Clinical trial NCT01938001
Conditions: Lymphoma, Non-Hodgkin
Keywords: Non-Hodgkins Follicular lymphoma, Non-Hodgkins Marginal zone lymphoma, treatment for follicular lymphoma, treatment for Marginal zone lymphoma
Sponsor: Celgene
Start date: 2013-11-21; Completion date: 2022-01-26
Enrollment: 358 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This double-blind randomized, parallel group study will evaluate the efficacy and safety of lenalidomide (Revlimid, CC-5013) in combination with rituximab (MabThera/Rituxan) in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma. Patients will be randomized to receive either lenalidomide or placebo for twelve 28-day cycles in combination with rituximab. Anticipated time on study treatment is 1 year.

Detailed description:
Indolent lymphoma is a slow growing but incurable lymphoma which includes follicular lymphoma and marginal zone lymphoma. Follicular lymphoma and marginal zone lymphoma are cancers of the B lymphocyte, a type of white blood cell. Lenalidomide is an immunomodulatory drug (a drug that affects the immune system) which alters the body's immune system and it may also interfere with the development of tiny blood vessels involved in tumor growth. Therefore, lenalidomide may reduce or prevent the growth of cancer cells. Lenalidomide has also been shown to restore the immune cells' ability to attack and kill tumor cells, an ability that may be inhibited by follicular lymphoma and other lymphomas. The combination of rituximab and lenalidomide may eliminate the cancer while restoring the immune system's ability to attack tumor cells.

Arms: arm 1: Participants received rituximab 375 mg/m\^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days, up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but \< 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days. arm 2: Participants received riituximab 375 mg/m\^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up, to 12 cycles.
Interventions: intervention 1: Rituximab intervention 2: Lenalidomide intervention 3: Placebo
Intervention descriptions: intervention 1: Rituximab 375mg/m\^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) on Day 1 of every 28 day cycle from Cycles 2 to 5 intervention 2: Lenalidomide 20mg by mouth (PO) daily on Days 1 to 21 every 28 days up to 12 cycles intervention 3: Placebo (identical matched capsule) PO daily on Days 1 to 21 every 28 days

Protocol documents:
Prot_001.pdf: 
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
1
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
TITLE PAGE
A PHASE 3, DOUBLE-BLIND RANDOMIZED STUDY TO 
COMPARE THE EFFICACY AND SAFETY OF 
RITUXIMAB PLUS LENALIDOMIDE (CC-5013) VERSUS 
RITUXIMAB PLUS PLACEBO IN SUBJECTS WITH 
RELAPSED/REFRACTORY INDOLENT LYMPHOMA
The “AUGMENT” Trial
PROTOCOL NUMBER:
CC-5013-NHL-007 
DATE FINAL:
12 Apr 2013 
AMENDMENT 1 Final 
17 Jul 2013
AMENDMENT 2 Final
22 May 2014
AMENDMENT 3 Final
21 Oct 2015
AMENDMENT 4 Final
13 Dec 2018
EudraCT NUMBER:
2013-001245-14
IND NUMBER:
60100
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-NHL-007
Celgene Corporation
Confidential and Proprietary
2
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name: 
Title:
Address: Celgene Corporation, 86 Morris Avenue, Summit, NJ USA
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-NHL-007
Celgene Corporation
Confidential and Proprietary
3
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
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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-NHL-007
Celgene Corporation
Confidential and Proprietary
4
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
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, International Council for 
Harmonization (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
5
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
PROTOCOL SUMMARY
Study Title:
A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Rituximab 
Plus Lenalidomide (CC-5013) Versus Rituximab Plus Placebo in Subjects With 
Relapsed/Refractory Indolent Lymphoma.
Indication: Relapsed/refractory indolent lymphoma
Objectives: To evaluate the efficacy and safety of rituximab plus lenalidomide combination 
therapy in subjects with relapsed/refractory indolent lymphoma
Study Design:
This Phase 3 multicenter, double-blind, randomized study is designed to evaluate the efficacy 
and safety of rituximab plus lenalidomide versus rituximab plus placebo. The overall study 
design is described in Figure 1. The study is divided into the Screening Period, Treatment Period, 
and Follow-up Period. It is planned to randomize 350 subjects.
Upon giving written informed consent, the subject enters the Screening Period to determine 
eligibility. All Screening assessments must be completed within 28 days prior to randomization.
During the Screening Period, the subject will undergo safety and other assessments to determine 
eligibility for the study and undergo randomization to either the experimental arm (rituximab 
plus lenalidomide) or control arm (rituximab plus placebo) at 1:1 ratio.
The subject will enter the Treatment Period once the subject has fulfilled the required 
assessments in the Screening Period and has been randomized. The treatments will be given as 
described in detail in Section 8 and must begin as soon as possible after randomization but no 
later than 1 week after randomization. The subjects will receive protocol-specified treatments for 
a maximum of 12 cycles or until relapse or progression of disease, withdrawal of consent, or 
unacceptable toxicity. All randomized subjects will be assessed for disease progression (PD) and 
overall survival (OS) during the study using the schedule described in Table 1. This includes all 
subjects who discontinue the protocol-specified treatment for any reason without documented 
evidence of clinical and/or radiological disease progression. If a subject withdraws consent, but 
agrees to continued collection of outcome data, these follow-up activities will continue.
Upon completion or early discontinuation of the protocol-specified treatments (see Section 8, 
Description of Study Treatments), all subjects will enter the Follow-up Period. In the Follow-up 
Period, subjects will be followed for disease progression, subsequent anti-lymphoma therapy and 
 development of any second primary malignancies (SPMs) and OS using the 
schedule described in Table 1.
Efficacy determination for the primary endpoint will be based upon progression-free survival 
(PFS) as determined by the Independent Review Committee (IRC). See Section 10 for a 
description of the Statistical Analysis Plan (SAP).
An independent external Data Monitoring Committee (DMC) will review ongoing safety data 
throughout the study according to DMC charter.
The study will be conducted in compliance with Good Clinical Practices (GCPs).
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
6
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
Study Population
Subjects must have an investigator-assessed diagnosis of relapsed/refractory indolent lymphoma, 
defined in this clinical trial as Grade 1, 2 or 3a follicular lymphoma or marginal zone lymphoma.
Subjects must have been previously treated for their lymphoma with systemic therapy
(chemotherapy, immunotherapy, or chemoimmunotherapy), must be refractory to or have 
relapsed after their last treatment, as of Amendment 3, must have received at least two previous
doses of rituximab and must not be rituximab-refractory. Subjects must have at least one 
measurable lesion by computed axial tomography (CT) or magnetic resonance imaging (MRI)
scan, and must have adequate bone marrow function, liver function and renal function. 
Length of Study
The expected accrual duration is 40 months. Subjects will receive protocol-specified treatment 
for a maximum of 12 months or until relapse or progression of disease, withdrawal of consent or 
unacceptable toxicity. Subjects will be followed for survival, disease progression, subsequent
anti-lymphoma therapies, and second primary malignancies (SPMs) until 5 years after the last 
subject has been randomized. Thus, the duration of the entire study will be approximately 8 years 
(accrual period of approximately 3 years plus 5 years from last subject randomized).
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
Experimental arm: Rituximab + Lenalidomide
!
Rituximab - 375 mg/m2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 
22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 
plus
!
Lenalidomide - 20 mg once daily on Days 1 - 21 every 28 days up to 12 cycles. 
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Control arm: Rituximab + placebo
!
Rituximab - 375 mg/m2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 
1 of every 28-day cycle from cycle 2 to 5 
plus 
!
Placebo (identical matched capsule) - once daily on Days 1-21 of every 28-day cycle 
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Overview of Efficacy Assessments
The IRC will utilize the 2007 International working group (IWG) criteria for malignant 
lymphoma (Cheson, 2007), without the use of PET scan, for efficacy determination to assess 
response and PFS, as described in details in the IRC charter. The investigator will also use the 
2007 IWG criteria for assessment of response and progression/relapse. In addition to CT/MRI 
scan and bone marrow biopsy to assess response and progression, subjects with gastric MALT 
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
7
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
lymphoma will also undergo upper gastrointestinal endoscopy as part of response assessment.
Overall survival (OS), event free survival (EFS), time to next anti-lymphoma treatment 
(TTNLT), 
 
