, 118, 130, 
142, 154 (± 1 week); 180, 206, 258, and 310 (± 2 weeks) until first progression or the 12 Apr 
2019 primary analysis, whichever occurs first.
Vital Signs include blood pressure, pulse, and temperature and will be measured at Screening, 
every cycle on Day 1, during Cycles 1 - 2 on Day 8, and at End of Treatment Visit. If the most 
recent protocol scheduled or unscheduled assessment was performed within 7 days prior to End 
of Treatment, the assessment does not need to be repeated again at End of Treatment Visit.  If a 
subject has discontinued treatment for any reason other than disease progression or death, the 
assessment is required to continue during the Follow-up Period at Weeks 34, 46, 58, 70, 82, 94, 
106, 118, 130, 142, 154 (± 1 week); 180, 206, 258, and 310 (± 2 weeks) until first progression or 
the 12 Apr 2019 primary analysis, whichever occurs first.
Complete Blood Count (CBC) with Differential includes hemoglobin, hematocrit, white blood 
cell count (WBC) with differential, absolute neutrophil count (ANC), absolute lymphocyte count 
(ALC), and platelet count.  The test is performed at Screening, every cycle on Day 1, during 
Cycles 1-2 on Day 8, and at End of Treatment Visit.  If a subject has discontinued treatment for 
any reason other than disease progression or death, the assessment is required to continue during 
the Follow-up Period at Weeks 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154 (± 1 week); 180, 
206, 258, and 310 (± 2 weeks) until first progression or the 12 Apr 2019 primary analysis,
whichever occurs first. 
At Screening, all CBC testing is performed by the Central Laboratory.  If the Screening test is
completed within 7 days of Cycle 1 Day 1 dosing, the test does not need to be repeated again on 
Cycle 1 Day 1.  If Screening Central Laboratory results are not available and treatment needs to 
be urgently started, then local laboratory results may be used to confirm eligibility, however the 
Celgene medical monitor must be consulted.  Additionally, the data must be submitted to 
stem
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Scre


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
47
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Celgene in the CRF and the investigator must ensure that samples for the Central Laboratory are 
drawn before investigational product is administered and immediately sent to the Central 
Laboratory.
After the Screening Period, testing continues by the Central Laboratory.  However, in urgent 
cases, local laboratory results may be used to guide clinical decisions and dose modifications,
however, that data must be submitted to Celgene in the CRF, and whenever possible, a 
concurrent sample should be sent to the Central Laboratory.
If the most recent protocol scheduled or unscheduled test was performed within 7 days prior to 
End of Treatment Visit, the test does not need to be repeated again at End of Treatment Visit.
Lactate Dehydrogenase (LDH) is performed at Screening, every cycle on Days 1, during 
Cycles 1-2 on Day 8, and at End of Treatment Visit.  If a subject has discontinued treatment for 
any reason other than disease progression or death, the assessment is required to continue during 
the Follow-up Period at Weeks 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154 (± 1 week); 180, 
206, 258, and 310 (± 2 weeks) until first progression or the 12 Apr 2019 primary analysis,
whichever occurs first.  
At Screening, all testing is performed by the Central Laboratory.  If the Screening test is
completed within 7 days of Cycle 1 Day 1 dosing, the test does not need to be repeated again on 
Cycle 1 Day 1.  
If Screening Central Laboratory results are not available and treatment needs to be urgently 
started, then a local laboratory LDH result may be used. However, the data must be submitted to 
Celgene in the CRF and the investigator must ensure that samples for the Central Laboratory are 
drawn before investigational product is administered and immediately sent to the Central 
Laboratory.  
After the Screening Period, testing continues by the Central Laboratory.  However, in urgent 
cases, local laboratory results may be used to guide clinical decisions and dose modifications, 
however, that data must be submitted to Celgene in the CRF, and whenever possible, a 
concurrent sample should be sent to the Central Laboratory.
If the most recent protocol scheduled or unscheduled test was performed within 7 days prior to 
End of Treatment Visit, the test does not need to be repeated again at End of Treatment Visit.
Serum Chemistry includes albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate transaminase (AST), bilirubin (total), calcium, chloride, creatinine, glucose, 
phosphorous, potassium, sodium, total protein, blood urea nitrogen (BUN), and uric acid.  The 
test is performed at Screening, every cycle on Days 1, during Cycles 1-2 on Day 8, and at End of 
Treatment Visit.  Unscheduled tests may be ordered at any time.  
At Screening, all chemistry testing is performed by the Central Laboratory.  If the Screening test 
is completed within 7 days of Cycle 1 Day 1 dosing, the test does not need to be repeated again
on Cycle 1 Day 1.  If Screening Central Laboratory results are not available and treatment needs 
to be urgently started, then local laboratory results may be used to confirm eligibility, however 
the Celgene medical monitor must be consulted.  Additionally, the data must be submitted to 
Celgene in the CRF and the investigator must ensure that samples for the Central Laboratory are 
drawn before investigational product is administered and immediately sent to the Central 
Laboratory.
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C


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
48
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
After the Screening Period, testing continues by the Central Laboratory.  However, in urgent 
cases, local laboratory results may be used to guide clinical decisions and dose modifications, 
however, that data must be submitted to Celgene in the CRF, and whenever possible, a 
concurrent sample should be sent to the Central Laboratory.
If the most recent protocol scheduled or unscheduled test was performed within 7 days prior to 
End of Treatment Visit, the test does not need to be repeated again at End of Treatment Visit.
Thyroid Stimulating Hormone (TSH) is tested at Screening and at the End of Treatment Visit; 
the blood serum samples are analyzed by the Central Laboratory.
Serum Immunoglobulin (Ig) measurement includes IgA, IgG, IgM and will be collected at 
Screening and at End of Treatment Visit.  Testing is performed by the Central Laboratory.
Lenalidomide Counseling is conducted for all subjects at the following times: once during 
Screening prior to Cycle 1 Day 1 dosing; and while on treatment, once per cycle prior to 
dispensing lenalidomide.  Please consult the Pregnancy Prevention Risk Management Plan for 
details.
Pregnancy Testing is applicable to all subjects who are females of childbearing potential 
(FCBP). FCBP is defined as a: sexually mature female who: 1) has not undergone a 
hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical 
removal of both ovaries) or 2) has not been naturally postmenopausal (amenorrhea following 
cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., 
has had menses at any time during the preceding 24 consecutive months).
Prior to starting investigational product, two negative pregnancy tests are required (sensitivity of 
at least 25 mIU/mL).  The first test must be performed within 10 to 14 days prior to the start of
lenalidomide/placebo dosing, and the second within 24 hours prior to the start of
lenalidomide/placebo dosing.  During the Treatment Period testing is performed weekly for the 
first 28 days. Thereafter, FCBP with regular or no menstrual cycles continue testing at a 
minimum of every 28 days during the Treatment Period (Day 1 of every 21-day cycle is 
acceptable), at the Lenalidomide/Placebo End of Treatment, and 28 days following 
Lenalidomide/Placebo End of Treatment.  Thereafter, FCBP with irregular menstrual cycles
continue testing every 14 days during the Treatment Period, at Lenalidomide/Placebo End of 
Treatment, and at both 14 and 28 days following Lenalidomide/Placebo End of Treatment.  
Quality of Life Assessment will be completed using the EQ-5D and FACT-Lym questionnaires 
(Appendix 19.6 and 19.7).  These are required to be completed at the following time points: at 
Screening, Midcycle, once 3 – 4 weeks after completing Cycle 6; Weeks 34, 46, 58, 70, 82, 94, 
106, 118, 130, 142, 154 (± 1 week); 180, 206, 258, and 310 (± 2 weeks) until first progression or 
the 12 Apr 2019 primary analysis, whichever occurs first. To the extent possible, collect this 
assessment the same day the CT scan is performed.  If an additional CT scan is performed earlier 
than the specified time points due to changes in the subject’s clinical status, please also collect an 
additional questionnaire set at that time.  Once a subject has progressed, no further 
questionnaires are required.
Performance Status will be scored according to Table 6 and will be measured at Screening;
Midcycle; and once 3 – 4 weeks after completing Cycle 6.  If a subject has discontinued 
treatment for any reason other than disease progression or death, the assessment is required to 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
49
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
continue during the Follow-up Period at Weeks 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154 (± 
1 week); 180, 206, 258, and 310 (± 2 weeks) until first progression or the 12 Apr 2019 primary 
analysis, whichever occurs first.To the extent possible, collect this assessment the same day the 
CT scan is performed. 
Table 6:
Performance Status by Eastern Cooperative Oncology Group Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair
5
Dead
(Oken, 1982)
 
 
 
 
CT Scan of the Neck, Chest, Abdomen, and Pelvis is to be performed with contrast unless 
medically contraindicated; in this case magnetic resonance imaging (MRI) or a CT without 
contrast is acceptable. It is acceptable to perform a combined PET-CT, however, the CT portion 
should be of diagnostic quality.  
If the local preference is to perform a combined PET-CT without contrast, this will be acceptable 
for post baseline assessments only (unless contrast is medically contra indicated at baseline): 
Midcycle (once between Weeks 9 – 12 which is after Cycle 3 but before cycle 4); End of 
Treatment Visit; and for PET negative (CR) subjects only, also during the Follow-up Period.  If a 
combined PET-CT without contrast is performed, then progression may not be scored on PET
positivity alone, but must be confirmed by CT with contrast or a biopsy of the PET positive 
lesion. The same modality should be used throughout all post-baseline assessment time-points
for a given subject if possible. Consult the radiology manual for more detail.  
This procedure should be performed before initiating the optional pre-phase corticosteroid 
treatment. All scans will be sent to Central Radiology on an ongoing basis for subsequent 
efficacy assessment. Local interpretation of scans will determine eligibility and inform real-time 
treatment decisions during the study.  However, the CT scans collected 3 – 4 weeks after Cycle 6 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
50
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
should be forwarded immediately to Central Radiology for a real time assessment which will 
guide treatment decisions at the post Cycle 6 time point.
The CT scans are required at Screening, Midcycle (once between Weeks 9 – 12 which is after 
Cycle 3 but before Cycle 4); once 3 – 4 weeks after completing Cycle 6; Weeks 34, 46, 58, 70, 
82, 94, 106, 118, 130, 142, 154 (± 1 week); 180, 206, 258, and 310 (± 2 weeks) until first 
progression or the 12 Apr 2019 primary analysis, whichever occurs first. The radiological 
assessment schedule is the same for all subjects, regardless of whether the optional two doses of 
single agent rituximab are administered.  Therefore, the scan required at 3 – 4 weeks after 
completing Cycle 6 must be completed before the optional Cycle 7 dose of rituximab is 
administered.  If an additional scan is performed earlier than the specified time points due to 
changes in the subject’s clinical status, this extra scan should also be submitted to Central 
Radiology.  Once a subject has experienced first progression, no further CT scans are required.  
Below is a bulleted summary:
!
Screening 
∀
PET and CT with contrast to define lesions
!
Once between Weeks 9 – 12 
∀
CT with contrast, or PET-CT without contrast per local standard of care
!
Once 3-4 weeks after completing Cycle 6 
∀
PET and CT with contrast or PET-CT without contrast per local standard of care
!
If PET negative (CR), contrast CT not required
!
If PET positive, contrast CT or biopsy required to confirm PD before changing 
therapy
!
Follow-up for PET negative (CR) cases
∀
CT with contrast, or PET-CT without contrast per local standard of care
∀
Progression must be confirmed by contrast CT or biopsy
!
Follow-up for PET positive cases (PR and SD)
∀
CT with contrast
Scans previously acquired as standard of care up to 6 weeks prior to Cycle 1 Day 1 may be 
submitted to fulfill the Screening requirement as long as they meet the minimum technical 
standards specified by Central Radiology and include all required fields.  Fields missing from 
archival scans may be imaged separately during Screening and the complete set of scans may be 
submitted together to fulfill Screening requirements.
The scanning time points are the same for all subjects, including those who complete the full 
course of protocol specified treatment, who discontinue treatment early due to toxicity, as well as 
those who discontinue before progression to pursue a new antilymphoma/salvage therapy 
(chemotherapy, SCT, radiotherapy, etc.).  All scans are submitted to Central Radiology.  
However, in the case where a subject receives a new antilymphoma therapy before first 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
51
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
progression, and as part of another clinical trial, continue the scans to the extent possible and 
submit if possible to Central Radiology until first progression.   
Response Assessment includes review of current CT, PET, laboratory, and clinical data to 
determine the subject’s response status per the IWG Response criteria for NHL (Cheson, 2014).  
The response assessments are required at: Midcycle; once between 3 – 4 weeks after completing 
Cycle 6; Weeks 34, 46, 58, 70, 82, 94, 106, 118, 130, 142, 154 (± 1 week); 180, 206, 258, and 
310 (± 2 weeks) until first progression or the 12 Apr 2019 primary analysis, whichever occurs 
first. The response assessment schedule is the same for all subjects, regardless of whether the 
optional two doses of rituximab are administered.  If an additional CT scan is performed earlier 
than the specified time points due to changes in the subject’s clinical status, please also perform 
an additional response assessment at that time.  Once a subject has progressed, no further 
response assessments are required.
Bone Marrow Biopsy will be performed at Screening (before pre-phase corticosteroid 
treatment, if applicable) for all subjects; and at the End of Treatment only if the subject has an 
equivocal post Cycle 6 PET scan finding in the bone marrow, and had lymphomatous 
involvement of the bone marrow at Screening.  Therefore, if an EOT biopsy is required, the 
timing will be dependent on the post Cycle 6 PET scan results. Samples previously acquired as 
standard of care within 8 weeks prior to C1D1 may be used to fulfill the Screening bone marrow 
biopsy requirement.  Local pathology review of the Screening and End of Treatment Visit bone 
marrow samples is acceptable; Central Pathology does not review bone marrow biopsy samples.  
The Screening results do not impact study eligibility.  A unilateral biopsy is acceptable.
Bone Marrow Aspirate sample collection within 8 weeks prior to C1D1 is recommended, but is 
not required.  This procedure should be performed before initiating the optional pre-phase 
corticosteroid treatment.  Local pathology review of the aspirate is acceptable.  If a subject 
develops an SPM post C1D1, and if a Screening aspirate was collected, sponsor review of the 
sample and/or of the local pathology report may be requested.  
PET Scan of the neck, chest, abdomen, and pelvis is required once during Screening before 
receipt of investigational products (also before pre-phase corticosteroid treatment, if applicable);
and once between 3 – 4 weeks after completing Cycle 6.  The radiological assessment schedule 
is the same for all subjects, regardless of whether the optional two doses of single agent 
rituximab are administered. Therefore the scan required at 3 – 4 weeks after completing Cycle 6 
must be completed before the optional Cycle 7 dose of rituximab is administered.   
Scan interpretation is according to the Deauville Criteria with a score of 1 – 2 being negative, 
and score of 3 – 5 being positive (Itti, 2013; Meignan, 2013), (Appendix 19.3).  Although local 
interpretation at Screening is acceptable, all scans will be sent to Central Radiology on an 
ongoing basis for subsequent efficacy assessment.  However, the PET scan collected 3 – 4 weeks 
after Cycle 6 should be forwarded immediately to Central Radiology for a real time assessment 
which will guide treatment decisions at the post Cycle 6 time point.
Scans previously acquired as standard of care within 6 weeks prior to Cycle 1 Day 1 may be 
submitted to fulfill the Screening requirement as long as they meet the minimum technical 
standards specified by Central Radiology and include all required fields.  Screening PET scan 
results do not impact eligibility.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
52
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Administer Investigational Product as described in Section 8.2. 
IP Accountability and Compliance is described in Sections 8.7 and 8.8.
Administer Mandatory Primary Neutropenia Prophylaxis as described in Section 8.2.3
Tumor Lysis Syndrome (TLS) Assessment includes review of uric acid, potassium, 
phosphorous, calcium, and serum creatinine laboratory values; hydration status check; and 
clinical assessment / grading using the Cairo-Bishop Definition of TLS in Appendix 19.5.  
(CTCAE is not used to grade TLS in this study.)  TLS assessment is to be performed at Cycles 1-
2 Days 1, 8, and thereafter as clinically indicated.  Note that the TLS assessment has a smaller 
window than the other assessments.  The Day 1 TLS assessment must always be performed on 
the same day as dosing; the Day 8 TLS assessment must be performed within ± 1 day.  TLS 
prophylaxis treatment is discussed in Section 9.3.5.
Adverse Events will be collected from signing of informed consent through 28 days after the 
last dose of investigational product, which includes the optional two additional doses of single 
agent rituximab, if administered.
Concomitant Medications / Procedures will be collected from signing of informed consent 
through 28 days after the last dose of investigational product, which includes the optional two 
additional doses of single agent rituximab, if administered.  These also include blood products 
transfused (packed red blood cells, platelets, etc.).
Subsequent Antilymphoma Treatment and Progression
will be recorded, 
specifically the individual drug names, dates of treatment, and progression date, as long as the 
subject does not revoke consent, and the study remains open at the investigator’s center.
 
 
 Data through first progression may be collected at scheduled protocol clinic 
visits,
 
. After the 12 Apr 2019 primary analysis, this information will not be 
collected.
Second Primary Malignancy (SPM) will be monitored as an event of interest and must be 
reported as an SAE regardless of the treatment arm the subject is in.  This includes any SPM, 
regardless of causal relationship to IP, occurring at any time for the duration of the study, from 
the time of signing the ICD until the subject has died, revokes consent, or for up to 5 years from 
the date the last subject is randomized, whichever occurs first.  Events of SPM are to be reported 
using the SAE report form and must be considered an “Important Medical Event” even if no 
other serious criteria apply; these events must also be documented in the appropriate page(s) of 
the CRF and subject’s source documents.  Documentation on the diagnosis of the SPM must be 
provided at the time of reporting as an SAE (eg, any confirmatory histology or cytology results, 
x-rays, CT scans, etc.).  If a tissue biopsy is collected related to an SPM, sponsor review of the 
sample and/or a local pathology report may be requested. For this particular study, SPM will 
include cases of DLBCL transformation to acute lymphoblastic leukemia (ALL).
As part of the SPM follow-up on all subjects, regardless of whether the subject actually 
experiences an SPM, information about subsequent antilymphoma therapies, first and second 
progression, and survival will also be collected.  This is described in the Table of Events
(Table 5) and earlier in Section 6.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
53
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Survival Information will be collected on all subjects at scheduled protocol clinic visits until 
first progression.  Thereafter, information will be collected via subject contact (phone, email, 
visit, etc.) as long as the subject does not revoke consent, and the study remains open at the 
investigator’s center.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
54
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
This study will enroll approximately 560 subjects in the ITT population which are anticipated to 
come from the regions of North America, Europe, and Asia.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Histologically confirmed CD20+ DLBCL of the below World Health Organization 
(WHO) sub-classifications as assessed by Central Pathology.  In the rare case that local 
and Central pathology disagree on DLBCL diagnosis and/or CD20+ status, and if ABC 
type is confirmed by Central Pathology (inclusion criterion 2), then the subject may still 
be enrolled on the basis of a local DLBCL diagnosis and/or CD20+ status at investigator 
discretion.  A retrospective adjudication will be performed by a second Central 
Pathologist.
a.
Not otherwise specified (NOS)
b. Associated with chronic inflammation
c.
Epstein-Barr virus positive (EBV+) of the elderly
2. ABC type determined using a validated GEP assay performed on 
 
 as assessed by Central Pathology.  (ABC type subjects 
are reported by the GEP assay as eligible for this inclusion criterion, whereas subjects 
with an indeterminate, unclassifiable, or GCB type are not eligible).
3. Adequate lymph node or tumor biopsy specimen available for Central Pathology review 
and GEP profiling by the 
.  A formalin fixed 
paraffin embedded lymph node or tumor biopsy acquired by a surgical incision or 
excision biopsy is strongly preferred.  Core needle biopsy is allowed, and typically 3 – 4 
passes embedded in two FFPE blocks are adequate for both local and Central Pathology 
evaluation (one block for local and one block for Central Pathology).  Other commonly 
used devices (e.g. endoscopy forceps or grasp biopsy) are also acceptable provided they 
yield an equivalent amount of tissue.  Material from a fine needle aspiration is not 
acceptable.  If an archival specimen is not available or is not acceptable, a re-biopsy is 
required prior to randomization.
4. Measurable disease on cross section imaging by CT that is at least 1.5 cm in the longest 
diameter and measurable in two perpendicular dimensions.
5. Ann Arbor stage II-IV disease.
6. No prior treatment for DLBCL, except as allowed in Section 8.2.1.
7. Appropriate candidate for 6 cycles of R-CHOP21. 
8. International Prognostic Index score of 2 or greater.
9. Performance status < 2 on the Eastern Cooperative Oncology Group (ECOG) scale. 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
55
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
10. Must be between the ages of 18 and 80 years on the date of the informed consent 
document signature.  At the discretion of the investigator, subjects over 80 years may be 
included if their ECOG performance status is ≤ 1; each of their individual organ system 
scores is ≤ 2 using the Modified Cumulative Illness Rating Scale (CIRS) for co-morbidity
(Salvi, 2008; Salvi, 2008a); and if they would otherwise be eligible for full-dose R-
CHOP per local practice.
11. Must fulfill the following laboratory requirements:
a.
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 (1.5 x 109/L) unless secondary to 
bone marrow or spleen involvement by lymphoma; in this case the limit is ≥ 1,000 
cells/mm3 (1.0 x 109/L). Bone marrow involvement by lymphoma is demonstrated by 
recent bone marrow aspiration, bone marrow biopsy, or PET scan finding.  Spleen 
involvement by lymphoma is demonstrated by splenomegaly.
b. Platelet count ≥ 75,000/mm3 (75 x 109/L) unless secondary to bone marrow or spleen 
involvement by lymphoma; in this case the limit is ≥50,000/ mm3 (50 x 109/L). Bone 
marrow involvement by lymphoma is demonstrated by recent bone marrow 
aspiration, bone marrow biopsy, or PET scan finding.  Spleen involvement by 
lymphoma is demonstrated by splenomegaly.
c.
Hemoglobin ≥ 7.5 g/dL (4.7 mmol/L)
d. Serum aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) ≤
3.0 x upper limit of normal (ULN).  In the case of documented liver involvement by 
lymphoma, the requirement is ≤ 5.0 x ULN.
e.
Serum total bilirubin ≤2.0 mg/dl (34 μmol/L).  In the case of Gilberts Syndrome, or 
documented liver or pancreatic involvement by lymphoma, the requirement is ≤ 5.0 
mg/dl (86 μmol/L).
f.
Calculated creatinine clearance (Cockcroft-Gault formula) of ≥30 mL/min
12. Understand and voluntarily sign an informed consent document prior to conducting study 
assessments or procedures. 
13. Able to adhere to the study visit schedule and other protocol requirements.
14. Females of childbearing potential (FCBP) must:
a.
Have two negative pregnancy tests as verified by the study doctor prior to starting 
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 subject practices 
complete abstinence 1 from heterosexual contact.
b. Either commit to complete abstinence1 from heterosexual contact (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 therapy, during the 
study therapy (including dose interruptions), and for 12 months after discontinuation 
of study therapy. 
                                               
1 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
56
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15. Male subjects must:
a.
Practice complete abstinence1 or agree to use a condom during sexual contact with a 
pregnant female or a female of childbearing potential while participating in the study, 
during dose interruptions and for at least 28 days following investigational product
discontinuation, even if he has undergone a successful vasectomy. 
b. Agree to not donate semen during investigational product therapy and for 28 days 
after discontinuation of investigational product therapy. 
16. All subjects must:
a.
Have an understanding that the investigational product could have a potential 
teratogenic risk.  
b. Agree to abstain from donating blood while taking investigational product therapy 
and for 28 days after discontinuation of investigational product therapy. 
c.
Agree not to share investigational product with another person.
d. Agree to be counseled about pregnancy precautions and risk of fetal exposure.
e.
Females must agree to abstain from breastfeeding during study participation and for 
at least 12 months after investigational product discontinuation.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. The following WHO subcategories of DLBCL:
a.
Active CNS or meningeal lymphoma
b. Primary cutaneous, leg type
c.
Primary mediastinal (thymic)
d. Lymphomatoid granulomatosis
e.
ALK-positive lymphoma
f.
Plasmablastic lymphoma
g. Large B-cell lymphoma arising in HHV8 associated multicentric Castleman disease
h. Primary effusion lymphoma
i.
Intravascular large B-cell
j.
B-cell unclassifiable cases with features intermediate between DLBCL and Burkitt
k. Unclassifiable cases with features intermediate between DLBCL and classical 
Hodgkin’s lymphoma
l.
T cell / histiocyte rich.
2. Post-transplant Lymphoproliferative Disorder (PTLPD) cases, even if they are B-cell 
type and ABC subtype, are excluded.
3. Histology other than DLBCL. Evidence of composite DLBCL and FL, or of 
transformed NHL.
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3


Lenalidomide (CC-5013)
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Celgene Corporation
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4. Seropositive for or active viral infection with hepatitis B virus (HBV): 
a.
HBV surface antigen (HBsAg) positive
b. HBV surface antigen (HBsAg) negative, HBV surface antibody (anti-HBs) positive 
and/or HBV core antibody (anti-HBc) positive, and detectable viral DNA
Notes:
c.
Subjects who are seropositive because of a successfully treated, prior infection are 
eligible (HBsAg negative, anti-HBs positive, and/or anti-HBc positive, but viral DNA 
negative)
d. Subjects who are seropositive because of HBV vaccination are eligible (anti-HBs
positive, anti-HBc negative, and HBsAg negative)
5. Hepatitis C virus (HCV) positive subjects with chronic hepatitis C, or subjects with an 
active hepatitis C infection requiring anti-viral medication (at time of randomization).  
Note: 
a.
HCV positive subjects who do not have active hepatitis C, and who are otherwise 
acceptable candidates for R-CHOP chemotherapy, as documented by the investigator, 
are eligible.  
6. Known seropositive for or active viral infection with human immunodeficiency virus 
(HIV).
7. Contraindication to any drug in the chemotherapy regimen, and specifically:
a.
LVEF < 45% as assessed by MUGA, or LVEF < local institutional normal limits for 
R-CHOP administration as assessed by echocardiography
b. Peripheral neuropathy ≥ Grade 2 
8. Major surgery (excluding lymph node or bone marrow biopsy) within 28 days from 
signing the informed consent document, unless the subject is recovered
9. Life expectancy < 6 months
10. History of other malignancies, unless the subject has been free of the disease for ≥ 5
years.  Exceptions to the ≥ 5-year time limit include history of the following:
a.
Localized non-melanoma skin cancer
b. Carcinoma in situ of the cervix
11. Prior use of lenalidomide
12. Known allergy to thalidomide
13. Known sensitivity or allergy to murine products 
14. Use of any investigational agent within 28 days or five half lives, whichever is longer, 
of Cycle 1 Day 1
15. Subjects who are unwilling to take VTE prophylaxis
16. Pregnant or lactating females
17. Uncontrolled intercurrent illness
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
58
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
18. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form
19. Any condition, such as an active, severe infection, or the presence of laboratory 
abnormalities, which places the subject at unacceptable risk if he/she were to participate 
in the study
20. Any condition that confounds the ability to interpret data from the study
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
59
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Products
Celgene will provide lenalidomide 2.5 mg, 5 mg, 10 mg, and 15 mg capsules and the respective 
matching placebo capsules for oral administration.  
Celgene will provide commercial supplies, for countries where rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone or prednisolone are designated as investigational 
product, labeled appropriately for investigational use as per the regulations of the relevant 
country health authority.  Subjects enrolled in countries where rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone or prednisolone are designated as non-investigational, 
should obtain commercially available product through their local hospital pharmacy or licensed 
distributer.  
Required medications for neutropenia will be selected by the investigator according to local 
practice and provided by the investigative site.
Recommended medications such as aspirin and allopurinol, if used, will be selected by the 
investigator according to local practice and provided by the investigative site.
8.2.
Treatment Schedule and Administration
Please see Section 9.3 for information about recommended prophylactic treatments related to 
CNS lymphoma, infections, nausea, rituximab infusion reactions, HBV reactivation, TLS, and 
VTE.  There is a ± 1 day window for Day 1 dosing during Cycles 2-6.  However, no window is 
applicable to Cycle 1 Day 1 dosing.
8.2.1.
Optional Prephase Treatment
For elderly subjects or for subjects with bulky disease, systemic symptoms, compressive disease, 
elevated bilirubin due to lymphoma, or rapidly progressing adenopathies, prephase treatment 
with corticosteroids according to local practice is permitted prior to beginning the Treatment 
Period, at the discretion of the investigator (Pfreundschuh, 2010).  It is recommended to limit the 
prephase treatment to up to 100 mg / day prednisone or equivalent for 10 days.  In the case of 
prephase corticosteroid treatment, there is no protocol specified definition of bulky disease.  A 
washout period is not required; prephase treatment may be given, immediately followed by the 
prednisone as part of R-CHOP, and then a corticosteroid taper is allowed.  However, the 
Screening PET, CT, lymph node biopsy, and bone marrow biopsy (and if applicable, also the 
bone marrow aspirate) should be completed before initiating corticosteroids.  
In cases of medical emergencies (e.g., superior vena cava or spinal cord compression) in which 
prephase treatment with corticosteroids is not considered adequate, it may be acceptable for local 
radiation to be administered; however, the Celgene medical monitor must be consulted.  In such 
case, the radiated lesion(s) cannot be used as measurable (target) lesion(s).
Prephase treatment with vincristine or any other chemotherapy is prohibited.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
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8.2.2.
Optional Consolidation Treatment (Pre-Specified)
The investigator may prospectively choose to give local radiotherapy after study chemotherapy 
per local practice, such as for the treatment of a particular site of bulky disease or a large mass, 
or in subjects at higher risk for CNS lymphoma.  In the case of consolidation treatment, bulky 
disease is defined as ≥ 7.0 cm.  However, the decision to treat and the location to be treated must 
be determined during the Screening Period and registered in the IVRS.  In this case, the 
consolidation radiotherapy will not count as a treatment event for the EFS endpoint.  
If the investigator should decide at anytime after Cycle 1 Day 1 to give consolidation treatment, 
or to switch treatment to a different lesion, receipt of consolidation treatment will count as an 
EFS event.  
8.2.3.
Mandatory Primary Neutropenia Prophylaxis
Primary neutropenia prophylaxis with either granulocyte-colony stimulating factor (G-CSF) or 
granulocyte macrophage-colony stimulating factor (GM-CSF) is required for all subjects at every 
cycle during Cycles 1 – 6.  The selection of a particular drug, for example filgrastim, 
pegfilgrastim, lenograstim, sargramostim, molgramostim, is per local practice.  The dose and 
schedule of the selected drug is also determined per local practice. However, it is recommended
that investigators follow either of the below schedules, at every cycle:
!
Pegfilgrastim (or equivalent biosimilar product) once per cycle, starting on Day 2-4 (i.e. 
1-3 days after chemotherapy)
OR
!
Filgrastim (or equivalent biosimilar product) for at least 7 days in each cycle, starting on 
Day 2-4 (i.e. 1-3 days after chemotherapy)
8.2.4.
Lenalidomide/Placebo-R-CHOP Regimen
The R2-CHOP or placebo-R-CHOP regimen will be administered over a 21-day cycle (with the 
possible exception of Cycle 1, which may last 22 days; see Section 8.2.6 Rituximab).  
Treatment will continue until the R2-CHOP or placebo-R-CHOP regimen of 6 cycles is 
complete, or until unacceptable toxicity, inadequate response to treatment is determined, disease 
progression, or withdrawal of consent, whichever occurs first.  
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Lenalidomide (CC-5013)
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Celgene Corporation
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CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Table 7:
Lenalidomide/Placebo-R-CHOP Regimen
Drug
Dose
Dosing Days
(21-day cycle)
Lenalidomide / Placebo PO
15 mg 
1-14
Rituximab IV
375 mg/m2
-1 OR 1
Cyclophosphamide IV
750 mg/m2
1
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50 mg/m2
1
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1.4 mg/m2 (max of 2.0 mg total)
1
Prednisone / Prednisolone PO
(Day 1 IV administration is acceptable)
100 mg
1-5
IV=intravenous, PO= per os, oral administration
8.2.5.
Lenalidomide / Placebo 
Lenalidomide is initiated on Day 1 of Cycle 1 at a dose of 15 mg (oral administration) PO once 
daily for 14 days in each 21-day cycle. 
On Day 1 of every cycle, lenalidomide will be administered in the clinic.  For subsequent dosing 
days, subjects should be instructed to take lenalidomide / placebo at approximately the same time
each day as the Day 1 dosing for that cycle. There is no requirement for taking lenalidomide / 
placebo with or without food, or with or without certain types of foods or liquids.
A 7-day rest period following the 14 days of dosing is required, unless the allowed -1 day visit 
window around Day 1 is used; in this case the minimum rest period is 6 days.  A rest period may 
be extended for toxicity as needed (Section 8.2.12).
If a subject misses a dose of lenalidomide / placebo and it is within 12 hours of their normal 
dosing time, the subject should be instructed to make up the missed dose, and to then take their 
next dose according to their regular schedule. Lenalidomide concentration is low at 12 hours 
post dose, therefore making up a missed dose and then resuming regular dosing with a greater 
than or equal to (≥) 12 hour interval between the two doses will not cause considerable drug 
accumulation.  
Dose modifications are per Table 8. The dose may also be interrupted and/or reduced for 
reasons in addition to those listed in Table 8 per investigator discretion.  If a dose is reduced, re-
escalation is not permitted.
8.2.6.
Rituximab
The investigator may choose whether to administer rituximab on Day 1 of the cycle or one day 
prior to the start of the cycle.  During Cycle 1, if rituximab is administered one day prior to the 
start of the other chemotherapy drugs, then Cycle 1 may last 22 days instead of the usual 21 (Day 
-1 plus Days 1 – 21); and first receipt of rituximab will mark the beginning of the Treatment 
Period.  Additionally, the investigator may choose to administer rituximab over two days at the 
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Lenalidomide (CC-5013)
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CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
beginning of each cycle per local practice (for example Day -1 and Day 1; or Day 1 and Day 2; 
or Day 2 and Day 3).
It is permissible to administer an additional two doses (1 dose per 21-day cycle) of single agent 
rituximab after the 6 cycles of study treatment are complete if it is considered standard of care 
per local practice.  However, the decision to administer these extra two doses must be pre-
specified in IVRS prior to randomization.  The radiological and response assessment schedule is 
the same for all subjects regardless of whether the optional two doses of rituximab are 
administered.  Therefore, the scan required at 3 – 4 weeks after completing Cycle 6 must be 
completed before the optional Cycle 7 dose of rituximab is administered.  
Preparation, infusion rate, dose modification, and guidance on pregnancy prevention should be 
performed according to the locally approved rituximab prescribing information or your local 
institutional practice.
8.2.7.
Cyclophosphamide
Preparation and infusion rate are according to the package insert and local practice.  
Recommended dose modifications are provided in Table 10 and may be applied at investigator 
discretion.  For toxicities not covered by Table 10 it is recommended to follow the package insert 
and local practice.  
8.2.8.
Doxorubicin
No other anthracycline may be substituted for doxorubicin.  Liposomal doxorubicin is not 
permitted.  
Preparation and infusion rate are according to the package insert and local practice.  
Recommended dose modifications are provided in Table 10 and may be applied at investigator 
discretion.  For toxicities not covered by Table 10, it is recommended to follow the package 
insert and local practice.  
8.2.9.
Vincristine
Preparation and infusion rate are according to the package insert and local practice.  
Recommended dose modifications are provided in Table 11 and may be applied at investigator 
discretion.  For toxicities not covered by Table 11, it is recommended to follow the package 
insert and local practice.  
8.2.10.
Prednisone
The prednisone start dose is a flat 100 mg PO or intravenous (IV) dose (Moreno, 2000).
Subsequent doses may be reduced for medical reasons at investigator discretion.
Subjects should be instructed to take prednisone in the morning on scheduled dosing days.  
In countries where prednisone is not available it will be acceptable to substitute prednisolone on 
a 1:1 basis for prednisone. It is also acceptable to administer the prednisone or prednisolone by 
IV rather than PO on Day 1 of the cycle for convenience.  In countries where local practice is to 
use an IV formulation on Day 1, it will be acceptable to substitute an equivalent (80 mg) or local 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
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practice dose of IV methylprednisone on Day 1 only of each cycle.  It will also be acceptable to 
substitute with a local practice dose of IV dexamethasone on Day 1 only of each cycle.  
8.2.11.
Lenalidomide/Placebo-R-CHOP Regimen Modifications
Recommended regimen modifications are provided in Table 12 and may be applied at 
investigator discretion.  For toxicities not covered by Table 12, it is recommended to follow the 
respective package inserts and local practice.  
8.2.12.
Requalification Criteria For Subsequent Treatment Cycles
The next cycle of treatment may begin on the next scheduled Day 1 if all of the following 
Requalification Criteria are met:
!
ANC ≥1,000 cells/mm³ (1.0 x 109/L), unless secondary to lymphoma bone marrow 
or spleen involvement per investigator assessment
!
Platelet count ≥ 75,000 cells/mm³ (75 x 109/L), unless secondary to lymphoma bone 
marrow or spleen involvement per investigator assessment
!
All other non-hematological toxicities have resolved to ≤ Grade 2 
!
A 7-day rest period has elapsed following the last dose of lenalidomide/placebo (a
6-day rest period applies if the early rituximab dosing option is used; Section 8.2.6)
If the Requalification Criteria are not met (after the rest period has elapsed) on Day 1 of the new 
cycle, the subject will be evaluated again within 7 days.  If the requalification criteria are still not 
met after 7 days delay, the subject will be evaluated again in another 7 days.  If the 
requalification criteria are again not met after 14 days total delay, hold lenalidomide/placebo, 
and if clinically appropriate, continue R-CHOP alone (continue in the Treatment and Follow-up 
Periods per Table 5).  Lenalidomide/placebo may be resumed later if the requalification criteria 
are met; however, skipped doses of lenalidomide/ placebo may not be made up, and rest periods 
must be observed.
Other toxicity delays for any of the individual chemotherapy drugs rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are allowed.  Other 
toxicity delays for R-CHOP as a unit are allowed to a maximum of two 14-day delays over all 6 
cycles.  At investigator discretion, lenalidomide/placebo may be continued alone if R-CHOP is 
discontinued, provided the above re-qualification criteria are otherwise met, and rest periods are 
observed.
If the requalification criteria are fulfilled, but the subject develops toxicity as described in
Table 8 due to lenalidomide / placebo, the R-CHOP drugs should continue even if lenalidomide / 
placebo is held.  There is no maximum delay limit for lenalidomide / placebo.  Lenalidomide / 
placebo may be resumed later if the requalification criteria are met; however, skipped doses of 
lenalidomide/ placebo may not be made up and rest periods must be observed. 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
64
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Table 8:
Dose Modification Rules – Lenalidomide / Placebo
NCI CTCAE (v 4.03)
Toxicity Grade
Action Required
Neutropenia*
Sustained (≥ 7 days) Grade 4 
(neutrophil count < 500 
cells/mm³ [0.5x109/L])
*unless secondary to lymphoma 
bone marrow or spleen
involvement per investigator 
assessment
!
Withhold dose for the remainder of the cycle
!
Monitor CBC at least every seven days
!
At the next cycle, when the Requalification Criteria For 
Subsequent Treatment Cycles (Section 8.2.12) are met, restart at 
the same dose level
Febrile Neutropenia*
Grade 3 or 4
*unless secondary to lymphoma 
bone marrow or spleen 
involvement per investigator 
assessment
!
Withhold dose for the remainder of the cycle
!
Monitor CBC at least every seven days
!
At the next cycle, when the Requalification Criteria For 
Subsequent Treatment Cycles (Section 8.2.12) are met, restart at 
the next lower dose level
Thrombocytopenia*
Grade 4 (platelet count < 25,000 
cells/mm³ [25x109/L]) 
*unless secondary to lymphoma 
bone marrow or spleen
involvement per investigator 
assessment
!
Withhold dose for the remainder of the cycle
!
Monitor CBC at least every seven days
!
If at Day 1 of the next cycle, the Requalification Criteria For 
Subsequent Treatment Cycles (Section 8.2.12) are met, restart at 
the same dose level
!
If at Day 1 of the next cycle, the Requalification Criteria For 
Subsequent Treatment Cycles (Section 8.2.12) are not met, restart 
at the next lower dose level when Requalification Criteria are met
Rash
Grade 2 or 3 non-desquamating 
(blistering)
------------
Desquamating (blistering) ≥
Grade 3 
OR
Non-desquamating Grade 4
!
Determine causative investigational product and if attributable to 
lenalidomide then: 
-
Hold dose; administer antihistamines or short course of ≤ 20 
mg prednisone (or equivalent)
-
When toxicity resolves to ≤ Grade 1, restart at the same dose 
level
-----------------
!
Determine causative investigational product and if attributable to 
lenalidomide then: 
-
Discontinue lenalidomide / placebo
Allergic reaction or 
hypersensitivity
Grade 2
------------
Grade 3– 4
!
Determine causative investigational product and if attributable to 
lenalidomide then: 
-
Withhold dose.  Follow at least every seven days
-
When the toxicity resolves to ≤ Grade 1, restart lenalidomide / 
placebo at next lower dose level
-----------------
-
Discontinue lenalidomide 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
65
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Table 8:
Dose Modification Rules – Lenalidomide / Placebo (Continued)
NCI CTCAE (v 4.03)
Toxicity Grade
Action Required
Constipation
Grade 1–2
-----------------
≥ Grade 3
!
Initiate bowel regimen and maintain dose level
-----------------
!
Withhold dose.  Follow at least every seven days 
!
When the toxicity resolves to ≤ Grade 2, restart at same dose level
Venous thrombosis/embolism
≥ Grade 3
!
Withhold dose and start therapeutic anticoagulation; restart at 
investigator’s discretion (maintain dose level)
Tumor Lysis Syndrome (TLS)
Grading is per Cairo-Bishop, and
not per NCI CTCAE, for TLS 
only
Lab TLS or Grade 1 TLS
-----------------
Grade 2 – 4
!
Continue lenalidomide (maintain dose), or at the investigator’s 
discretion, continue lenalidomide and reduce dose by one level
!
Provide vigorous IV hydration and appropriate medical 
management according to the local standard of care, until 
electrolyte abnormalities are corrected.  Rasburicase therapy is 
appropriate (if approved by the local Health Authority) as needed 
to reduce hyperuricemia
!
Hospitalization will be at investigator’s discretion
-----------------
!
Withhold dose
!
When symptoms resolve to Grade 0, restart at same dose level
!
If lenalidomide is resumed prior to the start of the subsequent 
cycle, a chemistry test should be performed every other day for 
the first week following re-initiation of lenalidomide
AST or ALT > 3 x ULN
!
Withhold lenalidomide dose; re-test at least weekly until AST or 
ALT < 2.5 x ULN or return to baseline
!
If the event is considered related to lenalidomide, restart 
lenalidomide at next lower dose level
!
If the event is considered NOT related to lenalidomide, restart the 
same dose level of lenalidomide
!
For subjects with Gilbert’s syndrome or liver involvement, consult
the Celgene medical monitor regarding dose reductions 
Bilirubin > 3 x ULN
!
Withhold lenalidomide dose; re-test at least weekly until bilirubin 
< 1.5 x ULN
!
If the event is considered related to lenalidomide, restart 
lenalidomide at next lower dose level
!
If the event is considered NOT related to lenalidomide, restart the 
same dose of lenalidomide
!
For subjects with Gilbert’s syndrome or liver involvement, consult
the Celgene medical monitor regarding dose reductions
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
66
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Table 8:
Dose Modification Rules – Lenalidomide / Placebo (Continued)
NCI CTCAE (v 4.03)
Toxicity Grade
Action Required
Other lenalidomide related non-
hematologic AEs ≥ Grade 3
!
Withhold dose
!
When the AE resolves to ≤ Grade 2, restart at the same or next 
lower dose level per the investigator’s discretion
AE= adverse event, ALT= alanine transaminase; AST= aspartate transaminase CBC= complete blood count, NCI 
CTCAE=National Cancer Institute Common Terminology Criteria for AE, Lab = laboratory, ULN= upper limit of 
normal
Table 9:
Dose Reduction Levels – Lenalidomide
Starting Dose
15 mg Daily on Days 1-14, Every 21 Days
Level –1 Dose
10 mg daily on Days 1–14, every 21 days
Level –2 Dose
5 mg daily on Days 1– 14, every 21 days
Level –3 Dose
2.5 mg daily on Days 1–14, every 21 days
Table 10:
Recommended Dose Modification Rules – Cyclophosphamide and/or
Doxorubicin
NCI CTCAE (v 4.03)
Toxicity Grade
Action Required
Neutropenia
Sustained (≥ 7 days) Grade 4
!
If toxicity occurs after discontinuing lenalidomide, decrease both 
cyclophosphamide and doxorubicin by 25% and follow standard 
dosing guidelines
Thrombocytopenia
Sustained (≥ 7 days) Grade 4
OR
≤10,000 cells/mm3 or 10 x109
cells/L) at any time
!
If toxicity occurs after discontinuing lenalidomide, decrease both 
cyclophosphamide and doxorubicin by 25% and follow standard 
dosing guidelines
Cystitis, noninfective
Grade 2
!
Withhold cyclophosphamide for the current cycle and until 
resolution of cystitis
!
At next cycle decrease current cyclophosphamide dose by 50%  
!
For subsequent cycles, if all renal / genitourinary toxicity is Grade 
< 2, re-escalate to the previous cyclophosphamide dose
Left ventricular systolic 
dysfunction
≥ Grade 3
!
Discontinue doxorubicin
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
67
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Table 10:
Recommended Dose Modification Rules – Cyclophosphamide and/or 
Doxorubicin (Continued)
NCI CTCAE (v 4.03)
Toxicity Grade
Action Required
Mucositis / Stomatitis
≥ Grade 2
!
At next cycle decrease current doxorubicin dose by 25%
!
For subsequent cycles, if toxicity resolves to < Grade 2, re-
escalate to the previous doxorubicin dose
NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
Table 11:
Recommended Dose Modification Rules – Vincristine
NCI CTCAE
Toxicity Grade (v 4.03)
Action Required
Peripheral neuropathy- motor
Grade 2
-----------------
Grade 3
!
Withhold vincristine for the current cycle and until toxicity 
improves to < Grade 2 
!
At next cycle decrease current dose by 50%  
-----------------
!
Discontinue vincristine
Peripheral neuropathy- sensory
Grade 3
-----------------
Grade 4
!
Withhold vincristine for the current cycle and until toxicity 
improves to < Grade 2
!
At next cycle decrease current dose by 50%  
-----------------
!
Discontinue vincristine
NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
Table 12:
Recommended Dose Modification Rules – Lenalidomide/Placebo R-CHOP 
Regimen 
NCI CTCAE (v 4.03)
Toxicity Grade (as applicable)
Action Required
Nausea / Vomiting 
Grade 3
!
Maximize anti-emetic therapy; if anti-emetic therapy is 
ineffective, discontinue lenalidomide/placebo or entire regimen at 
investigator discretion 
Infection 
with ANC ≥ 1000/mm3 and 
requiring IV antibiotics or 
hospitalization 
------------
with ANC < 1000/mm3 and 
requiring IV antibiotics or 
hospitalization 
!
Withhold regimen; restart at the same dose level when infection is 
controlled.  
!
If AE reoccurs on subsequent cycles, decrease 
lenalidomide/placebo to next lower dose level and consider 
prophylactic antibiotics
------------
!
Withhold regimen; restart when infection is controlled, decrease 
lenalidomide/placebo to the next lower dose level. 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
68
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Table 12:
Recommended Dose Modification Rules – Lenalidomide/Placebo R-CHOP 
Regimen (Continued)
NCI CTCAE (v 4.03)
Toxicity Grade (as applicable)
Action Required
!
If AE reoccurs despite discontinuation of lenalidomide/placebo, 
then on subsequent cycles reduce cyclophosphamide by 25% and 
doxorubicin by 25%; consider prophylactic antibiotics.
Viral Hepatitis B, C
new infection, or reactivation 
!
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Other non-hematologic 
toxicity
Grade 3
!
Withhold regimen until toxicity resolves to ≤ Grade 2 or baseline, 
then restart
8.2.13.
Overdose
Overdose, as defined for this protocol, refers to lenalidomide / placebo, rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone / prednisolone.  On a per-dose basis, 
an overdose is defined as the following amount over the protocol-specified dose of these drug(s) 
assigned to a given subject, regardless of any associated AEs or sequelae:
PO
any amount over the protocol-specified dose
IV
10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.  On an infusion rate basis, an overdose is defined as any 
rate faster than the protocol-specified rate.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the CRF.  See Section 11 for the 
reporting of AEs associated with overdose.  
8.2.14.
Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from study 
treatment:
!
Treatment was completed per protocol
!
Adverse event(s)
!
Locally assessed outcome of the Midcycle CT scan indicates a treatment change
!
Disease progression
!
Protocol violation
!
Withdrawal of consent
!
Lost to follow up
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
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CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
!
Death
The following events are considered sufficient reasons for discontinuing a subject from the 
overall study:
!
Withdrawal of consent
!
Lost to follow up
!
Death
The reasons for both treatment and study discontinuation should be recorded in the CRF and in 
the source documents.
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
70
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
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8.5.
Method of Treatment Assignment
An IVRS will be employed to accomplish randomization, to record pre-specification of optional 
consolidation radiotherapy, and to manage subject medications.  
Subjects will be typed as GCB, ABC, or unclassifiable by the Central Pathology laboratory as 
part of screening.  Disease diagnosis, subtype, and CD20 status will be entered by the Central 
Pathology laboratory into the IVRS.  
Once the subject is determined eligible, the investigator or designee will access the IVRS within 
the 28-day Screening Period to obtain the randomized treatment assignment for the subject.  
Subjects will be stratified as follows: 
!
IPI score:  2 / ≥ 3 
!
Age: < 65 / ≥ 65
!
Presence of bulky disease: ≥ 7.0 cm (bulky) / < 7.0 cm (non-bulky)
Subjects will be randomized in a 1:1 ratio to either R2-CHOP or placebo-R-CHOP.  The subject 
identification number (subject ID) assigned by the IVRS will identify the subject for all aspects 
of the study, including drug re-supply requests, result reporting from all central laboratories, 
central radiology data submission, and CRF data.  The randomization schedule will be generated 
by the IVRS vendor.
8.6.
Packaging and Labeling
Lenalidomide / placebo will be packaged in bottles, and each bottle will contain 14 capsules.  
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
72
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number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
8.7.
Investigational Product Accountability and Disposal
The investigator(s) or designee is responsible for taking an inventory of each shipment of 
investigational product received and comparing it with the accompanying shipping 
order/packaging slip.  The investigator(s) will verify the accuracy of the information on the 
shipping order/packaging slip and call IVRS to register receipt at the site of the investigational 
product.  
At the study site, investigational product will be stored in a locked, safe area to prevent 
unauthorized access and should be stored as directed on the product label.
An accurate accounting of the dispensing and return of investigational product for each study 
subject will be maintained in source documents on an ongoing basis by a member of the study 
site staff.  Additionally, if any investigational product is lost or damaged or if the study subject
misses a dose, this information should be documented in the study subject’s CRF and source 
documents.  
Celgene will instruct the investigator on the return, disposal, and/or destruction of unused
investigational product.   
8.8.
Investigational Product Compliance
For the oral medications of prednisone (or prednisolone) and lenalidomide / placebo, study 
personnel will review the dosing instructions with the subject prior to dispensing investigational 
product. The subject will be instructed to return the investigational product bottles, including 
any unused investigational product, to the site at the end of the applicable treatment cycle. To 
monitor treatment compliance, the subject will be interviewed at each applicable visit regarding 
whether they took their medication, and a reconciliation of capsules will be done upon bottle 
return.  Subject compliance will be noted in the source records and on the appropriate CRFs 
based upon the interview and capsule count.
For the IV medications of rituximab, cyclophosphamide, doxorubicin, and vincristine, the 
planned and administered dosage will be recorded in the source records and on the appropriate   
CRFs.
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Lenalidomide (CC-5013)
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9.
CONCOMITANT MEDICATIONS AND PROCEDURES
9.1.
Prohibited Concomitant Medications 
Anticancer therapy other than R-CHOP plus lenalidomide or placebo is prohibited during the 
entire Treatment Period of the study.  
Other investigational therapy (drug or otherwise) is prohibited 28 days prior to Day 1 dosing and 
during the entire Treatment Period of the study.  
9.2.
Permitted Concomitant Medications 
9.2.1.
Hematopoietic Growth Factors and Transfusions
Growth factors (eg erythropoietin, platelet growth factors) and blood product transfusions 
(packed red blood cells, platelets, etc.) may be prescribed during the Treatment and Follow-up 
Periods at the investigator’s discretion and should be used in accordance with the American 
Society of Clinical Oncology’s (ASCO) guidelines or the European Society for Medical 
Oncology (ESMO) guidelines.  With the exception of packed red blood cells, which may be 
administered at any time as needed, including during Screening; other growth factors or blood 
product transfusions should not be administered during the Screening Period to increase a 
subject’s blood values in order to meet entry criteria.  Note that primary neutropenia prophylaxis 
during the Treatment Period is mandatory (Section 8.2.3).  
9.2.2.
Pneumocystis Pneumonia Prophylaxis
Pneumocystis prophylaxis is permitted for all subjects according to local practice.
9.3.
Recommended Concomitant Medications 
9.3.1.
CNS Lymphoma Prophylaxis
Subjects at risk for CNS involvement may receive CNS lymphoma prophylaxis treatment.  The 
following may be considered by the investigator: 4 – 8 doses of intrathecal methotrexate and/or 
cytarabine administered during the R2-CHOP or placebo-R-CHOP induction treatment.  CNS 
prophylaxis with IV drugs is not permitted.
9.3.2.
Nausea Prophylaxis
Premedication with an antiemetic is recommended according to local practice.
9.3.3.
Rituximab Infusion Reaction Prophylaxis
Premedication with acetaminophen and diphenhydramine to prevent a rituximab infusion 
reaction is recommended according to local practice.  It is acceptable to use glucocorticoid 
steroids to treat an active rituximab infusion reaction as per local practice.
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9.3.4.
HBV Reactivation Prophylaxis
Subjects who are HBsAg negative, anti-HBs positive, and or anti-HBc positive, but viral DNA 
negative are eligible.  For these subjects, DNA monitoring and prophylactic medication for HBV 
reactivation are recommended per local practice.
9.3.5.
TLS Prophylaxis
It is recommended that subjects receive TLS prophylaxis (allopurinol, rasrubricase or equivalent 
as per institutional guidelines) and be well hydrated (orally) during the first week of treatment 
administration in the first cycle, or as clinically indicated.  Hydration levels should be adjusted 
according to age and clinical status.  To monitor for TLS, the subjects will have blood samples 
drawn for serum chemistry on Days 1, and 8 of the first 2 cycles and additionally as clinically 
indicated.  TLS will be assessed by the Cairo-Bishop Grading system (not by CTCAE) and the 
assessment includes both laboratory tumor lysis syndrome (LTLS) criteria and clinical TLS 
criteria. If a subject develops LTLS (defined by the presence of two or more serum value 
abnormalities of uric acid, potassium, phosphorous, or calcium) or ≥ Grade 1 TLS (defined by 
the presence of laboratory TLS and one or more of the following criteria: creatinine ≥ 1.5 x ULN, 
arrhythmia, or seizures), appropriate medical management should be initiated according to the 
local standard of care in each institution, along with vigorous IV hydration.  Rasburicase 
treatment is considered appropriate if it is approved by the local Health Authority.
Refer to Table 8 for further instructions and dose modifications for TLS. 
9.3.6.
Venous Thromboembolism Prophylaxis
It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in 
conjunction with lenalidomide may lessen the potential for venous thromboembolism. In this 
double-blind placebo-controlled clinical trial, in which the investigator does not know the 
subject’s treatment arm assignment, the decision to take prophylactic measures should be made
carefully after an assessment of an individual subject’s underlying risk factors.
As reference information, for subjects receiving lenalidomide in open-label trials, it is strongly 
recommended that subjects at risk for VTE receive either aspirin (70 – 325 mg PO daily) or 
another prophylaxis agent while on lenalidomide. In those subjects with a high risk of VTE, it is 
strongly recommended that the subject receive prophylactic anticoagulation therapy with low 
molecular weight (LMW) heparin, or heparin (dose recommended for the prophylaxis of 
DVT/PE per the package insert), or warfarin (to maintain an INR of 2.0). These prophylactic 
agents should be considered for subjects enrolling in this blinded, placebo-controlled clinical 
trial. The choice of VTE prophylaxis agent relies upon the investigator’s discretion and should 
be tailored to the subject’s individual risk/benefit profile by taking into account the individual 
thrombotic risk, bleeding risk, and the quality of compliance with the VTE prophylaxis.
The use of clopidogrel or ticlopidine alone is not recommended as VTE prophylaxis in this trial.
9.4.
Mandatory Concomitant Medication
9.4.1.
Primary Neutropenia Prophylaxis
Please refer to Section 8.2.3.
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10.
STATISTICAL ANALYSES
The objectives of the statistical analyses are to investigate the efficacy and safety of R2-CHOP 
versus placebo-R-CHOP in subjects with previously untreated, ABC type DLBCL.  One interim 
analysis at 50% information level for futility and one final analysis for superiority are 
pre-planned for the primary efficacy endpoint.
10.1.
Overview
Eligible subjects will be randomized to either the R2-CHOP or placebo-R-CHOP regimen in a 
1:1 ratio.  Treatment will continue until 6 cycles of treatment are completed, or until 
unacceptable toxicity, or the outcome of the Midcycle CT scan indicates a treatment change, 
disease progression, or withdrawal of consent, whichever occurs first.  Upon treatment 
completion or premature discontinuation, subjects will be followed for progression, subsequent 
antilymphoma therapies, and overall survival.
The efficacy analyses will be based on subjects’ response to treatment evaluated by the 
investigator and by the IRAC using the IWG Response Criteria for NHL (Cheson, 2014).   
The safety analyses will include AEs, physical examinations, vital signs, and laboratory tests.
All statistical analyses specified in this protocol will be conducted using SAS® version 9.2 or 
higher. 
10.2.
Study Population Definitions
In this study the following three populations will be defined for the analysis and used in 
presentation of the data.
Intent-to-Treat (ITT) Population: The ITT population is defined as all subjects who are 
randomized into the trial, regardless of whether they received study treatment or not.  
Modified Intent-to-Treat (mITT) Population: The mITT population is defined as all
subjects who satisfy the following conditions: 
!
are randomized
!
have received at least one dose of investigational product
!
are CD20+, ABC type DLBCL as determined by Central Pathology 
!
are previously untreated
!
have measurable disease at baseline
!
have at least one post-baseline tumor assessment or died after randomization but 
before the assessment
Safety Population: The safety population is defined as all subjects who have received at 
least one dose of investigational product. 
 