 
Overview of Safety Assessments
Safety will be monitored throughout the study. Safety evaluations will include adverse event 
(AE) reporting, SPM reporting, physical examinations, vital sign measurements, concomitant 
medications/procedures, and clinical laboratory safety tests. All AEs and concomitant 
medications will be assessed and recorded from the time informed consent is obtained.
Dose modification rules and rules for discontinuation due to toxicity are outlined in Section 8. 
Subjects who discontinue treatment due to toxicity will enter the Follow-up Period.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
8
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................5
1.
INTRODUCTION..................................................................................................15
1.1.
Indolent Lymphoma ...............................................................................................15
1.1.1.
Follicular Lymphoma .............................................................................................15
1.1.1.1.
Therapy in Follicular Lymphoma............................................................................15
1.1.2.
Marginal Zone Lymphoma .....................................................................................17
1.1.2.1.
Therapy in Marginal Zone Lymphoma....................................................................18
1.2.
Lenalidomide..........................................................................................................18
1.3.
Preclinical Studies of Lenalidomide and Rituximab in Lymphoma .........................19
1.4.
Clinical Studies of Lenalidomide or Rituximab-Lenalidomide in FL.......................20
1.5.
Clinical Studies of Lenalidomide or Rituximab-Lenalidomide in MZL...................22
2.
STUDY OBJECTIVES...........................................................................................23
2.1.
Primary Objective...................................................................................................23
2.2.
Secondary Objectives .............................................................................................23
3.
STUDY ENDPOINTS............................................................................................24
3.1.
Primary Endpoint(s) ...............................................................................................24
3.2.
Secondary Endpoint(s)............................................................................................24
4.
OVERALL STUDY DESIGN ................................................................................25
4.1.
Study Design ..........................................................................................................25
4.1.1.
Screening Period.....................................................................................................25
4.1.2.
Treatment Period ....................................................................................................26
4.1.3.
Follow-up Period....................................................................................................26
4.2.
Study Design Rationale ..........................................................................................27
4.3.
Study Duration .......................................................................................................29
4.4.
End of Trial ............................................................................................................29
5.
TABLE OF EVENTS.............................................................................................31
6.
PROCEDURES......................................................................................................35
6.1.
Screening Procedures..............................................................................................35
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
9
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
6.2.
Assessments During Treatment Phase.....................................................................37
6.2.1.
Efficacy Assessments .............................................................................................38
6.2.2.
Safety Assessments.................................................................................................39
6.2.2.1.
Assessments for Tumor Flare..................................................................................40
6.2.2.2.
Assessments for tumor lysis....................................................................................41
6.2.2.3.
Deep vein thrombosis .............................................................................................42
6.3.
Assessments at Treatment Discontinuation/Completion..........................................45
6.4.
Follow-up Assessments ..........................................................................................45
7.
STUDY POPULATION.........................................................................................47
7.1.
Number of Subjects ................................................................................................47
7.2.
Inclusion Criteria....................................................................................................47
7.3.
Exclusion Criteria...................................................................................................49
8.
DESCRIPTION OF STUDY TREATMENTS........................................................52
8.1.
Description of Investigational Product(s)................................................................52
8.2.
Treatment Administration and Schedule .................................................................52
8.2.1.
Lenalidomide or Placebo dosing .............................................................................53
8.2.2.
Rituximab therapy ..................................................................................................53
8.2.3.
Requalification Criteria for Subsequent Treatment Cycles ......................................53
8.2.4.
Dose Modification or Interruption...........................................................................54
8.2.4.1.
Dose Adjustment for Lenalidomide or Placebo .......................................................54
8.2.4.2.
Dose Adjustment for Rituximab..............................................................................60
8.2.4.3.
Overdose ................................................................................................................60
8.3.
Blinding..................................................................................................................61
8.4.
Emergency Unblinding...........................................................................................61
8.5.
Discontinuation ......................................................................................................61
8.5.1.
Treatment Discontinuation......................................................................................61
8.5.2.
Study discontinuation .............................................................................................62
8.6.
Method of Treatment Assignment...........................................................................62
8.6.1.
Stratification...........................................................................................................62
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8.7.
Packaging and Labeling..........................................................................................62
8.8.
Study Drug Receipt and Storage .............................................................................62
8.9.
Investigational Product Accountability and Disposal ..............................................63
8.10.
Investigational Product Compliance........................................................................63
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................64
9.1.
Permitted Concomitant Medications and Procedures...............................................64
9.1.1.
TFR Treatment .......................................................................................................64
9.1.2.
Thromboembolism Prophylaxis ..............................................................................64
9.1.3.
Growth Factors and Transfusions............................................................................64
9.2.
Prohibited Concomitant Medications and Procedures..............................................65
9.3.
Required Concomitant Medications and Procedures................................................65
9.3.1.
TLS Prophylaxis.....................................................................................................65
9.3.2.
Rituximab premedication........................................................................................65
9.3.3.
Rituximab and Hepatitis B......................................................................................66
10.
STATISTICAL ANALYSES..................................................................................67
10.1.
Overview................................................................................................................67
10.2.
Study Population Definitions ..................................................................................67
10.3.
Sample Size and Power Considerations...................................................................67
10.4.
Background and Demographic Characteristics........................................................68
10.5.
Subject Disposition.................................................................................................68
10.6.
Efficacy Analysis....................................................................................................68
10.6.1.
Primary Efficacy Endpoint......................................................................................68
10.6.2.
Secondary Efficacy Endpoints ................................................................................69
10.7.
Safety Analysis.......................................................................................................70
10.8.
Interim Analysis .....................................................................................................71
10.9.
Other Topics...........................................................................................................71
11.
ADVERSE EVENTS..............................................................................................72
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................72
11.2.
Evaluation of Adverse Events.................................................................................72
11.2.1.
Seriousness.............................................................................................................72
11.2.2.
Severity / Intensity..................................................................................................74
11.2.3.
Causality ................................................................................................................74
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11.2.
1.2.
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11.2.4.
Duration .................................................................................................................75
11.2.5.
Action Taken..........................................................................................................75
11.2.6.
Outcome.................................................................................................................75
11.3.
Abnormal Laboratory Values..................................................................................75
11.4.
Pregnancy...............................................................................................................75
11.4.1.
Females of Childbearing Potential ..........................................................................76
11.4.2.
Male Subjects.........................................................................................................76
11.5.
Reporting of Serious Adverse Events......................................................................76
11.5.1.
Safety Queries ........................................................................................................77
11.6.
Expedited Reporting of Adverse Events..................................................................77
12.
EMERGENCY PROCEDURES.............................................................................79
12.1.
Emergency Contact.................................................................................................79
12.2.
Emergency Identification of Investigational Products .............................................79
13.
REGULATORY CONSIDERATIONS...................................................................80
13.1.
Good Clinical Practice............................................................................................80
13.2.
Investigator Responsibilities ...................................................................................80
13.3.
Subject Information and Informed Consent.............................................................81
13.4.
Confidentiality........................................................................................................81
13.5.
Protocol Amendments.............................................................................................81
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................81
13.7.
Ongoing Information for Institutional Review Board / Ethics Committee................82
13.8.
Closure of the Study ...............................................................................................82
14.
DATA HANDLING AND RECORDKEEPING.....................................................83
14.1.
Data/Documents.....................................................................................................83
14.2.
Data Management...................................................................................................83
14.3.
Record Retention....................................................................................................83
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................85
15.1.
Study Monitoring and Source Data Verification......................................................85
15.2.
Audits and Inspections............................................................................................85
16.
PUBLICATIONS ...................................................................................................86
17.
REFERENCES.......................................................................................................87
18.
APPENDICES........................................................................................................95
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.......76
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18.1.
Appendix A: Response Criteria for NHL ................................................................95
18.1.1.
Tumor Assessment by the 2007 IWG Response Criteria .........................................95
18.1.3.
Additional Response Assessment In Gastric MALT subjects with 
Radiological Response of at Least a PR by 2007 IWG Criteria ...............................96
18.3.
Appendix C: Ann Arbor staging ...........................................................................105
18.4.
Appendix D: Performance Status Criteria .............................................................106
18.5.
Appendix E: Cairo - Bishop Definition of Tumor Lysis Syndrome .......................107
18.6.
Appendix F: Pregnancy Prevention Risk Management Plans ................................108
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LIST OF TABLES
Table 1:
Schedule of Study Assessments ..............................................................................31
Table 2:
Dose Modification for Lenalidomide or Placebo.....................................................55
Table 3:
Dose Reduction Steps for Adverse Events Related to Study Drug for 
Subjects Initiating Treatment at 20 mg Daily on Days 1 to 21, Every 28 
Days .......................................................................................................................59
Table 4:
Dose Modification Steps for Subjects Initiating Treatment at 10 mg Daily on 
Days 1 to 21, Every 28 Days...................................................................................60
Table 5:
GELA Histological Scoring System for Evaluation of Gastric MALT 
lymphoma...............................................................................................................96
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60
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................27
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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 the 
investigational product (IP).
1.1.
Indolent Lymphoma 
Non-Hodgkin’s lymphoma (NHL) is a heterogeneous group of lymphoproliferative malignancies 
with differing patterns of clinical behavior and responses to treatment (Armitage, 1993). Most of 
the NHLs are of B-cell origin. Indolent NHLs (iNHL), also referred to as low grade lymphomas,
are a group of incurable slow-growing lymphoma and represent more than half of NHL 
(Swerdlow, 2008; Arcaini, 2012; Sousou, 2010). The major types of iNHL include follicular 
lymphoma (FL), marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia (WM), and 
small lymphocytic lymphomas (SLL). The most common subtype of iNHL is FL, constituting 
approximately 70% of the iNHL (Sousou, 2010; Bello, 2012). MZL accounts for 5 to 17% of all 
NHL in the adults (Zinzani, 2012), while SLL constitutes approximately 6% and WM 
approximately 1%.
1.1.1.
Follicular Lymphoma
Follicular lymphoma (FL) is one of the most common indolent NHLs. BCL-2 gene deregulation 
involving a t(14,18) translocation is frequently seen in FL, although it is not diagnostic of FL 
(Rambaldi, 2002). Mutations in histone-modifying genes have recently been described as being 
involved in its pathogenesis (Morin, 2012). Follicular lymphoma typically follows an indolent 
course with a median overall survival (OS) of 7-10 years. Although FL initially responds well to 
treatment it is characterized by recurrent relapses or progressions with progressively shorter 
intervals in between (Salles, 2007). Transformation to diffuse large B-cell lymphoma and other 
aggressive lymphoma occurs at a rate of approximately 2% to 3% per year (Bastion, 1997).
The prognosis depends on the histologic grade, stage, treatment and age of the patient. The 
disease is considered incurable in advanced stage, and eventually most FL patients die of 
lymphoma regardless of the treatment. Follicular Lymphoma International Prognostic Index 
(FLIPI) score and its revised version, FLIPI2 (Federico, 2009), have been developed for the 
assessment of newly diagnosed FL patients, but their use in relapsed FL has not yet been fully 
studied.
In addition to clinical demographic parameters in prognostic indices, biological (immune 
signature) prognostic factors (Solal-Celigny, 2004; Federico, 2009; Dave, 2004; Gribben, 2010) 
and lymphoma-mediated immunosuppression (Ramsay, 2009a) have been noted to be common 
in FL, pointing to the importance of the impaired host immune response in the pathogenesis of
this disease. 
1.1.1.1.
Therapy in Follicular Lymphoma
There is no standard treatment for relapsed/refractory FL patients. Treatment options include 
radiation, single-agent or combination chemotherapy, rituximab monotherapy, rituximab 
containing chemoregimens such as BR (bendamustine, rituximab), fludarabine plus rituximab, 
R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-CVP
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(rituximab, cyclophosphamide, vincristine, prednisone), R-FCM (rituximab, fludarabine, 
cyclophosphamide, mitoxantrone), radioimmunotherapy or autologous/allogeneic stem cell 
transplant in some select patients (NCCN guideline, 2013 and Ghielmini, 2013 [European 
Society for Medical Oncology (ESMO) guideline]. In addition, repetition of a previously applied 
regimen is a valid option depending on the duration of the response obtained previously. A 
watch-and-wait strategy is sometimes employed for patients with low tumor burden progressing 
after the first-line therapy.
Rituximab is approved in the US, Europe and other countries for treatment of relapsed or 
refractory FL as single agent and is extensively used in the treatment of FL as monotherapy or in 
combination with chemotherapy. Several studies have demonstrated the efficacy and safety of 
rituximab monotherapy in relapsed/refractory FL or other low grade NHL patients, and three 
multicenter single-arm studies have led to regulatory approval in the US, Europe and other 
countries. In the first study 166 relapsed/refractory FL patients were treated with 375 mg/m2 of 
rituximab weekly for 4 doses. Results demonstrated a 48% overall response rate (ORR) with 6% 
CR and median duration of response of 11.2 months (McLaughlin, 1998). In the second study,
37 relapsed/refractory low-grade NHL patients received an additional 4 weekly doses of 
rituximab for a total of 8 doses, resulting in increased ORR of 57% and CR of 14% (Piro, 1999). 
The third study demonstrated that the retreatment of 60 relapsed/ refractory patients who had 
clinical response to prior rituximab treatment with 4 weekly doses of rituximab resulted in ORR 
of 38% and CR of 10% (Davis, 2000a). Thus, in some countries, the approved number of 
rituximab doses is four to eight. A recent update of the results from the SAKK 35/98 trial 
evaluating prolonged single agent rituximab (Martinelli, 2010) in relapsed/refractory FL patients 
treated with 4 weekly doses of rituximab followed by additional 4 maintenance doses every 2 
months reported a durable response with 35% of responders still in remission at 8 years.  In a 
Phase 3 study to evaluate the safety and efficacy of rituximab in patients with bulky relapsed or 
refractory low-grade or FL (Davis, 1999), the ORR was 43% with a median TTP of 8.1 months 
and median DOR of 5.9 months. The average decrease in lesion size in patients who achieved a 
partial response was 76%, and patients with stable disease had a decrease in average lesion size 
of 26%.
The importance of rituximab has also been demonstrated in clinical trials that evaluated the 
addition of rituximab to combination chemotherapy and as a maintenance agent after 
chemotherapy in patients with relapsed FL. Forstpointner et al (Forstpointner, 2004) reported the 
results from a Phase 2 randomized study evaluating R-FCM versus FCM (fludarabine, 
cyclophosphamide, mitoxantrone) in FL (N = 93) and MCL (N = 40) patients showing improved 
response rate (79% versus 58%, respectively) and median PFS (16 months versus 13 months, 
respectively) in R-FCM group compared to FCM. Van Oers (Van Oers, 2010) evaluated the role 
of rituximab (R) both in remission induction and maintenance treatment of relapsed/refractory 
FL; patients were randomized to induction with CHOP (cyclophosphamide, doxorubicin, 
vincristine, prednisone) or R-CHOP, and those in complete or partial remission were randomized 
to maintenance or observation. The median PFS from first randomization was 20.2 months after 
CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab 
maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 
months with observation. A randomized Phase 3 trial (RESORT) comparing two different 
rituximab dosing strategies (rituximab continuous maintenance until treatment failure, RM) or 
rituximab re-treatment at progression, RR) for untreated, low tumor burden (LTB) FL was not 
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able to demonstrate differences in time to treatment failure (TTF) (Kahl, 2011). The mean 
number of rituximab doses per patient (including the 4 induction doses) was 15.8 (range 5– 31) 
for MR and 4.5 (range 4–16) for RR. The time to initiation of cytotoxic therapy was delayed in 
both arms compared to historical watch and wait strategies. Rituximab re-treatment at 
progression produces outcomes comparable to MR in this patient population.
The combination of rituximab and bendamustine, an alkylating agent, is approved in the US, 
Europe and many other countries for the treatment of rituximab refractory iNHL and showed a 
response rate of 90% and median PFS of 2 years in relapsed/refractory indolent low grade 
lymphoma and MCL in single-arm Phase 2 studies (Robinson, 2008; Rummel, 2005). Major 
reported toxicities of bendamustine were myelosuppression (Grade 3 or 4 neutropenia and 
thrombocytopenia), nausea, infection, and fatigue. The two anti-CD20 radioimmunotherapy 
agents, yttrium Y90 ibritumomab tiuxetan and iodine I131 tositumomab, have demonstrated high 
activity in patients relapsed/refractory to chemotherapy or rituximab. Patients achieved a 
response rate of 60% to 80% but with significant toxicities including prolonged 
myelosuppression with potential risk of treatment-associated myelodysplastic syndrome (MDS) 
and acute myelogenous leukemia (Cheson, 2003). A randomized Phase 3 trial comparing yttrium 
Y90 ibritumomab tiuxetan to rituximab in relapsed indolent NHL demonstrated significantly 
higher ORR (80% versus 56%) and CR rate (30% versus 16%) but with no significant 
differences in median time to progression (11.2 months versus 10.1 months) (Witzig, 2002).
More recently, efforts have been made to find novel regimens for the treatment of relapsed FL
that do not contain cytotoxic agents. Such efforts include combinations of rituximab with a 
second monoclonal antibody, such as galiximab (Czuczman, 2005; Czuczman, 2012) and anti-
CD22 epratuzumab (Leonard, 2005), and with targeted agents such as bortezomib (Baiocchi,
2010), interferon (Davis, 2000b; Sacchi, 2001) and cytokines granulocyte macrophage colony 
stimulating factor (GM-CSF) (Cartron, 2008) and IL-12 (Ansell, 2002), as well as lenalidomide.
Of these combinations, a Phase 3 study comparing bortezomib plus rituximab versus rituximab 
single agent has been reported (Coiffier, 2011). In this study 676 rituximab-naïve or rituximab-
sensitive patients with relapsed Grade 1 or 2 FL were randomly assigned in 1:1 ratio to receive 
rituximab alone (weekly during first cycle x 4 doses and then on Day 1 of cycles 2 to 5) or in 
combination with bortezomib (weekly x 4 doses of cycles 1 to 5). While the difference in the
PFS was statistically significant (p = 0.039), the magnitude of the difference in the median PFS 
was < 2 months (11.0 months in the rituximab-only arm and 12.8 months in the rituximab-
bortezomib arm). 
1.1.2.
Marginal Zone Lymphoma
Marginal zone lymphoma (MZL) is a subtype of B-cell lymphoma, constituting approximately 
8% of NHL. Considered an indolent NHL, it is distinguished from other NHLs in that it is 
negative for CD5, CD10, Cyclin D1 and CD23 (Higgins, 2008; Stamatopoulos, 2000).
Three types of MZL have been described:  Extranodal mucosa-associated lymphatic tissue 
(MALT) lymphoma, splenic MZL and nodal MZL. Although these subtypes of B-cell lymphoma 
share morphologic, immunophenotypic and genetic characteristics, there are also important 
differences in their frequency, clinical presentation, and pathogenesis. MALT is most common 
and accounts for approximately 70% of all MZLs; splenic MZL accounts for approximately 20% 
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of all MZLs; and Nodal MZL is the least common, representing approximately 10% of all MZLs 
(Isaacson, 2008; Matutes, 2008; Campo, 2011; Arcaini, 2009).
There is no specific immunohistochemical marker for MALT lymphoma. MALT lymphoma 
usually arises in mucosal sites where lymphocytes are not normally present and where MALT is 
acquired in response to either chronic infectious conditions or autoimmune processes, such as 
Hashimoto thyroiditis or Sjogren syndrome. Helicobacter pylori gastritis is the best studied 
condition, but other infectious agents have been implicated in the pathogenesis of MALT 
lymphomas arising in the skin (Borrelia burgdorferi), in the ocular adnexa (Chlamydophila 
psittaci), and in the small intestine (Campylobacter jejuni) (Bertoni, 2005).
Splenic MZL patients present with an enlarged spleen, involvement of abdominal lymph nodes, 
and bone marrow disease. Liver and leukemic involvement occurs in a subset of patients. 
Approximately 40% to 50% of splenic MZLs are associated with deletions of chromosome 7q 
(Isaacson, 2008).
Patients with nodal MZL, predominantly have lymph node-based disease. The molecular 
pathogenesis of nodal MZL is not well understood.
1.1.2.1.
Therapy in Marginal Zone Lymphoma
Front-line treatment of MZL depends on the stage of disease, histological subtype, location of 
disease and the presumed source of antigenic stimulation. H. pylori eradication therapy is 
recommended in all H. pylori positive gastric MALT lymphoma patients independent of stage or 
histological grade [Dreyling, 2013 (ESMO guideline); NCCN guideline, 2013]. For H. pylori
negative patients and non-gastric MALT lymphoma patients, radiation therapy is the preferred 
option, while rituximab monotherapy or in combination with chemotherapy is treatment of 
choice for patients with contraindications to RT or for patients in need of systemic treatment
[NCCN guideline, 2013; Dreyling, 2013 (ESMO guideline)].
Advanced stage disease and relapsed disease requiring systemic treatment is managed like 
follicular lymphoma - rituximab with or without chemotherapy, being the preferred option
[NCCN guideline, 2012 and Dreyling, 2013 (ESMO guideline)]. Nodal MZL is also treated like 
follicular lymphoma, although no studies of large series have been published so far in this type 
of MZL.
1.2.
Lenalidomide
Lenalidomide (REVLIMID® Celgene Corp., NJ, USA) is a member of a class of pharmaceutical 
compounds known as immunomodulatory drugs (IMiD®) and has potent immuno-stimulatory, 
anti-angiogenic, and pro-apoptotic activities in vitro.
It offers potential benefit over the first commercially available IMiD® compound, thalidomide, in 
terms of both safety and efficacy in human patients (Galustian, 2004). The key to its therapeutic 
potential lies in the fact that it has multiple mechanisms of action in vitro, which act to produce 
both immunomodulatory and antitumor effects. These effects are thought to be contextual in that 
they depend on both the cell type and the triggering stimulus. Lenalidomide has been associated 
with TNF-α inhibitory, T-cell costimulatory, and antiangiogenic activities (Galustian, 2004).
Lenalidomide is approved in the United States and other countries for the treatment of patients 
with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a 
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deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in 
combination with dexamethasone for patients with previously treated multiple myeloma. In 
addition, it is approved in the US for the treatment of patients with mantle cell lymphoma whose 
disease has relapsed or progressed after two prior therapies, one of which included bortezomib.
Lenalidomide is being investigated as treatment for various hematologic and oncologic 
indications.
1.3.
Preclinical Studies of Lenalidomide and Rituximab in Lymphoma
The direct tumoricidal and immunomodulatory activities of lenalidomide are likely important for 
its clinical activity in the treatment of various hematologic malignancies. This activity is at least 
in part mediated by enhanced T-cell and NK-cell effector function to eliminate tumor B cells, 
attributed to restoration of impaired T-cell activity and formation of immunologic synapses. 
There are also direct effects on tumor cells, including upregulation of tumor suppressor genes, 
leading to cell cycle arrest.
Preclinical studies have shown an enhancement of antibody-dependent cellular cytotoxicity 
(ADCC) (Wu 2008) and anti-tumor effects in vivo (Hernandez-Ilizaliturri, 2005; Zhang, 2009) 
when lenalidomide was combined with rituximab. Lenalidomide has shown to augment ADCC
mainly by increasing CD16 expression on NK cells (Zhang, 2009). In a murine NHL model, 
lenalidomide induced significant increase in the recruitment of NK cells to tumor sites resulting 
in enhanced anti-tumor activity of rituximab (Reddy, 2008). When combined with rituximab, 
lenalidomide improved survival in a mouse NHL model and the anti-tumor activity was shown to 
be NK-mediated. (Hernandez-Ilizaliturri, 2005).
Recent preclinical studies also suggest that lenalidomide may promote restoration of anti-tumor 
immunological effects in patients with certain hematological malignancies. Ramsay et al 
reported that impaired T cell immunological synapse formation was seen in both CD4 and CD8 
T cells from chronic lymphocytic leukemia (CLL) and FL patients compared to age-matched 
healthy donors (Ramsay, 2008; Ramsay, 2009a; Ramsay, 2009b; Gorgun, 2009) and that the 
immune synapse defects were repaired by treatment of the cells in vitro with lenalidomide. In 
both FL and CLL, treatment of both tumor B cells and autologous T cells with lenalidomide was 
required to repair the defective immunological synapse formation (Ramsay, 2009a; Ramsay,
2009b), by preventing the induction of impaired actin synapse formation by down-regulating 
tumor-cell-inhibitory molecule expression (Ramsay, 2012). These findings are supported by 
preclinical studies conducted by the sponsor. Lenalidomide treatment induced actin cytoskeleton 
reorganization and polarization in a process termed “capping,” which is considered an important 
subcellular component of the immune synapse formation (Gaidarova, 2009), and lenalidomide 
induces CD20-localization within the “cap.” The combined use of lenalidomide and rituximab 
enhances NK cell-mediated immune synapse formation, the resultant cytotoxicity (Gaidarova,
2009). The capping of CD20 is accompanied by redistribution of proteins such as Vav1 and Rac1 
that become part of the immune synapse complex. More recently, lenalidomide has been 
reported to bind to a target protein cereblon in T cells, which then induces certain biochemical 
events of T cell activation such as IL-2 secretion (Lopez-Girona, 2012).
These laboratory observations of direct lenalidomide and rituximab effects on tumor cells and on 
the host immune cells serve as the biological basis for the use of rituximab-lenalidomide 
combination described in this clinical trial protocol.
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1.4.
Clinical Studies of Lenalidomide or Rituximab-Lenalidomide in FL 
Single agent lenalidomide was studied in patients with relapsed/refractory indolent NHL, 
including FL (Witzig, 2009). The dose/regimen used in this study was 25 mg once daily (QD) x 
21 days every 28 days for maximum of 52 weeks. Forty-three subjects were enrolled. Patients 
had received a median of three prior systemic therapies (range, 1 to 17) and half were refractory 
to last therapy. ORR was 23% (10 of 43), including a 7% complete response (CR) or 
unconfirmed (CRu) rate. Twenty-seven percent (six of 22) of patients with FL Grade 1 or 2 
responded to therapy. Median duration of response (DOR) was not reached, but was longer than 
16.5 months with seven of 10 responses ongoing at 15 to 28 months for the entire group 
including FL. Median PFS for the whole group was 4.4 months (95% CI, 2.5 to 10.4 months). 
The most common Grade 3 or 4 AEs were neutropenia (30% and 16%, respectively) and 
thrombocytopenia (14% and 5%, respectively).
Recently, Leonard et al (2015) updated results and provided the final analysis on data first
reported in 2012 from a multicenter, randomized, Phase 2 clinical trial conducted by the US 
cooperative group Cancer and Leukemia Group B (CALGB). This study evaluated the 
lenalidomide-rituximab (LR) combination therapy versus lenalidomide monotherapy in patients 
with recurrent FL who had prior therapy with rituximab alone or in combination, and time to 
progression of ≥ 6 months from last rituximab dose. Subjects were randomly assigned 1:1 to 
lenalidomide alone or LR.  Lenalidomide 15 mg/day was administered during Cycle 1 on Days 1 
to 21, followed by 7 days of rest and then 20 mg/day on Days 1 to 21, followed by 7 days of rest 
in Cycles 2 through 12. Ninety-one patients in total received treatment with lenalidomide, (n=45; 
LR, n=46). The median age was 63 and most patients had advanced-stage disease with low 
(42.2%) and intermediate (35.3%) risk by FLIPI.  In the lenalidomide and LR arms, Grade 3 to 4 
adverse events occurred in 58% and 53% of patients, with 9% and 11% of patients experiencing 
Grade 4 toxicity, respectively. Grade 3 to 4 adverse events included neutropenia (16% versus
20%, respectively), fatigue (9% versus 13%, respectively), and thrombosis (16% versus 4%). 
Thirty-six percent of lenalidomide patients and 63% of LR patients completed 12 cycles. 
Lenalidomide alone was associated with more treatment failures, with approximately 20% of 
patients in both arms discontinuing treatment as a result of adverse events.  Overall response rate 
was 53% (20% complete response) for lenalidomide alone and 76% (39% complete response) for 
LR. At a median follow up of 2.5 years, median time to progression was 1.1 years for 
lenalidomide alone and 2 years for the LR combination.
The results of the CALGB study are further supported by findings from two smaller single 
institution studies reported by Tuscano et al (Tuscano, 2014) and Ahmadi et al (Ahmadi, 2014). 
Tuscano et al (Tuscano, 2014) conducted a clinical trial of the combination of rituximab and 
lenalidomide in 30 patients with relapsed/refractory indolent lymphoma. Patients received 
lenalidomide 20 mg daily for three weeks in 4-week cycles and also rituximab 375 mg/m2
weekly x 4 doses starting on Day 15. Lenalidomide was continued until disease progression. The 
median age was 60.5 years old, median lines of prior therapy was 3, and 13 patients were 
refractory to rituximab. Of the 27 evaluable patients, 22 had FL. In this subset of FL patients, the 
ORR was 77% and CR/CRu was achieved in 9 patients (40.9%).
Activity of the rituximab plus lenalidomide combination has been also demonstrated in patients 
refractory to rituximab (defined as relapse within 6 months of last rituximab). Ahmadi et al 
(Ahmadi, 2014) reported the results from a Phase II trial of lenalidomide-dexamethasone-
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rituximab in patients with indolent B-cell or mantle cell lymphomas refractory to rituximab. 
Patients initially received two 28-day treatment cycles of lenalidomide 10 mg daily and 
dexamethasone 8 mg once weekly. After assessment of response at 8 weeks (part 1), all patients 
received the addition of rituximab 375 mg/m2 weekly for 4 doses starting with cycle 3. 
Lenalidomide-dexamethasone therapy continued with the addition of rituximab (part 2). Of the 
27 patients enrolled, the histologies were follicular (n = 18), mantle cell (n = 5), small 
lymphocytic (n = 3), and marginal zone (n = 1) lymphomas. For 24 patients, the overall response 
rate after part 1 was 29% (4 patients had a CR or CRu, and 3 patients had a PR), and the ORR 
after part 2 was 58% (8 patients had a CR, and 6 patients had a PR). For 27 patients, at a median 
follow-up of 12.2 months, the median PFS was 23.7 months.
The rituximab plus lenalidomide combination has also been studied as frontline therapy in FL. In
2012, Fowler et al (Fowler, 2012) reported the results of an ongoing Phase 2 study evaluating the 
efficacy and safety of rituximab-lenalidomide in patients with untreated, Stage III/IV, indolent 
NHL. Patients with previously untreated indolent NHL received 20 mg/day of lenalidomide on 
Days 1 to 21 and rituximab 375 mg/m2 on Day 1 of each 28 day cycle for up to 6 cycles. 
Response was assessed after every 3 cycles using the International Working Group (IWG)
(Cheson, 1999) criteria. At the time of this report, 110 patients had completed treatment or were 
off-study. The median age was 58 (34-84) years, 53% of patients were male, and 103 patients 
were evaluable for response. Among all evaluable patients, the overall response rate was 90%. 
Complete responses (CR) were attained in 64% of patients, 27 patients (26%) had a partial 
response (PR), and stable disease (SD) was seen in 8 (8%). Among the subset of patients with 
FL, 40/46 (87%) evaluable patients attained a CR. Forty five evaluable pts with FL had a 
positive PET scan prior to therapy and 42 (93%) attained a complete metabolic response 
following treatment. At a median follow up of 22 months, the estimated two year PFS was 83% 
for all patients and 89% in patients with FL. Grade 3/4 AEs were rash (8 patients), neutropenia 
(44 patients), muscle pain (7 patients), thrombocytopenia (4 patients), fatigue (3 patients), and 
thrombosis (3 patients). Six patients were removed from treatment due to AEs but were eligible 
for toxicity assessment. 
Martin et al (2013) reported the results of a Phase 2 clinical trial of the rituximab-lenalidomide 
combination given for 12 months in previously untreated FL in a multi-center cooperative group 
study, CALGB 50803. Lenalidomide 20 mg/day was administered on days 1-21 of a 28-day 
cycle for 12 cycles plus rituximab weekly x 4 in Cycle 1 and on day 1 of Cycles 4, 6, 8, and 10.
Sixty-six patients were enrolled. Three patients did not receive protocol treatment and were 
dropped from analyses. The median age of the remaining 63 patients was 53 years; 49.2% were 
male; 31% were FLIPI < 2. Grade 3 or 4 toxicity that occurred in >5% of patients included 
neutropenia (20%), lymphopenia (8%), rash (8%), fatigue (6%), and leukopenia (5%). Grade 2 or 
more toxicity in > 5% of patients included fatigue (25%), infusion reaction (17%), upper 
respiratory reaction (13%), nausea (8%), constipation (7%), increased ALT (7%), hyperglycemia 
(7%), hypophosphatemia (7%), pain (6%), oral mucositis (5%), and myalgia (5%). Febrile 
neutropenia occurred in 1 patient (2%). Fifty-one patients (81.0%) completed 12 cycles of 
lenalidomide. Reasons for early termination included adverse events (6) and patient refusal (5). 
One patient stopped due to disease progression after initial response. Among the 54 patients with 
adequate data to evaluate response, the overall response rate was 92.6%, including 39 (72.2%) 
complete responses and 11 (20.4%) partial responses. Complete responses were not associated 
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with FLIPI, grade, or bulky disease. At a median follow-up of 1.3 years, 6 patients had 
progressed.
1.5.
Clinical Studies of Lenalidomide or Rituximab-Lenalidomide in 
MZL
Single agent lenalidomide has been studied in patients with histologically confirmed advanced 
stage MALT lymphoma (Kiesewetter, 2012). The patients received 25 mg once daily (QD) x 21 
days every 28 days for maximum of six cycles if the patient had achieved at least stable disease 
(SD) after third cycle. A total of 18 patients were enrolled with 11 previously untreated and 7
relapsed/refractory patients. An overall response rate of 61% was seen (11 of 18; 6 complete and 
5 partial remissions). Three patients had stable disease while 2 progressed. The most common 
Grade 3 or 4 AE was neutropenia (Grade 3 in 3 patients). After a median follow up of 20.3 
months, one patient has died from lymphoma while the other patients were alive and relapse-
free. 
The rituximab and lenalidomide combination therapy is being studied in previously untreated 
and also relapsed/refractory MZL patients. In the recent report discussed in Section 1.4 , Fowler 
et al (Fowler, 2012), the combination therapy was also evaluated in MZL lymphoma. Twenty-
seven of the 100 NHL patients enrolled were MZL. Eighty-nine percent (n=24) of the patients 
with MZL responded with 67% patients achieving CR/CRu (Fowler, 2012). At a median follow-
up of 22 months, the estimated 2 year PFS was 83% for all (FL, MZL, SLL) patients.
In the study already discussed above in Section 1.4 (Tuscano, 2014),  3 patients had MZL. In this 
subset of MZL patients, CR/CRu was achieved in 2 patients and the ORR was 66.7%.
Early data of rituximab and lenalidomide combination therapy in relapsed/refractory MZL 
patients was recently reported by Kiesewetter et al (Kiesewetter 2013). A total of 21 patients 
were included in the trial, and at the time of reporting, 10 patients were evaluable for response. 
Three patients had completed six cycles and achieved CR, whereas seven additional patients had 
CR after cycle 3 with treatment currently ongoing. Hematologic adverse events were mild with 
neutropenia Grade 2 in three patients, thrombocytopenia Grade 1 in three patients and anemia 
Grade 1 in one patient. Other adverse events reported were mild fatigue (n = 5), pruritus (n = 6, 
Grade 3 in one patient), mild constipation (n = 4), vertigo (n = 4, Grade 3 in one patient) and 
mild exanthema (n =3). Dose reduction was required in four patients to manage toxicity 
(nausea/emesis, headache/exanthema and infection).
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2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the study is to compare the efficacy of rituximab plus lenalidomide to 
rituximab plus placebo in subjects with relapsed/refractory indolent lymphoma. Efficacy 
determination will be based upon PFS as the primary endpoint, as assessed by the Independent 
Review Committee (IRC) using the 2007 International working group (IWG) criteria (Cheson, 
2007) but without PET.
2.2.
Secondary Objectives
The secondary objectives of the study are:
!
to compare the safety of rituximab plus lenalidomide versus rituximab plus placebo
!
to compare the efficacy of rituximab plus lenalidomide versus rituximab plus placebo 
using other parameters of efficacy:
o
Durable complete response rate (DCRR), overall response rate (ORR),
complete response (Cr) rate, duration of response (DoR) and duration of 
complete response (DoCR) by IWG 2007 without PET See Section 18.1
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3.
STUDY ENDPOINTS
Progression free survival (PFS), best overall response including ORR, CR rate, durable CR rate, 
and DoR will be assessed per 2007 IWG criteria (Cheson, 2007). In addition to CT/MRI scan to 
assess response and progression, subjects with gastric MALT lymphoma will also undergo 
endoscopy as part of response assessment (see Section 18.1.3). See section 10 for details and 
definitions.
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Primary Endpoint(s)
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PFS, as assessed by the IRC using the 2007 IWG criteria
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Lenalidomide (CC-5013)
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4.
OVERALL STUDY DESIGN
4.1.
Study Design
This Phase 3, multicenter, double-blind, randomized study is designed to evaluate the efficacy 
and safety of rituximab plus lenalidomide versus rituximab plus placebo in subjects with 
relapsed/refractory indolent lymphoma. The overall study design is described in Figure 1. The 
study is divided into the Screening Period, Treatment Period, and Follow-up Period. It is planned 
to randomize 350 subjects at a 1:1 ratio. 
All efficacy assessments will be based on central review including central radiology and clinical 
review by an IRC. For gastric MALT patients, results of upper gastrointestinal endoscopy will be 
included in the clinical data review by the IRC which will be composed of two external 
radiologists (with an additional radiologist in case adjudication is needed) and a 
hematologist/oncologist. The IRC will perform a blinded, independent assessment of radiological 
data and selected clinical data for each patient to determine response, date of response, and date 
of disease progression. The IRC will utilize the 2007 IWG criteria (Cheson, 2007; see 
Section 18.1) without PET for primary efficacy determination based on CT/MRI scan to assess 
progression, which will be used to calculate PFS. Best overall response including ORR, CR rate, 
DOR, and durable complete response rate will also be evaluated by IRC using the 2007 response 
criteria (see Section 18.1).
 