 
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The ITT population will be used for the primary efficacy analysis. Subjects will be analyzed 
according to the treatment arm to which they are initially assigned. 
The mITT population will be used as supportive analysis for efficacy.  Subjects will be analyzed 
according to the treatment arm to which they are initially assigned.  
The safety population will be used for all safety analyses.  Subjects will be analyzed according to 
the treatment which they actually received.
 
10.3.
Sample Size and Power Considerations
The sample size of this study is determined to provide adequate power to evaluate the treatment 
effect on PFS, the primary endpoint.    
Accrual
This study will accrue a total of 560 subjects over approximately a 34-month accrual period.  
However, if the actual number of PFS events toward the end of the accrual period is far less than 
expected or if the subject dropout rate is unusually high, an additional number of subjects may be 
enrolled.
Sample Size for the PFS Analysis
The PFS endpoint will be analyzed after a total of 192 PFS events in the ITT population have 
been observed.  This sample size will have 90% power to detect a hazard ratio (HR) of 0.625, 
i.e., a 37.5% reduction in the PFS hazard rate, at a two-sided 0.05 significance level, with an 
interim analysis for futility at 50% of the information pre-planned.  In case the event rate falls 
below 2 events per month before reaching 192 events, the final analysis will be performed when 
at least 170 events have occurred.  The power of the study will be at least 86%.    
With an adequate enrollment rate and the assumption that the median PFS in the control arm is 
about 24 months, it is estimated that the required 50% information, or 96 PFS events, for the 
interim PFS futility analysis will be available approximately 28 months from the start of 
enrollment, and the required 192 PFS events for the final PFS analysis will be available in about 
42 months from the start of enrollment.
This sample size is calculated using the software EAST 5.4 with a β-spending function of 
Gamma(-4).  Since there is no intention to declare efficacy at the interim PFS analysis, no 
α-spending function is specified.  For a detailed description of stopping boundaries please refer 
to Section 10.8 Interim Analysis.
The treatment effect assumption for the sample size determination is based on limited 
information available from two investigator initiated studies (Section 1.5.2.1 study MC078E and 
Section 1.5.2.2 study REAL07). In the event that new data from an external, randomized study 
suggests a substantially different effect from the assumptions made in this protocol, the sample 
size or analysis plan of the present study may be adjusted.  However, the adjustment should be 
made prior to any un-blinded analysis.
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10.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations.  Medical history data will be summarized using frequency tabulations by system 
organ class and preferred term.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, randomization status, discontinued treatment,
primary reason for early treatment discontinuation, discontinued the study, primary reason for 
early study discontinuation) will be summarized using frequency and percent for both treatment
arms.  A summary of subjects randomized by country/site will be provided. Protocol 
deviations/violations will be summarized using frequency tabulations.
10.6.
Efficacy Analysis
10.6.1.
Primary Efficacy Endpoint Definition
The primary efficacy endpoint of this study is PFS, which is defined as the time from 
randomization to objective disease progression or death from any cause, whichever occurs first.
The PFS events will be determined by the IRAC using the Revised Response Criteria for 
Malignant Lymphoma (Cheson, 2014).  The PFS analysis based on the IRAC assessment will 
serve as the primary analysis.  The PFS analysis based on the local investigator’s assessment will 
serve as the sensitivity analysis. 
Subjects who did not experience disease progression and who did not die before the clinical data 
cut-off date will be censored at the time of the last visit with adequate response assessment.
In addition, the following two sets of censoring rules will be applied to the PFS analysis.  
The first set of censoring rules will follow FDA’s “Guidance for industry: Clinical trial endpoints 
for the approval of cancer drugs and biologics” (FDA, 2007).  Specifically, subjects who 
received new anticancer therapy without objective disease progression will be censored at the 
date of the last radiological assessment prior to the new anticancer therapy.  The analysis with 
this set of censoring rules will serve as the primary analysis for PFS. 
In order to avoid possible informative censoring, e.g. the administration of new anticancer 
therapy may be related to factors associated with the actual survival time, a sensitivity analysis 
for PFS will be performed using the second set of censoring rules that follows EMA’s guideline 
“Appendix 1 to the Guideline on the Evaluation of Anticancer Medicinal Products in Man” 
(EMA, 2012).  Specifically, outcome data will be collected according to the intended schedule of 
assessment and the date of progression or recurrence will be assigned based on the time of the 
first evidence of objective progression or recurrence regardless of violations, discontinuation of 
investigational product or change of therapy.  Detailed censoring rules for PFS analysis will be 
provided in the Statistical Analysis Plan (SAP).
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10.6.2.
Secondary Efficacy Endpoint Definitions
Key Secondary Endpoint
The key secondary efficacy endpoint of the study is EFS, which is defined as the time from 
randomization until occurrence of one of the following events, whichever occurs first: 
!
Disease progression 
!
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!
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!
Death due to any cause 
Pre-specified consolidation radiotherapy after study chemotherapy per local practice, such as for 
the treatment of a particular site of bulky disease or a large mass, or in subjects at higher risk for 
CNS lymphoma as described in Section 8.2.2 will not count as subsequent systemic 
antilymphoma therapy or an EFS event if the decision to treat and the location to be treated is 
determined during the Screening Period.  Similarly, pre-specified additional two doses of single 
agent rituximab as described in Section 8.2.6 will be handled in the same way.
Subjects who did not experience any of these events defined in the four categories above before 
the clinical data cutoff date will be censored at the last time known to be alive and without these 
events.
Other Secondary Endpoints
Overall Survival
The OS is defined as the time between randomization and death from any cause.  Subjects who 
complete the study and are still alive at the time of the clinical data cutoff date will be censored
at the last visit date or the last contact date, whichever is later.  Subjects who were lost to follow-
up prior to the clinical data cut-off date will also be censored at the time of the last contact.
CR Rate by IWG (Cheson, 2014)
The CR rate is calculated as the proportion of subjects who have achieved CR prior to any 
treatment change.
Duration of CR
Duration of CR is defined only for the subjects who have achieved CR prior to any treatment 
change.  It is calculated as the time from the first CR prior to treatment change to the first event 
of disease progression or death.  Subjects who have not progressed or died at the time of the 
clinical data cutoff date will be censored at the last assessment showing no progression.  Subjects 
who change treatment without evidence of disease progression will be censored at the last 
assessment showing no progression prior to treatment change.  
Time to Next Lymphoma Treatment
The TTNLT is defined as the time from randomization to the time of treatment change for the 
next lymphoma treatment.  Subjects without treatment change will be censored at the last visit. 
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Objective Response Rate
The ORR is defined as the proportion of subjects who have achieved either CR or PR prior to 
any treatment change.
Health Related Quality of Life 
Data on health related quality of life will be collected using the standardized EQ-5D and FACT-
Lym health measurement instruments.
EQ-5D is a standardized measure of health status developed by the EuroQol Group. The EQ-
5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, 
some problems, extreme problems. The respondent is asked to indicate his/her health state by 
ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 
dimensions. The EQ visual analog scale records the respondent’s self-rated health on a vertical, 
visual analogue scale where the endpoints are labeled “Best imaginable health state” and “Worst 
imaginable health state.” This information can be used as a quantitative measure of health 
outcome as judged by the individual respondents. It should be noted that the numerals 1-3 have 
no arithmetic properties and should not be used as a cardinal score.
The FACT-Lym questionnaire was developed as part of the FACIT measurement system to 
address HRQL issues for NHL patients. The FACT-Lym questionnaire is a validated and reliable 
self-report instrument for assessing the impact of lymphoma on HRQL and a useful targeted 
endpoint in NHL clinical research (Hlubocky, 2012).
It contains 42 questions covering HRQL and common lymphoma symptoms and treatment side-
effects, and consists of five general HRQL subscales (Cella, 2005). It begins with the Functional 
Assessment of Cancer Therapy - General (FACT-G), which contains 27 questions covering four 
core subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing 
(6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns 
subscale (15 questions) used to assess NHL-related symptoms such as pain, itching, night sweats, 
trouble sleeping, fatigue and trouble concentrating. The FACT-Lym also asks patients about their 
concerns regarding lumps and swelling, fevers, infections, weight, appetite, emotional stability 
and treatment.  All questions are answered on a 5-point scale ranging from “not at all” (0) to 
“very much” (4).
Both HRQoL instruments (EQ-5D and Fact – Lym) will be examined as secondary endpoints to 
identify changes in HRQoL measures relative to the comparator arm. The analysis of these 
HRQoL instruments will be predefined in the SAP prior to database lock.
 
 
 
 
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10.6.4.
Analysis Method
Demographics and Baseline Characteristics
Subjects’ demographics and baseline characteristics will be summarized for the ITT population, 
mITT population, and Safety population.
Subjects’ age, weight, and baseline characteristics will be summarized using descriptive statistics 
(mean, standard deviation, median, minimum and maximum), while gender, race, and other 
categorical variables will be provided using frequency tabulations. Medical history data will be 
summarized using frequency tabulations by system organ class and preferred term.
Subject disposition (analysis population allocation, randomized, premature treatment 
discontinuation along with primary reason for treatment discontinuation, premature study 
discontinuation along with primary reason for study discontinuation) will be summarized using 
frequency and percentage for both treatment arms.  Protocol deviations and violations will be 
summarized using frequency tabulations.
Time-to-Event Endpoints
The efficacy analysis will be performed on both ITT and mITT populations where the analysis 
on ITT population is the primary analysis and analysis on mITT population is supportive.
For the time-to event endpoints, the Kaplan-Meier estimates of the survival function will be 
calculated and graphically presented.  The stratified log-rank test will be performed to evaluate 
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treatment efficacy.  The stratification factors for analysis include subject disease severity (IPI 
score 2 vs 3 or above), presence of bulky disease (tumor diameter ≥ 7.0 cm vs < 7.0 cm), and age 
category (< 65 vs 65 or older).  The experimental arm will be declared superior if the 2-sided p-
value from the stratified log-rank test is ≤ 0.05 in favor of the experimental arm. The un-
stratified log-rank test will be performed as sensitivity analysis.  
Conventionally, hazard ratio with two-sided 95% confidence interval (CI) will be estimated 
using the Cox proportional hazards model. But the treatment effect will be determined by the p-
value from the stratified log-rank test, not by this 95% CI for the hazard ratio. Subgroup analysis 
for EFS and PFS will be performed as appropriate. 
Binary Endpoints
The binary endpoints such as CR rate will be summarized in frequency and percent by treatment 
arm.  The stratified Cochran-Mantel-Haenszel (CMH) test will be performed to evaluate 
treatment efficacy.  The stratification factors include subject disease severity (IPI score 2 vs 3 or 
above), presence of bulky disease (tumor diameter ≥ 7.0 cm vs < 7.0 cm), and age category (< 65
vs 65 or older).  The un-stratified CMH test will be performed as sensitivity analysis.  
10.7.
Safety Analysis
Safety analysis will include all subjects in the Safety population. 
Investigational product exposure will be summarized for each treatment arm including duration 
of investigational product, total dose taken, and dose reductions.  
Adverse events, vital sign measurements, clinical laboratory measurements, physical 
examination and concomitant medications will be summarized by treatment arm. 
Adverse Events
AEs will be coded according to Medical Dictionary for Drug Regulatory Activities (MedDRA) 
and classified using the NCI CTCAE. The incidence rates of AEs will be tabulated by system 
organ class and preferred term. The incidence of AEs will also be tabulated by severity within 
each system organ class and preferred term.  The most severe grade of each preferred term for a 
subject will be utilized for summaries of AEs by NCI CTCAE grade.
Subsets of AEs to be summarized include SAEs, suspected treatment-related AEs, and AEs that 
resulted in withdrawal of investigational product. 
All AEs with corresponding attributes will be displayed in a by-subject listing. AEs leading to 
death or to discontinuation from treatment, events classified as NCI CTCAE grade 3 or higher, 
suspected treatment-related events, and SAEs will also be displayed in separate by-subject
listings.  
Laboratory Tests
Laboratory data will be graded according to NCI CTCAE severity grade. The frequencies of the 
worst severity grade observed during treatment will be displayed in cross-tabulations by baseline 
status for each treatment arm. 
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For variables for which an NCI CTCAE scale does not exist, the frequency of subjects with 
values below, within, and above the normal ranges pretreatment and during treatment will be 
summarized by treatment.
Change from baseline will be descriptively summarized at each post-baseline visit by treatment 
arm.
Lab shift tables will be produced by treatment arm.
Physical Examination and Vital Signs
Physical examination data will be tabulated by treatment.  Vital signs data will be descriptively 
summarized by treatment in terms of means, medians, standard deviations, minimum, and 
maximum.
10.8.
Interim Analysis
Interim Analysis for PFS
An interim analysis for futility only is planned for the PFS at 50% information level, ie, when 96
PFS events among the enrolled ITT subjects have been developed across all treatment arms.  
According to the projected enrollment rate and the hypothesized treatment effect, it is estimated 
that the required 96 PFS events will be observed in about 28 months after the first subject is 
randomized.  
The boundary for declaring futility of the experimental arm over the control arm is based on a 
ß-spending function of Gamma(-4) with overall β = 90%.  A normalized log-rank statistic will be 
calculated and compared with the futility boundary.  
If the 1-sided p-value is ≥0.478 at the interim PFS analysis, the alternative hypothesis may be 
rejected, and the DMC may recommend stopping the trial for futility.  However, this futility 
boundary is a non-binding boundary, which means that the study does not have to stop if the 
futility boundary is crossed at the interim analysis.  The study may continue, if so desired by the 
sponsor, to the final analysis for efficacy without inflating the Type 1 error or losing power.
Since there is no intention to declare efficacy at the interim PFS analysis, no penalty in α should 
be imposed.  Treatment efficacy will be declared at the final PFS analysis if the 1-sided p-value 
is ≤ 0.025 in favor of the experimental arm, after the required 192 PFS events in the ITT 
population are observed.
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d.d.


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
83
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
11.
ADVERSE EVENTS
11.1.
Monitoring, Recording, and Reporting of Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, 
including laboratory test values (as specified by the criteria in Section 11.3), regardless of 
etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or 
intensity of a pre-existing condition) should be considered an AE.  A diagnosis or syndrome 
should be recorded on the AE page of the CRF rather than the individual signs or symptoms of 
the diagnosis or syndrome.
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF. (See Section 8.2.13 for the definition of overdose.) Any sequela 
of an accidental or intentional overdose of an investigational product should be reported as an 
AE on the AE CRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on an SAE report form and on the AE CRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and CRF but should not be reported 
as an SAE itself.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs will be recorded by the investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP and those SAEs made known to the investigator at any time 
thereafter that are suspected of being related to IP.  AEs and SAEs will be recorded on the AE 
page of the CRF and in the subject’s source documents.  All SAEs must be reported to Celgene 
Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, or other 
appropriate method, using the SAE Report Form, or approved equivalent form.
11.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all adverse events as to: 
11.2.1.
Seriousness 
A serious adverse event (SAE) is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (i.e., in the opinion of the investigator, the subject is at immediate 
risk of death from the AE);
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
oms of 
ms of 
reported as
eported as
n AE shoul
AE shou
erdose.)
erdose.) An
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ould be repo
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e sequela m
 sequela m
g g in the SA
n the S
CRF b
CRF ut sh
Assessmen
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s clinical s
s clinical s
sical exami
sical exam
r from 
r from the t
the t
those SAE
those SAE
related to IP
related to IP
s source do
source d
he i
he invest
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dv
gator will ev
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iousness 
adverse ev
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Resu
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!
I


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
84
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events regardless of the treatment arm the subject is in (see Section 11.5).  This 
includes any second primary malignancy, regardless of causal relationship to IP (lenalidomide / 
placebo or control), occurring at any time for the duration of the study, from the time of signing 
the ICD through follow-up for overall survival.  For this particular study, SPM will include cases 
of DLBCL transformation to ALL.  The Follow-up Period involves subject contact per Table 5, 
until the subject dies, revokes consent, or until 5 years from the date the last subject is 
randomized, whichever occurs first.  Events of second primary malignancy are to be reported 
using the SAE report form and must be considered an “Important Medical Event” if no other 
serious criteria apply; these events must also be documented in the appropriate page(s) of the 
CRF (i.e., AE and SPM CRF) and subject’s source documents.  Documentation on the diagnosis 
of the second primary malignancy must be provided at the time of reporting as an SAE (e.g., any 
confirmatory histology or cytology results, X-rays, CT scans, etc.).
Events not considered to be SAEs are hospitalizations for:
!
A standard procedure for protocol therapy administration.  However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE.
!
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE.
!
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
A procedure that is planned (i.e., planned prior to starting of treatment on study); 
must be documented in the source document and the CRF.  Hospitalization or 
prolonged hospitalization for a complication remains a reportable SAE.
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in the a
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at the tim
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n.  However
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h transfusio
transfusio
procedure f
rocedure
endoscopy
endoscopy
hospi
hospital
ta
i
rem
em
!
H


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
85
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
!
An elective treatment of or an elective procedure for a pre-existing condition 
unrelated to the studied indication. 
!
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
11.2.2.
Severity / Intensity
For both AEs and SAEs, the investigator must assess the severity / intensity of the event. 
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the current active minor version of the Common Terminology Criteria for Adverse Events 
(CTCAE, Version 4.0); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
AEs that are not defined in the CTCAE should be evaluated for severity / intensity according to 
the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
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ife or funct
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sness, not s
sness, not s


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
86
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
11.2.3.
Causality 
The investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means a causal relationship of the adverse event to IP
administration is unlikely or remote, or other medications, 
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event.
Suspected:
Means there is a reasonable possibility that the administration 
of IP caused the adverse event.  ‘Reasonable possibility’ means 
there is evidence to suggest a causal relationship between the IP 
and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
11.2.4.
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(e.g., discontinuation, interruption, or reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
11.2.6.
Outcome
The investigator will report the outcome of the event for both AEs and SAEs.  All SAEs that 
have not resolved upon discontinuation of the subject’s participation in the study must be 
followed until recovered, recovered with sequelae, not recovered or death (due to the SAE). 
11.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
!
is judged to be of significant clinical importance.
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or, ancillar
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provide th
provid
ide a recor
ide a recor
taken wi
taken w th
i
or reductio
r reducti
re given for
re given for
eport the ou
eport the o
pon discon
on discon
covered, re
covered, r
Abnorm
Abnorm
normal labo
normal labo
!
re
!


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
87
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.  
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (e.g., record thrombocytopenia rather than decreased platelets).
11.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject or partner of a 
male subject are immediately reportable events.
11.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 28 days of the 
subject’s last dose of IP, are considered immediately reportable events.  IP is to be discontinued 
immediately and the subject instructed to return any unused portion of the IP to the Investigator.  
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Celgene
Drug Safety immediately by facsimile, or other appropriate method, using the Pregnancy Initial 
Report Form, or approved equivalent form.  The exposure of any pregnant female (e.g., caregiver 
or pharmacist) to lenalidomide is also an immediately reportable event.  The female subject 
should be referred to an obstetrician-gynecologist, preferably one experienced in reproductive 
toxicity for further evaluation and counseling.  
The investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (e.g., spontaneous abortion), the investigator 
should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
11.4.2.
Male Subjects
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately.   
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M
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bjec
bj


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
88
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form. This 
instruction pertains to initial SAE reports as well as any follow-up reports.
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events regardless of the treatment arm the subject is in (see Section 11.2.1).  This 
includes any second primary malignancy, regardless of causal relationship to IP (lenalidomide / 
placebo or control), occurring at any time for the duration of the study, from the time of signing 
the ICD through follow-up for overall survival.  For this particular study, SPM will include cases 
of DLBCL transformation to ALL.  The Follow-up Period involves subject contact per Table 5,
until the subject dies, revokes consent, or until 5 years from the date the last subject is 
randomized, whichever occurs first.  Events of second primary malignancy are to be reported 
using the SAE report form and must be considered an “Important Medical Event” if no other 
serious criteria apply; these events must also be documented in the appropriate page(s) of the 
CRF (i.e., AE and SPM CRF) and subject’s source documents.  Documentation on the diagnosis 
of the second primary malignancy must be provided at the time of reporting as an SAE (e.g., any 
confirmatory histology or cytology results, X-rays, CT scans, etc.).
The investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) and any 
SPM occurring at any time during the study including the follow-up period, or any SAE made 
known to the investigator at anytime thereafter that are suspected of being related to IP.  SAEs
occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the investigator is responsible for informing the IRB/EC of 
the SAE and providing them with all relevant initial and follow-up information about the event. 
The investigator must keep copies of all SAE information on file including correspondence with 
Celgene and the IRB/EC.
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (e.g., missing causality assessment) may be handled by phone.
11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to lenalidomide based on the Investigator Brochure.
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days.  Ur


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
89
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical trials on investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.  
Adverse events such as disease progression, death related to disease progression (in the absence 
of serious IP-related events) and serious events due to the relapse of the studied indication will 
not be subject to expedited reporting by the sponsor to regulatory authorities.
Celgene or its authorized representative shall notify the investigator of the following information 
(In Japan, Celgene KK shall notify the Heads of the Institutes in addition to the investigators):
!
Any AE suspected of being related to the use of IP in this study or in other studies
that is both serious and unexpected (i.e., SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
!
In Japan, measures taken in foreign countries to ensure subject safety, study reports 
that indicates potential risk of cancer, etc., or biannual SAE report according to the 
local regulations.
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
&(/*(1(35235,(7$5<,1)250$7,21
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lines or to t
lines or t


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
90
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
12.
DISCONTINUATIONS
Discontinuation may be from the investigational product or from the overall study.  Since this 
study includes overall survival as an endpoint, the reasons for discontinuing both investigational 
product and the study will be collected for all subjects, as long as the study remain open at an 
investigator’s site. The reasons for discontinuation should be recorded in the CRF and in the 
source documents.
12.1.
Discontinuation of Investigational Product
The following events are considered sufficient reasons for discontinuing a subject from 
investigational product:
!
Completed investigational product regimen per protocol
!
Locally assessed outcome of the Midcycle CT scan indicates a treatment change
!
Progression
!
Adverse event(s)
!
Protocol violation
!
Withdrawal of consent
!
Death
!
Lost to follow up
12.2.
Discontinuation from the Study
The following events are considered sufficient reasons for discontinuing a subject from the 
overall study: 
!
Withdrawal of consent
!
Death
!
Lost to follow up
&(/*(1(35235,(7$5<,1)250$7,21
tment chang
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up


Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
91
CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the investigator should contact the responsible Medical Monitor or 
designee by telephone at the number(s) listed on the Emergency Contact Information page of the 
protocol (after title page).
In the unlikely event that the Medical Monitor or designee cannot be reached, please contact the 
global Emergency Call Center by telephone at the number listed on the Emergency Contact 
Information page of the protocol (after title page).  This global Emergency Call Center is 
available 24 hours a day and 7 days a week. The representatives are responsible for obtaining 
your call-back information and contacting the on call Celgene/CRO Medical Monitor, who will 
then contact you promptly.
Note: The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the Medical Monitor or designee for emergency calls. 
13.2.
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unless in the opinion of the 
investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued, if, in the opinion 
of the investigator, continuing IP can negatively affect the outcome of the subject’s treatment.  
The investigator or authorized person may call the IVRS for unblinded dose information.  The 
reason for breaking the blind must be documented in the source documents.
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Lenalidomide (CC-5013)
Protocol CC-5013-DLC-002
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14.
REGULATORY CONSIDERATIONS 
14.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative,
and investigator abide by Good Clinical Practice (GCP), as described in International Conference 
on Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles 
outlined in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
investigators who in turn will select their staff.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions. 
The investigator should maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties.
The investigator is responsible for keeping a record of all subjects who sign an informed consent 
document and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The investigator, or a designated member of the investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (e.g., 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The investigator must ensure timely and accurate completion of CRFs and queries.
At the time results of this study are made available to the public, Celgene will provide
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
14.3.
Subject Information and Informed Consent
The investigator must obtain informed consent of a legal representative prior to any study related 
procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original informed consent document signed and dated by the study 
subject and by the person consenting the study subject prior to the study subject’s entry into the 
study, must be maintained in the investigator’s study files and a copy given to the study subject.  
In addition, if a protocol is amended and it impacts on the content of the informed consent, the 
informed consent document must be revised.  Study subjects participating in the study when the 
amended protocol is implemented must be re-consented with the revised version of the informed 
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consent document.  The revised informed consent document signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the investigator’s 
study files and a copy given to the study subject.  
14.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent document, it is the responsibility of the investigator to obtain 
such permission in writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Medical Monitor.  
Amendments will be submitted to the IRB/EC for written approval.  Written approval must be 
obtained before implementation of the amended version occurs.  The written signed approval 
from the IRB/EC should specifically reference the investigator name, protocol number, study 
title and amendment number(s) that is applicable. Amendments that are administrative in nature 
do not require IRB/IEC approval but will be submitted to the IRB/IEC for information purposes.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document, and any other 
appropriate documents will be submitted to the IRB/EC with a cover letter or a form listing the 
documents submitted, their dates of issue, and the site (or region or area of jurisdiction, as 
applicable) for which approval is sought.  If applicable, the documents will also be submitted to 
the authorities in accordance with local legal requirements.
IP can only be supplied to an investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene or its authorized representative.  This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications.  If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP.  For 
example, the IRB General Assurance Number may be accepted as a substitute for this list.  
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed.  It must mention the date on which the decision was made and must be 
officially signed by a committee member.  Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements.  Amendments must be evaluated to 
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determine whether formal approval must be sought and whether the informed consent document 
should also be revised.
The investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating investigator and the IRB/EC. This statement also applies to any 
communication between the investigator (or coordinating investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
14.7.
Ongoing Information for Institutional Review Board / Ethics 
Committee
If required by legislation or the IRB/EC, the investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible 
!
Periodic reports on the progress of the study
!
Deviations from the protocol or anything that may involve added risk to subjects
14.8.
Closure of the Study
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons.  Any premature discontinuation will be appropriately documented 
according to local requirements (e.g., IRB/EC, regulatory authorities).
In addition, the investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment
!
GCP noncompliance
!
Inaccurate or incomplete data collection
!
Falsification of records
!
Failure to adhere to the study protocol
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15.
DATA HANDLING AND RECORDKEEPING
15.1.
Data/Documents
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
15.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene SOPs.  This 
data will be electronically verified through use of programmed edit checks specified by the 
clinical team.  Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary.  Resolutions to these issues will be reflected in the 
database.  An audit trail within the system will track all changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP.  The investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer.  Essential documents include, but are not limited to, the following:
!
Signed informed consent documents for all subjects
!
Subject identification code list, screening log (if applicable), and enrollment log
!
Record of all communications between the Investigator and the IRB/EC
!
Composition of the IRB/EC
!
Record of all communications between the investigator, Celgene, and their authorized 
representative(s)
!
List of Sub-investigators and other appropriately qualified persons to whom the 
investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures
!
IP accountability records
!
Record of any body fluids or tissue samples retained
!
All other source documents (subject records, hospital records, laboratory records, 
etc.) 
!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
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Celgene Corporation
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The investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The investigator must obtain approval in writing from Celgene prior to destruction of any 
records.  If the investigator is unable to meet this obligation, the investigator must ask Celgene 
for permission to make alternative arrangements.  Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities.  
investigator/institution should take measures to prevent accidental or premature destruction of 
these documents.
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16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  Before the study is initiated at a site visit or at an investigator meeting, all aspects of 
the study are reviewed with the investigator and the staff.  Prior to enrolling subjects into the 
study, a Celgene representative will review the protocol, CRFs, procedures for obtaining 
informed consent, record keeping, and reporting of AEs/SAEs with the investigator.  Monitoring 
will include on-site visits with the investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  At each monitoring visit, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative for accuracy, adherence 
to the protocol and Good Clinical Practice.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the investigator and/or his/her 
staff.  Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (e.g., FDA, EMA, Health Canada) 
and company authorized representatives.  The investigator should make every effort to be 
available for the audits and/or inspections.  If the investigator is contacted by any regulatory 
authority regarding an inspection, he/she should contact Celgene immediately.
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17.
PUBLICATIONS
The results of this study will be submitted for publication in a peer reviewed, scientific journal. 
Study results may also be presented at one or more medical congresses, and may be used for 
teaching purposes.  Additionally, this study and its results may be submitted for inclusion in all 
appropriate health authority study registries, as well as publication on health authority study 
registry websites, as required by local health authority regulations.  Eligibility for external 
authorship, as well as selection of first authorship, will be based on several considerations, 
including, but not limited to, contribution to protocol development, study recruitment, data 
quality, participation in data analysis, participation in study steering committee (when 
applicable) and contribution to abstract, presentation and/or publication development. 