In addition to CT/MRI scan to assess response and 
progression, subjects with gastric MALT lymphoma will also undergo endoscopy as part of 
response assessment (see Section 18.1.3). Details of the efficacy assessments will be described in 
the IRC charter.
Since the study primary endpoint is PFS based on CT/MRI scan as determined by IRC, 
progression or relapse will be based on CT/MRI scans and/or clinical data supporting 
progression or relapse of disease. Because all protocol-specified analyses including the planned 
interim analysis are based on IRC review, all CT/MRI scans and all biopsies performed must be 
sent for central radiology and pathology review respectively as described in Section 6.2.1.
An independent external Data Monitoring Committee (DMC) will review ongoing safety data 
throughout the study according to DMC charter. In addition the DMC will conduct the planned 
interim analysis at approximately 50% information (96 events) for futility only. 
See Section 10 for a detailed description of Statistical Analyses.
The study will be conducted in compliance with Good Clinical Practice (GCP).
4.1.1.
Screening Period
Upon giving written informed consent, the subject will enter the Screening Period to determine 
eligibility (the Screening Period timing begins on the day (Day -28) the first study procedure is 
performed after the subject has provided written informed consent). All screening assessments 
must be completed within 28 days prior to randomization. During the Screening Period, the 
subject will undergo safety and other assessments to determine eligibility for the study and 
undergo randomization to either the experimental arm (rituximab plus lenalidomide) or control 
arm (rituximab plus placebo).
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Subject eligibility will be based on investigator assessment of the pathologic diagnosis.
However, subject’s disease diagnosis will be assessed retrospectively by central pathology to 
confirm the FL or MZL diagnosis. Thus, the investigator must confirm that archival formalin-
fixed paraffin embedded (FFPE) tumor or lymph node tissue specimen exists during the 
Screening Phase. If an archival specimen is not available for submission, then a rebiopsy is 
required prior to randomization. All tumor specimens must be sent to the central pathology 
laboratory, preferably during the screening period and no later than 8 weeks after randomization. 
Subjects with a diagnosis of splenic MZL for whom a spleen specimen is not available, will 
undergo central pathology review based on the following: (1) clinical information including a CT 
scan of the spleen, WBC count and differential; (2) available bone marrow biopsy specimen and 
report for morphological evaluation and local bone marrow aspirate smear report. Flow 
cytometry analysis of the peripheral blood or bone marrow, HCV status, Coomb’s test results 
and M-protein test results may be requested. 
Confirmation of FL or MZL by the central pathologist is not required for entry into the study.
4.1.2.
Treatment Period
The Treatment Period begins with Cycle 1 Day 1 dosing of the therapy drugs as described in 
Section 8 and must begin as soon as possible after randomization but no later than 1 week after 
randomization. The subjects will receive protocol-specified treatments and undergo efficacy and 
safety assessments for a maximum of 12 cycles, or until relapse or progression of disease, 
withdrawal of consent, or unacceptable toxicity. A central laboratory will be used for the analysis 
of hematology and serum chemistry. Clinical decisions and dose modifications during the study 
can be based on local laboratory results.
All randomized subjects will be followed for disease progression and OS using the same 
schedule described in Table 1. This includes all subjects who discontinue the protocol-specified
treatment for any reason without documented evidence of disease progression. A subject’s 
withdrawal from the protocol-specified treatment for disease progression will be based upon 
investigator assessment.
4.1.3.
Follow-up Period
The Follow-up Period begins upon study treatment completion or discontinuation. 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 anti-lymphoma / 
salvage therapy (chemotherapy, Stem cell transplants, radiotherapy, etc.). In the Follow-up 
Period, the subjects will be followed for disease progression, OS, subsequent anti-lymphoma 
therapies,
 
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Figure 1:
Overall Study Design
Screening Period
   
Treatment Period a
Follow-up Period  
0.5 years                             2 years
4.2.
Study Design Rationale
Follicular lymphoma and marginal zone lymphoma are distinct histologic types within the broad 
category of B-cell NHL according to the WHO classification (Harris, 2008). For FL, this 
histology is further divided into three different grades – Grades 1 to 3 – based on histologic 
appearance. These grades reflect some degree of heterogeneity in the biology of the disease, and 
in fact, follicular Grade 3 is often further subdivided in Grades 3a and 3b. This 3a versus 3b 
distinction has implications for treatment decisions, since Grade 3b FLs are clinically more 
similar to aggressive lymphomas, with more infiltration of large cells. Grade 3a is typically 
treated as a FL, while Grade 3b is treated as an aggressive lymphoma. Thus, FL Grade 3b is 
excluded from this study.
Marginal zone lymphoma is also a group of individual subtypes: extranodal MZL of MALT-
lymphoma, nodal MZL and splenic MZL. As with FL grades, these individual histologies are 
ICD: informed consent document; FL: Follicular lymphoma; MZL: Marginal zone lymphoma.
a Treatment must begin as soon as possible after randomization but no later than 1 week after randomization.
b 10 mg if CrCl ≥ 30 mL/min but < 60 mL/min; 20 mg if CrCl ≥ 60 mL/min.
cCycle defined as Lenalidomide/ Placebo cycle of 28 days (21 days treatment and 7 days rest period)
d All randomized subjects are followed for disease progression and overall survival using the same schedule 
described in Table 1.This includes patients who discontinue the protocol-specified treatment or the study 
early for any reason without documented evidence of PD or relapse.
ICD 
Signature 
Screening, 
Eligibility
Stratification
-Previous Rituximab 
treatment
-Time since last anti-
lymphoma therapy
-FL/ MZL
Randomizationa
350 subjects
[1:1]
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last subject randomized, 
- for the following: 
disease progression 
(PD)/relapse,  overall 
survival, subsequent 
anti-lymphoma 
therapies 
 
 
and  second primary 
malignancies.
LENALIDOMIDE
10 mg or 20 mg b
On Days 1-21 of Cycles c 1 to 12
RITUXIMAB
375 mg/m2
Weekly [Days 1, 8, 15, 22] in Cycle c 1 and then
on Day 1 of Cycles c 2 to 5
PLACEBO
10 mg or 20 mg b
On Days 1-21 of Cycles c 1 to 12
RITUXIMAB
375 mg/m2
Weekly [Days 1, 8, 15, 22] in Cycle c 1 and then
on Day 1 of Cyclesc 2 to 5
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Lenalidomide (CC-5013)
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associated with different clinical behavior and require different management. For example, 
gastric MALT stage 1 (that is, stage IE) is often treated with antibiotics to eradicate H. pylori.
Despite these heterogeneities in the biology and treatment practices between FL and MZL, it is 
important to note that in advanced stage disease and in relapsed disease, the clinical behavior and 
treatments are very similar among the indolent lymphomas. These similarities for example are 
reflected in the nearly identical treatment guidelines for the management of advanced stage FL 
versus advanced stage MZL [NCCN guideline, 2013; Dreyling, 2013 (ESMO guideline)]. For 
this reason, FL and MZL are studied together in this clinical trial.
Rituximab is approved in a number of countries for the treatment of relapsed/refractory low-
grade NHL or FL. “Low-grade” is a terminology which in the recent years has been replaced by 
the term “indolent.” Clinically, “low grade” lymphoma can be used interchangeably with 
“indolent lymphoma”.
Subsequent to the initial rituximab approval, the treatment of relapsed/refractory indolent 
lymphoma, including FL and MZL has continued to evolve, so that multiple options now are 
available. Thus, rituximab has become the backbone of combination therapy. In some instances, 
rituximab is used in combination with cytotoxic regimens such as cyclophosphamide-containing 
regimens, anthracycline-containing regimens, fludarabine containing regimens, and 
bendamustine, but these regimens have not been proven to increase OS compared to rituximab 
monotherapy. Among the available options, rituximab monotherapy remains an appropriate
treatment option for relapsed indolent lymphomas of the FL and MZL types. As reviewed in 
Section 1.4, the combination of rituximab and lenalidomide has been reported to have activity in 
indolent lymphomas. Waldenstrom macroglobulinemia (WM) is assessed by different response 
criteria (Owen, 2013) and the rituximab-lenalidomide combination has been previously reported 
to be associated with acute anemia in patients with this disease (Treon, 2009). Small lymphocytic 
lymphomas (SLL) is considered to be the same disease entity as chronic lymphocytic leukemia.
Lenalidomide has been noted to have a different safety profile in previously conducted trials in 
CLL (Wiernik, 2013) and is being investigated in separate CLL clinical trials. For these reasons, 
WM, and SLL are not studied in this clinical trial. 
The current study is a Phase 3, double-blind, randomized, multicenter, placebo-controlled study, 
designed to evaluate the efficacy and safety of lenalidomide plus rituximab combination therapy 
in subjects with relapsed/refractory indolent lymphomas of the FL and MZL types. The 
multicenter nature of the study provides assurance that the results are likely to have general 
applicability. The double-blinding and placebo control will reduce bias.
Subjects are required to have measurable disease according to the IWG criteria and will have 
frequent periodic disease assessments for an accurate determination of PFS, the primary endpoint 
of this study. The IWG response criteria were selected to provide an established international 
standard for the assessment of lymphoma, including both nodal and extranodal disease as 
measurable lesions (Cheson, 2007; Cheson, 1999). The use of this established tool and an IRC
will ensure that data across centers are evaluated consistently and also allow for comparison to 
historical data. In addition, in this clinical trial, these criteria exclude the use of positron emission 
tomography (PET) scan, which is less established as an indicator of response to treatment in 
indolent lymphomas compared to other lymphomas such as aggressive lymphomas. 
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The primary endpoint of PFS is a measure of clinical benefit well accepted by clinicians and by 
regulatory authorities in view of the long OS of subjects with this disease.
Safety will be assessed by evaluation of AEs and laboratory data. Adverse events and abnormal 
laboratory value severity will be graded using version 4.03 of the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE). Tumor flare reaction (TFR)
will be graded using NCI CTCAE v 3.0.
Monitoring for certain events (see Section 6.2.2 for details), including tumor flare reactions 
(TFR), TLS, and thromboembolic events (TE), will be performed along with safety assessments 
routinely conducted in investigational studies of hematologic malignancies. Thromboembolic 
events prophylaxis is recommended for subjects who are at risk for a TE. Thromboembolic 
events, TFR and TLS will be recorded as AEs.
4.3.
Study Duration 
The expected accrual duration is 40 months. Subjects will receive protocol-specified treatment 
for a maximum of 12 months, until relapse or progression of disease, withdrawal of consent or 
unacceptable toxicity. Subjects will be followed for survival, disease progression, subsequent
anti-lymphoma therapies, and SPMs until 5 years after the last subject has been randomized. 
Thus, the duration of the entire study will be approximately 8 years (accrual period of 
approximately 3 years plus 5 years from last subject randomized).
4.4.
End of Trial
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. After completion of the primary efficacy 
analysis, follow-up tests including but not limited to CT scans/ MRI, biopsies (bone marrow, 
tumor, gastric) and blood tests are no longer required for the study protocol and may be 
performed at the investigator’s discretion. A central review of these tests is no longer mandatory
(see Section 5 for details on the tests).
 