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18.
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-κB in diffu
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Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, et al. Long-term 
follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide 
plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 
2009;23(11):2147-52.
Ding H, Jin x, Ding N, Fu Z, Song Y, Zhu J.  Single nucleotide polymorphisms of CD20 gene 
and their relationship with clinical efficacy of R-CHOP in patients with diffuse large B cell 
lymphoma. Cancer Cell Int 2013;13(1):58-65.
Dutia M, DeRoock I, Chee K, et al. Analysis of a Phase 2 study of lenalidomide and rituximab in
relapsed or refractory non-Hodgkin’s lymphoma. Haematologica 2010; 118, Abstract # 0295. 
European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (EU).  
Methodological consideration for using progression-free survival or disease-free survival (DFS) 
in confirmatory trials. EMA/CHMP/27994/2008/Rev.1; 2012.
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venous thromboembolic events in lymphoma. Am J Med 2010 Oct;123(10):935-41.
Zhu YX, Braggio E, Shi CX, Bruins A, Schmidt J, Van Wier S, et al. Cereblon expression is 
required for the antimyeloma activity of lenalidomide and pomalidomide.  Blood 
2011;118:4771-79.


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19.
APPENDICES
19.1.
Ann Arbor Staging System 
!
Stage I:
∀
I: Involvement of a single lymph node region
∀
IE: Localized involvement of a single extralymphatic organ or site.
!
Stage II:
∀
II: Involvement of 2 or more lymph node regions on the same side of the 
diaphragm
∀
IIE: Localized involvement of a single associated extralymphatic organ or site and 
its regional lymph nodes with or without other lymph node regions on the same 
side of the diaphragm
!
Stage III:
∀
III: Involvement of lymph node regions on both sides of the diaphragm
∀
IIIE: Involvement of lymph node regions on both sides of the diaphragm 
accompanied by localized involvement of an extralymphatic organ or site
∀
IIIS: Involvement of lymph node regions on both sides of the diaphragm 
accompanied by involvement of the spleen
∀
IIIS+E: Both IIIS+IIIE
!
Stage IV:
∀
IV: Disseminated (multifocal) involvement of 1 or more extralymphatic sites with 
or without associated lymph node involvement or isolated extralymphatic organ 
involvement with distant (non regional) nodal involvement
∀
IVE: Extranodal lymphoid malignancies arise in tissues separate from, but near, 
the major lymphatic aggregates.
Source: American Joint Committee on Cancer. Non Hodgkin’s lymphoma. In: AJCC Staging 
Manual. 5th ed. Philadelphia, PA: Lippincott-Raven;1997:289-94.
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19.2.
Modified Cumulative Illness Rating Scale (Salvi, 2008a) 
RATING SUGGESTIONS (GENERAL PRINCIPLES)
Every single disease must be classified in the appropriate system. If there are several problems in 
the same system, only the most severe is rated. Example: for a patient suffering from a well-
controlled angina (Rated 2) and terminal heart failure (Rated 4), only the higher rated condition 
would be scored in the Cardiac system (e.g. rating is 4).
The spread of a cancer may lead to rate the condition in more than one category. For example, a 
lung cancer with bone metastases treated with nonsteroidal anti-inflammatory drugs (NSAID) is 
Rated 4 in Respiratory and 2 in Musculoskeletal.
General rules for severity rating:
0 - No problem affecting that system or past problem without clinical relevance.
1 - Current mild problem or past significant problem.
2 - Moderate disability or morbidity and/or requires first line therapy.
3 - Severe problem and/or constant and significant disability and/or hard to control chronic 
problems (complex therapeutic regimen).
4 - Extremely severe problem and/or immediate treatment required and/or organ failure and/or 
severe functional impairment.
LEVEL 0
No problem or healed minor injuries; past childhood illnesses (chickenpox); minor surgery 
(carpal tunnel completely healed, caesarean); uncomplicated healed fractures; other past 
problems healed without sequel, residual or complication (pneumonia).
LEVEL 1
Any current medical problem that causes mild discomfort or disability, or has occasional 
exacerbations, having only minor impact on morbidity (asthma controlled with PRN 
bronchodilators, occasional heartburn relieved with PRN antiacids). Medical problems that are 
not currently active but were significant problems in the past (passage of a kidney stone) or 
required major surgery (hysterectomy, cholecystectomy, appendectomy).
LEVEL 2
Medical conditions that require daily treatment or first line therapy (asthma controlled with 
inhaled steroids, gastro-esophageal reflux treated with daily medication, osteoarthritis requiring 
daily NSAID, etc.) and/or have moderate disability or morbidity.
LEVEL 3
Chronic conditions that are not controlled with first line therapy (asthma needing continuous 
corticosteroid therapy, symptomatic angina despite medical regimes, heart failure with symptoms 
or uncontrolled hypertension despite complex therapeutic regimen) and/or constant significant 
disability, but not severe disability.
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LEVEL 4
Any acute condition that requires immediate treatment or hospitalization (unstable angina, acute 
myocardial infarction, stroke, but also bladder outlet obstruction) and/or extremely severe 
problems; organ failure (end-stage renal disease needing dialysis, oxygen-dependent chronic 
obstructive pulmonary disease, terminal heart failure); severe sensory impairment (almost 
complete blindness or deafness, being wheelchair bound) and/or severely affected quality of life, 
severe impairment in function; delirium by medical (organic) conditions.
RATING MALIGNANCIES
Consistent scoring of severity ratings for various malignancies is a difficult problem. Each 
malignancy has its own rating system and prognostic indicators, the complexity of which would 
quickly exceed the aim of the intended simplicity and ease of use of CIRS.
The following general guidelines are intended to provide a reasonably accurate delineation of 
medical burden for cancer without excessive complexity.
Level 1: Cancer diagnosed in the remote past without evidence of recurrence or sequel in the past 
10 years or skin cancer excised in the past without major sequel (other than melanoma).
Level 2: No evidence of recurrence or sequel in the past 5 years.
Level 3: Required chemotherapy, radiation, hormonal therapy or surgical procedure for cancer in 
the past 5 years.
Level 4: Recurrent malignancy or metastasis (other than to lymph glands) or palliative treatment 
stage.
These ratings are to be made in the appropriate organ category for a given malignancy.
ORGAN SPECIFIC CATEGORIES
The following organ specific categories will attempt to provide guidelines for consistent rating of 
comparable severity. Common conditions will be stressed with the focus on the “judgement 
strategy” that can be applied to other problems not listed. 
If there are several problems in the same system, only the most severe is rated.
HEART
In this category only heart and coronary disease have to be considered (not vascular): coronary 
arteries disease, heart failure, valvular heart diseases, heart disease secondary to hypertension, 
endocardities, miocardities, pericardities, arrhythmias (extrasystoles, bundle-branch blocks, atrial 
fibrillation, PMK placement), heart malignancies. Functional impact must be considered too, e.g. 
NYHA II heart failure has different value between dependent and independent persons.
0 - No problems
1 -Remote MI (>5 years ago); occasional [exertion] angina; asymptomatic valvular disease
2 -CHF compensated with meds (NYHA I-II); daily anti-angina meds; left ventricular 
hypertrophy; atrial fibrillation, bundle branch block, daily anti-arrhythmic drugs (even for 
prophylaxis); PMK placement for asymptomatic bradycardia (relieved by Holter EKG 
monitoring); valvular disease requiring medical treatment
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3 -Previous MI (<5 years ago); abnormal stress test; status post (previous) percutaneous coronary 
angioplasty, coronary artery bypass graft surgery or other cardiac surgery (valve 
replacement); moderate CHF (NYHA II-III) or complex medical treatment; bifascicular 
block; PMK placement for cardiogenic syncope; pericardial effusion or pericarditis
4 -Acute coronary syndrome, unstable angina or acute MI; intractable CHF (NYHA III-IV acute 
or chronic); marked restriction to the normal activity of daily living secondary to cardiac 
status
HYPERTENSION
Consider only hypertension severity; organ damage (complications) should be considered into 
the respective categories.
0 -Normotension
1 -Borderline hypertension; hypertension compensated with salt restriction and weight loss, drug 
free (when drug therapy is indicated, but the patient does not take meds, the score is at least 2)
2 -Daily antihypertensive meds: hypertension controlled by 1 pill therapy (even fixed doses 
combinations)
3 -Hypertension requiring two or more pills for control
4 -Malignant hypertension, or hypertension non controlled by complex therapeutic regimen
VASCULAR-HEMATOPOIETIC
Artery disease: carotid atherosclerosis, peripheral arteries disease (PAD), aneurysms (every site);
Venous disease: venous insufficiency, varices, deep venous thrombosis (DVT), pulmonary 
embolism, primary pulmonary hypertension;
Hematopoietic disease: anemia, leucopenia, thrombocytopenia, hematological malignancy;
Lymphopoietic disease: chronic lymphatic edema, lymphoma, spleen and thymus disease;
Immunologic disease: systemic lupus erythematosus, systemic sclerosis (scleroderma), 
sarcoidosis, hypersensitivity
0 -No problem
1 -Venous insufficiency, varices, lymphedema; carotid stenosis <70%; hemoglobin 10-12 g/dl 
(in females), 12-14 g/dl (in males); anemia of chronic “inflammatory” disease
2 -Previous DVT; one symptom of atherosclerosis disease (claudication, bruit, amaurosis fugax, 
absent pedal pulses) or daily meds (e.g. anti-platelets drugs); PAD IIa-IIb by Fontaine; carotid 
stenosis >70%; aortic aneurysm <4 cm; hemoglobin 8-10 g/dl (in females), 10-12 g/dl (in 
males); anemia secondary to iron, B12 vitamin or folate deficiency, or to chronic renal failure; 
total white blood cell (WBC) 2000-4000/mmc; mild thrombocytopenia (50000-150000/mmc)
3 -DVT or recent DVT (<6 months ago); two or more symptoms of atherosclerosis (see above); 
PAD Fontaine III or recent/previous angioplasty (with or without stenting); hemoglobin 
<8g/dl (in females), <10 g/dl (in males); dyserythropoietic anemia; WBC <2000/mmc; severe 
thrombocytopenia (<50000/mmc)
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4 -Pulmonary embolism (acute or recent/previous); atherosclerosis requiring surgical 
intervention (e.g. aortic aneurysm >4 cm, symptomatic carotid stenosis >70%, PAD Fontaine 
IV or amputation for vascular causes, etc.); recent/previous vascular surgery; any 
hematological or vascular malignancy (including multiple myeloma)
In case of immunological disease, score should be assigned by considering blood abnormalities, 
stadium of organ damage and/or functional disability (2: symptoms controlled by daily meds; 3: 
symptoms not well controlled; 4: symptoms impossible to be controlled or short time poor 
prognosis).
RESPIRATORY
In this category we consider COPD, asthma, emphysema, restrictive pulmonary interstitial lung 
diseases, malignancies of lung and pleura, pneumonia, and smoking status too.
0 -No problem
1 -Recurrent episodes of acute bronchitis; currently treated asthma with prn inhalers when 
required; cigarette smoker >10 but <20 pack years
2 -Instrumental diagnosis of COPD or pulmonary interstitial disease (x-ray, TC, spirometry); 
daily prn inhalers (≤2 pharmacological classes); two or more episodes of pneumonia in the 
last 5 years; cigarette smoker <20 but <40 pack years
3 -exertion dyspnea secondary to limited respiratory capacity, not well controlled by daily meds; 
required oral steroids for lung disease; daily prn inhalers (3 pharmacological classes); acute 
pneumonia treated as an outpatient
4 -Chronic supplementation of oxygen; respiratory failure requiring assisted ventilation, or 
previous (at least one episode); any lung or pleural neoplasm; acute pneumonia requiring 
hospitalization
Smoking is an important respiratory and cardiovascular risk, so it is considered as a disease, and 
it is rated according to lifetime pack years: 
Number of cigarette packs smoked per day X Number of years smoked in their lifetime
e.g.    1 pack year = 20 cigarettes/die (1 pack) X 1 year
Ex-smokers should be rated too, but those who have been smoke free for the most recent 20 
years would merit a lower rating than currently smoking
Examples:
A. Patient smoking 20 cig/die (1 pack) for 25 years = 25 pack years - CIRS score: 2
B. Patient smoking 40 cig/die (2 packs) for 25 years = 50 pack years – CIRS score: 3
C. Ex-smoker of 20 cig/die (1 pack) for 25 years, he stopped 5 years ago – CIRS score: 2
D. Ex smoker of 20 cig/die (1 pack) for 25 years, he stopped 20 years ago – CIRS score: 1
Classification of COPD could be more specific when instrumental data (objective evidence) are 
available: blood gases, forced expiratory volume in 1 second (FEV1), etc.
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EYES, EARS, NOSE & THROAT, and LARYNX
To simplify the potential complexity of this category it was decided to score according to the 
severity of the disability created by sensory diseases (degree of limited autonomy and 
communication), and avoid rating each type of pathology. Sensory impairments should be rated 
after instrumental correction (corrective lenses, hearing aid, etc.).
Eyes: glaucoma, cataracts, macular degeneration (diabetic/hypertensive retinopathy), any other 
pathology
Ears: otitis, dizziness, any cause of hearing impairment
Nose & Throat: rhinitis, pharyngitis, nasal polyps, sinusitis, malignancies
Larynx: dysphonia, acute and chronic laryngitis, malignancies
0 -No problems
1 -Corrected vision with glasses; mild hearing loss; chronic sinusitis
2 -Difficulty in reading newspaper or drive although glasses; required hearing aid; chronic 
sinonasal complaints requiring medication; vertigo/dizziness requiring daily meds
3 -Severe low vision, partially blind (required an escort to venture out, unable to read 
newspaper); severe ear impairment (conversational heading still impaired with hearing aid); 
laryngeal dysphonia (not neurological dysarthria)
4 -Functional blindness/deafness: unable to read, recognize a familiar face, unable to 
conversational heading, even if “organically” he is not completely blind or deaf; 
laryngectomy (every cause, especially malignancies); required surgical intervention for 
vertigo; aphonia secondary to laryngeal impairment.
UPPER GASTROINTESTINAL SYSTEM
This category is comprehensive of the intestinal tract from esophagus to duodenum, and 
pancreatic trees: dysphagia, GERD, hiatal hernia, esophageal diverticula, any type of gastritis 
(consider also H. Pylori eradication or not), gastric/duodenal ulcer, acute or chronic pancreatitis, 
malignancies (comprehensive of gastric lymphoma).
Pay attention that type 1 diabetes is rated under “metabolic”.
0 -No problem
1 -Hiatal hernia, GERD or gastritis requiring prn meds; previous ulcer (>5 years ago); previous 
H. Pylori eradication therapy (>5 years ago)
2 -Daily proton pump inhibitor/anti-acid meds; documented gastric or duodenal ulcer or H.P. 
eradication therapy within 5 years
3 -Active gastric or duodenal ulcer; positive fecal occult blood test; any swallowing disorder or 
dysphagia; chronic pancreatitis requiring supplemental pancreatic enzymes for digestion; 
previous episode of acute pancreatitis
4 -Any type of malignancies (see “Rating Malignancies”); previous gastric surgery because of 
cancer; history of perforated ulcer (gastric surgery not because of cancer, ulcorrhaphy); 
melena/heavy bleeding from upper GI source; acute pancreatitis
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LOWER GASTROINTESTINAL SYSTEM
Comprehensive of the rest of the G.I. system, from small bowel to anus: Whipple’s disease, 
diverticulosis, irritable bowel, malignancies. Constipation is rated, too, by type and frequency of 
laxatives required, or by history of impaction.
0 -No problems, previous appendectomy, previous hernia repair (without complications)
1 -Constipation managed with prn meds; active hemorrhoids; intestinal hernia requiring surgery; 
previous hernia repair with complications (intestinal adherences, laparocele, etc.); irritable 
bowel syndrome (few symptoms)
2 -Constipation requiring daily bulk laxatives (psyllium, policarbophil, sterculia, guar gum, etc.), 
or stool softeners; diverticulosis (previous diverticulitis); inflammatory bowel disease in 
remission with meds (>5 years ago)
3 -Bowel impaction/diverticulitis within the last year; daily use of stimulant (irritant) or osmotic 
laxatives (bysacodil, senna, glycerol, sodium docusate; lactulose, polyethylene glycol) or 
enemas; chronic bowel inflammation in remission with meds (<5 years ago)
4 -Diverticulitis flare up; active inflammatory disease; current impaction; hematochezia/active 
bleeding from lower GI source; bowel carcinoma
LIVER AND BILIARY TREES
Comprehensive of liver, gallbladder, biliary trees, portal system: acute and chronic hepatitis 
(viral, alcoholic, toxic, autoimmune, idiopathic), cirrhosis, portal hypertension, 
hemochromatosis, primary biliary cirrhosis, cholelithiasis, cholangitis, primary malignancies. As 
the hepato-biliary system is difficult to assess through the physical examination, therefore, 
laboratory results must be used.
0 -No problem
1 -History of hepatitis (actually normal values of transaminases); cholecystectomy
2 -Cholelithiasis; chronic hepatitis or previous hepatitis (<5 years ago) or any other liver disease 
(hemochromatosis, primary biliary cirrhosis) with mildly elevated transaminases (within 3-
times normal values); heavy alcohol use within 5 years (to rate in “psychiatric”, too)
3 -Chronic hepatitis or any other liver disease with marked elevation of transaminases (>3-times 
normal values); elevated bilirubin
4 -Acute cholecystitis; any biliary obstruction; active hepatitis/liver cirrhosis; any liver or biliary 
tree carcinoma
RENAL
This category is exclusive of kidney: kidney stones, acute/chronic renal failure, 
glomerulonephritis; nephrosic/nephritic syndrome; active/chronic pyelonephritis, diabetic or 
hypertensive nephropathy (albuminuria/proteinuria), renal carcinoma.
Bence-Jones proteinuria in multiple myeloma should not be considered.
0 -No problem
1 -Asymptomatic kidney stone; kidney stone passage within the last ten years; pyelonephritis 
within 5 years; kidney cysts without hematuria
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2 -Serum creatinine >1.5 but <3 mg/dl without diuretic or antihypertensive medication 
(particularly ACE-inhibitors or SRAA blockers); kidney calculi requiring daily meds
3 -Serum creatinine >3 mg/dl or >1.5 mg/dl in conjunction with diuretics, antihypertensive, or 
bicarbonate therapy; active pyelonephritis; nephrosic syndrome; colic symptoms treated as an 
outpatient
4 -Required dialysis; renal carcinoma; colic symptoms requiring hospitalization
GENITOURINARY
Ureters, bladder, urethra.
Genitals, prostate, testicles, penis, seminal vesicles.
Uterus, ovaries. Mammary gland is rated under “metabolic”.
This category is comprehensive of all GU tract impairments: ureteral or bladder stones, benign 
prostate hypertrophy (BPH), urinary tract infections (UTI’s), prolapses, etc. Urinary incontinence 
and indwelling catheter should also be considered.
0 -No problem
1 -Stress incontinence; BPH without urinary symptoms; hysterectomy or ovariectomy (uterine 
fibroma, benign neoplasm)
2 -Pathological pap smear (or 2 consecutives abnormal); frequent UTI’s (3 or more in the past 
year) in female or current UTI’s; urinary incontinence (not stress) in females; BPH with 
urinary symptoms (frequency, urgency, hesitancy); status post TURP; any urinary diversion 
procedure; indwelling catheter; bladder calculi
3 -Prostatic cancer in situ (e.g. incidentally found during TURP); vaginal bleeding; cervical 
carcinoma in situ; hematuria (any cause); urinary incontinence (not stress) in males; bladder 
polyps
4 -Acute urinary retention; current urosepsis; any GU malignancies except as above
MUSCULOSKELETAL/INTEGUMENT
This is a very wide category, including: osteoarthritis, osteoporosis, any bone fracture; primary 
neoplasm (bone, muscle, connective tissue, skin), distinguishing melanoma from other localized 
skin cancers; rheumatoid arthritis and polymyalgia rheumatica; muscular injuries (rotator cuff, 
long head of the biceps); pressure sores; any dermatological disease.
The scores of this category are strictly correlated to the disability they cause; for the evaluation 
of the level of disability, refer to BADL and IADL.
NOTICE: score the severity of each illness according to the level of disability caused by the 
same illness in this category, without considering the disability caused by other diseases. For 
example: a patient affected both by osteoarthritis and hemiplegia from a previous stroke has a 
high level of disability, but you have to score 2 for disability by osteoarthritis (in this category) 
and 4 for disability by stroke (in the neurological category); for a patient with both a deforming 
rheumatoid arthritis and a previous stroke without remaining outcomes you have to score 4 for 
disability from arthritis (in this category) and 2 for disability from stroke (in the neurological 
category).
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0 -No problem
1 -Requires PRN meds for osteoarthritis (NSAID) or has mildly limited IADL from joint 
pathology; excised skin cancers (except melanoma); skin infections requiring antibiotics 
within a year
2 -Daily anti-osteoarthritis meds (NSAID) or use of assisitive devices or little limitation in ADL 
(previous arthroprosthesis or treated fracture with a low level of remaining disability); 
osteoporosis without vertebral fractures; daily meds for chronic skin diseases (even local, as 
psoriasis or pressure sores); non metastatic melanoma; daily meds for rheumatoid arthritis 
(except steroids) with a low level of disability
3 -Osteoarthritis with a moderate level of disability in ADL; requires chronic treatment with 
steroids for arthritic conditions or joints’ deformities or severely impaired; osteoporosis with 
vertebral compression fractures
4 -Wheelchair bound for osteomuscular disease; severe joint deformities or severely impaired 
usage; osteomyelitis; any bone or muscle or connective tissue neoplasm (see “Rating 
Malignancies”); metastatic melanoma.
Fractures and/or arthroprosthesis (both recent and old) have to be scored according to the level of 
disability they cause (considering outcomes too), in order to avoid confusion about possible 
classifications of different fractures or joints. The same for muscular diseases.
CENTRAL AND PERIPHERAL NERVOUS SYSTEM
This category includes the “somatic” pathologies of the central and peripheral nervous system: 
any kind of stroke, neurodegenerative diseases (Parkinson’s disease and parkinsonism, multiple 
sclerosis, amyotrophic lateral sclerosis, etc.), myelopathies, traumas with neurological outcomes, 
primary or secondary epilepsy, neuropathies (diabetic, alcoholic, any other etiology), primary 
tumors, chronic headaches (migraine), insomnia, etc. It must carefully estimate the severity and 
prognosis of the illness but also the functional impairment that the illness causes.
0 -No problem (or fewer convulsions in childhood)
1 -Frequent headaches requiring PRN meds without impairment in Advanced ADL; previous 
TIA (one event); previous epilepsy, actually not treated, without crisis since more than 10 
years ago.
2 -Chronic headache requiring daily meds (even for prophylaxis) or with regularly functional 
impairment in Advanced ADL (bed rest, job withdrawal, etc.); actual TIA or more than one 
previous TIA; previous stroke without significant residual; mild severity neurodegenerative 
diseases (see above), treated and well controlled; epilepsy controlled with drugs.
3 -Previous stroke with mild residual dysfunction (hemiparesis, dysarthria); any neurosurgical 
procedure; moderate severity neurodegenerative diseases (see above), not well controlled by 
meds; epilepsy in treatment but with periodic crisis.
4 -Acute stroke or previous stroke with severe residual dysfunction (hemiplegia, aphasia, severe 
vascular dementia) or more than one previous stroke (multi-infarct encephalopathy); severe 
neurodegenerative diseases (see above) causing disability in ADL; neurological coma.
Alzheimer’s disease and dementia should not be rated into this category (Psychiatric and 
behavioral diseases): Alzheimer’s disease should be listed only under psychiatric disorders; if 
dementia stems from vascular and/or mixed dementia and/or other neurological condition (e.g. 
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Parkinson’s Disease), both “neurologic” and “psychiatric” categories should be endorsed at the 
appropriate level for severity, considering in this category the stroke and the multi-infarct 
encephalopathy responsible for the cognitive impairment (score 3 for stroke with remaining 
outcomes, score 4 for multi-infarct encephalopathy).
ENDOCRINE-METABOLIC SYSTEM AND BREAST (systemic infections and poisonings 
too)
Type 1 and type 2 diabetes (organ damage should be considered into the respective categories, 
like for hypertension), obesity and dyslipidemia (hypercholesterolemia) represent the core of this 
category; it includes also hypo- and hyper-thyroidism, hypo- and hyper-parathyroidism, adrenal 
pathologies (Cushing’ or Addison’ disease), hypogonadism, hypopituitarism, etc. Malignancies 
of these glands, both benignant (like thyroid nodules) and malignant (like thyroid or adrenal 
cancer, vipoma, etc.) are included too.
Even if it is an exocrine gland, breast was included in this category because the authors didn’t 
find a more appropriate one; so it includes the breast cancer too.
Moreover, it includes: electrolyte disorders, sepsis, systemic infections (like tuberculosis, 
syphilis, AIDS) scored according to their severity and the functional impairment they cause (see 
general indications) and poisonings (chronic by metals or acute by pesticides or carbon 
monoxide).
0 -No problem
1 -Diabetes and/or dyslipidemia compensated with diet; mild obesity (BMI 30-35 kg/m2); 
hypothyroidism in replacement therapy (L-thyroxin); hyperthyroidism caused by Plummer’ 
adenoma surgically treated.
2 -Diabetes compensated with oral hypoglycemic drugs or insulin (hemoglobin A1c <7%); 
dyslipidemia well controlled by daily meds (c-LDL lower than the recommended target 
according to the individual global cardiovascular risk); moderate obesity (BMI 35-45 kg/m2); 
hyperthyroidism (Basedow, Plummer) in pharmacologic treatment; asymptomatic or 
surgically treated hyperparathyroidism; fibrocystic breast disease.
3 -Diabetes not well compensated by therapy (hemoglobin A1c 7-8.5%, presence of 
complications); dyslipidemia not well controlled (c-LDL higher than the recommended target 
according to the individual global cardiovascular risk; for instance, c-LDL>100 mg/dl in 
patients with previous myocardial infarction or stroke); severe obesity (BMI >45 kg/m2); 
symptomatic hyperparathyroidism (for instance, hypercalcaemia); replacement therapy for 
adrenal failure; any electrolytes disorder requiring hospitalization.
4 -Uncontrolled diabetes (hemoglobin A1c >8.5%) or one diabetic ketoacidosis or nonketotic 
hyperosmolar coma during the past year; genetic uncontrolled dyslipidemia; acute adrenal 
failure during hormonal replacement therapy; any neoplasm of thyroid, breast, adrenal gland 
(see “Rating Malignancies”).
NOTICE: when the patient is not treated with drug therapy for diabetes or dyslipidemia but he 
should be for the optimal control of the pathology (for instance, hemoglobin A1c >7%, total 
cholesterol >250 mg/dl), score the pathology according to the laboratory values, which really 
define its severity.
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PSYCHIATRIC AND BEHAVIORAL DISEASES
This category includes both dementia and related behavioral disorders (psychosis, anxiety, 
depression, agitation) and all the pre-existing and/or not related to dementia psychiatric 
disorders. Since this is the only item analyzing patient’s mental status (all the others refer to 
physical status), it is very important to evaluate it considering carefully further information 
derived from the Comprehensive Geriatric Assessment (MMSE; Geriatric Depression Scale, 
Neuro-Psychiatric Inventory if available) (8, 9).
0 -No psychiatric problem or history thereof
1 -Minor psychiatric condition or history thereof: previous (occasional) psychiatric treatment 
without hospitalization; major depressive event and/or use of antidepressants more than 10 
years ago without hospitalization; occasional use of minor tranquilizers (e.g. BDZ; even if as 
hypnotherapy for insomnia); mild cognitive impairment (MMSE 25-28).
2 -A history of major depression (according to DSM-IV criteria) within the last 10 years (treated 
or untreated); mild dementia (MMSE 20-25); previous admission to Psychiatric Department 
for any reason; history of substance abuse (more than ten years ago, including alcoholism).
3 -Current major depression (according to DSM-IV criteria) or more than two previous major 
depression episodes in the past 10 years; moderate dementia (MMSE 15-20); current and 
usual usage of daily anti-anxiety meds (even as hypnotherapy for insomnia); current or within 
the past ten years substance abuse or dependence (according to DSM-IV criteria); requires 
daily antipsychotic medication; previous attempt at suicide.
4 -Current mental illness requiring psychiatric hospitalization, institutionalization, or intensive 
outpatient management (psychiatric emergency, as attempt at suicide or severe depression 
with suicide purpose, acute psychosis or acute decompensation of chronic psychosis, severe 
substance abuse; severe agitation from dementia); severe dementia (MMSE <15); delirium
(acute confusion or altered mental status for medical (organic) reasons: in this case you have 
to codify also the medical cause in its own category with the appropriate level of severity).
It could be requested psychiatric consult for this category; dementia and depression, the most 
frequent diseases in the elderly, can be scored in details using the MMSE and GDS. The severity 
of any mental disorder (dementia, depression, anxiety, psychosis, substance abuse and all the 
others) has to be scored according to the level of functional impairment or disability they cause.
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19.3.
Deauville Criteria for PET Scan Interpretation (Meignan, 2009)
Interpretation
!
A visual analysis using the 5-point scale should be applied
!
The preferable reference scale should be the mediastinum and the liver
Scoring per the five point scale 
1. No uptake
2. Uptake ≤ mediastinum
3. Uptake > mediastinum but ≤ liver
4. Uptake moderately increased compared to the liver at any site.
5. Uptake markedly increased compared to the liver at any site and/or new sites of disease.
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19.4.
IWG Response Criteria for NHL (Cheson, 2014)
Table 16:
IWG Response Criteria for NHL (Cheson, 2014)
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Table 16:
IWG Response Criteria for NHL (Cheson, 2014) (Continued)
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19.5.
Cairo-Bishop Definitions of Tumor Lysis Syndrome
Table 17:
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS)
Laboratory Parameter
Laboratory Result
Uric Acid
≥ 476 μmol/L(≥ 8.0 mg/dL) or 25% increase from baseline
Potassium
≥ 6.0 mmol/L (≥ 6.0 mEq/L) or 25% increase from baseline
Phosphorous
≥1.45 mmol/L (≥ 4.5 mg/dL) or 25 % increase from baseline
Calcium
≤ 1.75 mmol/L(≤ 7.0 mg/dL) or 25% decrease from baseline
Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or below normal, as 
defined above, for any two or more serum values of uric acid, potassium, phosphate, and calcium within 3 days 
before or 7 days after the initiation of chemotherapy.  This assessment assumes that a patient has or will receive 
adequate hydration (± alkalinization) and a hypouricaemic agent(s) (Cairo, 2004).  
Table 18:
Cairo-Bishop Definition of Clinical TLS 
The presence of laboratory TLS and one or more of the following criteria:
1.
Creatinine:  ≥ 1.5 ULN (age > 12 years or age adjusted)
2.
Cardiac arrhythmia / sudden death
3.
Seizurea
ULN = Upper limit of normal. (Cairo, 2004)
a Not directly attributable to a therapeutic agent.
Table 19:
Cairo-Bishop Grading System for TLS
Grade
LTLS
Creatinine
Cardiac Arrhythmia
Seizure
0
-
≤ 1.5 x ULN
None
None
1
+
1.5 x ULN
Intervention not 
indicated
None
2
+
> 1.5 – 3.0 x ULN
Non-urgent medical 
intervention indicated
One brief generalized seizure; seizure(s) 
well controlled or infrequent; focal motor 
seizures not interfering with ADL
3
+
> 3.0 – 6.0 x ULN
Symptomatic and 
incompletely controlled 
medically or controlled 
with device
Seizure in which consciousness is altered; 
poorly controlled seizure disorder; 
breakthrough generalized seizures despite 
medical intervention
4
+
> 6.0 x ULN
Life-Threatening
Seizures of any kind that are prolonged, 
repetitive, or difficult to control
5
+
Deatha
Deatha
Deatha
ADL= activities of daily living; LTLS = laboratory tumor lysis syndrome; TLS= tumor lysis syndrome; ULN =
upper limit of normal (Cairo, 2004)  
a Probably or definitely attributable to clinical TLS.
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19.6.
EQ-5D
Health Questionnaire
(English version for the UK)
(validated for use in Eire)
K)
Eire)
Eire)