For subjects who have completed treatment or discontinued treatment due to reasons other than 
progressive disease or relapse, subjects will be followed every 6 months (± 2 weeks) and the 
follow-up assessments will include:
!
OS
!
SPM
!
For subjects who discontinue treatment due to progressive disease or relapse, subjects will be 
followed every 6 months (± 2 weeks) and the follow-up assessments will include: 
!
OS
!
SPM
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Lenalidomide (CC-5013)
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Lenalidomide (CC-5013)
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5.
TABLE OF EVENTS
Table 1:
Schedule of Study Assessments
Procedure
Screening
(Day -28
to Day -1)
Treatment Period 12 Months
At 
Treatment
Discontinuation 
or
Completion
Follow-up
Cycles 1 to 12:
Every
Cycle
Day 1
(±3 days)
Additional Assessments
If no PD
then follow
the CT 
scan 
assessment 
schedule6 or 
otherwise
specified
If progressed
then
every 6
months
(±2 weeks)
Cycle 1
Days 1, 8, 15, 
22 (±1 day)
Cycles 2
to 5 
Day 1 
(±3 days)
Cycle 1
Days 1, 8, 
15
(±1 day)
Cycles 2  
to 4
Day 15
(±1 day)
Cycle 4 &
Cycle 7  
Day 1
(± 3 days)
Cycle 10
Day 1
(±3 days)
Informed Consent
X
-
-
-
-
-
-
-
-
-
Inclusion/Exclusion Criteria
X
-
-
-
-
-
-
-
-
-
Complete Medical History
X
-
-
-
-
-
-
-
-
-
CNS Lymphoma Evaluation
X
-
-
-
-
-
-
-
-
-
Creatinine Clearance
(Cockcroft-Gault 
estimation)
X
-
-
-
-
-
-
-
-
-
12-Lead ECG
X
-
-
-
-
-
-
-
-
-
HBV Screening
X
-
-
-
-
-
-
-
-
-
FFPE Tumor Specimen1
X
-
-
-
-
-
-
-
-
-
Eastern Cooperative 
Oncology Group (ECOG) 
Performance Status
X
X
-
-
-
-
-
X
X12
-
Vital Signs2, 13
X
X
-
-
-
-
-
X
-
-
Hematology 3, 13
X
X
-
X
X
-
-
X
X12
-
Serum Chemistry3, 13
X
X
-
X
X
-
-
X
X12
-
Serum Immunoglobulin 
(IgG, IgA, IgM)
X
-
-
-
-
-
X
-
-
-
Thyroid Stimulating 
Hormone (TSH)
X
-
-
-
-
X
X
-
-
-
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Lenalidomide (CC-5013)
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Table 1:
Schedule of Study Assessments (Continued)
Procedure
Screening
Treatment Period 12 Months
Follow-up
(Day -28
to Day -1)
Cycles 1 to 
12:
Every
Cycle
Day 1
(±3 days)
Additional Assessments
At 
Treatment
Discontinuation
or
Completion
If no PD
then follow
the CT 
scan 
assessment 
schedule6 or
otherwise 
specified
If progressed
then
every 6
months
(±2 weeks)
Cycle 1
Days 1, 8, 15, 
22 (±1 day)
Cycles 2
to 5 
Day 1 
(±3 days)
Cycle 1
Days 1, 8, 
15
(±1 day)
Cycles 2to 
4
Day 15 
(±1 day)
Cycle 4 &
Cycle 7 
Day 1
(± 3 days)
Cycles 10
Day 1
(±3 days)
Tumor Flare and Tumor 
Lysis Assessments4
-
-
-
X
-
-
-
-
-
-
Pregnancy Testing - for 
FCBP with Regular or No 
Menstrual Cycles
Once between
Days -10 to -14, and 
within 24h prior to 
C1D1
Weekly during first 28 days; every cycle on Day 1 thereafter
X
-
-
Pregnancy Testing - for 
FCBP with Irregular 
Menstrual Cycles
Once between
Days -10 to -14, and 
within 24h prior to 
C1D1
Weekly during first 28 days; every cycle on Days 1 and 14 thereafter
X
-
-
Birth Control and 
Lenalidomide 
Counseling5
Once between Days
-10 to -14
X
-
-
-
-
-
X
-
-
Distribute Lenalidomide
Counseling Sheet5
X
X
-
-
-
-
-
X
-
-
Adverse Events
X
After signing the informed consent document through 28 days after last dose.
Assessment of Second 
Primary Malignancy 
(SPM)6
X
After signing the informed consent document up to and including a follow-up period of up to 5 years from the date of the last subject 
randomized
Prior/Concomitant 
Medications/ Procedures / 
Record Hospitalizations
X
After signing the informed consent document through 28 days after last dose.
Physical Examination 13
X
X
-
-
-
-
-
X
X12
-
B Symptoms 13
X
X
-
-
-
-
-
X
X12
-
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
33
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
Table 1:
Schedule of Study Assessments (Continued)
Procedure
Screening
Treatment Period 12 Months
Follow-up
(Day -28
to Day -1)
Cycles 1 to 
12:
Every
Cycle
Day 1
(±3 days)
Additional Assessments
At 
Treatment
Discontinuation 
or
Completion
If no PD
then follow
the CT 
scan 
assessment 
schedule6 or 
otherwise 
specified
If progressed
then
every 6
months
(±2 weeks)
Cycle 1
Days 1, 8, 15, 
22 (±1 day)
Cycles 2
to 5 
Day 1 
(±3 days)
Cycle 1
Days 1, 8, 
15
(±1 day)
Cycles 2 to 
4
Day 15 
(±1 day)
Cycle 4 &
Cycle 7  
Day 1
(± 3 days)
Cycles 10
Day 1
(±3 days)
CT or MRI of Neck, Chest, 
Abdomen and Pelvis
and
Response Assessment 7, 13
X
Years 1-3: Every 12 weeks (± 1 week)
Year 4: Every 16 weeks (± 1 week)
Year 5: Every 6 months (± 2 weeks)
Years onwards: Every year (± 3 weeks) and up to PD
-
Bone Marrow Biopsy13
X9
For subjects with radiological CR/CRu and conditions as defined in section 6.2.1
Upper Gastrointestinal 
Endoscopy and Gastric 
Biopsy10, 13
X
Years 1: Cycle 7 Day 1 (± 2 weeks); After cycle 12 (+ 2 months)
Year 2-3: Every 6 months (± 2 weeks)
Year 4 onwards: Every year (± 2 weeks) and up to PD or CR
-
Dispense Study Drug11
-
X
-
-
-
-
-
-
-
-
Rituximab11
-
-
X
-
-
-
-
-
-
-
Study Drug Return/
Accountability
-
X
-
-
-
-
-
X
-
-
Subsequent Anti-Lymphoma 
Therapies 
 
-
-
-
-
-
-
-
X
-
X
Detailed information for each row, if applicable, is provided in Section 6.
Note:  Safety assessments (including labs) must be performed prior to dosing at each treatment visit.
C1D1: Cycle 1 Day 1; CBC: Complete blood count; CNS: Central nervous system; CRF: Case report form; CT: Computed tomography; ECG: 
Electrocardiogram; FCBP: females of childbearing potential; FFPE: Formalin-fixed paraffin embedded; HBV: Hepatitis B virus; MRI: magnetic resonance 
imaging; PD: disease progression; TLS: Tumor lysis syndrome; TSH: Thyroid stimulating hormone.
1.
If an FFPE tumor block cannot be sent, one hematoxylin and eosin (H and E) stained slide and 10 unstained slides or 11 unstained slides will be acceptable.
2.
Vital signs include weight, height (only at Screening), blood pressure, temperature, and pulse.
3.
If Screening labs are drawn within 1 week before receipt of study drug on Cycle 1 Day 1, they do not need to be repeated on C1D1.
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Lenalidomide (CC-5013)
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CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
4.
The site should make every effort to contact the subject on Day 5 (± 1 day) of the first cycle to inquire about the subject’s condition and to make sure that 
he/she is continuing with TLS prophylaxis measures by keeping hydrated and taking the TLS prophylaxis as instructed (see Section 9.3.1 for more details).
5.
All subjects enrolled into this study must conform to all aspects of the lenalidomide pregnancy prevention risk management plan (standalone document, see 
Section 18.6).  
6.
Medical history of any prior cancer other than the disease under study will be reported and, in addition, SPMs will be monitored as events of interest and must 
be reported as serious adverse events (SAE) regardless of the treatment arm the subject is in. This includes any second primary malignancy, regardless of 
causal relationship to study drug[s], occurring at any time for the duration of the study, from the time of signing the Informed consent (ICD) up to and 
including the follow-up period and until 5 years after the last subject randomized.  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 second primary malignancy must be provided at the time of reporting as a serious 
adverse event (eg, any confirmatory histology or cytology results, X-ray reports, CT scan reports, etc.).
7.
Efficacy assessment to be performed until progression or relapse. See section 6.2.1 for details.
 
 
 
9.
Bone marrow biopsy is required at Screening (for staging) only for subjects with abnormal CBC. See section 6.1 and 6.2.1 for more details.
10. Upper gastrointestinal endoscopy including biopsies (from stomach, duodenum, gastroesophageal junction and from any abnormal-appearing site) is required 
only in subjects with gastric mucosa-associated lymphatic tissue (MALT) lymphoma. See section 6.1 and 6.2.1 for more details.
11. See Sections 8.1 and 8.2 for more details regarding treatment administration. There is no window for study drug administration.
12. During Follow-up, at same time as the CT/MRI scan evaluation and every 6 months (± 2 weeks) after year 5 (see section 6.4).
13. Once the primary efficacy analysis is done; follow up specified tests are no longer required per protocol and may be performed at the investigator’s
discretion. (see Section 4.4)
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Lenalidomide (CC-5013)
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6.
PROCEDURES
6.1.
Screening Procedures
Subjects must approve and sign the informed consent document (ICD) prior to undergoing any 
study-related screening assessments.
Subjects will be screened for protocol eligibility (see Section 7) during a period of no more than 
28 days prior to randomization as outlined in the Schedule of Study Assessments (the screening 
period timing begins on the day [Day -28] the first study procedure is performed after the subject 
has provided written informed consent).
Screening assessments including physical exam, medical history, prior concomitant medication 
or procedures, B symptoms (fever (>38°C), night sweats, weight loss greater than 10% within 
the prior 6 months), Eastern Cooperative Oncology Group (ECOG) performance, vital signs, and 
recording of AEs/serious adverse events (SAEs) including SPMs will begin once the subject has 
signed the informed consent form.
The physical examination should include height (Screening only), weight, vital signs (including 
BP, temperature, and pulse), and an assessment of the ECOG performance status (see 
Section 18.4).
A medical history will be obtained by the investigator or qualified designee. Medical history
(including HIV and HCV infection) judged as relevant to the study and to the safety of the study 
subject will be recorded in the source documents and CRF. Subjects with a presence of CNS 
lymphoma involvement are excluded from the study. Subjects with suspicion of CNS 
involvement must undergo neurologic evaluation and a CT/MRI of the brain and lumbar 
puncture to exclude active CNS disease.
A12-lead ECG is performed at Screening and as clinically indicated thereafter. 
Hepatitis B screening is required in all subjects and includes hepatitis B surface antigen 
(HBsAg), hepatitis B core antibody (anti-HBc), hepatitis B surface antibody (anti-HBs). If 
subjects are anti-HBs positive and/or anti-HBc positive, and HBsAg negative, additional 
HBV-DNA testing is required. See Exclusion Criterion # 6 (Section 7.3) for further details.
Eligibility for the study is based on the local HBV tests. HBV tests performed as standard of care 
may be used as screening HBV tests if they are obtained within 28 days prior to Cycle 1 Day 1
(in such case the Screening Period would start at the HBV tests date).
Bone marrow biopsy (BMB) is required at Screening for subjects with abnormal CBCs (defined
as per local laboratory lower ranges for ANC, Platelets and Hemoglobin values). For all subjects, 
if a BMB was performed within 12 weeks prior to Cycle 1 Day 1 and is available, it may be used
as the screening biopsy. BMB samples must be submitted to central pathology within 8 weeks 
after randomization. The biopsy may be unilateral or bilateral at the discretion of the 
investigator. A block is preferred, but if a block cannot be sent, then an H&E slide and 
representative unstained slides must be submitted. If no such recent bone marrow biopsy samples 
are available, then rebiopsy will be required prior to randomization. The details of sample 
requirement will be discussed in the pathology manual. Pathology reports associated with these 
tissues also must be sent to the central pathology laboratory with the tissue and/or slides.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
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CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
The FFPE tumor block of diagnostic tumor mass or lymph node must be confirmed to be 
available at the time of randomization and must be submitted to central pathology within 8 
weeks after randomization. A fresh biopsy is ideal, but if not available, an archival biopsy 
preferably should be 2 years old or less. If the archival tissue sample is between 2 and 5 years 
old, the Celgene Medical Monitor must be notified to determine if the biopsy can be used. 
However, if archival tumor tissue was not available prior to randomization or the archival sample 
is older than 5 years old, a newly obtained tumor biopsy (excisional or core) is required prior to 
randomization. If a block cannot be sent, one Hematoxylin and Eosin (H and E) stained slide and 
10 unstained slides, or 11 unstained slides will be acceptable. Details will be discussed in the 
separate pathology manual. Pathology reports associated with these tissues are also required and 
must be sent to the central pathology laboratory with the tissue and/or slides. Detailed 
instructions and materials for sample handling and shipping will be provided. It is noted that 
diagnosis based on core biopsy is acceptable but fine needle aspiration is not considered 
acceptable pathologic data for entry into this study.
 
 
Eligibility will be based on local pathology review; confirmation of diagnosis by central 
pathology laboratory is not required for entry or initiation of treatment. However, if archival 
tumor tissue was not available prior to randomization, a newly obtained tumor biopsy (excisional 
or core) is required prior to randomization. 
For subjects with gastric MALT lymphoma, upper gastrointestinal endoscopy including biopsies 
(from stomach, duodenum, gastroesophageal junction and from any abnormal-appearing site) is 
required during screening. A recent endoscopy and histological evaluation conducted within 12 
weeks prior to Cycle 1 Day 1, is acceptable as the screening assessment. If no such recent 
evaluation is available, then gastric rebiopsy and histological evaluation will be required prior to 
randomization. Histological evaluation will be based on local pathology for study entry but 
tumor tissue samples must be submitted to central pathology within 8 weeks after randomization. 
The sample requirement will be discussed in detail in the pathology manual.
Hematology and serum chemistry tests will be required during Screening and Day 1 (± 3 days) 
and at additional times of every treatment cycle as described in Table 1. However, if Screening 
labs are drawn within 1 week before receipt of study drug on Cycle 1 Day 1, they do not need to 
be repeated on Cycle 1 Day 1. Eligibility for the study is based either on the central laboratory or 
the local laboratory results. However, the eligibility value concerning the creatinine clearance 
(CrCl) will be calculated only by the central laboratory.
!
A central laboratory will be used for the analysis of hematology and chemistry tests. 
Clinical decisions and dose modifications during the study can be based on local 
laboratory results as long as the reason is reported accordingly. Hematology 
laboratory tests will include hemoglobin, hematocrit, total white blood cell (WBC) 
count without differential (neutrophils, eosinophils, basophils, lymphocytes, 
monocytes), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and 
platelet count.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
37
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
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Serum chemistry will include total protein, albumin, calcium, phosphorous, glucose, 
uric acid, total bilirubin, alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), sodium, potassium, chloride, blood urea nitrogen or 
urea, creatinine, and lactate dehydrogenase (LDH).
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assess any risks for infections not associated with neutropenia and to determine any 
effect of treatment on immunoglobulin levels.
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Creatinine clearance will be calculated by the central laboratory utilizing actual body 
weight (Cockcroft, 1976; Luke, 1990; Griggs, 2012) and the creatinine clearance data 
will be sent to the site. Cockcroft-Gault estimation of creatinine clearance (CrCl) will 
be used:
CrCl (mL/min) = (140 – age) (weight [kg]) / 72 x (serum creatinine [mg/dL]); for 
females, the formula is multiplied by 0.85.
By SI units, CrCl (mL/min) = (140-age) x weight x 1.23 / serum creatinine [μmol/L]; 
for females, the formula is multiplied by 0.85.
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted. During counseling, subjects must be reminded to not share study drug and to not 
donate blood. For females of childbearing potential (FCBP)1 two pregnancy tests must be 
performed (medically supervised; urine tests are provided and preferred method; if use of other 
test method (blood), the minimum sensitivity is 25 mIU/mL): (1) one during Screening Period 
(all FCBP, between Day -10 and -14) and (2) one within 24 hours prior the start of lenalidomide 
(for FCBP only) (See Pregnancy Prevention Risk Management Plan document for more details).
The preferred imaging modality is CT with contrast. The imaging modality used for lesion 
evaluation at Screening must be consistently used throughout the study for each subject (see 
Section 6.2.1- for details on modalities). A CT of neck, chest, abdomen and pelvis is required to 
confirm one measurable disease greater than 1.5 cm in diameter or at least one extranodal lesion 
greater than 1.0 cm in both long and short diameter. A CT (or MRI) scan performed as standard 
of care may be used as screening CT (or MRI) scan if it is obtained within 28 days prior to Cycle 
1 Day 1 (in such case, the Screening Period would start at date of CT or MRI). 
 
6.2.
Assessments During Treatment Phase
Treatment will start on Cycle 1 Day 1. A 1-week window between randomization and Cycle 1 
Day 1 is allowed, but should not be exceeded.
Serial assessments of safety and efficacy will be performed as outlined in the Schedule of Study 
Assessments (Table 1). A central laboratory will be used for the analysis of hematology and 
                                               
1 See Section Appendix 18.6 for details.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
38
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
chemistry. Clinical decisions and dose modifications during the study can be based on local 
laboratory results. 
6.2.1.
Efficacy Assessments
Radiological assessments for efficacy will be CT (preferred) or MRI scan. A CT (or MRI) scan
should be performed with contrast unless it is medically contraindicated. MRI may be used only 
if CT with contrast is medically contraindicated as assessed by the investigator or if CT scans at 
a frequency as per the defined schedule of assessment are not accepted by local IRB/Ethics 
Committee. If scans with and without contrast are performed at the same time-point, both 
modalities should be submitted for central review. All CT or MRI scan assessments will be 
determined from first dose date and will follow the counting of calendar days and not the dosing 
cycles. The same imaging modality (CT or MRI) and technique (e.g. the use of contrast, slice 
thickness for scans) that was used at Screening should be used throughout the study for each 
subject. The scans must be performed at:
!
every 12 weeks (± 1 week) for 3 years (Years 1-3)
!
then every 16 weeks (± 1 week) for 1 year (Year 4)
!
then every 6 months (± 2 weeks) for 1 year (Year 5)
!
and then every year (± 3 weeks) until disease progression or relapse
All CT/MRI scans performed must be submitted for central review no later than 4 weeks after 
they are performed.
All randomized subjects are followed for disease progression (PD) or relapse using the 
schedule described in Table 1. This includes subjects who discontinue the protocol-specified 
treatments or the study early for any reason without documented evidence of PD or relapse. If a 
subject withdraws consent, but agrees to continued collection of outcome data, these follow-up 
activities will continue. For equivocal progression, the investigator is strongly recommended to 
contact the sponsor Medical Monitor or Steering Committee Members for evaluation in a “real 
time” manner.
Protocol-defined efficacy endpoints except OS and time to next treatment will be assessed by an 
IRC. The IRC review includes central radiology and clinical review. Since the study endpoint is 
PFS based on CT as determined by IRC, progression will typically be based on CT scans. In 
limited instances where progression is evident only by assessments other than CT, CT scans 
must still be provided along with the non-CT documentation of progression.
The radiological assessments (CT or MRI) are considered the primary method of response 
assessment. The additional assessments – clinical assessments, bone marrow biopsy assessments 
and endoscopic assessments (including gastric biopsy) are considered confirmatory. Bone 
marrow assessments are considered in the response assessment in all subjects (see below 
paragraph for more details). Endoscopic gastric biopsy and evaluation of the biopsy findings are 
required only in subjects with an investigator-assessed diagnosis of gastric MALT lymphoma. In 
those subjects whose CT/MRI response assessments require consideration of biopsy findings 
before a final response assessment can be determined, the date of achievement of a response 
status will be the initial date of CT or MRI showing a response. 
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
39
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
Bone marrow assessments: all subjects who have achieved a CR/CRu by radiological imaging 
will need to undergo a BMB to confirm the radiological response, unless a BMB collected at 
baseline (within 12 weeks of Cycle 1 Day 1), was negative. The confirmatory BMB should be 
performed within 28 days after the criteria for CR/CRu have otherwise been met. The BMB 
sample must be submitted to central pathology within 8 weeks.
Subjects with gastric MALT lymphoma will have an upper gastrointestinal endoscopic 
assessment and repeat gastric biopsy for histological evaluation during the study if the subject 
has fulfilled the IWG criteria for response of at least a SD and had positive biopsy at baseline. 
The endoscopic assessment and repeat biopsies will be performed at Cycle 7 Day 1 (±2 week),
within 2 months after Cycle 12 (treatment completion), then every 6 months for 2 years, and 
thereafter annually. For subjects achieving radiological CR/CRu, two biopsies performed at two 
separate time points within 3 months after the criteria for CR/CRu were first met are required to 
confirm response. The biopsy samples must be submitted to central pathology review within 8 
weeks. Histological evaluation will be performed using the Groupe d' Etude des Lymphomes de 
l' Adulte (GELA) grading system (Copie-Bergman, 2003; Copie-Bergman, 2012). The 
Investigator may make treatment decisions based on histological evaluation of bone marrow 
biopsy, gastric biopsy or other biopsies by local pathology. However, response assessments and 
determination of progression will be by central pathology. For equivocal biopsy findings, the 
investigator is strongly recommended to contact the sponsor Medical Monitor for evaluation of 
the equivocal biopsy by the central pathologist in a “real time” manner.
 
 
Subjects who relapse or progress will continue to be followed for OS, TTNLT, 
, all 
subsequent anti-lymphoma therapy 
 
.
6.2.2.
Safety Assessments
Adverse events will be assessed, concomitant medication or procedure and hospitalizations 
recorded from signing of informed consent form until 28 days post-last dose of treatment.
The physical examination including ECOG PS and B symptoms assessments should be 
repeated at the beginning of each cycle, at treatment discontinuation, according to the CT scan 
schedule during the follow-up, every 6 months (±2 week) after year 5 and at any additional times 
as deemed necessary by the Investigator.
Vital signs (including blood pressure, pulse, and temperature) will be measured on Day 1 of 
every cycle, at treatment discontinuation and at designated times thereafter. Investigators are to 
report any clinically significant abnormal findings as AEs.
Hematology laboratory evaluations and serum chemistry laboratory evaluations will be 
collected at Day 1 (± 3 days) of every treatment cycle, Days 8 and 15 (± 1 day) of Cycle 1, Day 
15 of Cycles 2 to 4 (± 1 day), and at treatment discontinuation. During the follow-up period, 
hematology and serum chemistry assessments will follow the CT scan schedule, and will be 
collected every 6 months (±2 weeks) after year 5.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
40
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
TSH will be collected every 3 months after screening up to Cycle 10 (Cycle 4 Day1, Cycle 7 
Day1, and Cycle 10 Day 1; ± 3 days) and thereafter as clinically indicated. 
Serum immunoglobulin assessment (IgG, IgA, IgM) is performed on Cycle 10 Day 1 (± 3 
days).
In addition, any or all laboratory evaluations may be repeated more frequently if clinically 
indicated.
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted on Day 1 of every treatment cycle. All subjects must also be counseled against sharing 
lenalidomide and donating blood during and within 28 days of discontinuing protocol-specified 
therapy. Pregnancy tests for FCBP will be performed weekly during the first cycle, every 28 
days (Day 1 of every cycle) during treatment. FCBP with regular or no menstrual cycles must 
have pregnancy tests at treatment discontinuation and at Day 28 following lenalidomide or 
placebo discontinuation and if menstrual cycles are irregular, the pregnancy testing must occur 
at treatment discontinuation and at Days 14 and 28 following lenalidomide or placebo 
discontinuation (Section 18.6).
All subjects including the subjects who relapse or progress will continue to be followed for 
SPMs. 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 SPM as SAEs regardless of causal relationship to the study drug[s], occurring at any 
time for the duration of the study, from the time of signing the ICD up to and including the 
Follow-up Period (up to 5 years from last subject randomized).
6.2.2.1.
Assessments for Tumor Flare
Assessments for tumor flare reaction (TFR) are conducted in Cycle 1: Days 1, 8, and 15 (±1 
day), and when clinically indicated thereafter.
Tumor flare reaction 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). 
Tumor flare reaction 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 at a lower rate than in CLL patients (Witzig, 2011; Eve, 2010; Corazzelli, 
2010). The clinical manifestations of TFR seen in lymphoma subjects treated with lenalidomide 
are similar to those subjects with CLL; a sudden and tender increase in the size of the disease 
bearing sites, including the lymph nodes, spleen and/or the liver, typically accompanied by pain 
and sometimes accompanied by low-grade fever and non-pruritic diffuse rash, typically 
occurring in the first cycle (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 and is within the first 2-3 weeks of the first cycle in the vast majority of TFR cases 
(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).
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
41
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
The experience with tumor flare in Celgene-sponsored studies of single agent lenalidomide in 
NHL is now summarized. Over 400 subjects with relapsed or refractory aggressive or indolent 
non-Hodgkin’s lymphoma have received lenalidomide in four Phase 2 clinical studies. Four 
studies (NHL-001, NHL-002, NHL-003, and MCL-001) were Phase 2 multicenter, single-arm, 
open-label studies that evaluated lenalidomide 25 mg/day for 21 days of a 28-day cycle in 43 
previously treated subjects with indolent NHL (Witzig, 2009), 49 subjects with 
relapsed/refractory aggressive NHL (Wiernik, 2008), 217 subjects with relapsed/refractory 
aggressive NHL (Witzig, 2011), and 134 subjects with MCL (Goy, 2012), respectively. TFR 
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)], 13 of 134 subjects in the MCL-001 study [Grade 1 (n = 7), and Grade 2 (n = 6)]
and in 17 (10.2%) out of 167 subjects in the lenalidomide arm in the MCL-002 study.. These 
protocols suggested that subjects experienced TFR during the first 1 to 2 weeks of Cycle 1 and 
the TFR may be treated symptomatically with non-steroidal anti-inflammatory drugs (NSAIDs).
In a single-center, open-label Phase II investigator initiated study, Ahmadi et al evaluated the use 
of lenalidomide, dexamethasone and Rituximab in subjects with relapsed or refractory indolent 
B-cell or MCL resistant to rituximab (Ahmadi, 2014). Tumor flare was reported in 1 of the 27
subjects.
It is important to note that the increased lymphadenopathy seen in TFR may mimic PD.
Therefore, careful monitoring and evaluation to differentiate TFR from PD is necessary for 
addressing treatment of individual subjects including making decisions 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 case of TFR, inflammation and edema may reduce or disappear after short term 
treatment with NSAIDs and/or corticosteroids.
Management of TFR is described in Section 9.1.1.
6.2.2.2.
Assessments for tumor lysis
Tumor lysis syndrome assessments are conducted in Cycle 1: Days 1, 8, and 15 (± 1 day), and 
when clinically indicated thereafter.
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 and the prevention of TLS 
development with the initiation of preventive measures, as well as the careful monitoring for 
early signs of laboratory TLS and the prompt initiation of supportive care are critical to prevent 
potentially life-threatening metabolic derangements (Cairo, 2010).
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
42
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
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 in 43 previously treated 
subjects with indolent non-Hodgkin lymphoma (NHL-001; Witzig, 2009), 49 subjects with 
relapsed/refractory aggressive NHL (NHL-002; Wiernik, 2008), 217 subjects with 
relapsed/refractory aggressive NHL (NHL-003; Witzig, 2011) and 134 subjects with 
relapsed/refractory MCL (MCL-001; Goy, 2012). In addition, in the MCL-002 study, a Phase 2 
randomized, two-arm, open-label study of lenalidomide versus Investigator’s Choice in 
relapsed/refractory MCL, 167 subjects received lenalidomide 25 mg/day for 21 days of a 28 day 
cycle. One subject 
 had Grade 1 TLS reported.
 
 
 
In an investigator initiated study, a single-center, open-label Phase II study, Tuscano et al 
(Tuscano, 2014) 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 tumor lysis. Thus, the lenalidomide dose was reduced to 20 mg and allopurinol 
prophylaxis was used in all subsequent subjects with no further TLS events recorded. In the 
current study, it is required that subjects receive prophylaxis (allopurinol, rasburicase, or 
equivalent as per institutional guidelines) during the first week of the first cycle or for a longer 
period if clinically indicated (see Section 9.3.1 for more information).
6.2.2.3.
Deep vein thrombosis
6.2.2.3.1. Deep vein thrombosis in Multiple Myeloma
Venous thromboembolic events (VTE), such as deep venous thrombosis and pulmonary 
embolism, have occurred in patients with multiple myeloma treated with lenalidomide 
combination therapy, and patients with MDS or lymphoma treated with lenalidomide 
monotherapy. A significantly increased risk of DVT and PE has been observed in patients with 
multiple myeloma who were treated with lenalidomide and dexamethasone therapy (Hussein, 
2006; Revlimid prescribing information USA, February 2013). Clinical data in multiple 
myeloma patients treated with lenalidomide suggest 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 patients treated with 
lenalidomide (Leleu, 2011).
In the two pivotal randomized studies (MM-009 and MM-010) in subjects with multiple 
myeloma receiving lenalidomide plus dexamethasone, deep venous thrombosis and pulmonary 
embolism were reported in 9.3% and 4.3% of subjects, respectively compared to 4.0% and 0.9% 
of subjects receiving placebo and dexamethasone. The studies did not require systematic DVT 
prophylaxis. An analysis of pooled data from the MM-009 and MM-010 studies demonstrated 
thromboembolic events were significantly higher in subjects treated with 
lenalidomide/dexamethasone in 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 
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Lenalidomide (CC-5013)
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erythropoietin (P=0.14) (Weber, 2007). The 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 venous thromboembolism 
(VTE) including DVT and PE occurred in 26% of 223 subjects in the RD arm and 12% of 220 
subjects in the Rd arm (Rajkumar, 2010). DVT prophylaxis was to be used in both arms. 
6.2.2.3.2. 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 but not limited to the underlying disease, family history, age, 
obesity, immobilization, hormonal therapy, central venous catheter, recent DVT, and
doxorubicin (Zhou, 2010; Park, 2012; Lyman 2013).
Venous thromboembolism including deep venous thrombosis (DVT) and pulmonary embolism 
(PE) has been reported in patients during treatment for NHL, occurring at incidences from ~7% 
up to 20% (Ottinger, 1995, Komrokji, 2006, Mohren, 2005, Zhou, 2010), the risk being 
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 
(Ottinger, 1995) analyzed incidence, risk factors, causes and prognostic significance of VTE in 
high-grade non-Hodgkin's lymphoma in a prospective clinical trial. In 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.
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) and in 5 (4%) and 3 (2%) of 134 subjects with relapsed or refractory MCL 
receiving lenalidomide in the clinical study MCL-001 (Goy 2012). In the Lenalidomide arm of 
the MCL-002 study, pulmonary embolism was the most frequently reported VTE event (7 
subjects, 4.2%), followed by deep vein thrombosis (3 subjects, 1.8%). Most events of both 
pulmonary embolism and deep vein thrombosis occurred within the first 5 cycles of treatment. 
All events of pulmonary embolism were considered Grade 3-5 AEs and all but one event were 
SAEs, whereas no events of deep vein thrombosis were SAEs and only one event was Grade 3-5. 
DVT and PE were reported in 0 (0%) and 1 (2.3%) of 43 subjects with indolent relapsed 
refractory NHL (Witzig, 2009). Anti-thrombotic prophylaxis was not suggested in NHL-001 or 
NHL-002 but required for subjects considered to be high risk of developing DVT in NHL-003.
In the recent 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 
lenalidomide plus rituximab arm versus 7 (16%) of 45 subjects in lenalidomide arm (Leonard, 
2012).
Thus, when the available data are taken together, the increased risk of DVT reported thus far 
with lenalidomide monotherapy in lymphoma patients does not appear to be as high as when
lenalidomide is added to dexamethasone in multiple myeloma subjects. However, we cannot rule 
out that the risk of VTE is increased in the subjects participating in this study treated with 
rituximab and lenalidomide. Thus, in the current study, it is recommended that all subjects at risk 
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Lenalidomide (CC-5013)
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for thromboembolic events receive anti-thrombotic prophylaxis (see Section 9.1.2) and all 
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6.3.
Assessments at Treatment Discontinuation/Completion
!
Physical examination including vital signs, and ECOG PS 
!
B symptoms
!
Hematology and serum chemistry laboratory tests
!
Pregnancy testing for FCBP
!
Lenalidomide counseling
!
Adverse events including SPM
!
Hospitalization
!
Concomitant medication and procedure
!
Study drug return/accountability
!
Subsequent anti-lymphoma therapy 
6.4.
Follow-up Assessments
Follow-up Period will start at the end of treatment (end of cycle 12, day 28) or at treatment 
discontinuation. 
Adverse events, concomitant treatments, pregnancy testing for FCBP, and hospitalization will be 
recorded up to 28 days after the last dose of study drug(s).
Subjects will be followed until 5 years after the last subject is randomized, for disease 
progression, long-term follow-up for OS, subsequent anti-lymphoma therapy,
 
and SPM. The 
frequency of the visit and assessments will be based on the disease status. If a subject withdraws 
consent, but agrees to continued collection of outcome data, these follow-up activities will 
continue.
For subjects who have completed treatment or discontinued treatment due to reasons other than 
progressive disease or relapse, follow-up assessments include the following and will follow the 
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Lenalidomide (CC-5013)
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CT scan assessment schedule (as described in Section 6.2.1), and every 6 months (± 2 weeks)
after year 5 or as specified below:
!
Physical examination including ECOG PS 
!
B symptoms 
!
Hematology laboratory evaluations (hemoglobin, hematocrit, WBC count, ANC, and 
platelet count) 
!
Serum chemistry laboratory evaluations
!
CT or MRI scans will follow the assessment schedule as described in Section 6.2.1.
!
Upper gastrointestinal endoscopy and gastric biopsies every 6 months (± 2 weeks) in 
year 2 and 3 and then annually until disease progression. For subjects achieving 
radiological CR/ a biopsy performed at two separate time points within 3 months after 
the criteria for CR were first met is required to confirm response
!
OS
!
SPM
 
 
 
For subjects who discontinue treatment due to progressive disease or relapse, subjects will be 
followed every 6 months (± 2 weeks) and the follow-up assessments will include: 
!
OS
!
Next subsequent anti-lymphoma therapy 
 
 
!
SPM 
Once the primary efficacy analysis is completed, follow-up tests including but not limited to CT 
scans, biopsies (bone marrow, tumor, gastric) and blood tests are no longer required for the study 
protocol and may be performed at the investigator’s discretion. A central review of these tests 
will no longer be required (see Section 4.4 for details).
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Lenalidomide (CC-5013)
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CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
7.
STUDY POPULATION
Subjects must have an Investigator-assessed diagnosis of relapsed indolent lymphoma, defined in 
this clinical trial as Grade 1, 2 or 3a FL or MZL, must have been previously treated for their 
lymphoma with systemic therapy, must be refractory or must have relapsed after their last 
treatment, must have at least one measurable lesion by CT or MRI scan, and must have adequate 
bone marrow function, liver function and renal function.
7.1.
Number of Subjects 
It is planned to randomize 350 subjects in this study.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Must be ≥18 years at the time of signing the ICD. 
2. Understand and voluntarily sign an ICD prior to any study related 
assessments/procedures are conducted. 
3. Histologically confirmed MZL or Grade 1, 2 or 3a FL (CD20+ by flow cytometry or 
histochemistry) as assessed by investigator or local pathologist: 
a.
A formalin fixed paraffin embedded specimen must be available for central 
review. If an archival specimen is not available, a rebiopsy is required prior to 
randomization.
4. Must have been previously treated with at least one prior systemic chemotherapy, 
immunotherapy or chemoimmunotherapy and must have received at least 2 previous 
doses of rituximab (as of Amendment 3):
a.
Systemic therapy does not include, for example:
i. Local involved field radiotherapy for limited stage disease
ii. H. Pylori eradication
b. Prior investigational therapies will be allowed provided the subject has received at 
least one prior systemic therapy.
5. Must have documented relapsed, refractory or progressive disease (PD) after treatment 
with systemic therapy, and must not be rituximab-refractory. 
a.
Relapsed lymphoma: relapsed after initial response of CR to prior therapy.
b. Progressive lymphoma: PD after initial response of PR or SD to the prior therapy.
c.
Refractory lymphoma: Subject who received a non-rituximab containing systemic 
therapy and who experienced the best response of PD to this therapy is considered 
to have refractory lymphoma.
d. Rituximab-refractoriness is defined as:
i.
Did not respond (at least a PR) to rituximab or R-chemoregimen therapy 
and/or
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ii.
Time to disease progression < 6 months after last rituximab dose.
e.
Rituximab-sensitive MZL or FL defined as
i.
Responded (at least a PR) to rituximab or R-chemoregimen therapy and
ii.
Time to disease progression ≥ 6 months after last rituximab dose
f.
Subjects with gastric MALT lymphoma and evidence of H. pylori (HP) infection 
must have documented non-response to antibiotic therapy as judged by a 
minimum follow up of 12 months after successful HP-eradication.
6. Investigator considers that rituximab monotherapy is appropriate.
7. Bi-dimensionally measurable disease on cross sectional imaging by CT or MRI with
a.
At least one nodal lesion > 1.5 cm in diameter or
b. At least one extranodal lesion > 1.0 cm in both long and short diameter
8. Must be in need of treatment for relapsed, progressed or refractory disease as assessed by 
the investigator
9. Performance status ≤ 2 on the ECOG scale (Appendix 18.4) 
10. Must fulfill the following laboratory requirements: 
a.
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 (1.5 x 10
9
/L) unless secondary 
to bone marrow involvement by lymphoma as demonstrated by recent bone marrow
biopsy
b. Platelet count ≥ 75,000/mm3 (75 x 10
9/L) unless secondary to bone marrow 
involvement by lymphoma as demonstrated by recent bone marrow biopsy
c.
Hemoglobin ≥ 8.0 g/dL (80.0 g/L; 5 mmol/L)
d. Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) 
≤3x upper limit of normal (ULN) except in subjects with documented liver 
involvement by lymphoma
e.
Serum total bilirubin ≤ 2.0 mg/dL (34 μmol/L) except in cases of Gilberts Syndrome, 
or documented liver or pancreatic involvement by lymphoma 
f.
Creatinine clearance of ≥30 mL/min (≥0.5mL/sec), from central laboratory
calculation
g.
Absolute lymphocyte count ≤25,000/mm3 (25 x 109/L)
11. Must be able to adhere to the study visit schedule and other protocol requirements
12. 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 
                                               