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By placing a tick in one box in each group below, please indicate which statements best describe 
your own health state today.
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care
I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (eg work, study, housework, family or
leisure activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression
I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed

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To help people say how good or bad a health state is, we
have drawn a scale (rather like a thermometer) on which the
best state you can imagine is marked 100 and the worst
state you can imagine is marked 0.
We would like you to indicate on this scale how good or bad
your own health is today, in your opinion. Please do this by
drawing a line from the box below to whichever point on the
scale indicates how good or bad your health state is today.
9
0
8
0
7
0
6
0
5
0
4
0
3
0
2
0
1
0
100
Worst  imaginable
health state
0
Best imaginable
health state
Your own
health state
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19.7.
FACT-LYM


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19.8.
Pregnancy Prevention Risk Management Plan
The Pregnancy Prevention Risk Management Plan is a standalone document.
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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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Lenalidomide (CC-5013)
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CC-5013-DLC-002 Amendment #4 Final: 12 Jun 2019
1.
JUSTIFICATION FOR AMENDMENT
The ROBUST clinical database was locked on 12 Apr 2019 for the primary analysis.  All 
patients have been off study treatment for over 1 year.  The study did not meet the primary 
endpoint of demonstrating superiority in progression-free survival (PFS) compared to placebo 
plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy (R-CHOP).  
Protocol Amendment 4 removes the requirement of follow-up assessments for subjects 
continuing in the study except for overall survival (OS) and second primary malignancy (SPM) 
follow-up. Given the study outcome, observed significant slowing of the event rate, and expected 
course of the disease, it is reasonable to make this change.  
For many patients, diffuse large B-cell lymphoma (DLBCL) is a curable disease. Most relapses 
occur within the first 12 to 18 months and the event rate slows significantly approximately 12 
months after diagnosis, as has been observed in the ROBUST Study. While some patients may 
relapse after 2 years (defined as late relapses), the rate of late relapse after this time is low and 
patients who are event free at 24 months are considered to have an overall survival equivalent to 
that of the age- and sex-matched general population (Maurer, 2014; Feldman 2014).  Therefore, 
extensive follow-up of the remaining patients in the ROBUST study would place a significant 
burden on patients and clinical professionals without any reasonable expectation of acquiring 
data which would benefit patients or add to the scientific understanding of the disease. 
 
These changes will also decrease study related radiation exposure and blood draws and allow 
greater flexibility to investigators and patients for overall disease management. The specified 
assessments (summarized in Table 5) will no longer be required after the 12 Apr 2019 final 
analysis and will not be subject to case report form data collection. Long-term follow-up and 
data collection for OS and SPM remain mandatory. Specific guidance is provided in the 
amendment.
Changes to the protocol due to the above rationale are summarized below:
!
Protocol Summary: Study Design and Length of Study - After the primary analysis, only 
SPM and OS information will be collected.
!
Section 4.1.7: Follow-up Period - After the primary analysis, only SPM and OS 
information will be collected.
!
Section 4.2: Figure 3 Overall Study Design - After the primary analysis, only SPM and 
OS information will be collected.
!
Section 4.3: Study Duration - After the primary analysis, only SPM and OS information 
will be collected.
!
Table 5: Table of Events - Clarified that the following assessments will no longer be 
required for data collection after the 12 Apr 2019 primary analysis: 
∀
Physical examination, vital signs, complete blood count with differential, lactate 
dehydrogenase, quality-of-life assessment, performance status,
 
, computed 
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tomography, response assessment, subsequent antilymphoma therapy, and 
progression 
!
Section 6: Procedures - Select follow-up assessments (specified in Table 5), are no longer 
required after the 12 Apr 2019 primary analysis.
Minor grammatical edits were included to ensure consistent word use and clarity in protocol 
changes described above.
The following administrative change was also made:
!
Changed the Medical Monitor from 
due 
to internal Celgene staff changes.
References
Feldman T, Gromko L, Protomastro EA, Starovoitova L, Mato AR, Glisch C, et al. Relapses of 
diffuse large b-cell lymphoma in rituximab era are limited to the first two years after frontline 
therapy. Blood 2014;124:1307.
Maurer MJ, Ghesquieres H, Jais JP, Witzig TE, Haioun C, Thompson CA, et al. Event-free 
survival at 24 months is a robust endpoint for disease-related outcome in diffuse large b-cell 
lymphoma treated with immunochemotherapy. JCO 2014;32(10):1066-73.
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Lenalidomide (CC-5013)
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CC-5013-DLC-002 Amendment #3 FINAL 04 Feb 2019
1.
JUSTIFICATION FOR AMENDMENT
The amendment includes two changes:
!
Changed the Medical Monitor from 
due to 
internal Celgene staff changes (Page 2).
!
 
  
For many patients DLBCL is a curable disease. However, approximately a third of patients will 
either not respond well to initial therapy or respond but relapse early, usually in the first year 
after the first treatment.  Most relapses occur within the first 12 to 18 months and the event rate 
slows significantly approximately 12 months after diagnosis.  While some may relapse after 2 
years (defined as late relapses) the rate of late relapse after this time is low and patients who are 
event free at 24 months are considered to have an overall survival equivalent to that of the age-
and sex-matched general population (Maurer, 2014; Feldman 2014).  Therefore, incorporation of 
these late events can be complicated by competing risks, especially in older patients with 
comorbid health conditions.  
A recent retrospective study demonstrated that relapse rate after 2 years was low (5.9%) in patients 
with DLBCL who achieved complete response (CR) after R-CHOP (Kang, 2018).  Of particular interest, late 
relapse was associated with favorable baseline clinical characteristics such as GCB subtype and lower IPI 
scores (IPI 2 versus IPI2) compared with patients with early relapse.  Early relapses were associated with 
the ABC subtype and higher IPI scores which have substantially worse outcomes (Kang, 2018).
The ROBUST trial is Phase 3 study of oral lenalidomide plus R-CHOP21 × 6 versus placebo-R-
CHOP21 × 6 in patients with previously untreated ABC-type DLBCL.  These patients have the 
highest unmet need with associated worse outcomes and early relapse (within first year) 
following initial therapy.  However, those who respond and achieve 2 years event free could be 
considered to have an overall survival rate similar to people in the general population. 
A significant slowing of the PFS event rate in the ROBUST study was observed over the past 
year and this may be explained by the information described above.  An early relapse is expected
in the ABC population followed by a falling event rate as subjects have a decreasing probability 
of progression the longer they remain event free and reach the 18 months to 2-years post 
treatment start time period.  (The median follow-up for the ROBUST study subjects through the 
end of 2018 was approximately 24.4.months.)  Following this time period, it is anticipated that 
future events can be characterized as late events that are potentially not lymphoma related, and 
that will potentially complicate analysis. 
 
 
 
 
Over the course of the past year the Independent Radiology Adjudication Committee (IRAC) 
assessed PFS event rate has fallen from approximately 8 events per month to the current rate of 2 
to 3 events per month (~6 per quarter) 
  
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Confidential and Proprietary
5
CC-5013-DLC-002 Amendment #3 FINAL 04 Feb 2019
2.
REFERENCES
Feldman T, Gromko L, Protomastro EA, Starovoitova L, Mato AR, Glisch C, et al. Relapses of 
diffuse large b-cell lymphoma in rituximab era are limited to the first two years after frontline 
therapy. Blood 2014;124:1307.
Kang J, Lee K, Hong JY, Yoon DH, Kim S, Park JS, et al. Low relapse rate after 2 years in patients with 
diffuse large b-cell lymphoma (DLBCL) treated with R-CHOP and achieved complete response [abstract]. 
In: The 60th Annual Meeting of the American Society of Hematology; 2018 Dec 2; San Diego, CA. Abstract 
nr 2996.
Maurer MJ, Ghesquieres H, Jais JP, Witzig TE, Haioun C, Thompson CA, et al. Event-free 
survival at 24 months is a robust endpoint for disease-related outcome in diffuse large b-cell 
lymphoma treated with immunochemotherapy. JCO 2014;32(10):1066-73.
 
 
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
3
CC-5013-DLC-002 Amendment #2 Final: 24 Jan 2017
1.
JUSTIFICATION FOR AMENDMENT
Major changes included in this amendment are summarized below:
!
Revised lenalidomide / placebo dose modification rules for neutropenia and 
thrombocytopenia toxicities. Considering the aggressive nature of the disease under 
study, diffuse large B-cell lymphoma (DLBCL), and the known overlapping
hematologic toxicity of R-CHOP and lenalidomide, the dose modification rules were 
re-evaluated based on the investigators’ feedback. This revision has been 
recommended by the Study Steering Committee (SSC) after careful benefit/risk 
evaluation. The purpose of this revision is to maintain the dose and intensity of the 
regimen as much as possible, while managing the hematology toxicity effectively,
thus aiming to provide optimized overall benefit for the patients (Table 8).
The amendment also includes several other minor clarifications and corrections:
!
The ‘All Cycles Day 1’ column under the Treatment Period of the Table of Events 
was revised to state ‘Cycles 1-6 Day 1’ (Table 5).
!
Changed the 3 months prior to Cycle 1 Day 1 (C1D1) tumor biopsy and bone marrow
biopsy/aspirate collection windows to 8 weeks prior to C1D1.  Upon further 
evaluation with the SSC, it was assessed that subjects enrolling after an 8-week 
interval are likely to have a more indolent course of disease than the expected patient 
population for this study, which takes into account the aggressive nature of DLBCL.  
Therefore, patient selection bias may be introduced if a significant number of these 
subjects are enrolled (Table 5, Section 4.1.2, and Section 6).
!
Clarified that ‘Pregnancy Testing – for FCBP with Regular or No Menstrual Cycles’
and ‘Pregnancy Testing – for FCBP with Irregular Menstrual Cycles’ is required 24 
hours prior to lenalidomide/placebo dosing (instead of 24 hours prior to C1D1), and 
once during day -10 to -14 to highlight that the timing of the pregnancy testing is 
dependent on lenalidomide/placebo dosing and not on other components of R-CHOP
dosing. The abbreviation ‘FCBP’ stated above means females of childbearing 
potential (Table 5 and Section 6).
!
Typographical error was deleted for Quality of Life Assessment in the Table of 
Events, as it incorrectly indicated a collection time point at Cycle 6 Day 1. The timing 
of this assessment is the same as for computed tomography (CT) scan collection and 
was correctly stated in Section 6 (Procedures). Consequently, this table has been 
updated to align with the timing stated in Section 6 (Table 5).
!
Clarification that the need to perform a Bone Marrow Biopsy at the End of Treatment 
Visit is dependent on the post Cycle 6 positron emission tomography (PET) scan 
results, and is required only if the Bone Marrow Biopsy at Screening is positive and 
there is an equivocal post Cycle 6 PET scan finding in the bone marrow. The post 
Cycle 6 PET scan is performed once, 3-4 weeks after completing Cycle 6 (Table 5
and Section 6).
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
4
CC-5013-DLC-002 Amendment #2 Final: 24 Jan 2017
!
Administration of Mandatory Primary Neutropenia Prophylaxis added to the Table of 
Events and Procedures section, to emphasize the protocol requirement of primary 
neutropenia prophylaxis at every cycle during Cycles 1-6 (Table 5 and Section 6).
!
Further clarified that the Tumor Lysis Syndrome (TLS) Assessment at Cycles 1-2 
Day 8 has a window of ± 1 day (Table 5 and Section 6).
!
Clarification added to Adverse Event and Concomitant Medications/Procedures 
collection schedule to emphasize that the period through 28 days after the last dose of 
investigational product, applies to the optional two additional doses of single agent 
rituximab, if administered (Table 5 and Section 6).
!
Allowed local laboratory results to confirm eligibility if Screening Central Laboratory 
results are not available and it is necessary to urgently start treatment.  This applies to 
eligibility laboratory requirements for Hepatitis B Virus (HBV), Hepatitis C Virus 
(HCV), Creatinine Clearance, Complete Blood Count (CBC) with Differential, and 
Serum Chemistry. In this case, the Celgene medical monitor must be consulted, the 
data submitted on the case report form (CRF), and a central laboratory sample must 
still be collected prior to first dose.  Due to the aggressive nature of DLBCL, there are 
cases in which treatment must be urgently and immediately started at the 
investigator’s discretion.  In these cases, it may be possible for eligibility criteria to be 
confirmed against local laboratory results instead of Central Laboratory results
(Section 6).
!
Allowed Lactate Dehydrogenase (LDH) local laboratory results to be used at 
Screening, if Central Laboratory results are not available and it is necessary to 
urgently start treatment (Section 6).
!
Clarified that if RNA viral load for Hepatitis C Virus (HCV) testing is needed, the 
test is done by local laboratory, as it is not automatically performed by the Central 
Laboratory (as opposed to HBV viral DNA load testing, which is automatically 
performed by the Central Laboratory when indicated by the protocol) (Section 6).
!
Clarified that local pathology CD20+ status may be used to determine eligibility,
instead of the Central Pathology result, if the local and Central Pathology disagree on 
CD20+ status for patients with activated B-cell (ABC) type confirmed by Central 
Pathology. The intent of protocol amendment 1 was for the disagreement on 
diagnosis between local and Central Pathology to also apply to CD20+ status (Section 
7.2).
!
Added PET scan finding as another option to determine bone marrow involvement by 
lymphoma, when assessing absolute neutrophil count (ANC) and platelet count for 
eligibility (Section 7.2).
!
Corrected typographical error to state that both AST and ALT values must be ≤3.0 x 
upper limit of normal (ULN) or ≤ 5.0 x ULN in the case of documented liver 
involvement by lymphoma. The intent was to always require both values to determine 
eligibility (Section 7.2).
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
5
CC-5013-DLC-002 Amendment #2 Final: 24 Jan 2017
!
Allowed possibility for local radiation to be administered as optional prephase 
treatment to subjects in cases of medical emergencies, in which prephase treatment 
with corticosteroids is not considered adequate.  This is not expected to be a common 
occurrence (Section 8.2.1).
!
Revised situations in which an investigator may prospectively choose to give local 
radiotherapy after study chemotherapy per local practice, including subjects at higher 
risk for central nervous system (CNS) lymphoma, which may be standard practice for 
these subjects (Section 8.2.2, Section 10.6.2).
!
Added recommended dosing schedules for administration of mandatory primary 
neutropenia prophylaxis, along with clarification that this requirement applies to all 
subjects at every cycle during Cycles 1 – 6.  These two schedules of administration 
were recommended by the SSC and was endorsed by the Data Monitoring Committee 
(DMC) (Section 8.2.3).
!
Removed requirement to administer lenalidomide as the first investigational product 
taken on Day 1 of every cycle. 
 
 
(Section 8.2.5).
!
Clarified that dose interruptions (in addition to reductions) can be done for reasons in 
addition to what is stated in Table 8, per the investigator’s discretion.  In previous 
protocol versions, only reductions are mentioned (Section 8.2.5).
!
Allowed intravenous dexamethasone as a substitution for prednisone on Day 1 of 
every cycle to accommodate local practice and formulation availabilities (Section 
8.2.10).
!
Clarified the intent of the Requalification Criteria for Subsequent Treatment Cycles is 
for non-hematological toxicities to be resolved to ≤ Grade 2, instead of all other 
toxicities, as originally stated.  Exceptions to ANC and platelet count criteria were 
also clarified for cases of spleen involvement secondary to lymphoma, per 
investigator assessment (Section 8.2.12).
!
Clarified exceptions to neutropenia and thrombocytopenia lenalidomide / placebo 
dose modification rules for cases of spleen involvement secondary to lymphoma, per 
investigator assessment (Table 8).
!
Clarification added to the titles of Tables 8, 10, 11, and 12 (Table 8, Table 10, Table 
11, and Table 12).
!
Corrected typological errors throughout the document (Table 2, Section 7.2, Section 
18, and Table 19).
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
3
CC-5013-DLC-002 Amendment #1 Final:  25 Aug 2015
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
 
 
!
Allowed submission of core needle tumor biopsy material for eligibility.  
 
 provided technical validation data in 
 showing that core 
needle biopsy tissue was acceptable for use in the gene expression profiling (GEP)
assay that is the basis for Activated B-cell (ABC) subtype subject selection in this 
protocol.  The validation data demonstrates that the GEP assay can be performed with 
core needle tumor biopsy specimens without compromising assay performance.  In 
certain situations a surgical biopsy would pose an unacceptable risk and previously 
such subjects had to be excluded.  With this amendment it will be possible to screen 
subjects who must use a core needle biopsy. (Sections 6 and 7.2)
!
Allowed local pathology diffuse large B-cell lymphoma (DLBCL) diagnosis to 
prevail in the event that Central Pathology confirms ABC subtype but is not able to 
confirm a DLBCL diagnosis.  In this case, the subject may enroll at investigator 
discretion.  A retrospective adjudication by a second Central Pathologist will be 
performed for the purposes of defining the modified intent to treat (mITT) population; 
primary analysis is per the intent to treat (ITT) population.  According to an 
internationally recognized, expert hematopathologist, 
 
, this 
should be a rare (< 1%) occurrence, and therefore does not pose a major risk to the 
existing ITT sample size.  This provision was added to allow the possibility of 
adjudication by an expert pathologist in difficult cases. (Section 7.2)
!
Changed the hemoglobin inclusion criterion 11c from ≥10 g/dL (6.2 mmol/L) to ≥7.5 
g/dL (4.7 mmol/L) for all subjects, and allow packed red blood cell (PRBC) 
transfusions as needed during Screening (PRBC transfusions were already permitted 
during the Treatment Period).  Many DLBCL patients will have depressed 
hemoglobin values regardless of whether they have documented bone marrow 
involvement by lymphoma.  Additionally, lenalidomide impact on hemoglobin value 
is much less common than neutropenia and thrombocytopenia and the protocol does
allow transfusions as needed. (Sections 7.2 and 9.2.1)
!
Included, at investigator discretion, subjects > 80 years if their Eastern Cooperative 
Oncology Group (ECOG) performance status is ≤ 1; each of their individual organ 
system scores is ≤ 2 using the Modified Cumulative Illness Rating Scale (CIRS); and 
if they would otherwise be eligible for full-dose rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP) per local practice.  (Other entry 
criteria address specific co-morbidities such as cardiac function [left ventricular 
ejection fraction < 45% excluded] and adequate bone marrow, kidney, and liver 
function [minimum laboratory values]). In the ECOG MC078E study, 9% of the 
subjects were ≥ 80 years, and the safety profile of the elderly study subjects was 
approximately the same as for the study subjects < 80 years, with no significant safety 
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
4
CC-5013-DLC-002 Amendment #1 Final:  25 Aug 2015
signal.  Additionally, this option will more closely align the protocol with standard 
practice in some countries. (Table 5 and Sections 6, 7.2, and 19.2)
!
Included hepatitis C virus (HCV) positive subjects who do not have an active 
hepatitis C infection and who are otherwise acceptable candidates for R-CHOP 
chemotherapy.  All subjects will be tested for HCV antibodies at Screening by the 
Central Laboratory, and the investigator must further test HCV+ subjects by either 
FibroScan® (liver ultrasound for fibrosis), liver biopsy, ribonucleic acid (RNA) viral 
load or other local practice. Within the current Revlimid∀Investigator’s Brochure 
(edition 18) Hepatitis C reactivation is not noted as a treatment-emergent adverse 
event.  In addition, there was an effective HCV drug (Gilead) approved recently, and 
DLBCL subjects with acceptable liver function and fully controlled infection are 
routinely treated with R-CHOP in areas of high endemic HCV infection.  (Table 5, 
Sections 6, 7.2, and 7.3)
!
Excluded T-cell / histiocyte rich DLBCL cases from the study population.  This 
change was made on the recommendation of the expert hematopathologist, 
 
 
  The GEP of such subjects would not be typical because of the 
limited number of large B cells that are embedded within a background of abundant T 
cells and histiocytes, resulting in a very low tumor cellularity.  Additionally, the high 
inflammatory component of the microenvironment could potentially overlap with 
Hodgkin’s Lymphoma, potentially making it difficult to discriminate from ABC type 
DLBCL. (Sections 7.2 and 7.3)
!
Excluded Post-transplant Lymphoproliferative Disorder (PTLPD) cases from the 
study population even if they are a B-cell type and the ABC subtype.  The rationale is 
that PTLPD is considered a separate entity from mature B-Cell neoplasms, which 
include DLBCL, according to the World Health Organization 2008 classification.  
(Section 7.3)
!
Allowed pre-phase corticosteroid treatment per local practice, with a recommended 
limit of 100 mg/ day prednisone or equivalent for 10 days; rather than mandating a 
limit of 1 mg/kg/day for 7 days.  This would accommodate the variety among local 
practices without unnecessarily excluding an otherwise eligible subject and without 
impacting the essential intent of no prior anti-lymphoma treatment.  Additionally, 
pre-phase corticosteroid treatment for elderly subjects in general may be useful 
(Pfreundschuh 2010). (Sections 7.2 and 8.2.1)
!
Changed pneumocystis prophylaxis from “required” for all subjects to “permitted”.  
At most sites pneumocystis prophylaxis is a local standard of care for all patients 
receiving R-CHOP-14, and for the elderly who receive R-CHOP-21; however, the 
practice varies for patients < 65 years who receive R-CHOP-21.  Additionally, there 
is potential overlap with the myelotoxicity profile of Bactrim®, a common 
prophylactic drug, and lenalidomide + R-CHOP.  Therefore, the protocol requirement 
was changed to accommodate local practice and to allow the investigator to weigh the 
risk / benefit on an individual subject basis.  (Section 9.2.2)
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
5
CC-5013-DLC-002 Amendment #1 Final:  25 Aug 2015
!
Allowed lenalidomide/placebo - R-CHOP regimen modifications, at investigator 
discretion, in the event of HCV infection or reactivation; or for the following grade 3 
toxicities: nausea/vomiting, infection requiring intravenous (IV) antibiotics or 
hospitalization, or other non-hematologic toxicities.  For other toxicities, modification 
should be in accordance with respective product labels. (Section 8.2.11 and Table 12)
!
Allowed individual drug dose modifications for cyclophosphamide, doxorubicin and 
vincristine. Certain clinical situations may require the modification of individual 
drugs of the R-CHOP regimen, for example if the toxicity is clearly attributable to 
just one or two of these drugs, and when it would still be reasonable to continue with 
the chemotherapy regimen. (Sections 8.2.7; 8.2.8; 8.2.9; Table 10 and Table 11)
!
Allowed rituximab administration over two days at the beginning of each cycle from 
Day – 1 through Day 3 to better manage potential infusion reactions on account of 
high tumor burden or bulky disease; and to accommodate various standard regional 
practices on this global study.  (Section 8.2.6)
!
Allowed IV methylprednisone as a substitution for either IV or PO prednisone on 
Day 1 only of every cycle to accommodate local practice, compound, and formulation 
availability.  (Section 8.2.10)
!
Changed to the most current International Working Group (IWG) Response Criteria 
for non-Hodgkin’s lymphoma (NHL) (Cheson 2014 from Cheson 2007).  As a 
consequence, the End of Treatment bone marrow biopsy for subjects otherwise in CR 
was removed; this is according to the new criteria where a positron emission 
tomography (PET) negative bone marrow will suffice to confirm a complete response 
(CR).  (A subject with lymphomatous involvement of the bone marrow at Screening, 
who has an equivocal post Cycle 6 PET scan finding in the bone marrow, requires a 
repeat bone marrow biopsy; if the biopsy is negative the subject may then be 
classified as a CR.)  However, the baseline bone marrow biopsy will be retained to 
document any discordant small cell component; it is also useful to screen out 
myelodysplastic syndrome; and there are other entry criteria related to neutrophil and 
platelet counts that require confirmation of baseline bone marrow involvement.  As a 
second consequence, the B-symptom assessment will also be removed as this is not a 
component of the revised criteria.  (Protocol Summary, Section 4.1.2, Table 5, 
Section 6, Appendix 19.4, and article references throughout the text)
!
Allowed for combined PET-computed tomography (CT) without contrast as per local 
standards at Midcycle; End of Treatment; and for PET negative (CR) subjects only, 
also during the Follow-up Period.  There is a key restriction that progression may not 
be scored on PET positivity alone, but must be confirmed by CT with contrast or a 
biopsy of the PET positive lesion.  This option is consistent with the new IWG 
Response Criteria for NHL (Cheson 2014).  (Sections 4.1.3, 4.1.4, 4.1.5. and 6)
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
6
CC-5013-DLC-002 Amendment #1 Final:  25 Aug 2015
Minor clarifications and corrections included in this amendment are summarized below: 
!
Added the informal study name “ROBUST” to the title page.  The study was named 
to allow easier conversational identification for subjects and health care professionals.
!
Explained that the assay used for ABC subtype subject selection is technically 
validated, but that it does not have the marketing approval by a health authority 
beyond Conformité Européenne (CE) marking in the European Union. (Section 1.2.1)
!
Defined the protocol specific meaning of the term Midcycle (once between Weeks 9 
– 12 which is after Cycle 3 but before Cycle 4) and thereafter treated it as a proper 
noun with capitalization. (Protocol Summary; Sections 4.1.3, 6; and throughout the 
text)
!
Clarified that while it is acceptable to perform a combined PET-CT, or a standalone 
PET in addition to the protocol required CT scan at the Midcycle evaluation, 
treatment decisions to switch therapy should not be based solely on the PET results.  
This position is supported by the International Conference on Malignant Lymphoma 
Imaging Working Group recommendations which explain that the positive 
predicative value of interim PET in DBLC is variable.  (Section 4.1.4)
!
Corrected the visit window inconsistencies for the Day 1 assessments for Cycles 2-6.  
Dosing and tumor lysis syndrome (TLS) assessment have a ± 1 day window and 
should occur on the same day.  All other assessments have a ± 3 day window.  (Table 
5, and Sections 6 and 8.2)
!
Split and re-ordered the first few inclusion criteria, so that more precise reasons for 
screen failure may be quantitatively tracked. (Section 7.2)
!
Clarified that the eligible antibody and antigen profile described in exclusion criterion 
4c describes a successfully treated hepatitis B-virus (HBV) infection. (Section 7.3)
!
Removed the requirement to take prednisone after lenalidomide on Days 2-5.  The 
two drugs are not expected to have any PK interactions.  (Section 8.2.10)
!
Confirmed that mandatory neutropenia prophylaxis is “primary” prophylaxis where 
growth factors are to be administered at the beginning of R-CHOP treatment and 
prior to a decrease in absolute neutrophil count (ANC) value. (Sections 8.2.3 and 
9.2.1)
!
Changed the 2 months prior to Cycle 1 Day 1 (C1D1) tumor biopsy and bone marrow 
biopsy/aspirate collection windows to be 3 months prior to C1D1.  This minor change 
will reduce re-biopsies just for this trial in subjects who have already been diagnosed 
and staged.  (Table 5, and Sections 4.1.2 and 6)
!
Changed the 28 days prior to C1D1 PET and CT scan collection windows to be 6 
weeks prior to C1D1.  This change will require fewer subjects who have already had 
imaging to repeat their scans just for this trial, and thus reduce radiation exposure.  
(Table 5, and Sections 4.1.2 and 6.)
!
Revised pregnancy testing to occur at a minimum of every 28 days rather than exactly 
at every 28 days.  The option to do more frequent testing was actually more 
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
7
CC-5013-DLC-002 Amendment #1 Final:  25 Aug 2015
convenient for study subjects as the treatment cycles, which are followed by a safety 
and pregnancy assessment, are 21 days in length, not 28 days.  This schedule is 
consistent with the Pregnancy Prevention Plan applicable to all lenalidomide studies 
and with the RevAssist pregnancy prevention guidelines applicable to Revlimid 
marketed product. (Table 5, Section 6.0)
!
Corrected pregnancy counseling at baseline to require a single counseling session one 
time between signing the informed consent form (ICF) and Day 1 dosing.  This is 
consistent with the Pregnancy Prevention Plan which requires one counseling session 
prior to every dispensing of lenalidomide. (Table 5, Section 6.0)
!
Deleted the explanation of how to subdivide tumor biopsy formalin-fixed paraffin-
embedded (FFPE) blocks for Central Pathology submission.  Central Pathology will 
be responsible for sample slide preparation from a submitted tumor block; and the 
separate Central Pathology Laboratory Manual will provide necessary sample 
processing details.  (Section 6.0)
!
Allowed the lower threshold for ANC and / or platelet counts to include lymphoma 
involvement of the spleen, in addition to the previously allowed lymphoma 
involvement of the bone marrow.  Patients with spleen involvement by lymphoma (as 
evidenced by splenomegaly) often have depressed ANC and / or platelet values and 
R-CHOP treatment would still be warranted. (Section 7.2)
!
 
 
  
 
 
!
Changed the 2-sided p-value to a 1-sided p-value in the interim analysis section at the 
recommendation of the data monitoring committee statistician 
 
since the 1-sided p-value is more appropriate and easier to understand for futility 
analysis. (Section 10.8)
!
Clarified that in medical emergency cases, investigators are free to un-blind their 
subject’s treatment assignment via the IVRS.  In such cases it is not required to 
contact the Medical Monitor prior to breaking the blind; Celgene permission is not 
required.  Additionally, there is no emergency unbinding PIN required. (Section 13.2)
!
Added the requirement for investigators to share a summary of study results with 
their subjects at the time results of the study are made available to the public.  
Celgene will provide the relevant summary written for a lay person to the 
investigator. (Section 14.2.)
!
Added additional references to Section 18 and cited throughout the document as 
appropriate.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, MULTICENTER 
STUDY TO COMPARE THE EFFICACY AND SAFETY OF LENALIDOMIDE (CC-5013) 
PLUS R-CHOP CHEMOTHERAPY (R2-CHOP) VERSUS PLACEBO PLUS R-CHOP 
CHEMOTHERAPY IN SUBJECTS WITH PREVIOUSLY UNTREATED ACTIVATED 
B-CELL TYPE DIFFUSE LARGE B-CELL LYMPHOMA
INVESTIGATIONAL 
PRODUCT (IP):
LENALIDOMIDE (CC-5013)
PROTOCOL NUMBER:
CC-5013-DLC-002
DATE Final Amendment 3
04-FEB-2019
Prepared by:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION..................................................................................................10
3.
STUDY OBJECTIVES...........................................................................................11
3.1.
Primary Objective...................................................................................................11
3.2.
Secondary Objectives .............................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................12
4.1.
Overall Study Design and Plan ...............................................................................12
4.2.
Study Endpoints .....................................................................................................14
4.2.1.
Primary Efficacy Endpoint......................................................................................14
4.2.2.
Secondary Efficacy Endpoints ................................................................................14
4.2.4.
Safety Endpoints.....................................................................................................14
4.3.
Stratification, Randomization, and Blinding............................................................15
4.4.
Sample Size Determination.....................................................................................15
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................17
5.1.
Reporting Conventions ...........................................................................................17
5.2.
Analysis Populations ..............................................................................................18
5.2.1.
Intent-to-treat Population........................................................................................18
5.2.2.
Modified Intent-to-treat Population.........................................................................18
5.2.3.
Safety Population....................................................................................................19
6.
SUBJECT DISPOSITION......................................................................................20
7.
PROTOCOL DEVIATIONS ..................................................................................22
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................23
8.1.
Demographics.........................................................................................................23
8.2.
Baseline Characteristics..........................................................................................23
8.3.
Medical History......................................................................................................24
8.4.
Prior Therapy..........................................................................................................24
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
3
8.5.
Prior and Concomitant Medications........................................................................24
8.5.1.
Prior Medications ...................................................................................................25
8.5.2.
Concomitant Medications .......................................................................................25
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................26
9.1.
Treatment Duration and Cycles...............................................................................26
9.2.
Cumulative Dose ....................................................................................................28
9.3.
Dose Intensity.........................................................................................................28
9.4.
Relative Dose Intensity...........................................................................................28
9.5.
Dose Reduction/Interruption...................................................................................29
9.6.
Treatment Compliance............................................................................................29
10.
EFFICACY ANALYSIS ........................................................................................31
10.1.
Multiplicity.............................................................................................................31
10.2.
Analysis of Primary Efficacy Endpoint...................................................................31
10.3.
Analyses of Secondary Efficacy Endpoints.............................................................34
10.3.1.
Key Secondary Endpoint ........................................................................................34
10.3.2.
Other Secondary Endpoints ....................................................................................35
10.4.
Subgroup Analysis..................................................................................................37
 
10.6.
Assessing Study Center Effect and Treatment-by-Center Interaction.......................39
11.
SAFETY ANALYSIS ............................................................................................40
11.1.
Adverse Events.......................................................................................................40
11.1.1.
Overview of TEAE.................................................................................................40
11.1.2.
TEAEs by System Organ Class and Preferred Term................................................41
11.1.3.
Death......................................................................................................................42
11.2.
Selected Adverse Events.........................................................................................42
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
4
11.2.1.
AE of Special Interest.............................................................................................42
11.2.2.
Second Primary Malignancy...................................................................................43
11.3.
Clinical Laboratory Evaluations..............................................................................44
11.3.1.
Hematology............................................................................................................45
11.3.2.
Clinical Chemistry..................................................................................................45
11.3.3.
Other Laboratory Tests ...........................................................................................45
11.4.
Vital Sign Measurements........................................................................................45
11.5.
Physical Examination .............................................................................................45
11.6.
Cardiac Function Tests ...........................................................................................46
12.
QUALITY OF LIFE ANALYSIS...........................................................................47
13.
INTERIM ANALYSIS...........................................................................................48
13.1.
General Information................................................................................................48
13.2.
Statistical Approaches for Control of Alpha............................................................48
15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................51
16.
REFERENCES.......................................................................................................52
17.
APPENDICES........................................................................................................53
17.1.
Handling of Dates...................................................................................................53
17.1.1.
Calculation Using Dates .........................................................................................53
17.1.2.
Calculation of Cycles..............................................................................................54
17.2.
Date Imputation Guideline......................................................................................55
17.2.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications Dates.............55
17.2.2.
Impute Incomplete Dates of PD, second PD, and Subsequent Anti-
Lymphoma Therapy ...............................................................................................56
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES AND FIGURES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Censoring Rule for PFS Endpoint (Primary Analysis).............................................32
Table 3:      Censoring Rule for PFS Endpoint (Sensitivity Analysis).........................................32
Figure 1:
Overall Study Design..............................................................................................13
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
6
SIGNATURE PAGE
STATISTICAL ANALYSIS PLAN (SAP) AND SAP AMENDMENT APPROVAL SIGNATURE PAGE 
SAP VERSION, DATE
Final, ddMMMyyyy
SAP AUTHOR
 
{See appended electronic signature page}
Printed Name and Title
Date
PROTOCOL TITLE
PHASE 3 RANDOMIZED, DOUBLE-BLINDED, PLACEBO CONTROLLED, 
MULTICENTER STUDY TO COMPARE THE EFFICACY AND SAFETY OF 
LENALIDOMIDE (CC-5013) PLUS R-CHOP CHEMOTHERAPY (R2-CHOP) 
VERSUS PLACEBO PLUS R-CHOP CHEMOTHERAPY IN SUBJECTS WITH 
PREVIOUSLY UNTREATED ACTIVATED B-CELL TYPE DIFFUSE LARGE B-
CELL LYMPHOMA
INVESTIGATIONAL PRODUCT
CC-5013 (lenalidomide)
PROTOCOL NUMBER
CC-5013-DLC-002
PROTOCOL VERSION, DATE
Final Amendment 3, 04 February 2019
SIGNATURE STATEMENT
By my signature, I indicate I have reviewed this SAP and find its contents to be 
acceptable.
Statistical Therapeutic Area Head
Signature
{See appended electronic signature page}
Printed Name
Date
Lead Clinical Research Physician / Clinical Research Physician
Signature
{See appended electronic signature page}
Printed Name
Date
Lead Product Safety Physician
Signature
{See appended electronic signature page}
Printed Name
Date
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
ABC
Activated B-cell
AE
Adverse Event
ALC
Absolute Lymphocyte Count
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AST
Aspartate Transaminase
ATC
Anatomical Therapeutic Chemical
ATE
Arterial Thromboembolism
BMI
Body Mass Index
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CMH
Cochran-Mantel-Haenszel
CR
Complete Response
CrCl
Creatinine Clearance
CRF
Case Report Form
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DBP
Diastolic Blood Pressure
DI
Dose Intensity
DLBCL
Diffuse Large B-cell Lymphoma
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
EAIR
Exposure Adjusted Incidence Rate
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
8
EFS
Event-free Survival
EMA
European Medicines Agency
EQ-5D
EuroQuol 5 Dimension Scale
FACT-Lym
Functional Assessment of Cancer Therapy for Patients with Lymphoma 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEP
Gene Expression Profiling
HLT
Higher Level Term
HR
Hazard Ratio
HRQoL
Health Related Quality of Life
ID
Identification Number
Ig
Immunoglobulin
IHC
Immunohistochemistry
IP
Investigational Product
IPI
International Prognostic Index
IRAC
Independent Response Adjudication Committee
ITT
Intent-to-treat
IVRS
Interactive Voice Response System
LDH
Lactate Dehydrogenase
LVEF
Left Ventricular Ejection Fraction
Max
Maximum
Min
Minimum
mITT
Modified Intent-to-Treat
MedDRA
Medical Dictionary for Regulatory Activities
MUGA
Multi Gated Acquisition 
NCI
National Cancer Institute
NGS
Next Generation Sequencing
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
9
ORR
Objective Response Rate
OS
Overall Survival
PFS
Progression-free Survival
Placebo-R-CHOP
Placebo plus rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone or equivalent chemotherapy (R-CHOP)
PP
Per-protocol
PR
Partial Response
PT
Preferred Term
Q1
First Quartile
Q3
Third Quartile
R2-CHOP
Lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone or equivalent chemotherapy (R-CHOP)
RDI
Relative Dose Intensity
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Standard Deviation
SMQ
Standardized MedDRA Query
SOC
System Organ Class
SPM
Second Primary Malignancy
TEAE
Treatment-emergent Adverse Event
TFR
Tumor Flare Reaction
TSH
Thyroid Stimulating Hormone
TTNLT
Time to Next Lymphoma Therapy
VTE
Venous Thromboembolism
WBC
White Blood Cell
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
10
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-5013-DLC-002 “Phase 3 Randomized, Double-Blind, Placebo Controlled, 
Multicenter Study to Compare the Efficacy and Safety of Lenalidomide (CC-5013) Plus 
R-CHOP Chemotherapy (R2-CHOP) Versus Placebo Plus R-CHOP Chemotherapy in Subjects 
with Previously Untreated Activated B-cell Type Diffuse Large B-cell Lymphoma” which was 
issued on 16 May 2014. It contains definitions of analysis populations, derived variables, and 
statistical methods for the analysis of efficacy and safety.
The study includes one interim analysis for futility and one final analysis. This SAP covers both 
interim analysis and final analysis. Throughout this SAP, the treatment arms will be referred to 
as R2-CHOP (lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone or equivalent chemotherapy) and placebo-R-CHOP (placebo plus R-CHOP). The 
purpose of the SAP is to ensure the credibility of the study findings by pre-specifying the 
statistical approaches to the analysis of study data prior to the database lock and any data 
analysis for the interim/final analysis. This SAP will be finalized and signed off prior to the 
clinical database subset lock for the final analysis. All statistical analyses detailed in this SAP 
will be conducted using SAS® Version 9.2 or higher.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
11
3.
STUDY OBJECTIVES
Primary Objective
The primary objective of the study is to compare the efficacy of R2-CHOP versus 
placebo-R-CHOP.
Secondary Objectives
The secondary objective of this study is to compare the safety of R2-CHOP versus 
placebo-R-CHOP.  
 
 
 
 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
12
4.
INVESTIGATIONAL PLAN
Overall Study Design and Plan
This randomized, placebo-controlled study is designed to evaluate the efficacy and safety of 
R2-CHOP chemotherapy versus placebo-R-CHOP chemotherapy in subjects with previously 
untreated CD20+, activated B-cell (ABC) type diffuse large B-cell lymphoma (DLBCL).
Stratification for randomization will be employed to reduce bias related to subject international 
prognostic index (IPI) score, presence of bulky disease, and age.  Randomization in this parallel 
treatment design is in a 1:1 ratio to either R2-CHOP or placebo-R-CHOP.  Celgene, as well as 
the investigator and subject, will be blinded to treatment assignment. 
This study is divided into Screening, Treatment and Follow-Up Periods as summarized below 
and graphically presented in the Figure 1.  Details of the study design are described in Sections
4.1.1, 4.1.2 and 4.1.5 of the protocol.  Details of the study treatments are described in Section 8 
of the study protocol.
During the Screening Period, subjects will undergo safety and other assessments to determine 
eligibility for the study.  If subject eligibility is confirmed, then randomization via the interactive 
voice response system (IVRS) is the final part of the Screening Period.  Pre-specification of the 
optional therapies such as the extra 2 doses of single agent rituximab or consolidation 
radiotherapy will also be registered in IVRS prior to randomization.
The Treatment Period begins with Cycle 1 Day 1 dosing.  Subjects will receive 
protocol-specified treatments for 6 cycles.  Treatment will continue to completion; or until the 
outcome of the computed tomography (CT) scan between Weeks 9 and 12 (after Cycle 3 but 
before Cycle 4) indicates a treatment change based on response assessment; disease progression;
unacceptable toxicity; death; or withdrawal of consent, whichever occurs first.
The Follow-up Period begins upon study treatment completion or upon early discontinuation of 
study treatment.  Subjects will be followed for first and second progressions, subsequent 
antilymphoma therapy, development of any second primary malignancies (SPMs), and overall 
survival (OS) according to the schedule described in Table 5 of the protocol.
Approximately 560 subjects will be randomized.  Subjects who discontinue/withdraw from the 
study will not be replaced.  There is one planned interim analysis for futility at 50% information 
level and one planned final analysis for superiority.  
The study will be conducted in compliance with Good Clinical Practice (GCP). 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
13
Figure 1
Overall Study Design
Screening Period   
Treatment Period
Follow Up Period
Day -28 to -1
Informed 
Consent
Central 
pathology 
assessment of 
disease and 
subtype; 
eligibility review; 
stratification 
(IPI, bulky 
disease, age); 
and
randomization
Lenalidomide + R-CHOP21 
x 6 cycles*
Follow for first 
and second 
progressions, 
OS, subsequent 
antilymphoma 
therapy, and 
SPM**
Placebo + R-CHOP21
x 6 cycles*
ABC
GCB, 
unclassifiable
Ineligible
* It is permissible to administer an additional two doses (1 dose per 21-day cycle) of single agent rituximab 
after the 6 cycles of study treatment are complete if it is considered standard of care per local practice.  
However, the decision to administer these extra two doses must be pre-specified in IVRS prior to 
randomization.   
Study treatment will continue until 6 cycles of treatment are complete; or until unacceptable toxicity; or until 
the outcome of the CT scan conducted once between weeks 9-12 (after Cycle 3 but before Cycle) indicates a 
treatment change based on response assessment; disease progression; or withdrawal of consent; whichever 
occurs first.
** All subjects who discontinue treatment and who maintain consent, will proceed directly to the Follow-up 
Period.  This includes subjects who complete the full course of treatment, who discontinue treatment due to 
progression or toxicity, as well as those who discontinue before progression to pursue a new antilymphoma 
therapy (chemotherapy, SCT, radiotherapy, etc.).  During the Follow-up Period scans continue at protocol 
specified time points until first progression and are submitted to central radiology.   
Subjects who are alive at the time of primary analysis will still be followed exclusively for second primary 
malignancies, subsequent antilymphoma therapies, first and second progression and survival for up 
to 5 years from the date the last subject is randomized.
IPI= international prognostic index, ABC= activated B-cell, GCB= germinal center B-cell, OS=overall survival, SPM= second primary 
malignancy
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
14
Study Endpoints
4.2.1.
Primary Efficacy Endpoint
!
Progression-free Survival (PFS)
4.2.2.
Secondary Efficacy Endpoints
Key secondary endpoint
!
Event-free Survival (EFS)
Other secondary endpoints
!
Overall Survival
!
Complete Response (CR) rate
!
Duration of Complete Response
!
Duration of Response (PR + CR)
!
Time to Next Lymphoma Therapy (TTNLT)
!
Objective Response Rate (ORR)
!
Health-related quality of life (HRQoL) as measured by the EuroQuol 5 Dimension 
Scale (EQ-5D) and the Functional Assessment of Cancer Therapy for Patients with 
Lymphoma (FACT–Lym) standardized measures of health status
 
4.2.4.
Safety Endpoints
!
Adverse Events (AEs) including SPMs
!
Physical examinations
!
Vital signs
Safet
afe
!
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
15
!
Laboratory tests based on central laboratory
Stratification, Randomization, and Blinding
An IVRS will be employed to accomplish randomization, to record pre-specification of optional 
consolidation radiotherapy, and to manage subject medications.  
Once the subject is determined eligible, the investigator or designee will access the IVRS within 
the 28-day Screening Period to obtain the randomized treatment assignment for the subject.  
Subjects will be stratified as follows: 
!
IPI score:  2 versus ≥ 3 
!
Age:  < 65 versus ≥ 65 years
!
Presence of bulky disease: ≥ 7.0 cm (bulky) versus < 7.0 cm (non-bulky)
Subjects will be randomized in a 1:1 ratio to either R2-CHOP or placebo-R-CHOP.  The subject 
identification number (ID) assigned by the IVRS will identify the subject for all aspects of the 
study.  The randomization schedule will be generated by the IVRS vendor based on a permuted-
block randomization method.  
This study is a double-blind study, which means that Celgene, as well as the investigator and 
subject, will be blinded to treatment assignment (R2-CHOP or placebo-R-CHOP).  
Sample Size Determination
For the primary endpoint PFS, the superiority of R2-CHOP versus placebo-R-CHOP will be 
tested.  The hypotheses on superiority are defined as: 
H0: HR (test versus control) = 1 versus H1: HR (test versus control) < 1
where HR (test versus control) is the hazard ratio of R2-CHOP arm (test) over placebo-R-CHOP 
arm (control). One hundred and ninety-two (192) PFS events (progression or deaths) out of 560
subjects will have 90% power to detect a 37.5% hazard reduction in disease progression, ie, HR 
(test versus control) = 0.625 for the R2-CHOP arm versus placebo-R-CHOP arm using a 2-sided
test with a significance level of 0.05.  This sample size has already taken into account the pre-
planned interim analysis for futility at 50% of the information.      
With an adequate peak enrollment rate of 18 subjects per month that is reached in 9 months and 
the assumption that the median PFS in the control arm (placebo-R-CHOP) is about 24 months, it 
is estimated that the required 50% information, or 96 PFS events, for the interim PFS futility 
analysis will be available approximately 28 months from the start of enrollment, and the required 
192 PFS events for the final PFS analysis will be available in about 42 months from the start of 
enrollment.
This sample size is calculated using the software EAST 5.4 with a β-spending function of 
Gamma (-4).  Since there is no intention to declare efficacy at the interim PFS analysis, no 
α-spending function is specified.  For a detailed description of stopping boundaries please refer 
to Section 13 Interim Analysis. 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
16
In case the event rate falls below 2 events per month before reaching 192 events, the final 
analysis will be performed when at least 170 events have occurred.  The power of the study will 
be at least 86%.
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
17
5.
GENERAL STATISTICAL CONSIDERATIONS
Reporting Conventions
The summary tables, listings, and any supportive SAS output will include the explanatory 
“headers” that indicate, at a minimum:
!
protocol number
!
data cutoff date
The Summary tables, listings, and any supportive SAS output will include the explanatory 
“footers” that indicate, at a minimum:
!
program source (ie, SAS program name, including the path, run date)
!
data extraction date 
The purpose of the data extraction date is to link the output to the database, either active or 
archived, that is write-protected for replication and future reference.  The program run date is the 
output date which will appear on each output page and will indicate the date the output was 
generated by the analysis program.  Individual source listings will display all the relative values 
supporting corresponding table and figure.
In addition, the following reporting conventions will be implemented:
!
Data from all study centers will be combined for analysis;
!
All stratified efficacy analyses will use the stratification factors including IPI score 
(2 versus ≥ 3), age (< 65 versus ≥ 65 years), and presence of bulky disease (≥ 7.0 cm 
[bulky] versus < 7.0 cm [non-bulky]);  
!
All statistical tests of the treatment effect will be conducted as 2-sided tests;
!
P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as ‘<0.0001’ and p-values that round to 1.000 will be presented as 
‘>0.9999’;
!
Confidence intervals (CIs) will be presented as 2-sided 95% CIs unless otherwise 
specified;
!
Summary statistics will consist of the number and percentage of subjects in each 
category for discrete variables, and the sample size, mean, median, Standard 
Deviation (SD), first quartile (Q1), third quartile (Q3), minimum (Min), and 
maximum (Max) for continuous variables;
!
All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal 
places than the measured value;
!
All percentages will be rounded to one decimal place. The number and percentage of
responses will be presented in the form xx (xx.x), where the percentage is in the 
ry
e, either ac
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The program
The progra
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ll display a
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
18
parentheses.  In the case the numerator is equal to the denominator, the percentage 
should be presented as (100) instead of (100.0);
!
All listings will be sorted for presentation in order of study center, subject, and date 
of procedure or event;
!
All analysis and summary tables will have the analysis population sample size (ie, 
number of subjects) wherever applicable;
!
Baseline is defined as the latest value collected on or before the date when the first 
dose of study treatment is administered.  When the latest values contain retest, the 
retest value will be used as baseline for the analysis.  For subjects who were not 
treated, the baseline value will be defined as the latest value collected on Day 1 of the 
Cycle 1 visit if available; otherwise, the latest value on or prior to the randomization 
date will be used.
Analysis Populations
In this study the following four populations will be defined and used in the analysis and 
presentation of the data.
5.2.1.
Intent-to-treat Population
The Intent-to-treat (ITT) population is defined as all subjects who are randomized into the trial, 
regardless of whether they received study treatment or not. 
The ITT population will be used for the primary efficacy analysis. Subjects will be analyzed 
according to the treatment arm to which they are initially assigned. 
5.2.2.
Modified Intent-to-treat Population 
The modified Intent-to-treat (mITT) population is defined as all subjects who satisfy the 
following conditions: 
!
are randomized
!
have received at least one dose of investigational product 
!
are CD20+, ABC type DLBCL as determined by Central Pathology 
!
are previously untreated
!
have measurable disease at baseline
!
have at least one post-baseline tumor assessment or died after randomization but 
before the assessment
The mITT population will be used as supportive analysis for efficacy.  Subjects will be analyzed 
according to the treatment arm to which they are initially assigned. 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
19
5.2.3.
Safety Population
The Safety population is defined as all subjects who have received at least one dose of 
investigational product.
The Safety population will be used for all safety analyses.  Subjects will be analyzed according 
to the treatment which they actually received.
0$