† See Appendix 18.6 for details
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the study, and after end of study therapy. This applies even if the subject practices 
true abstinence‡ from heterosexual contact.
b. Either commit to true abstinence‡ 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 drug, 
during the study therapy (including dose interruptions), for 28 days after 
discontinuation of lenalidomide/placebo therapy and according to the approved 
rituximab product/prescribing information. 
13. Male subjects must:
a.
Must practice true abstinence‡ 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 study drug 
discontinuation, even if he has undergone a successful vasectomy. 
b. Agree to not donate semen during study drug therapy and for 28 days after 
discontinuation of study drug therapy.
14. All subjects must:
a.
Have an understanding that the study drug could have a potential teratogenic risk.
b. Agree to abstain from donating blood while taking study drug therapy and for 28 
days after discontinuation of study drug therapy. 
c.
Agree not to share study medication 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 28 days after lenalidomide/placebo discontinuation and according to 
the approved rituximab product/prescribing information.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Histology other than FL and MZL or clinical evidence of transformed lymphoma by 
investigator assessment. 
2. Grade 3b follicular lymphoma. 
3. Subjects taking corticosteroids during the last 1 week prior to Cycle 1 Day 1, unless 
administered at a dose equivalent to ≤20 mg/day prednisone or prednisolone (over this
week). 
4. Major surgery (excluding lymph node or bone marrow biopsy) within 28 days prior to 
signing informed consent. 
                                               
‡ True abstinence: When this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception].
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5.
Systemic therapy within 28 days prior to Cycle 1 Day 1 dosing or use of the following:
a.
Antibody agents within 8 weeks prior to Cycle 1 Day 1 dosing
b. Radioimmunotherapy within 6 months prior to Cycle 1 Day 1 dosing
6. Seropositive for or active viral infection with hepatitis B virus (HBV): 
!
HBsAg positive
!
anti-HBs positive and/or anti-HBc positive, and HBsAg negative and detectable 
viral DNA
Notes:- Subjects who are anti-HBs positive and/or anti-HBc positive, and HBsAg 
negative but viral DNA negative are eligible (see Section 9.3.3)
- Subjects who are seropositive because of HBV vaccination are eligible (anti-
HBs positive, anti-HBc negative, and HBsAg negative)
7. Hepatitis C virus (HCV) positive subjects with chronic HCV hepatitis or subjects with 
an active HCV infection requiring anti-viral medication (at time of randomization).
Note: - HCV positive subjects who do not have active HCV hepatitis and are 
otherwise acceptable candidates for the study treatment, as documented by the 
investigator, are eligible. The Investigator must confirm that the patient does not have 
an active HCV infection or unacceptable liver damage as documented by one of the 
following options: liver ultrasound for fibrosis, liver biopsy, zero RNA viral load, or 
other local practice test.
8.
Known seropositive for or active viral infection with human immunodeficiency virus 
(HIV)
9. Life expectancy < 6 months 
10. Known sensitivity or allergy to murine products 
11. Prior history of malignancies, other than FL or MZL, unless the subject has been free of
the disease for ≥ 5 years. Exceptions include a history of previously treated:
a.
Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and related 
localized non-melanoma skin cancer
b. Carcinoma in situ of the cervix
12. Prior use of lenalidomide
13. Known allergy to thalidomide
14. Neuropathy > Grade 1
15. Presence or history of CNS involvement by lymphoma. 
16. Subjects who are at a risk for a thromboembolic event and are not willing to take VTE 
prophylaxis.
17. Uncontrolled intercurrent illness.
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18. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
19. Pregnant or lactating females.
20. Any condition, including for example coronary artery disease, congestive heart failure, 
pulmonary disease, active, severe infections, chronic renal or immunological disease, or 
the presence of laboratory abnormalities that places the subject at unacceptable risk if 
he/she were to participate in the study or that confounds the ability to interpret data 
from the study.
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8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Product(s)
Celgene Corporation will supply lenalidomide 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg capsules 
and the respective matching placebo capsules for oral administration. Subjects will receive 21 
days of lenalidomide or placebo per cycle.
Study drug will be packaged in bottles containing study capsules for 21 days. Commercially 
available IV formulation of rituximab background therapy will be used. Celgene will provide 
commercial supplies of rituximab for IV administration, labeled appropriately for investigational 
use as per the regulations of the relevant country health authority. Subjects enrolled in countries 
where rituximab is designated as non-investigational product, should obtain commercially 
available product through the local hospital pharmacy or licensed distributor. Subjects enrolled 
in countries where rituximab is designated as IP, will have rituximab supplied and packaged by 
Celgene Corporation.
8.2.
Treatment Administration and Schedule
Eligible subjects entering the Treatment Phase will be randomized in a 1:1 ratio using an 
Interactive Voice Response System (IVRS) into one of two arms (experimental or control). 
Randomization will be stratified as described in Section 8.6.1.
!
Experimental:  Rituximab + Lenalidomide 
o
rituximab 375 mg/m2 every week in cycle 1 (Days 1, 8, 15, 22) and on Day 1 
of every 28-day cycle from Cycle 2 to 5 
plus
o
Lenalidomide once daily (please see Section 8.2.1 for details) on Days 1 to 21 
of every 28-day cycle 
!
Control:  Rituximab + placebo
o
rituximab 375 mg/m2 every week in cycle 1 (Days 1, 8, 15, 22) and on Day 1 
of every 28-day cycle from Cycle 2 to 5 
plus
o
Placebo (identical matched capsule) once daily (please see Section 8.2.1 for 
details) on Days 1 to 21 of every 28-day cycle 
Treatment must begin as soon as possible after randomization but no later than 1 week after 
randomization. There is no window for study drug administration.
Co-administration (ie, lenalidomide intake during the rituximab infusion) should be avoided. 
Due to the duration of the rituximab infusion and potential infusion-related reactions to 
rituximab, administration of lenalidomide before rituximab should be considered.
The Treatment Period for each subject starts with first intake of study drug, which is defined as 
Study Day 1 of Cycle 1.
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Lenalidomide (CC-5013)
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Celgene Corporation
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53
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
8.2.1.
Lenalidomide or Placebo dosing
Lenalidomide or placebo dosing will be based on subjects creatinine clearance calculated using 
the Cockcroft-Gault formula utilizing actual body weight. This calculation will be performed by 
the central laboratory based on actual body weight. 
!
Subjects who have a creatinine clearance ≥ 60 mL/min (≥1.0 mL/sec) will receive 
oral lenalidomide or placebo at a dose of 20 mg once daily on Days 1 to 21 in each 28 
day cycle.
!
Subjects who have moderate renal insufficiency (creatinine clearance ≥ 30 mL/min 
but < 60 mL/min; ≥ 0.5 mL/sec but < 1.0 mL/sec) will receive a lower starting dose 
of lenalidomide or placebo of 10 mg once daily on Days 1 to 21 of 28-day cycle in 
Cycle 1 and in Cycle 2. If the subject remains free of drug-related Grade 3 or 4 
toxicities for at least 2 cycles, the dose may be increased to 15 mg once daily on Days 
1 to 21 of a 28-day cycle at the discretion of the treating physician from Cycle 3 
onwards.
Lenalidomide or placebo should be taken at approximately the same time every day. There is no 
requirement for taking lenalidomide or placebo with or without food, or with or without certain 
types of foods or liquids. If a subject misses a dose of lenalidomide or 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.
8.2.2.
Rituximab therapy
The planned dose of rituximab is 375 mg/m2 every week in Cycle 1 (days 1, 8, 15, 22) and on 
Day 1 of every 28-day cycle from Cycles 2 to 5. Premedication should be administered (see 
package insert or where applicable refer to the instruction in pharmacy manual and protocol 
Section 9.3.2).
All dosage calculations for rituximab will be based on the subject‘s body surface area (BSA), 
using actual weight for calculations. This will be determined within 1 week prior to or on the 
first day of study drug administration of Cycle 1. For rituximab, no dosage adjustments for 
changes in subjects’ weight during the study should be performed.
Refer to approved product/prescribing information for further information on rituximab therapy 
including warning, precautions, contraindications, and guidance on pregnancy prevention.
8.2.3.
Requalification Criteria for Subsequent Treatment Cycles
The new cycle of treatment may begin on the scheduled Day 1 of the next cycle if all of the 
following Requalification Criteria are met:
!
A 7-day rest period has elapsed following the last dose of lenalidomide / placebo;
!
The ANC is ≥1,000 cells/mm³ (1.0 X 109/L);
!
The platelet count is ≥ 50,000 cells/mm³ (50 X 109/L);
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
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CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
!
Study-drug-related allergic reaction or hypersensitivity not requiring discontinuation 
has resolved to ≤ Grade 1 severity;
!
Any other study-drug-related AE not requiring discontinuation has resolved to ≤ 
Grade 2 severity.
If these Requalification Criteria are not met, the subject will be evaluated at least once every 
seven days and a new cycle of study drug will not be initiated until the criteria have been met as 
described above. If a new cycle is delayed for more than 28 days, the Celgene Medical Monitor 
must be notified. The treatment can be resumed according to the treating physicians’ and 
Medical Monitor’s clinical judgment.
The criteria above do not apply to laboratory abnormalities of subjects who are randomized with 
these laboratory abnormalities due to lymphoma infiltration of the bone marrow or documented 
liver involvement by lymphoma. In the absence of evidence of treatment emergent toxicity, the 
new cycle of treatment may begin at the discretion of the investigator.
The study assessments should remain in line with dosing days (actual number of days that 
lenalidomide or placebo plus rituximab has been administered) but the tumor assessments will be 
determined from Cycle 1 Day 1 and will follow the counting of calendar days and not the dosing 
cycles. 
If a subject experiences an AE that requires a dose interruption, the subject cannot be re-started 
on study medication (lenalidomide or placebo) until the AE has resolved or reached acceptable 
grade as described in Table 2. Once the AE has resolved, the subject may restart study drug (at 
the dose level required in Table 2, and refer to Table 3 and Table 4 for the actual dose) for the 
remainder of the cycle. Doses that were missed, because of toxicity or any other reason, will not 
be rescheduled. 
If the start of the next cycle is delayed due to an AE, the subject can re-start study drug 
(lenalidomide or placebo) for that next cycle once the AE has resolved and the requirements 
mentioned above have been met.
8.2.4.
Dose Modification or Interruption
Subjects will be evaluated for AEs at each visit with the NCI CTCAE Version 4.03 used as a 
guide for the grading of severity. However, TFR will be graded using NCI CTCAE Version 3.0. 
Prior to dose modification or interruption, the investigator should first determine which is the 
offending study drug(s) causing the toxicity.
8.2.4.1.
Dose Adjustment for Lenalidomide or Placebo 
a) Dose modification or interruption 
The dose of lenalidomide or placebo for each subject will be interrupted and modified following 
toxicity as described below. Refer to Table 2 for instructions on dose modifications and Table 3
and Table 4 for dose reduction instructions for study drug. 
If lenalidomide or placebo has been discontinued due to toxicity, rituximab treatment may
continue as per protocol. If rituximab treatment is continued following discontinuation of 
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
55
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
lenalidomide or placebo, the subject will continue study treatment with rituximab alone and will 
be followed as per protocol after the last dose of rituximab (Cycle 5 Day 1 at the latest).
Table 2:
Dose Modification for Lenalidomide or Placebo
NCI CTCAE Toxicity 
Grade
ACTION REQUIRED
Grade 3 Neutrophil count 
decreased (neutropenia)
Absolute neutrophil count 
<1,000 cells/mm³ [1.0x109/L]
(one time reading)
!
Follow CBC at least every seven days
Neutrophil count decreased 
(Neutropenia)
Sustained (≥ 7 days) Grade 3 
OR
≥ Grade 3 associated with 
fever (temperature ≥ 38.5º C)
OR 
Grade 4 
!
Hold (interrupt dose)
!
Follow CBC at least every seven days
!
If neutropenia has resolved to ≤ Grade 2 restart at next lower 
dose level
!
Use of growth factors (G-CSF, GM-CSF) is permitted as per 
ASCO and ESMO guidelines
Platelet count decreased 
(Thrombocytopenia)
≥ Grade 3 (platelet count < 
50,000 cells/mm³ [50x109/L])
!
Hold (interrupt dose)
!
Follow CBC weekly 
!
If thrombocytopenia resolves to ≤ Grade 2 restart at next lower 
dose level
Rash
a
Grades 1-2
!
Start supportive measuresb if Grade 2
!
No dose adjustment
Grade 3 (Non-
desquamating or non-
blistering)
!
Hold (interrupt dose)
!
Start supportive measuresb
!
Evaluate at least weekly 
!
If rash resolves to ≤ Grade 1 restart at next lower dose
  Grade 4c
!
Discontinue lenalidomide or placebo
!
Dermatology evaluation
!
Consider supportive measuresb
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
56
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
Table 2:
Dose Modification for Lenalidomide or Placebo (Continued)
NCI CTCAE Toxicity 
Grade
ACTION REQUIRED
  Desquamating 
(blistering) rash
  Any Gradec
!
Discontinue lenalidomide or placebo
!
Dermatology evaluation
!
Consider supportive measuresb
Stevens-Johnson Syndrome or 
Toxic epidermal necrolysis
!
Discontinue lenalidomide or placebo
!
Dermatology evaluation
Allergic reaction or 
hypersensitivity
  Grade 2
!
Hold (interrupt) dose.
!
Follow at least every seven days.
!
When the toxicity resolves to ≤ Grade 1 restart at next lower 
dose level
  Grade 3-4
!
Discontinue lenalidomide or placebo 
Constipation
  Grade 1-2
!
Initiate bowel regimen and maintain dose level
  ≥ Grade 3
!
Hold dose and initiate bowel regimen
!
When the toxicity resolves to ≤ Grade 2 restart at next lower 
dose level
Vascular access 
complication (Venous 
thrombosis/embolism)
≥ Grade 3
!
Hold (interrupt) dose and start anticoagulation; restart at 
investigator’s discretion (maintain dose level)
Peripheral Neuropathy
  Grade 3
!
Hold (interrupt dose)
!
When toxicity resolves to ≤ Grade 1 or to screening, restart at 
the next lower dose 
  Grade 4
!
Discontinue lenalidomide or placebo
Tumor Flare Reaction 
(TFR)a
Grade 1-2
!
Continue lenalidomide or placebo, maintain dose level 
!
At the investigator’s discretion may initiate therapy with 
NSAIDs, limited duration corticosteroids, and/or narcotics
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
57
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
Table 2:
Dose Modification for Lenalidomide or Placebo (Continued)
NCI CTCAE Toxicity 
Grade
ACTION REQUIRED
Grade 3-4
!
Hold (interrupt dose) and initiate therapy with NSAIDs, 
corticosteroids, and/or narcotics 
!
When symptoms resolved to ≤ Grade 1, restart at same dose 
level for the rest of the cycle
Hypothyroid
If the TSH is > ULN and 
subject is clinically 
euthyroid
!
Repeat TSH on Day 1 of next cycle
!
No dose decrease or interruption
If TSH is > ULN for more 
than 2 cycles, or if subject 
has clinical symptoms of 
hypothyroidism;
!
Endocrinology evaluation is recommended and thyroid 
hormone replacement is allowed if clinically indicated 
!
No dose decrease or interruption
Hyperthyroid
If TSH < LLN and subject is 
clinically euthyroid,
!
Repeat TSH every 3 months
!
No dose decrease or interruption
If TSH <LLN at repeat 
evaluation and subject is 
clinically euthyroid 
!
Recommend endocrine evaluation
!
No dose decrease or interruption
If TSH < LLN and subjects 
have symptoms of 
hyperthyroid (tremor, 
tachycardia, unintentional 
weight loss, or new onset
night sweats), 
!
Hold (interrupt dose)
!
Obtain endocrine evaluation and workup for alternative 
etiologies
!
Repeat TSH level on day 1 of next cycle and contact 
medical monitor
!
If endocrine evaluation rules out hyperthyroidism, restart 
lenalidomide or placebo at the same dose 
!
If hyperthyroidism confirmed and alternative etiologies 
eliminated, restart lenalidomide or placebo dosing at next 
lower dose.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
58
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
Table 2:
Dose Modification for Lenalidomide or Placebo (Continued)
NCI CTCAE Toxicity Grade
ACTION REQUIRED
Liver Functiond
ALT or AST Grade 2                        
( >3 - 5 x UNL)
and
Total bilirubin Grade 1
(> ULN - 1.5 x ULN)
!
Continue study drug: re-test at next scheduled visit
!
No dose modification
ALT or AST ≥ Grade 3
(>5 x ULN )
or
Total bilirubin ≥ Grade 2 (> 1.5 x 
ULN)
!
Hold (interrupt dose) and follow weekly ALT and total 
bilirubin until return to baseline (value at Screening) 
!
Resume the same dose of study drug if recovery (return 
to baseline) from the event is ∀14 days 
!
If recovery is prolonged beyond 14 days, weekly testing 
of liver functions should occur during that cycle and 
then decrease the dose by one level when recovered 
(returned to baseline)
Cairo-Bishop Toxicity Grade (see Appendix 18.5)
Laboratory TLS or Grade 1 TLS
!
Continue lenalidomide or placebo (maintain dose), or at 
the investigator’s discretion, continue lenalidomide or 
placebo and reduce dose by one level 
!
Provide vigorous intravenous hydration and appropriate 
medical management according to the local standard of 
care, until correction of electrolyte abnormalities. 
Rasburicase therapy is appropriate (if approved by the 
local Health Authority) as needed to reduce 
hyperuricemia
!
Hospitalization will be at investigator’s discretion
Clinical TLS ≥ Grade 2
!
Hold (Interrupt dose)
!
When the AE resolves to Grade 0, restart at next lower 
dose per investigator’s discretion
Other ≥ Grade 3 study drug-
related AEs
!
Hold dose and restart at same or next lower level per 
investigators discretion when toxicity resolves to ≤ 
Grade 2
a AEs are graded using the NCI CTCAE v 4.03; however TFR will be graded using NCI CTCAE v 3.0.
b Suggested supportive measures for rash – 1) initiate daily oral antihistamines, for example, loratadine 10 mg PO 
daily, cetirizine 10 mg PO daily or diphenhydramine 25 mg PO daily; 2) Short courses of low-dose steroids for 
example, prednisone 10 mg PO x 3 days (or equivalent) or hydrocortisone 20 mg PO QAM, 10 mg PO QPM x 3 
days. It is recommended that the daily oral anti-histamines treatment be continued for the rest the of the 
lenalidomide treatment.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
59
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
c In cases of Grade 4 or desquamating rash, prompt dermatologic evaluation with skin biopsy is strongly 
recommended.
d For subjects with Gilberts Syndrome or liver involvement by lymphoma, dose reductions should be made in 
consultation with the Medical Monitor.
b) Dose Reduction Levels Based On Starting Dose
The daily dose of lenalidomide or placebo may be reduced successively by one level from the 
starting dose. There will be no more than one dose reduction from one cycle to the next. No dose 
(re)escalation is permitted at any time unless as specified in Table 4.
For subjects with starting dose of 20 mg of lenalidomide/placebo daily on Days 1 to 21 every 28 
days (for subjects with a creatinine clearance ≥ 60 mL/min), the daily oral dose of study drug
shall be reduced by one level (decrements of 5 mg –refer to Table 3) at the next treatment cycle 
if toxicity requiring dose modifications (as per Section 8.2.3) has occurred during the previous 
treatment cycle.
Subjects who have moderate renal insufficiency [creatinine clearance ≥ 30 mL/min but < 60 
mL/min] (Refer to dose reduction steps in Table 4):
!
Will receive a lower starting dose of study drug of 10 mg once daily in Cycle 1 and 
Cycle 2 Days 1 to 21 for 28 days.
!
If the subject remains free of drug-related Grade 3 or 4 toxicities for at least 2 cycles, 
the dose may be increased to 15 mg once daily on Days 1 to 21 of a 28-day cycle at 
the discretion of the treating physician from Cycle 3 onwards.
!
The daily oral dose of study drug may be reduced successively by one level on event 
of toxicity as described in Table 2. Only 1 dose reduction should occur for concurrent 
AEs that require a dose reduction.
Table 3:
Dose Reduction Steps for Adverse Events Related to Study Drug for Subjects 
Initiating Treatment at 20 mg Daily on Days 1 to 21, Every 28 Days
Dose
Once Daily on Days 1-21, Every 28 Day Cycles
Level 1 (starting dose)
20 mg daily on Days 1-21, every 28 days
Level 2a  
15 mg daily on Days 1-21, every 28 days
Level 3a
10 mg daily on Days 1-21, every 28 days
Level 4a,b
5 mg daily on Days 1-21, every 28 days
a Once a subject’s dose has been reduced, no dose re-escalation will be permitted.
b Subjects who cannot tolerate Dose Level 4 are to be discontinued from the Treatment Phase of the study.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
60
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
Table 4:
Dose Modification Steps for Subjects Initiating Treatment at 10 mg Daily on 
Days 1 to 21, Every 28 Days
Dose
Once Daily on Days 1-21, Every 28 Days
Level -1a
15 mg daily on Days 1-21, every 28 days
Level 1 (starting dose)a,b,c
10 mg daily on Days 1-21, every 28 days
Level 2c,
5 mg daily on Days 1-21, every 28 days
Level 3c,d
2.5 mg daily on Days 1-21, every 28 days
a If the subject has not experienced any drug-related Grade 3 or 4 toxicity for at least 2 cycles, the dose may be 
increased to 15 mg once daily on Days 1 to21 of each 28 day cycle at the discretion of the treating physician from 
cycle 3 onwards
b Once the dose is escalated to 15 mg once daily for 21 days every 28 day, dose may be reduced successively by 1 
level, ie, to 10 mg.
c Once a subject’s dose has been reduced, no dose re-escalation is permitted.
d Subjects who cannot tolerate Dose Level 3 are to be discontinued from the Treatment period of the study.
8.2.4.2.
Dose Adjustment for Rituximab
The dose of rituximab should not be reduced. The dose of rituximab may be interrupted and 
modified according to the clinical practice of the Investigator’s institution (e.g., dose splitting or 
dose banding), and in line with the approved prescribing information including administration, 
warnings, precautions, contraindications, and adverse reactions, as applicable. 
In case a dose of rituximab is missed during the first cycle because of toxicity, it will not be 
rescheduled. In such situations, treatment with lenalidomide or placebo does not need to be 
interrupted.
In case of delay in the start of next cycle during (Cycles 2 to 5) due to toxicity, rituximab
administration will be postponed until AE has resolved, at which point the next cycle is started.
If rituximab is discontinued due to toxicity, lenalidomide/placebo should be continued as per 
protocol and the subject should continue on the study.
8.2.4.3.
Overdose
Overdose, as defined for this protocol, refers to lenalidomide / placebo and rituximab. 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 case report form. See 
Section 11.1 for the reporting of AEs associated with overdose.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
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8.3.
Blinding
For this trial, study subjects, Investigators, staff, and Celgene Corporation clinical and medical 
representatives will all be blinded to the treatment assignments until disease progression as 
determined by IRC. Both lenalidomide and placebo capsules are identical in appearance.
Randomization, drug dispensing, dose reduction/escalation, and drug discontinuation will be 
accomplished by an IVRS system. Authorized site personnel must contact the IVRS for 
randomization, study drug assignment at the beginning of each cycle, to register dose reductions 
or escalations, and treatment discontinuation. Confirmation of each call will be sent to the 
investigational site and Celgene.
8.4.
Emergency Unblinding
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 decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor. However, the investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. 
The investigator should ensure that the code is broken only in accordance with the protocol. The 
investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the investigator through the IVRS by using 
an emergency unblinding personal identification number (PIN), and the investigator should call 
the IVRS for unblinded dose information.
8.5.
Discontinuation 
8.5.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product:
!
Adverse Event(s)
!
PD or relapse
!
Withdrawal of consent 
!
Death
!
Lost to follow up
!
Protocol violation
The reason for discontinuation should be recorded in the CRF and in the source documents.
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The decision to treatment discontinue a subject remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor. However, prior to discontinuing 
a subject, the investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
8.5.2.
Study discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Withdrawal of consent
!
Death
!
Lost to follow up
!
Protocol violation
The reason for discontinuation should be recorded in the CRF and in the source documents.
The decision to study discontinue a subject remains the responsibility of the treating physician, 
which will not be delayed or refused by the sponsor. However, prior to discontinuing a subject, 
the investigator may contact the Medical Monitor and forward appropriate supporting documents 
for review and discussion.
8.6.
Method of Treatment Assignment
The treatment assignment will occur in the Screening period, once all the required screening 
procedures have been completed, and all required data have been submitted to the IVRS/IWRS 
system.
8.6.1.
Stratification
Subjects will be stratified by: previous rituximab treatment (yes/no), time since last anti-
lymphoma therapy (≤ 2, > 2 year), and disease histology (FL or MZL).
8.7.
Packaging and Labeling
The IP (lenalidomide or matching placebo) will be packaged in bottles and each bottle will 
contain 21 capsules.
The label(s) for IP will include Celgene name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
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.
8.8.
Study Drug Receipt and Storage
The Investigator(s) is responsible for taking an inventory of each shipment of study drug 
received and comparing it with the accompanying study drug shipping order form. The 
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8.8


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Investigator(s) will verify the accuracy of the information on the form and call the IVRS to 
register the study drug received at the site and retain a copy of the form in the study file.
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access.
The study drug should be stored as directed on the package label.
8.9.
Investigational Product Accountability and Disposal 
An accurate accounting of the dispensing/return of study drug 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 study drug 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 (or designee) will review with the Investigator or relevant site personnel the process for 
investigational product return, disposal and/or destruction including responsibilities for the site 
versus Celgene (or designee).
8.10.
Investigational Product Compliance
For the oral medications of lenalidomide or placebo, study personnel will review the dosing 
instructions with the subject prior to dispensing the study drug. The subject will be instructed to 
return the study drug bottle, including any unused study drug, to the site at the next visit. Subject 
compliance will be noted on the appropriate CRFs and source records based on a capsule count. 
To monitor treatment compliance, reconciliation of capsules will be done at each scheduled 
study visit.
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Lenalidomide (CC-5013)
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9.
CONCOMITANT MEDICATIONS AND PROCEDURES
9.1.
Permitted Concomitant Medications and Procedures
Therapies considered necessary for the subject’s well being may be administered at the 
discretion of the Investigator. All medications (prescription and non-prescription), growth 
factors, transfusions, treatments and therapies taken from 28 days prior to start of study drug 
through the last dose of study drug, must be recorded on the appropriate page of the CRF.
9.1.1.
TFR Treatment
Treatment of TFR is up to the discretion of the investigator depending upon the severity and 
clinical situation. It is suggested that Grades 1 and 2 TFR be treated with NSAIDs (ie, ibuprofen 
400 to 600 mg orally every 4 to 6 hours as needed), corticosteroids, and/or narcotic analgesics 
for pain management. Refer to Table 2 for further instructions and dose modifications for Grade 
3 and 4 TFR.
In mild to moderate (Grades 1 and 2) cases, it is suggested that study drug be continued along 
with symptomatic treatment as above. In more severe cases, study drug should be interrupted, as 
indicated Table 2.
During the Treatment Phase, emergency use of corticosteroids at any dose to treat TFR 
symptoms for a subject is allowed at the Investigator’s discretion.
9.1.2.
Thromboembolism Prophylaxis 
It is not known whether prophylactic anticoagulation or anti-platelet therapy prescribed in 
conjunction with lenalidomide may lessen the potential for venous thromboembolism. In this 
double-blind placebo controlled clinical trial, the decision to take prophylactic measures should 
be made carefully after an assessment of an individual patient’s underlying risk factors.
As reference information, for subjects receiving lenalidomide in open-label trials, it is strongly 
recommended that subjects at risk for a thromboembolic event receive prophylactic aspirin (70 to 
325 mg) daily or another prophylaxis agent while on lenalidomide. In those subjects with high 
risk of VTE, it is strongly recommended that the subject receive a 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.
9.1.3.
Growth Factors and Transfusions
Growth factors (eg, G-CSF, erythropoietin, etc) may be prescribed by the Investigator for rescue 
from severe hematologic events and should be used in accordance with the American Society of 
Clinical Oncology’s (ASCO) guidelines or the ESMO guidelines. Growth factors or platelet 
transfusions should not be used to meet eligibility.
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Growth factors or platelet transfusions are not to be administered prophylactically, except for 
high risk subjects in accordance with the ASCO guidelines or the ESMO guidelines. 
9.2.
Prohibited Concomitant Medications and Procedures
Systemic chronic corticosteroid use at doses above 20 mg / day (prednisone/ prednisolone or 
equivalent) is prohibited during the Treatment Phase. For subjects receiving systemic 
corticosteroids at doses above 20 mg / day (prednisone/ prednisolone or equivalent), a 7 day 
washout period prior to Cycle 1 Day 1 study drug dosing is required. 
Systemic doses above 20 mg/day (prednisone/ prednisolone or equivalent) are allowed for the 
treatment of TFR at any time, for rituximab cytokine release syndrome prophylaxis with each 
rituximab infusion, and treatment of infusion related reactions at any time.
In addition, short courses of steroids are permitted at high doses for short-term use if necessary 
for the well being of the subject. Examples of such short-term use include the treatment of 
exacerbation of chronic obstructive pulmonary disease and other conditions for which short-term 
steroid treatment is considered standard of care.
All investigational therapies (drug or otherwise) and anticancer therapies, other than 
lenalidomide or rituximab are prohibited during the entire Treatment Period of the study.
9.3.
Required Concomitant Medications and Procedures
9.3.1.
TLS Prophylaxis
All subjects must receive tumor lysis prophylaxis (allopurinol, rasburicase or equivalent as per 
institutional guidelines) and be well hydrated (orally) during the first week of the first cycle or 
for a longer period if clinically indicated. Hydration levels should be adjusted according to age 
and clinical status. To monitor for TLS and cytopenia(s), the subjects will have a complete blood 
count (CBC) and chemistry drawn on Days 1, 8 and 15 of the first cycle and additionally as 
clinically indicated. The site should make every effort to contact the subject on Day 5 (± 1 day) 
of the first cycle to inquire about the subject’s condition and to make sure that he/she is 
continuing with TLS prophylaxis measures by keeping hydrated and taking the TLS prophylaxis 
as instructed. Any subject contact that is made on Day 5 (± 1 day) should be documented in 
subject’s medical record and any AEs that are discovered should be captured on the CRF. TLS 
will be assessed by Cairo-Bishop Grading system (See Section 18.5).
9.3.2.
Rituximab premedication
Premedication consisting of acetaminophen and an antihistamine should be administered before 
each rituximab infusion (see package insert or where applicable refer to the instruction in 
pharmacy manual). Steroids may also be administered before the start of the rituximab infusion 
according to institutional practice (see Section 9.2 for the permitted doses). Surveillance 
measures during and after infusion of rituximab should be applied as recommended by the 
manufacturer/current guidelines.
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9.3.3.
Rituximab and Hepatitis B
In subjects with prior HBV infection, HBV reactivation may occur during or after rituximab 
treatment even if HBV-DNA is undetectable. For subjects with evidence of prior HBV exposure 
(positive for anti-HBs and/or anti-HBc with or without detectable HBV-DNA), liver disease 
experts should be consulted before start of rituximab treatment. Such subjects should be
monitored for clinical and laboratory signs of hepatitis and/or HBV reactivation during and 
following rituximab therapy. In subjects who develop HBV reactivation during rituximab
treatment, rituximab should be immediately discontinued. In subjects who develop HBV 
reactivation during or after rituximab treatment, appropriate HBV treatment (for example 
lamivudine) should be instituted as per local medical practice and locally approved rituximab
product/prescribing information.
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10.
STATISTICAL ANALYSES
10.1.
Overview
The objective of the statistical analysis is to evaluate the efficacy and safety of rituximab plus 
lenalidomide combination therapy in subjects with relapsed/refractory indolent lymphoma.
All data will be summarized by treatment group. In addition, where appropriate, a total column 
will be included to summarize subjects across treatment groups. Summaries of continuous 
variables will present the number of subjects included in the analysis (N), the mean and standard 
deviation (SDev) of the mean, the median, the minimum, and the maximum statistics, counts and 
percentages will be presented in summaries of categorical variables. The denominator for each 
percentage will be the number of subjects in the population treatment group unless otherwise 
specified. In general, missing data will not be imputed unless otherwise specified. 
All statistical analyses specified in this protocol will be conducted using SAS® version 9.1.3 or 
higher
10.2.
Study Population Definitions
The following three populations defined below will be used in the analysis.
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.
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. 
Modified ITT (mITT) population: The mITT population is defined as all randomized subjects
who have received at least one dose of study medication, have confirmed diagnosis of 
relapsed/refractory FL or MZL by central pathology review who are naïve or sensitive to 
rituximab, met all eligibility criteria, have baseline (Screening) and at least one post-baseline 
tumor assessment for efficacy.
The efficacy analysis will also be performed on the mITT population as supportive evidence 
and/or sensitivity analysis. Subjects will be analyzed according to the treatment arm to which 
they are initially assigned.
Safety population: The safety population is defined as all subjects who have received at least 
one dose of study medication. The safety population will be used for all safety analysis. Subjects 
will be analyzed according to the treatment which they actually received.
Subgroups analysis: Analyses will also be performed to compare treatments within the 
following stratification subgroups: previous rituximab treatment (yes/no), time since last anti-
lymphoma therapy (≤ 2, > 2 year), histology (FL or MZL).
Additional subgroups may be examined as needed.
10.3.
Sample Size and Power Considerations
The basis for the power and sample size determination will be a test of the equality of the overall 
survival curves between experiment and control treatment groups using a stratified log-rank test.
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The primary efficacy endpoint is PFS. To fulfill the primary objective of the study, it must be 
shown that the experimental arm is superior to the control arm on the primary endpoints at one-
sided α= 0.025 level. It is hypothesized that the median PFS is 17.6 months in the experimental 
arm and 11 months in the control arm (corresponding hazard ratio of 0.625. For 90% power to 
detect this difference with one-sided α= 0.025, a total of 193 PFS events will be required.
Based on the rate of accrual anticipated in this study, and annual dropout rate of 5%, it is planned 
to randomize a total of 350 subjects in 1:1 ratio to the two treatment arms and the study duration
to reach the PFS events is expected to be 43 months.
Sample size and power were calculated using the East® Version 5.4 software system (Cytel Inc., 
675 Massachusetts Avenue, Cambridge, MA 02139, http:// www.cytel.com).
10.4.
Background and Demographic Characteristics
Demographic and baseline (last non-missing observation prior to randomization) disease 
characteristics will be summarized by treatment group for the ITT, mITT and safety populations.
Subjects’ age, height, weight, and continuous baseline characteristics will be summarized using 
descriptive statistics (N, mean, SDev, median, minimum, maximum), while age group, gender, 
race, histology, and other categorical variables will be provided using frequency tabulations 
(count, percent) by treatment group. Medical history data (coded by MedDRA dictionary) will be 
summarized using frequency tabulations by treatment group, system organ class and preferred 
term for the ITT, mITT and safety populations.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases. A summary of subjects enrolled by site will be provided. Major protocol 
deviations will be summarized using frequency tabulations for ITT population. Supportive 
corresponding subject listings will be provided as well.
10.6.
Efficacy Analysis
All efficacy analysis will be performed on the ITT population. Key efficacy analysis will be 
performed on the mITT population as supportive evidence and to assess robustness our efficacy 
findings. Subjects will be analyzed according to randomized treatment group.
10.6.1.
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS assessed by the IRC using the 2007 IWG criteria (Cheson, 
2007) but without PET imaging (see Section 18.1).
PFS is defined as the time from date of randomization into the study to the first observation of 
documented disease progression or death due to any cause, whichever occurs first.
The primary endpoint will be compared between the two treatment arms when the required 193
events progression/death events after applying appropriate censoring rules (detailed censoring 
rules will be pre-specified in the Statistical Analysis Plan) are achieved. The Kaplan-Meier 
estimates of PFS will be provided. The experimental arm will be declared superior if the one-
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sided p-value from a stratified log-rank test is smaller than 0.025 in favor of the experimental 
arm. Conventionally, hazard ratio with two-sided 95% confidence interval (CI) will be estimated 
using the Cox proportional hazards model. 
10.6.2.
Secondary Efficacy Endpoints
Secondary efficacy endpoints will include overall survival, objective response rate, complete 
response rate, durable complete response rate, duration of response, duration of complete 
response, event free survival, and time to next anti-lymphoma treatment.
Overall survival (OS) is defined as time from date of randomization to death from any cause.
Durable complete response rate (DCRR) is defined as the proportion of subjects that stay in 
complete response (CR) for at least one year, i.e, have duration of CR no less than one year.
Objective response rate (ORR) is defined as the proportion of subjects with best response of at 
least PR during the trial without administration of new anti-lymphoma therapy.
Complete response rate (CR) is defined as the proportion of subjects with best response of 
complete response during the trial without administration of new anti-lymphoma therapy.
Duration of response (DoR) is defined as the time from the initial response (at least PR) to 
documented disease progression.
Duration of complete response (DoCR) is defined as the time from the first evidence of CR to 
documented disease progression.
Event-free survival (EFS) is defined as the time from date of randomization to date of first 
documented progression, relapse, institution of new anti-lymphoma treatment (chemotherapy, 
radiotherapy or immunotherapy) or death from any cause. Responding subjects and subjects who 
are lost to follow up will be censored at their last tumor assessment date.
Time to next anti-lymphoma treatment (TTNLT) is defined as the time from date of 
randomization to date of first documented administration of a new anti-lymphoma treatment
(including chemotherapy, radiotherapy, radioimmunotherapy or immunotherapy).
For binary type of endpoints (ORR, CR, DCCR), number and percent of subjects will be 
tabulated by treatment arm. A stratified Cochran-Mantel-Haenszel (CMH) test to adjust for 
possible confounding effects of the stratification factors will be performed and p-value provided.
For time to event type of endpoints (OS, DoR, DoCR, EFS, TTNLT), Kaplan-Meier estimates
will be provided. Stratified log-rank tests will be performed with p-value provided.
 