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
20
6.
SUBJECT DISPOSITION
All subjects randomized will be included in subject disposition analyses listed below.  
The following analysis populations will be summarized and the median follow-up time (months) 
in each population will be calculated and reported: 
1. ITT population
2. mITT population
3. Safety population
The study treatment includes a combination of both lenalidomide or placebo with R-CHOP.  
Each of the components (lenalidomide/placebo or R-CHOP) may be interrupted or even 
discontinued due to its own reasons, however, the study treatment should be viewed as an 
integrated unit (R2-CHOP or placebo-R-CHOP).  Subjects who completed both 6 cycles of 
lenalidomide/placebo and 6 cycles of R-CHOP are considered to have completed the protocol 
specified study treatment.  Subjects who discontinued either lenalidomide/placebo or R-CHOP 
during or before Cycle 6 are not considered to have completed the protocol specified study 
treatment.
The pre-specified optional extra 2 doses of rituximab and consolidation radiotherapy are not 
considered as study treatment for data analysis purpose.   
Subject disposition will be reported in the ITT, mITT, and Safety populations separately for the 
following categories: 
1. Subjects completed 6 full cycles of the protocol specified study treatment     
2. Subjects completed 6 cycles of R-CHOP but prematurely discontinued 
lenalidomide/placebo
-
primary reason for lenalidomide/placebo discontinuation
3. Subjects completed 6 cycles of lenalidomide/placebo but prematurely discontinued
R-CHOP
-
primary reason for R-CHOP discontinuation
4. Subjects prematurely discontinued both lenalidomide/placebo and R-CHOP
-
primary reason for lenalidomide/placebo discontinuation 
-
primary reason for R-CHOP discontinuation
5. Subjects prematurely discontinued lenalidomide/placebo while ongoing on R-CHOP 
-
primary reason for lenalidomide/placebo discontinuation
6. Subjects prematurely discontinued R-CHOP while ongoing on lenalidomide/placebo 
-
primary reason for R-CHOP discontinuation
7. Subjects ongoing on both lenalidomide/placebo and R-CHOP
8. Subjects entered the Follow-up Period
9. Subjects ongoing in the Follow-up Period
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
21
10. Subjects discontinued from the Study
-
primary reason for study discontinuation
Subjects in the categories of 4-8 are not considered to have completed the protocol specified 
study treatment.
A summary table of randomized subjects by country and site will be provided. A summary table 
of all screen failure subjects by screen failure reason will also be provided. Screened subjects 
include all patients who have signed ICF.
Separate listings will be provided for subjects who completed the protocol specified study 
treatment, for subjects who did not complete the study specified study treatment, and for subjects 
who are ongoing on the treatment.  Further listing will be provided for randomized subjects 
excluded from the mITT and Safety populations with primary reasons for exclusions.  A separate 
listing will be provided for subjects not randomized (ie, Screen Failures), including the primary 
reason for failing screening.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
22
7.
PROTOCOL DEVIATIONS
The protocol deviations and important protocol deviations are identified and assessed by the 
clinical research physician or designee following company standard operational procedure. The 
protocol deviations and important protocol deviations will be summarized by treatment arm in
the ITT population. 
A by-subject listing of subjects with protocol deviations and important protocol deviations in the 
ITT population will be provided. 
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
23
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The demographics and baseline characteristics will be summarized for the ITT, safety, and mITT
populations. Individual subject listings will be provided to support the summary tables.
Demographics
The following demographics will be summarized by treatment arm:
1. Age (years)
2. Weight (kg)
3. Height (cm)
4. Body Mass Index (BMI) (kg/m2)
5. Body Surface Area (BSA) (m2)
6. Sex
7. Race
8. Ethnicity
9. Reproductive Status
Continuous variables will be summarized descriptively (n, Mean, SD, Median, Q1, Q3, Min, 
Max), and categorical variables will be summarized with frequency counts.  
Baseline Characteristics
The following baseline clinical characteristics will be summarized by treatment arm:
1. Eastern Cooperative Oncology Group (ECOG) performance score
2. Baseline creatinine clearance (CrCl) (mL/min) and CrCl category
3. Disease stage of DLBCL at diagnosis
4. Baseline electrocardiogram (ECG)
5. IPI score from IVRS
6. Lactate dehydrogenase (LDH)
7. White blood cell (WBC) count
8. Presence of bulky disease from IVRS
9. Bone marrow involvement
10. Subjects with pre-specified optional two extra doses of rituximab
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
24
11. Subjects with pre-specified optional consolidation radiotherapy
Medical History
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®).  The version of the MedDRA will be indicated in the footnote of relevant tables 
based on the current version used in the clinical data.
A summary of medical and surgical history will be presented by MedDRA system organ class 
(SOC) and preferred term (PT), for the ITT population. A similar summary will be generated for 
the currently active abnormalities only and ITT population, by SOC and PT.
A frequency tabulation of the number of subjects who had at least one prior venous
thromboembolism (VTE) event will be produced by treatment arm, for the Safety population.  
The VTE events include deep venous thrombosis, pulmonary embolism, and other venous 
thrombosis.  In addition, the number of subjects with various number of thrombosis risk factors 
(0, 1, 2, 3, ≥4) will be summarized.  There are 16 thrombosis risk factors considered: Protein C 
deficiency, Protein S deficiency, Anti-thrombin-3 deficiency, Activated protein C resistance, 
Prothrombin gene mutation, Elevated homocysteine level, Antiphospholipid syndrome, Lupus 
Anticoagulant, Estrogen-use, Immobilization, Trauma within past 3 months, Post-operative, 
Obesity, Tamoxifen use, Central Venous Access Device, and Other.
By-subject listings will display medical history and history of VTE events including all relevant 
data collected on the CRF, for the ITT population.    
Prior Therapy
This study is to investigate the treatment effect on subjects with previously untreated ABC type
DLBCL, thus, all subjects enrolled into the study will not have prior therapy for DLBCL.  
However, for subjects with bulky disease, systemic symptoms, compressive disease, elevated 
bilirubin due to lymphoma, or rapidly progressing adenopathies, pre-phase treatment with 
corticosteroids according to local practice is permitted prior to beginning the Treatment Period, 
at the discretion of the investigator. It is recommended to limit the pre-phase treatment to up to 
100 mg / day prednisone or equivalent for 10 days.    
A frequency tabulation of the number of subjects who received the pre-phase prednisone or 
equivalent will be produced as part of prior medications, for the safety population.
Prior and Concomitant Medications
Medications initiated prior to the start of study treatment and continued after the start of study 
treatment will be counted as both prior and concomitant medications.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
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25
8.5.1.
Prior Medications
Prior medications are defined as non-study medications that were started before the date of the 
first dose of study treatment.  A summary showing the number and percentage of subjects who 
took prior medications will be presented for the safety population according to the World Health 
Organization Drug Dictionary (WHO-DD) coding system Anatomical Therapeutic Chemical 
(ATC) classification and drug preferred term. In addition, pre-phase Corticosteroid use will be 
summarized.
8.5.2.
Concomitant Medications
Concomitant medications are defined as any non-study medications that were taken while the 
subject is on the study treatment through 28 days after the last non-zero dose of 
lenalidomide/placebo or any component of R-CHOP, including the optional two additional doses 
of single agent rituximab if administered, whichever is later.  They include the medications that 
were initiated before the first dose of study treatment and continued during the study treatment as 
well as medications that were initiated between the date of the first dose of study treatment
through 28 days after the last non-zero dose of lenalidomide/placebo or any component of R-
CHOP, including the optional two additional doses of single agent rituximab if administered, 
whichever is later.    
A summary showing the number and percentage of subjects who took concomitant medications 
will be presented for the safety population by WHO therapeutic drug class and generic drug 
name. 
Any medications that were initiated more than 28 days after the last non-zero dose of 
lenalidomide/placebo or any component of R-CHOP, including the optional two additional doses 
of single agent rituximab if administered, are not considered concomitant medications.  
However, all non-study medications will be included in by-subject listings.
Growth factors usage will be summarized in three ways.  The number of subjects who received at 
least one growth factor will be summarized, and the days of each growth factor usage will be 
summarized in terms of median, min, and max.  The number of person-cycles with at least one 
growth factor usage during treatment (Cycle 1 – Cycle 6) will be calculated, and similarly, the 
number of person-cycles with a particular growth factor usage will be calculated, and the days of 
usage will be summarized in terms of median, min, and max.  Additionally, by cycle analysis will 
be performed for the number of subjects who received at least one growth factor, and the days of 
each growth factor usage will be summarized in terms of median, min, and max.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
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26
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Study treatment and extent of exposure summaries will be provided in the Safety population. By-
subject listings will be included to support the tabulations described in this section.
As presented in Section 6, study treatment consists of both lenalidomide/placebo and R-CHOP.  
Although either lenalidomide/placebo or R-CHOP, or both, may be discontinued early due to its 
own toxicity, the study treatment is viewed as an integrated regimen (R2-CHOP or 
placebo-R-CHOP).  A subject is classified as “Completed the Protocol Specified Study 
Treatment” only if the subject completed 6 full cycles of both lenalidomide/placebo and R-
CHOP.
All treatment exposures (duration in weeks and in cycles), dose modifications, and treatment 
compliance scores will be summarized based on the first 6 cycles. For subjects with optional 
extra 2 cycles of rituximab, a separate summary will be provided for these extra 2 cycles of 
rituximab in terms of cumulative dose, dose intensity, and relative dose intensity.   
Treatment Duration and Cycles
Lenalidomide/Placebo Treatment Duration (weeks) is defined as: 
[(date of end of lenalidomide/placebo) – (date of first lenalidomide/placebo) + 1]/7
Date of first lenalidomide/placebo is defined as the date of the first non-zero dose of 
lenalidomide/placebo.
Date of end of lenalidomide/placebo is defined as follows:
!
For subjects who completed 6 full cycles of lenalidomide/placebo, the end of 
lenalidomide/placebo is defined as Day 21 of Cycle 6, which is referred to as “date of 
completion” recorded on the eCRF called Treatment Disposition - Lenalidomide/Placebo.
!
For subjects who prematurely discontinued lenalidomide/placebo before or during Cycle 
6, the end of lenalidomide/placebo is the date either the investigator or subject decided to 
prematurely discontinue lenalidomide/placebo, which is referred to as “date of 
discontinuation” recorded on the eCRF called Treatment Disposition -
Lenalidomide/Placebo.
R-CHOP Treatment Duration (weeks) is defined as: 
[(date of end of R-CHOP) – (date of first R-CHOP) + 1]/7
Date of first R-CHOP is defined as the date of the first non-zero dose of rituximab, 
cyclophosphamide, doxorubicin, vincristine, or prednisone or equivalent, whichever is earlier.
Date of end of R-CHOP is defined as follows:
!
For subjects who completed 6 full cycles of R-CHOP, the end of R-CHOP is defined as 
Day 21 of Cycle 6, which is referred to as “date of completion” recorded on the eCRF 
called Treatment Disposition - RCHOP.
!
For subjects who prematurely discontinued R-CHOP before or during Cycle 6, the end of 
R-CHOP is the date either the investigator or subject decided to prematurely discontinue 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
27
R-CHOP, which is referred to as “date of discontinuation” recorded on the eCRF called 
Treatment Disposition - RCHOP.
R-CHOP Individual Component Duration (weeks) is defined as: 
[(date of end of individual component) – (date of first dose of individual component) + 1]/7
Date of first dose of individual component is defined as the date of the first non-zero dose of the 
individual component.
Date of end of individual component is defined as follows:
!
For subjects who completed 6 full cycles of the individual component, the end of 
individual component is defined as Day 21 of Cycle 6, which is referred to as “date of 
completion” recorded on the eCRF called Treatment Disposition - RCHOP.
!
For subjects who prematurely discontinued the individual component before or during 
Cycle 6, the end of individual component is the date either the investigator or subject 
decided to prematurely discontinue the individual component.
Total Treatment Duration (weeks) is defined as: 
[(date of end of treatment) – (date of first treatment) + 1]/7
Date of first treatment is defined as the date of first lenalidomide/placebo or the date of first R-
CHOP, whichever is earlier.
Date of end of treatment is defined as the date of end of lenalidomide/placebo or the date of end 
of R-CHOP, whichever is later.     
Please note that the pre-specified optional extra 2 doses of single agent rituximab at Cycles 7 and 
8 should not be counted as study treatment, therefore should be excluded in treatment duration 
calculation.
Descriptive statistics will be provided for the total treatment duration (weeks) as well as 
lenalidomide/placebo treatment duration and R-CHOP treatment duration.
Total Treatment Cycles is defined as the greatest number of cycles of either
lenalidomide/placebo or R-CHOP a subject completed.  If a subject discontinued R-CHOP 
during Cycle 3 and then discontinued lenalidomide/placebo during Cycle 6, the subject is 
considered as completed 2 cycles of R-CHOP and 5 cycles of lenalidomide/placebo, the total 
number of treatment cycles is 5.  If a subject discontinued R-CHOP during Cycle 3 and 
completed all 6 cycles of lenalidomide/placebo, the total number of treatment cycles is 6.
Lenalidomide/Placebo Treatment Cycles is defined as the number of cycles of 
lenalidomide/placebo the subject completed.
R-CHOP Treatment Cycles is defined as the number of cycles of R-CHOP the subject 
completed.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
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28
R-CHOP Individual Component Cycles is defined as the number of cycles of the individual 
component the subject completed.
The number and percentage of subjects who completed up to 6 cycles of total treatment will be 
provided by each category (ie, < 1 cycle, 1 cycle through 6 cycles).  In addition, the number and 
percentage of subjects who completed up to 6 cycles of lenalidomide/placebo or R-CHOP will be 
provided separately.  
Cumulative Dose
Cumulative dose will be calculated for each individual drug of study treatment
(lenalidomide/placebo, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
or equivalent).  Cumulative dose is defined as the sum of all doses of that drug taken across the 
treatment period in mg (for lenalidomide/placebo and prednisone or equivalent) or mg/m2 (for 
rituximab, cyclophosphamide, doxorubicin, and vincristine).  For placebo, the nominal doses 
recorded on the case report form (CRF) will be used, rather than “zero mg”.
Descriptive statistics of cumulative dose will be provided separately for lenalidomide/placebo, 
rituximab, and each component of chemotherapy.
Dose Intensity
Dose Intensity (DI) during the treatment is defined as the cumulative dose (in mg or mg/m2)
divided by the number of actual dose exposure days.  The days with no dose or zero dose 
recorded on the CRF are excluded from the denominator.
Dose intensity will be calculated separately for each drug of study treatment, and descriptive 
statistics will be provided.  
Relative Dose Intensity
Relative Dose Intensity (RDI) is defined as 100 times the dose intensity divided by the planned 
dose intensity. 
Planned DIs are:
1. For lenalidomide/placebo: 15 mg per day
2. For rituximab: 375 mg/m2 per day
3. For cyclophosphamide: 750 mg/m2 per day
4. For doxorubicin: 50 mg/m2 per day
5. For vincristine: 1.4 mg/m2 per day, noting that there might be a lower planned dose 
intensity (maximum 2 mg per day) for obese or very tall subjects, however, obese or very 
tall subjects are not well defined for programming purpose, thus, 1.4 mg/m2 per day has 
to be used for DI calculation  
6. For prednisone: 100 mg per day
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
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29
Relative dose intensity for each drug of study treatment will be categorized into ≤75%, > 75% to 
≤90%, > 90% to ≤100%, and > 100%, and frequency counts will be provided by treatment arm.
For rituximab, the Cumulative Dose, Dose Intensity, and Relative Dose Intensity will be 
summarized separately for Cycle – Cycle 6 and during the extra 2 cycles.
Dose Reduction/Interruption
Dose reduction/interruption due to AE and other reasons will be summarized by treatment arm. 
For lenalidomide/placebo, dose reduction is defined as any non-zero reduced dose. For any R-
CHOP drugs, dose reduction is defined as any non-zero dose with >20% reduction from the 
planned dose for the first dose, or any non-zero dose with >20% reduction from the previous 
dose for subsequent doses, with AE or any other reason recorded on the CRF for the dose 
assignment.  Dose interruption is defined as any zero dose of lenalidomide/placebo or any R-
CHOP drugs with AE or any other reason recorded on the CRF for the dose assignment. Time to 
first dose reduction/interruption will be calculated from the first dose of any study drug.
The overall number and percentage of subjects who have at least one dose reduction/interruption
for lenalidomide/placebo and R-CHOP will be separately provided for each reason by treatment 
arm.  Time to first dose reduction/interruption due to any reason will be descriptively provided.  
Time to first dose reduction/interruption due to AE will also be descriptively provided.   
In addition, the percent of cycles with dose reduction/interruption due to AE will be determined 
for each subject for lenalidomide/placebo and R-CHOP separately and summarized by treatment 
arm.  The percent of cycles with dose reduction/interruption due to AE for lenalidomide/placebo 
is defined as the number of cycles during which the dose of lenalidomide/placebo was 
reduced/interrupted due to AE divided by the total number of cycles of study drug the subject 
received.  The percent of cycles with dose reduction/interruption due to AE for R-CHOP is 
defined as the number of cycles during which the dose of any component of R-CHOP was 
reduced/interrupted due to AE divided by the total number of cycles of study drug the subject 
received.  The ratio is then multiplied by 100 for easy interpretation.
The percent of cycles with dose reduction/interruption due to AE will be reported as 
5 categories: 0% of cycles, > 0 to ≤ 25% of cycles, > 25 to ≤ 50% of cycles, > 50 to ≤ 75% of 
cycles, and > 75 to ≤ 100% of cycles. The number and percentage of subjects in each category 
will be reported for lenalidomide/placebo and R-CHOP separately by treatment arm.
Treatment Compliance 
The R2-CHOP or placebo-R-CHOP regimen will be administered over a 21-day cycle (with the 
possible exception of Cycle 1, which may last 22 days).  In each cycle of treatment 
lenalidomide/placebo should be administered for 14 days, prednisone or equivalent for 5 days,
and rituximab, cyclophosphamide, doxorubicin, and vincristine for 1 day.  
For each component of the IPs, the treatment compliance rate (%) for each subject will be 
defined below.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
30
Lenalidomide/placebo compliance rate (%) = 100 x 
	
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Rituximab compliance rate (%) = 100 x 
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Cyclophosphamide compliance rate (%) = 100 x 
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Doxorubicin compliance rate (%) = 100 x 
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Vincristine compliance rate (%) = 100 x 
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For each component of the IPs, the treatment compliance rate (%) will be presented with the 
following categories: < 75%, ≥ 75% to ≤ 100%, > 100% to < 120%, and ≥120%.
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Lenalidomide (CC-5013)
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Celgene Corporation
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31
10.
EFFICACY ANALYSIS
All efficacy evaluations will be conducted in the ITT population. Supportive analysis of the 
primary and key secondary efficacy endpoints in the mITT population will be conducted for the 
final analysis. 
Statistical comparisons will be made between R2-CHOP and placebo-R-CHOP arms. Efficacy 
results that will be considered statistically significant after consideration of the strategy for 
controlling the family-wise Type 1 error rate are described in Section 10.1, Multiplicity. All 
statistical tests will be 2-sided at the significance level of α = 0.05, and the corresponding 
p-values and 2-sided 95% CIs for intended point estimates will be reported.
Derived efficacy parameters will be displayed in a by-subject listing, and further listings will 
present all relevant information from the Independent Response Adjudication Committee (IRAC) 
assessments, survival status, subsequent anti-lymphoma therapy, and ECOG performance status.
Multiplicity
A step-down procedure will be used to control the family-wise Type 1 error rate for the primary 
efficacy endpoint PFS and the key secondary efficacy endpoint EFS. The primary efficacy 
endpoint PFS will be tested first. The key secondary efficacy endpoint EFS will only be tested if 
the primary efficacy endpoint demonstrates superiority at α = 0.05 level for R2-CHOP over 
placebo-R-CHOP.  The analyses will be based on the ITT population.
Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint is PFS, which is defined as the time (months) from the date of 
randomization to the date of disease progression or death (any cause), whichever occurs earlier.
Relapse from CR will be considered as disease progression throughout this document. Disease 
progression will be determined based on the Revised Response Criteria for Malignant 
Lymphoma (Error! Reference source not found., 2014).  The PFS analysis based on the IRAC 
assessment will serve as the primary analysis.  The PFS analysis based on the local investigator’s 
assessment will serve as the sensitivity analysis.
Subjects who did not experience disease progression and who did not die before the clinical data 
cutoff date will be censored at the date of last adequate response assessment.
In addition, the following two sets of censoring rules will be applied to the PFS analysis.  
The first set of censoring rules will follow the Food and Drug Administration’s (FDA’s)
“Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics” (FDA, 2007).  Specifically, subjects who received new anti-lymphoma therapy 
without objective disease progression will be censored at the date of the last adequate response 
assessment prior to the new anti-lymphoma therapy.  The analysis with this set of censoring rules 
will serve as the primary analysis for PFS.  The detailed censoring rules are illustrated in the 
Table 2 below.
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Table 2:
Censoring Rule for PFS Endpoint (Primary Analysis)  
Situation
Date of Progression or Censoring
Outcome
No baseline tumor assessments
Randomization
Censored
Progression documented at or 
between scheduled visits
Date of first adequate assessmenta showing 
disease progression
Event (Progressed)
Progression or death 
documented immediately after 
two or more missed scheduled 
tumor assessments   
Date of last adequate assessmenta with 
evidence of no progression
Censored 
Death at or between scheduled 
visits
Date of death
Event (Died)
Progression or death after 
subsequent systemic anti-
lymphoma therapy startedb
Date of last adequate assessmenta with 
evidence of no progression prior to the start 
of subsequent systemic anti-lymphoma 
therapy
Censored
No progression or death
Date of last adequate assessmenta with
evidence of no progression prior to the start 
of subsequent systemic anti-lymphoma 
therapy (if any).
Censored
FDA = Food and Drug Administration.
a Adequate assessment is defined as documented assessment recorded in the clinical data.
b The pre-specified optional extra 2 doses of rituximab and consolidation radiotherapy are not considered as 
subsequent systemic anti-lymphoma therapy, if determined before randomization.
Note: Only the first applicable date (either progressed or censored) will be assigned to each subject. 
Source: FDA’s “Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics” (FDA, 2007).  
In order to avoid possible informative censoring, eg, the administration of new anti-lymphoma 
therapy may be related to factors associated with the actual survival time, a sensitivity analysis 
for PFS will be performed using the second set of censoring rules that follows the European 
Medicines Agency’s (EMA’s) guideline “Appendix 1 to the Guideline on the Evaluation of 
Anticancer Medicinal Products in Man” (EMA, 2012).  Specifically, disease progression will be 
counted as PFS event regardless of whether subjects receive new anti-lymphoma therapy or miss 
more than one assessment prior to that.  The detailed censoring rules are illustrated in the Table 3
below:
Table 3:      Censoring Rule for PFS Endpoint (Sensitivity Analysis)
Situation
Date of Progression or Censoring
Outcome
No baseline tumor assessments
Randomization
Censored
Progression documented at or 
between scheduled visits
Date of first adequate assessmenta showing 
disease progression
Event (Progressed)
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Celgene Corporation
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Progression documented after 
two or more missed scheduled 
tumor assessments
Date of first adequate assessmenta showing 
disease progression
Event (Progressed)
Death after two or more missed 
scheduled tumor assessments
Date of death
Event (Died)
Death at or between scheduled 
visits
Date of death
Event (Died)
Progression after subsequent 
systemic anti-lymphoma therapy
startedb
Date of first adequate assessmenta showing 
disease progression
Event (Progressed)
No progression or death
Date of last adequate assessmenta with 
evidence of no progression
Censored
EMA = European Medicines Agency.
a Adequate assessment is defined as documented assessment recorded in the clinical data.
b The pre-specified optional extra 2 doses of rituximab and consolidation radiotherapy are not considered as 
subsequent systemic anti-lymphoma therapy, if determined before randomization.
Note: Only the first applicable date (either progressed or censored) will be assigned to each subject. 
Source: EMA’s guideline “Appendix 1 to the Guideline on the Evaluation of Anticancer Medicinal Products in Man” 
(EMA, 2012).
These censoring rules will be applied to determine PFS events as assessed by IRAC and by
investigator separately.
The final analysis for PFS will be conducted when a total of at least 192 PFS events in the ITT 
population occurred by IRAC assessment and PFS events will be re-determined per Table 2
censoring rule. In case the event rate falls below 2 events per month before reaching 192 events, 
the final analysis will be performed when at least 170 events have occurred.  The power of the 
study will be a least 86%.
The survival distribution of PFS will be estimated using Kaplan-Meier method (without 
adjusting for the stratification factors) and graphically presented.  The median PFS time (in 
months) including 2-sided 95% CI for each treatment arm will be provided.  In addition, the PFS 
rate at every 6 months will be provided along with its standard error.
The stratified log-rank test will be performed to evaluate treatment efficacy for the primary 
analysis. The stratification factors for analysis include IPI score (2 versus ≥ 3), presence of bulky 
disease (≥ 7.0 cm [bulky] versus < 7.0 cm [non-bulky]), and age (< 65 versus ≥ 65 years). The 
experimental arm 
(R2-CHOP) will be declared superior if the 2-sided p-value from the stratified log-rank test is 
≤ 0.05 in favor of the experimental arm. The un-stratified log-rank test will be performed as 
sensitivity analysis.
Conventionally, hazard ratio with 2-sided 95% CI will be estimated using the Cox proportional 
hazards model adjusting for the stratification factors. Proportional hazard assumption will be 
evaluated. Sensitivity analyses will be provided if deemed appropriate.
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Lenalidomide (CC-5013)
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Celgene Corporation
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In summary, the final PFS analysis will be performed based on IRAC assessments as well as 
based on investigator assessments, using the censoring rules in Table 2 and Table 3 below:
Table 3, both in ITT and mITT populations.  The stratified PFS analysis based on IRAC 
assessments using the censoring rules in Table 2 in the ITT population is the primary analysis, 
and other PFS analyses in the ITT population are sensitivity analyses.  All analyses in the mITT 
population are supportive.
Analyses of Secondary Efficacy Endpoints
All secondary efficacy endpoints will be analyzed in the ITT population.  The key secondary 
endpoint will also be analyzed in the mITT population.  
All secondary efficacy endpoints will be analyzed at the time of final PFS analysis.  
10.3.1.
Key Secondary Endpoint
The key secondary efficacy endpoint is EFS, which is defined as the time (months) from 
randomization until occurrence of one of the following events, whichever occurs first: 
!
Disease progression 
!
Initiation of subsequent systemic anti-lymphoma therapy
!
Death due to any cause 
Pre-specified optional therapies such as the extra 2 doses of single agent rituximab after Cycle 6 
or consolidation radiotherapy will not count as an EFS event (initiation of subsequent systemic 
anti-lymphoma therapy) if the decision to treat and the location to be treated is determined prior 
to randomization.
Subjects who did not experience any of these events defined in the categories above before the 
clinical data cutoff date will be censored at date last known alive.
The primary EFS will be EFS incorporating the IRAC assessments, while EFS incorporating 
investigator assessments will be supportive.
The survival distribution of EFS will be estimated using Kaplan-Meier method (without 
adjusting for the stratification factors) and graphically presented.  The median EFS time (in 
months) including 2-sided 95% CI for each treatment arm will be provided.  In addition, the EFS 
rate at every 6 months will be provided along with its standard error.
The stratified log-rank test will be performed to evaluate treatment efficacy. The stratification 
factors for analysis include IPI score (2 versus ≥ 3), presence of bulky disease (≥ 7.0 cm [bulky] 
versus < 7.0 cm [non-bulky]), and age (< 65 versus ≥ 65 years). The experimental arm will be 
declared superior if the 2-sided p-value from the stratified log-rank test is ≤ 0.05 in favor of the 
experimental arm. The unstratified log-rank test will be performed as sensitivity analysis.
Conventionally, hazard ratio with 2-sided 95% CI will be estimated using the Cox proportional 
hazards model adjusting for the stratification factors. But the treatment effect will be determined 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
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35
by the p-value from the stratified log-rank test, not by this 95% CI for the hazard ratio. In 
addition, hazard ratio with 2-sided 95% CI will be estimated using the Cox proportional hazards 
model without adjusting for the stratification factors
To control the family-wise Type 1 error rate, the sequential gate keeping approach is used so that 
the EFS analysis result in the ITT population is interpretable only if the primary PFS analysis 
result demonstrates superiority at α = 0.05 level for R2-CHOP over placebo-R-CHOP.
10.3.2.
Other Secondary Endpoints
The other secondary endpoints are OS, CR rate, ORR, Duration of Response, Duration of CR, 
TTNLT, and HRQoL as measured by EQ-5D and FACT-Lym.  Since only the primary endpoint 
PFS and the key secondary endpoint EFS are considered for controlling the family-wise Type 1 
error rate, any statistically significant treatment effect on these other secondary endpoints cannot 
be interpreted as confirmatory, but rather informatory.
Overall survival is defined as the time (months) from randomization until death due to any cause.  
Subjects who withdrew consent for the study will be censored at the time of withdrawal.  
Subjects who are still alive before the clinical data cutoff date and subjects who are lost to 
follow-up will be censored at date last known alive.
Overall survival will be analyzed in the same way as for the PFS and EFS except for its own 
censoring rule as described in the above paragraph. In addition, the OS rate at every 6 months
will be provided along with its standard error.
10.3.2.1.
Complete Response Rate and Objective Response Rate
The CR rate is defined as the percentage of subjects who ever achieved a complete response after 
initiation of the study treatment and prior to initiation of subsequent systemic anti-lymphoma
therapy.  Objective response rate is defined as the percentage of responders, defined as subjects 
who ever achieved at least a partial response (PR) after initiation of the study treatment and prior 
to initiation of subsequent systemic anti-lymphoma therapy. Subjects who do not have any 
adequate response assessments during this period will not be considered as responders.
The CR rate and ORR will be tested by Cochran-Mantel-Haenszel (CMH) method with the three 
stratification factors as strata.  The stratification factors include IPI score (2 versus ≥ 3), presence 
of bulky disease (≥ 7.0 cm [bulky] versus < 7.0 cm [non-bulky]), and age (< 65 versus ≥ 65
years).  The un-stratified (ie, Pearson’s chi-squared) test will also be performed as a sensitivity 
analysis.
The CR rate and ORR based on IRAC assessment and investigator assessment will be analyzed 
separately.
A cross-tabulation of the best responses by IRAC assessment versus best responses by 
investigator assessment will also be presented.
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Lenalidomide (CC-5013)
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Celgene Corporation
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36
10.3.2.2.
Duration of Complete Response
Duration of complete response will be calculated for complete responders only.  It is defined as 
the time (months) from documented initial complete response prior to initiation of subsequent 
systemic antilymphoma therapy until documented disease progression or death, whichever 
occurs earlier.  Subjects who have not progressed or died at the time of the analysis will be 
censored at the date of last response assessment demonstrating no disease progression.  Subjects 
who change treatment without evidence of disease progression will be censored at the last 
assessment showing no progression prior to treatment change. 
Duration of complete response will be analyzed in the same way as for the OS except for its own 
censoring rule as described in the above paragraph.
Duration of complete response based on IRAC assessment and investigator assessment will be 
analyzed separately.
10.3.2.3.
Duration of Response
Responders will be defined as subjects who ever achieved at least a partial response (PR) after 
initiation of the study treatment and prior to initiation of subsequent systemic anti-lymphoma 
therapy. Duration of response will be calculated for responders only.  It is defined as the time 
(months) from documented initial response prior to initiation of subsequent systemic 
antilymphoma therapy until documented disease progression or death, whichever occurs earlier.  
Subjects who have not progressed or died at the time of the analysis will be censored at the date 
of last response assessment demonstrating no disease progression.  Subjects who change 
treatment without evidence of disease progression will be censored at the last assessment 
showing no progression prior to treatment change. 
Duration of response will be analyzed in the same way as for the OS except for its own censoring 
rule as described in the above paragraph.
Duration of response based on IRAC assessment and investigator assessment will be analyzed 
separately.
10.3.2.4.
Time to Next Lymphoma Therapy (TTNLT)
Time to next lymphoma therapy is defined as the time (months) from randomization to the time 
of treatment change for the next lymphoma treatment.  Subjects without treatment change will be 
censored at date last known alive.  Pre-specified optional therapies such as the extra 2 doses of 
single agent rituximab after Cycle 6 or consolidation radiotherapy will not count as treatment 
change for the next lymphoma therapy if the decision to treat and the location to be treated are
determined prior to randomization.
Time to next lymphoma therapy will be analyzed in the same way as for the OS except for its 
own censoring rule as described in the above paragraph.
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own cens


Lenalidomide (CC-5013)
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Celgene Corporation
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37
10.3.2.5.
Health-related Quality of Life
Data on HRQoL will be collected using the standardized EQ-5D and FACT-Lym health 
measurement instruments.  The detailed analysis of ED-5D and FACT-Lym will be addressed in 
a separate analysis plan and performed by an external vendor.
Subgroup Analysis
In order to accurately evaluate treatment effect in a more homogeneous population, the primary 
endpoint PFS, key secondary endpoint EFS, and modified PFS will also be analyzed within the 
following subgroups:
!
IPI score (2 versus ≥ 3);
!
Presence of bulky disease (≥ 7.0 cm [bulky] versus < 7.0 cm [non-bulky]);
!
Age (< 65 versus ≥ 65 years versus ≥ 80 years);
!
Sex (male versus female);
!
Baseline creatinine clearance (≥ 30 to < 60 mL/min versus ≥ 60 mL/min).
!
Additional Cycle(s) of Rituximab (Yes vs No)
!
Pre-phase steroid (Yes vs No)
!
Central Pathology Lab (for primary endpoint only)
These subgroup analyses are almost identical to the PFS and EFS analysis specified in Sections 
10.2 and 10.3.1 with two exceptions.  The treatment effect will be evaluated by unstratified 
log-rank test and the hazard ratio will be estimated using the Cox proportional hazards model
without adjusting for the stratification factors.
These subgroup analyses will be performed in the ITT population.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
38
7,21
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-DLC-002
Celgene Corporation
Confidential and Proprietary
39
 
 
Assessing Study Center Effect and Treatment-by-Center Interaction
This study is a multicenter study and has planned to involve approximately 150 study sites to 
randomize a total of 560 subjects. No single site will have a sufficient number of subjects to 
allow a meaningful evaluation of the site effect and treatment-by-site interaction effect;
therefore, data from all sites will be pooled together in analysis.
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Lenalidomide (CC-5013)
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Celgene Corporation
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11.
SAFETY ANALYSIS
The purpose of this section is to define the safety parameters for the study. All analyses of safety 
data will be conducted in the Safety population.
The safety analysis will include AEs, laboratory evaluations, vital signs, physical examinations, 
and multi gated acquisition (MUGA) scans.
Adverse Events
All adverse events will be coded using the MedDRA®.  The version of the MedDRA will be 
indicated in the footnote of relevant AE tables based on the current version used in the clinical 
data.
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAEs) which 
are defined as any AEs that started between the date of first dose of study treatment and 28 days 
after the date of last non-zero dose of lenalidomide/placebo or any component of R-CHOP, 
including the optional two additional doses of single agent rituximab if administered, whichever 
is later.
A treatment-related TEAE is defined as a TEAE which the investigator considered suspected of 
being related to any component of the study drug.
TEAEs related to lenalidomide/placebo are those TEAEs that have “suspected” relationship to 
lenalidomide/placebo.
TEAEs related to R-CHOP are those TEAEs that have “suspected” relationship to rituximab, 
cyclophosphamide, doxorubicin, vincristine, or prednisone or equivalent. 
The frequency of TEAEs will be summarized by MedDRA SOC and PT. The intensity of AEs 
will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 or higher, except for tumor flare reaction (TFR), 
which will be defined using CTCAE version 3. For all other AEs not described in the CTCAE 
criteria, the intensity will be assessed by the investigator as mild (Grade 1), moderate (Grade 2), 
severe (Grade 3), life-threatening (Grade 4) or death (Grade 5).
If a subject experiences the same AE more than once with different toxicity grade, then the event 
with the highest grade will be tabulated once in “by grade” tables.    If a subject experiences 
multiple AEs under the same preferred term (system organ class), then the subject will be 
counted only once for that preferred term (system organ class).
11.1.1.
Overview of TEAE
The number and percentage of subjects experiencing TEAEs will be summarized in the 
following categories by treatment arm:
!
All TEAEs
!
Treatment-related TEAEs
!
All TEAEs with CTCAE Grade 3 or higher
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Lenalidomide (CC-5013)
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Celgene Corporation
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!
Grade 3 or 4 TEAEs
!
Treatment-related TEAEs with CTCAE Grade 3 or higher
!
Treatment-related Grade 3 or 4 TEAEs
!
All serious TEAEs
!
Treatment-related serious TEAEs
!
All TEAEs leading to discontinuation of lenalidomide/placebo
!
All TEAEs leading to discontinuation of R-CHOP
!
All TEAEs leading to discontinuation of both lenalidomide/placebo and R-CHOP
!
All TEAEs leading to lenalidomide/placebo dose reduction/interruption
!
All TEAEs leading to dose reduction/interruption in any component of R-CHOP 
!
All Grade 5 TEAEs 
11.1.2.
TEAEs by System Organ Class and Preferred Term 
In addition to summary tables for an overview of TEAEs, the number and percentage of subjects 
experiencing TEAEs will be tabulated by treatment arm and the MedDRA SOC and PT, in the 
same categories as listed in Overview of TEAE as well as additional categories as listed below:
!
All TEAEs leading to discontinuation of each component of R-CHOP
!
All TEAEs leading to dose reduction/interruption in any component of R-CHOP 
!
All TEAEs by maximum CTCAE Grade
!
Pre-treatment AEs
!
Common TEAEs (defined as events occurring for more than 5% of subjects in a 
treatment arm)
!
TEAEs by cycle of onset
Treatment-emergent adverse events will also be summarized in terms of exposure adjusted 
incidence rate (EAIR) per 100 person-years by treatment arm.  For a particular TEAE, the EAIR
per 100 person-years is defined as:
,-,./ # -0 ,ℎ., 2343 05-6 .// 789:;<,7 =85>?@ ,ℎ; ;?,>5; 7,8=A
∑(=.,; -0 ;?= -0 ,5;.,6;?, −=.,; -0 0>57, ,5;.,6;?, + 1)/(365.25 ∗100)
where the denominator is the sum of total dose exposures counting all subjects in terms of 100 
person-years.  Please refer to Section 9.1 for definition of date of end of treatment and date of 
first treatment.       
In addition, the number and percentage of subjects experiencing any TEAE will also be 
summarized by SOC and PT in the following subgroups: 
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Lenalidomide (CC-5013)
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Celgene Corporation
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42
∀
Age (< 65 versus ≥ 65 years versus ≥ 80 years) 
∀
Sex (male versus Female)
∀
Baseline creatinine clearance (≥ 30 to < 60 mL/min versus ≥ 60 mL/min)
∀
IPI score (2 versus ≥3)
∀
Presence of bulky disease (≥ 7.0 cm [bulky] versus < 7.0 cm [non-bulky])
The AE tables will be presented in descending order of frequency by SOC, and descending order 
of PT within each SOC. The frequency is determined by the R2-CHOP arm.  A table of TEAEs 
by decreasing frequency of PT only, and a table of TEAEs by decreasing frequency of SOC only
will be provided separately.
All AEs with corresponding attributes will be displayed in a by-subject listing. AEs leading to 
discontinuation from or reduction/interruption of treatment, events classified as NCI CTCAE 
grade 3 or higher, SAEs, selected AEs, and neoplasms benign, malignant and unspecified 
(including cysts and polyps) will also be displayed in separate by-subject listings. 
11.1.3.
Death 
The number of deaths and the primary cause of death will be tabulated by treatment arm.  The 
tabulation will include all deaths that occurred from the first dose of study treatment, deaths that 
occurred from the first dose of study treatment until 28 days after the last non-zero dose of 
lenalidomide/placebo or any component of R-CHOP, including the optional two additional doses 
of single agent rituximab if administered, whichever is later, and deaths that occurred more than 
28 days after the last non-zero dose of lenalidomide/placebo or any component of R-CHOP, 
including the optional two additional doses of single agent rituximab if administered, whichever 
is later.  All deaths will be presented in a by-subject listing, and a further listing will display 
deaths within 28 days of last non-zero dose of lenalidomide/placebo or any component of R-
CHOP, including the optional two additional doses of single agent rituximab if administered, 
whichever is later.  
Selected Adverse Events 
11.2.1.
AE of Special Interest
AE of special interest (AESI) categories will use standardized MedDRA query (SMQ) (search 
strategy according to MedDRA Version as used for AE coding), sub-SMQ, SOC, higher level 
term (HLT), or list of PTs. The SPMs are selected AEs, but the assessment of SPMs will be 
directly from the SPM clinical dataset and described in Section 11.2.2.  The following AESI
categories which are representative of the important identified and potential risks in the Revlimid 
Risk Management Plan will be included in the analysis:
!
Neutropenia
!
Infection
!
Thrombocytopenia
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!
Bleeding
!
Cardiac Arrhythmias
!
Cardiac Failure
!
Ischaemic Heart Disease (including Myocardial Infarction)
!
Arterial Thromboembolism (ATE) Events
!
Venous Thromboembolism (VTE) Events
!
Renal Failure
!
Peripheral Neuropathy
!
Diarrhea 
!
Constipation
!
Cutaneous Reactions
!
Hypersensitivity 
!
Angioedema
!
Hepatic Disorders
!
Tumour Lysis Syndrome
!
Tumor Flare Reaction
!
Teratogenicity
!
Interstitial Lung Disease (Interstitial pneumonitis)
!
Mixed Thromboembolism
Please note that these AESI categories might be updated/revised each time when the MedDRA 
version is updated.  
The number and percentage of subjects by SOC and PT will be summarized for the following AE 
categories:
!
Treatment-emergent AESIs
!
Grade 3 or 4 treatment-emergent AESIs
!
Treatment-emergent serious AESIs
11.2.2.
Second Primary Malignancy 
Events of SPMs will be tabulated by treatment arm for the following categories:
!
All SPMs (invasive and non-invasive SPMs)
!
All invasive SPMs (hematologic and solid tumor SPMs)
!
All hematologic SPMs 
l pneumo
pneumonin
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es might 
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Treatment
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!
All solid tumor SPMs
!
All non-invasive SPMs (non-melanoma skin cancers)
For each of the above SPM categories, SPMs will be further tabulated using the MedDRA 
preferred term.  Each subject is counted only once within each SPM category as well as within 
each preferred term.
Additionally, the number and percentage of subjects with SPMs who died and those who did not 
die will be tabulated by SPM category.  
It should be noted that these analyses with regard to SPMs are based on the number of subjects
with at least one SPM and not the total number of SPMs.
For each SPM category, time to onset will be calculated as time (in months) from the start of the 
study treatment to the onset of the SPM for each affected subject. For the subjects with more 
than one new malignancy within an SPM category, the onset of the earliest SPM will be used. 
Time to onset will be summarized descriptively by treatment arm for each SPM category.
For each SPM category, the incidence rate per 100 person-years will be calculated as: (the 
number of subjects with any SPM in the SPM category/total person-years) * 100.  Total person-
years are defined as the total time from the date of first treatment to the first onset date of the 
specified SPM for subjects with the specified SPM plus the total time from the date of first 
treatment to the date of the last follow-up or death for subjects without the specified SPM.  
Incidence rates per 100 person-years and the 95% confidence intervals will be calculated for 
each treatment arm and SPM category. 
By-subject listings of SPMs, demographic and baseline characteristics, prior cancer history and 
assessments, prior cancer regimen treatments and procedures (each for subjects with SPM), and 
SPM regimen treatments and procedures will be provided.  Subjects with SPM before any 
salvage therapy, and after any salvage therapy will also be presented in listings along with the 
response and survival status of subjects with SPM.
Clinical Laboratory Evaluations
Clinical laboratory values from the central laboratories will be graded according to CTCAE
version 4.03 or higher for applicable tests.
Laboratory values at baseline, at each post-baseline visit and change from baseline will be 
descriptively summarized by treatment arm.  Important laboratory parameters (hemoglobin, 
absolute neutrophil count, platelet count) at baseline and at each post-baseline visit will be 
graphically presented. 
The frequency distributions for shift from baseline to the worst (maximum) grade post-baseline 
will be presented by treatment arm for each laboratory test. For each laboratory test the baseline 
grade and the worst grade post-baseline will be determined for each subject.  For laboratory
values that are normal or slightly abnormal without a grade, the Grade 0 (G0) is assumed.
In addition, the frequency of subjects with values below, within, and above the normal ranges at 
baseline and at each post-baseline visit will be summarized by treatment arm.
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Listings of clinical laboratory data from central laboratory with abnormal flags will be provided 
by subjects and tests. Listings will also be provided for the local laboratory data.
11.3.1.
Hematology
Laboratory hematology tests include: hemoglobin, hematocrit, WBC count with differential, 
absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and platelet count.
11.3.2.
Clinical Chemistry
Laboratory chemistry tests include: albumin, alkaline phosphatase, alanine aminotransferase 
(ALT), aspartate transaminase (AST), bilirubin (total), calcium, chloride, creatinine, glucose, 
phosphorous, potassium, sodium, total protein, blood urea nitrogen (BUN), LDH, and uric acid. 
11.3.3.
Other Laboratory Tests
Other laboratory tests include: serum immunoglobulin (Ig) measurement includes IgA, IgG, IgM, 
and thyroid stimulating hormone (TSH).
For female subjects of childbearing potential, the pregnancy test results (negative, positive) will 
be summarized for each visit by treatment arm and all pregnancy data will be displayed in a by-
subject listing.
Vital Sign Measurements
Vital signs include weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), body 
temperature, and pulse.  The normal ranges of vital signs are defined below:
!
SBP
Normal (90 – 119 mmHg, inclusive)                                        
!
DBP
Normal (60 – 79 mmHg, inclusive)                                        
!
Body Temperature
Normal (36.1 – 37.8 °C, inclusive)
!
Pulse
Normal (60 – 100 bpm, inclusive) 
Vital signs at baseline, at each post-baseline visit and change from baseline will be descriptively 
summarized by treatment arm.  
In addition, the frequency distributions for shift from baseline to the treatment
discontinuation/completion visit in below, within, or above the normal ranges will be displayed 
in cross–tabulations for each treatment arm.
All vital sign results will also be presented in a by-subject listing.
Physical Examination
Physical examination findings at baseline and each post-baseline visit will be summarized in 
frequency tables and displayed in a by-subject listing.
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Cardiac Function Tests
The baseline ECG interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’ and ‘Abnormal, clinically 
significant’ by treatment arm with the other baseline characteristics (see Section 8.2).
The results of MUGA scan or echocardiography at baseline, at end of treatment and change from 
baseline will be descriptively summarized by treatment arm.  In addition, the frequency 
distributions for shift from baseline to end of treatment in left ventricular ejection fraction 
(LVEF) category ‘LVEF < 45%’ and ‘LVEF ≥ 45%’ will be displayed in cross–tabulations for 
each treatment arm.  A by-subject listing will display all LVEF results.   
   
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or r 


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12.
QUALITY OF LIFE ANALYSIS
Data on the standardized EQ-5D and FACT-Lym health measurement instruments will be 
collected in this study and analyzed as other secondary endpoints that are described in the
Section 10.3.2.5.
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13.
INTERIM ANALYSIS
An interim analysis for futility only is planned for the PFS at 50% information level, ie, when 
there are 96 PFS events assessed by IRAC and PFS events will be re-determined as per Table 2
censoring rule in the ITT population.  All subjects who have been randomized by the clinical 
data cutoff date for the interim analysis will be included in the interim analysis.
The PFS analysis specified in the Section 10.2 will be examined at interim for futility. The 
futility determination will be based on the PFS by IRAC assessment using Table 2 censoring 
rule.  The other PFS analyses are sensitivity analyses.  
A stratified log-rank test will be performed, and its p-value will be compared with the futility 
boundary.  The boundary for declaring futility of the experimental arm (R2-CHOP) to the control 
arm (Placebo-R-CHOP) is based on a ß-spending function of Gamma (-4) with overall β = 90%.
If a 2-sided p-value from the stratified log-rank test is ≤ 0.8373 in the direction in favor of the 
experimental arm at the interim analysis, the trial should continue until the required 192 PFS 
events in the ITT population are observed.
If the 2-sided p-value is > 0.8373 or the log-rank test finds in favor of the control arm at the 
interim analysis, the Data Monitoring Committee (DMC) may recommend stopping the trial for 
futility.  However, this futility boundary is a non-binding boundary, which means that the study 
does not have to stop if the futility boundary is crossed at the interim analysis.  The study can 
continue, if so desired, to the final analysis for efficacy without inflating the Type 1 error or 
losing power.
The analysis of PFS by investigator assessment and PFS using Table 3 censoring rule will also 
be provided.  In order to avoid potential multiplicity issues, the stopping rule for futility analysis 
is solely based on the primary analysis of PFS, ie, the PFS by IRAC assessment using Table 2 
censoring rule.
The results of other efficacy endpoints such as EFS, OS, and ORR may be provided if it is 
desirable to review them by DMC.
No subgroup analysis will be performed. The interim analysis will be based on ITT population 
only.
General Information
A DMC composed of oncologists and a biostatistician, who are all independent of and external to 
Celgene, will review ongoing safety data throughout the study according to the DMC charter, 
and may review interim efficacy data for futility.  The DMC will make recommendations 
regarding the continuation of the study, potential amendments, or necessary safety measures.
Statistical Approaches for Control of Alpha
Since there is no intention to declare efficacy at the interim PFS analysis, no penalty in α should 
be imposed.  Treatment efficacy will be declared at the final PFS analysis if a 2-sided p-value 
≤0.05 in favor of the experimental arm after the required 192 PFS events in the ITT population 
are observed.
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$7,21
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&(/*(1(35235,(7$5<,1)250$7,21
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15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
 
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16.
REFERENCES
Cheson B, Fisher R, Barrington S, Cavalli F, Schwartz L, Zucca E, et al. Recommendations for 
initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the 
Lugano classification. J Clin Oncol 2014;32(27):3059-68.
European Medicines Agency (EMA), Appendix 1 to the Guideline on the Evaluation of 
Anticancer Medical Products in Man.  EMA/CHMP/27994/2008/Rev.1; 13 December 2012.
Food and Drug Administration (FDA), Center for Drug Evaluation and Research, Center for 
Biologics Evaluation and Research (US). Guidance for industry: clinical trial endpoints for the 
approval of cancer drugs and biologics. Rockville, MD; 2007. 
Roschewski M, Pittaluga S, Dunleavey K, Kong K, Shovlin M, Jaffe E, etal. DNA 
sequencing-based monitoring of serum predicts clinical relapse before CT imaging in diffuse 
large B-cell lymphoma. Blood (American society of Hematology Annual Meeting Abstract), 
2013; 122 (21): 1767.
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17.
APPENDICES
Handling of Dates
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the date9. format in SAS).  Since medical history and prior 
medication often have incomplete dates, they can be reported as a character string in the YYYY-
MM-DD format.  Dates in the clinical database are classified into the categories of procedure 
dates, log dates, milestone dates, outcome dates, and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedures are 
performed.  They include the dates of laboratory testing, physical examinations, tumor 
scans, etc.  They should be present whenever data for a protocol-specified procedure is 
present and should only be missing when a procedure is marked as NOT DONE in the 
database.  Procedure dates will not be imputed.
!
Log Dates are the dates recorded in CRF data logs.  Specifically, they are the start and 
end dates for AEs and concomitant medications/procedures.  They should not be missing 
unless an event or medication is marked as ongoing in the database.  Otherwise, 
incomplete log dates will be imputed according to the rules in Appendix 17.2.1. 
However, in listings, log dates will be shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study treatment
start date, study termination, etc.  They should not be missing if the milestone occurs for 
a subject.  They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, progression, 
etc.  In most cases they are derived either from a milestone (eg, the survival date is 
derived from the death date), or a procedure date (eg, the progression date is derived from 
the date of the tumor scan that was used to determine progression).  They may be subject 
to endpoint-specific censoring rules if the outcome did not occur, but otherwise are not 
subject to imputation.
!
Special Dates cannot be classified in any of the above categories and they include the 
date of birth.  They may be subject to variable-specific censoring and imputation rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
17.1.1.
Calculation Using Dates
Calculations using dates (eg, subject’s age or relative day after the first dose of study medication) 
will adhere to the following conventions: 
!
Study days after the start day of study treatment will be calculated as the difference 
between the date of interest and the first date of dosing of study medication plus 
1 day. The calculation algorithm for relative study days is:
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Study Days = (Target Date – Study Day 1) + 1
where Study Day 1 is the date when the first dose of study treatment is administered.  
Negative and zero study days are reflective of observations obtained during the 
baseline/screening period.   
!
Age (expressed in days) is calculated as:
Age = Consent Date – Date of Birth + 1
In practice, age will be transformed into years by dividing the difference by 
365.25 days, then truncating.
o
Partial birth date: impute missing day as 15th of the month; impute missing 
month as July; set missing age for missing year.
o
The calculated age using Consent Date and Date of Birth will be preferred in 
analysis.  When either date is not available, it is permissible to use the age 
recorded directly on CRF or in IVRS.
!
Intervals that are presented in weeks will be transformed from days into weeks by 
using (without truncation) the following conversion formula:
Weeks = Days / 7
!
Intervals that are presented in months will be transformed from days into months by 
using (without truncation) the following conversion formula:
Months = Days / 30.4375
17.1.2.
Calculation of Cycles 
The study treatment regimen includes both lenalidomide/placebo and R-CHOP.  The cycle of 
lenalidomide/placebo and R-CHOP will be recorded on dose log page of CRF by the 
investigator.
The Cycle 1 Day 1 (C1D1) is defined as the date of the earliest non-zero dose of 
lenalidomide/placebo or any drugs in R-CHOP that are administered within Cycle 1.  Likewise, 
the Cycle i Day 1 (CiD1), i = 2, 3, 4, 5, and 6, is defined as the date of the earliest non-zero dose 
of lenalidomide/placebo or any drugs in R-CHOP that are administered within Cycle i, provided 
that the drug was not discontinued in previous cycle.
The total treatment cycles are defined as the longest cycles of lenalidomide/placebo or R-CHOP 
the subject completed.  If the subject completed 3 cycles of R-CHOP and 6 cycles of 
lenalidomide/placebo, the total treatment cycles is 6.
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Date Imputation Guideline
17.2.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications Dates
For AE and concomitant medications data, the incomplete or missing start or stop date will be 
imputed according to the following rules.  The purpose of this imputation is to determine if an 
AE is treatment-emergent or not, and if a non-study medication is a prior medication or 
concomitant medication.
These missing dates will be imputed for the analysis derived datasets only.  The missing dates in 
the original clinical datasets will not be imputed.  In listings the log dates will be shown as 
recorded without imputation. 
Incomplete Start Date:
Missing day and month
!
If the year is prior to the year of the first day on study medication, then 31 Dec will be 
assigned to the missing fields.
!
If the year is same as the year of the first day on study medication, then the day and 
month of the start date of study medication will be assigned to the missing fields.
!
If the year is after the year of the first day on study medication, then 1 Jan will be 
assigned to the missing fields.
Missing day only 
!
If the month and year are before the year and month of the first day on study medication, 
then the last day of the month will be assigned to the missing day.
!
If the month and year are same as the year and month of the first day on study 
medication, then the start date of study medication will be assigned to the missing day.
!
If the month and year are after the year and month of the first day on study medication, 
then the first day of the month will be assigned to the missing day.
Missing day, month, and year
!
The date of the first dose of study medication will be assigned to the missing fields.
Please note that if the stop date is non-missing and the imputed start date is after the stop date, 
the start date will be imputed by the stop date. 
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Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date.
Missing day and month
!
If the year is prior to the year of the last dose date of study medication, then 31 Dec will 
be assigned to the missing fields.
!
If the year is same as the year of the last dose date of study medication, then the day and 
month of the last dose date of study medication will be assigned to the missing fields.
!
If the year is after the year of the last dose date of study medication, then 1 Jan will be 
assigned to the missing fields.
Missing day only 
!
If the month and year are before the year and month of the last dose date of study 
medication, then the last day of the month will be assigned to the missing day.
!
If the month and year are same as the year and month of the last dose date of study 
medication, then the day of the last dose date of study medication will be assigned to the 
missing day.
!
If the month and year are after the year and month of the last dose date of study 
medication, then the first day of the month will be assigned to the missing day.
Missing day, month, and year
!
The date of the last dose of study medication will be assigned to the missing fields.
Please note that if the start date is non-missing and the imputed stop date is before the start date, 
the stop date will be imputed by the start date.
17.2.2.
Impute Incomplete Dates of PD, second PD, and Subsequent Anti-Lymphoma 
Therapy
!
If only day is missing, the first day of the month will be assigned. 
!
If both month and day are missing, the first day of January will be assigned.
!
If day, month, and year are all missing, date of randomization will be assigned.
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