 
 
 
 
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10.7.
Safety Analysis
Safety analysis will be based on all subjects in the Safety population. 
Study medication exposure will be summarized for each treatment arm including duration of 
study medication, total dose taken, and dose reductions.
Adverse events, vital sign measurements, clinical laboratory measurements, and concomitant 
medications will be summarized by treatment arm. 
AEs will be coded according to medical dictionary for drug regulatory activities (MedDRA) and 
classified using the NCI CTCAE Version 4.03. The incidence rates of AEs will be tabulated by 
system organ class and preferred term. Subsets of AEs to be summarized include serious AEs 
(SAEs), AEs of interest including SPM, VTE, and TFR, events of all CTCAE grade severities, 
suspected treatment-related AEs, and events that resulted in withdrawal of study medication. The 
most severe grade of each preferred term for a subject will be utilized for summaries of AEs by 
NCI CTCAE grade. All AEs with corresponding attributes will be displayed in a by-subject 
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Lenalidomide (CC-5013)
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listing. Adverse events leading to death or to discontinuation from treatment, events classified as 
NCI CTCAE Grade 3 or higher, suspected treatment-related events, all deaths, and SAEs will 
also be displayed in by-subject listings separately.
Clinical laboratory results will be summarized descriptively by treatment group, which will also 
include a display of change from baseline. Laboratory values outside of the normal ranges will 
be identified. Clinically significant hematologic and nonhematologic laboratory abnormalities 
that meet Grade 3 or Grade 4 criteria according to the CTCAE will be listed and summarized. 
Graphical display of selective lab parameters over the course of study will be provided.
Vital sign measurements will be listed for each subject at each visit. Descriptive statistics for 
vital signs, both observed values and changes from baseline, will be summarized by treatment 
group.
10.8.
Interim Analysis
One interim analysis is planned at 50% of information (96 events) for futility only. An external 
IRC will review all the disease progression events at the time of interim and final analyses. For 
the interim analysis, the date of the approximate 96th event, as determined by the IRC, will be 
used as the data cut-off dates. The results of the interim analysis will be reviewed by the 
independent external DMC.
A conditional power approach is used for futility analysis; if the interim analysis shows less than 
25% conditional power for success, the trial may stop for futility. 
10.9.
Other Topics
Not applicable.
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11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An 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 below), regardless of etiology. Any worsening 
(ie, 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. 
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be reported as an AE. If 
an overdose is associated with an AE, the overdose and AE should be reported as separate terms.
See Section 8.2.4.2 for the definition of overdose.
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 other appropriate tests and 
procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent to 
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 AEs as to: 
11.2.1.
Seriousness 
A SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, 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);
!
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.
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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 (study drug[s] or 
control), occurring at any time for the duration of the study, from the time of signing the ICD up 
to and including a follow-up period of up to 5 years from the date of the last subject randomized. 
Events of second primary malignancy 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 second primary malignancy must be provided at the time 
of reporting as a serious adverse event (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 (ie, 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.
!
An elective treatment of 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.
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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 of AEs will be graded based upon the subject’s symptoms according to the current 
active minor version of the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE, Version 4.03);
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. However, 
TFR will be graded using NCI CTCAE version 3.0.
AEs that are not defined in the NCI CTCAE should be evaluated for severity 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.
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:
The temporal relationship of the AE to IP administration makes 
a causal relationship unlikely or remote, or other 
medications, therapeutic interventions, or underlying conditions 
provide a sufficient explanation for the observed event.
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Suspected:
The temporal relationship of the AE to IP administration makes 
a causal relationship possible, and other medications, 
therapeutic interventions, or underlying conditions do not 
provide a sufficient explanation for the observed 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 or reduction of IP, as appropriate) and report if concomitant and/or 
additional treatments were given for the event. 
11.2.6.
Outcome
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 (death due to another 
cause) 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.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious AE.
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.
11.4.
Pregnancy
Refer to approved product/prescribing information for further information on rituximab 
pregnancy restrictions.
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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 subjects 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 or therapeutic 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.
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).
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 to 28 days after the last dose of IP) , any SPM 
occurring at any time during the study including the follow-up period and those made known to 
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the Investigator at anytime thereafter that are suspected of being related to IP. SAEs occurring 
prior to treatment will be captured.
The SAE report should provide a detailed description of the SAE and include summaries 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 will 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 Institutional 
Review Board (IRB)/ethics committee (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 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 IP based on the Investigator Brochure.
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.
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the other IP (rituximab) based on the 
Summary of Product Characteristics (SmPC). Adverse events such as disease progression or 
relapse, death related to disease progression or relapse (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 (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
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!
Other important safety information and periodic reports 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 14.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Local Drug Safety Affiliate Office contact information, please refer to the SAE Report Form 
/ Completion Guidelines or to the Pregnancy Report Form / Completion Guidelines.
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/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 Clinical Research Physician/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 or Contract Research 
Organization (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 Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
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. See Section 8.4 for more 
details.
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13.
REGULATORY CONSIDERATIONS
13.1.
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 GCP, as described in International Council 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.
13.2.
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,
including obligations of confidentiality of Celgene information. 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.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
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.
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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or the subject’s 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 ICD 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 ICD 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 consent document. The revised ICD 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.
13.4.
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.
13.5.
Protocol Amendments
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.
13.6.
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 
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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 
determine whether formal approval must be sought and whether the ICD 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.
13.7.
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 AEs 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.
13.8.
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, etc).
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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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
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.
14.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene standard 
operating procedures (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.
14.3.
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;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
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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15.
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.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during, and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an investigator meeting. 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 onsite visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
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.
15.2.
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 (eg, FDA, EMA, and 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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16.
PUBLICATIONS
The results of this study may be published in a medical publication, journal, or 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. Selection of first authorship 
will be based on several considerations, including but not limited to study participation, 
contribution to the protocol development, and analysis and input into the manuscript, related 
abstracts, and presentations in a study.
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17.
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olving con
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potenti
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.
phron
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new histo o
ut. 2003; 5
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tol
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og cal s
l
ho
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ma is fea
fe
or flare rea
r flare rea
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body
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et al. Phase
et al. Pha
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pfront imm
pfront imm
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B, Rosew
eatures of t
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hite CA, Gr
te CA, G
hodgkin’s l
hodgkin’s l
851-7.7.
is TA, Gril
is TA, Gril
herapy
erapy in N
n N
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sus confere
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drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined 
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study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa 
associated lymphoid tissue (MALT lymphoma). Haematol. 2013; 98: 353-356.
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18.
APPENDICES
18.1.
Appendix A:
Response Criteria for NHL
18.1.1.
Tumor Assessment by the 2007 IWG Response Criteria
In this clinical trial CT or MRI scan will be used.  PET scan will not be used for tumor 
assessment.
Response
Definition
Nodal Masses
a
Spleen, Liver
Bone Marrow
CR
Disappearance of 
all evidence of 
disease
Regression to normal size 
on CT or MRI
Not palpable, 
nodules 
disappeared
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative
PR
Regression of 
measurable disease 
and no new sites
≥ 50% decrease in SPD of 
up to 6 largest dominant 
masses; no increase in size 
of other nodes
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen
Irrelevant if positive 
prior to therapy; cell 
type should be specified
SD
Failure to attain 
CR/PR or PD
No new sites on CT or MRI
No change in size of 
previous lesions on CT or 
MRI
Relapsed 
disease or 
PD
Any new lesion or 
increase by ≥ 50% 
of previously 
involved sites from 
nadir
Appearance of a new 
lesion(s) > 1.5 cm in any 
axis
≥ 50% increase from nadir 
in SPD of previously 
involved nodes. 
≥ 50% increase in longest 
diameter of any single 
previously identified node 
> 10 mm in short axis.
> 50% increase 
from nadir in the 
SPD of any 
previous lesions
New or recurrent 
involvement
CR = complete remission; PR = partial remission; SD = stable disease; PD = progressive disease; (Cheson, 2007)
a Measurable extranodal lesion will be assessed as nodal disease
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18.1.3.
Additional Response Assessment In Gastric MALT subjects with Radiological 
Response of at Least a PR by 2007 IWG Criteria
Subjects with gastric MALT and a radiological (CT or MRI scan) response of at least a SD will 
also undergo histological evaluation by endoscopy at time points specified in Table 1 (see also 
Sections 6.2.1 and 6.4).  The histological scoring will be based on the GELA histological scoring 
system (Table 5). Final response assessment in subjects with gastric MALT will incorporate the
IWG criteria as well as the histological findings.
Table 5:
GELA Histological Scoring System for Evaluation of Gastric MALT 
lymphoma
Score
Lymphoid infiltrate
LEL
Stromal Changes
CHR (complete 
histological remission)
Absent or scattered plasma 
cells and small lymphoid 
cells in the LP
Absent
Normal or empty LP 
and/or fibrosis
pMRD (probable 
minimal residual disease)
Aggregates of lymphoid 
cells or lymphoid nodules 
in the LP/MM and/or SM
Absent
Empty LP and/or fibrosis
rRD (responding residual 
disease)
Dense, diffuse, or nodular 
extending around glands in 
the LP
Focal LEL or absent
Focal empty LP and/or 
fibrosis
NC (no change)
Dense, diffuse, or nodular
Present,  ‘may be absent’’
No changes
MM, muscularis mucosa; LP, lamina propria; SM, submucosa; LEL, lymphoepithelial lesions. (Copie-Bergman, 
2003; Copie-Bergman, 2012)
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The final response assessment of the subjects with gastric MALT lymphoma:
Complete remission (CR)
!
CR by IWG criteria and
!
normalization of endoscopic findings and 
!
histology of CHR in two subsequent follow-up investigations (the two investigation 
must be within 3 months after the radiological criteria for CR were first met).
Partial remission (PR)
Either 
!
PR by IWG criteria and
!
Normalization or reduction of macroscopic findings, histological signs of lymphoma 
regression (rRD) or negative histology (CR or pMRD) 
or
!
CR by IWG criteria and rRD by histological evaluation
Stable disease (SD): 
!
SD by IWG criteria and no worsening of macroscopic findings or dissemination of 
gastric MALT lymphoma or transformation into diffuse large B-cell lymphoma
Progressive disease (PD)
!
PD by IWG criteria or 
!
Any worsening of macroscopic findings or dissemination of gastric MALT 
lymphoma or transformation into diffuse large B-cell lymphoma.
Relapse
!
Relapse by IWG criteria 
or
!
Endoscopic findings of re-occurrence of histologically-confirmed lymphoma after a 
histological CR was previously documented and confirmed on at least two prior 
repeat biopsies
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18.3.
Appendix C:
Ann Arbor staging
!
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;1997:289-294.
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non reg
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
106
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
18.4.
Appendix D:
Performance Status Criteria
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, e.g., 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)
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
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107
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
18.5.
Appendix E:
Cairo - Bishop Definition of Tumor Lysis Syndrome 
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS)
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 subject has or will receive 
adequate hydration (± alkalinization) and a hypouricaemic agent(s) (Cairo, 2004).  
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.
a Not directly attributable to a therapeutic agent.
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
LTLS = laboratory tumor lysis syndrome; ULN = upper limit of normal; ADL = activities of daily living.
a Probably or definitely attributable to clinical TLS.
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
108
CC-5013-NHL-007 Amendment 4 Final: 13 Dec 2018
18.6.
Appendix F:
Pregnancy Prevention Risk Management Plans
Pregnancy Prevention Risk Management Plan is a standalone document.
CCI


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Lenalidomide (CC-5013)
Summary of Changes CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
3
CC-5013-NHL-007 Amendment 4 Final:13 Dec 2018
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 4 is written to reduce the frequency of follow-up tests including but not 
limited to computed tomography (CT) scans/ magnetic resonance imaging (MRI), biopsies (bone 
marrow, tumor, gastric) and blood tests sincethe primary efficacy analysis has been completed 
for this study. These changes to the protocol are being implemented to decrease subject exposure 
to radiation and to reduce the risk of bleeding, pain or infection from the above procedures. 
These tests will now be performed at the investigator’s discretion and will no longer require a 
central review. Further, this amendment provides specific guidance on the follow-up data that 
still needs to be mandatorily collected for this study in subjects who have reported progressive 
disease and in those who have not. 
Significant changes included in this amendment are summarized below:
The following changes were made to the study protocol and the associated sections of the 
Protocol Summary:
Changed Medical Monitor/ Emergency Contact Information
Section 4.4: End of Trial- Added guidance regarding the follow- up process and the tests 
required once the primary efficacy analysis has been completed.
Rationale for change: The frequency of follow-up tests was reduced and left to the investigator’s
discretion now that the primary efficacy analysis for the study has been completed. The 
requirement for central review for those tests was also removed as the primary efficacy analysis 
has been completed. Specific guidance was provided for the follow-up data to be collected for 
subjects who have progressive disease and for those subjects who have not yet reported a 
progression.
Section 5: TABLE OF EVENTS- Added footnote 13 to the table clarifying that after the primary 
analysis is done, specified follow up tests are no longer required per protocol and may be 
performed at the investigator’s discretion. 
 
 
Rationale for change: Since the primary efficacy end point has been reached and safety analyses 
for this study have been done, there is no need for a central review of the biopsy samples. An 
investigator diagnosis is sufficient.
Section 6.4: Follow-up Assessments- Added guidance on reducing follow-up tests, leaving them 
to the investigator’s discretion and removing the requirement for central review of those tests 
during follow-up as the primary efficacy analysis has been completed.
Section 11.6: Expedited Reporting of Adverse Events
!
Added a statement about the expedited reporting requirement per the United States 
regulations.
!
Removed the statement regarding providing information on steps taken in foreign 
countries for subject safety specific to Japan.
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52
352


Lenalidomide (CC-5013)
Summary of Changes CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
4
CC-5013-NHL-007 Amendment 4 Final:13 Dec 2018
!
Added statement regarding providing safety information and periodic reports to 
investigators according to local regulations.
Section 13.2- Investigator Responsibilities- Added wording on Celgene confidentiality
obligations for the investigators.
In addition, some aspects of the original protocol version were clarified, spelling, formatting and 
punctuation errors were corrected, and various abbreviations and acronyms were spelled out. 
This amendment includes several other minor clarifications and corrections.
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
3
CC-5013-NHL-007 Amendment  3 Final: 21 October 2015
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Modified the Inclusion Criterion number 4  to no longer allow rituximab naïve 
patients onto the study. This was also reflected in the study population bullet 
under the protocol Summary on page 6.  (Section 7.2)
 
 
Implementing this change at this point in the study should keep the number of 
rituximab patients under 25%.
!
Modified Inclusion Criterion number 5 to confirm that patients must have 
documented relapsed, refractory or progressive disease (PD) after treatment 
with systemic therapy, and must not be rituximab-refractory. Also defined 
refractoriness as (1) did not respond (at least a PR) to rituximab or R-
chemoregimen therapy and/or (2) time to disease progression < 6 months after 
last rituximab dose. (section 7.2)
The modification of Inclusion criterion number 4 led us to modify Inclusion Criterion 
number 5 to ensure that the two criteria are in line.
!
Revised Exclusion Criterion number 7 for hepatitis C virus (HCV) positive 
patients who do not have an active hepatitis C infection and who are otherwise 
acceptable candidates for the AUGMENT study.  All patients will be tested for 
HCV antibodies at Screening by the Central Laboratory, and the investigator 
must further test HCV positive patients by either liver ultrasound for fibrosis, 
liver biopsy, ribonucleic acid (RNA) viral load or other local practice.  Within 
the current Revlimid Investigator’s Brochure hepatitis C reactivation is not 
noted as a treatment-emergent adverse event (Section  7.3).  
The patients enrolled in this study are not at risk for hepatitis C reactivation, either by 
Revlimid or rituximab. Therefore, it was decided to allow patients who are HCV positive 
without active infection and who are otherwise acceptable candidates for the study, to be able 
to enter the study. This should allow more patients to be eligible in the Mediterranean region 
of Europe and Japan.
!
Revised to include a time limit on the age of the archival biopsy required for 
diagnosis prior to randomization. Also, clarified that if a formalin-fixed paraffin 
embedded (FFPE) tumor block cannot be sent, one hematoxylin and eosin (H 
and E) stained slide and 10 unstained slides or 11 unstained slides will be 
acceptable. (Section 6.1)
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
4
CC-5013-NHL-007 Amendment  3 Final: 21 October 2015
No time limit was previously defined in the protocol for the age of the archival biopsy 
required for diagnosis prior to randomization. In order to ensure that the disease is the same 
and transformation has not occurred, it was decided to limit the age of the biopsy moving 
forward. If a FFPE block cannot be sent, the specific slide requirements were also clarified.
!
Defined the requirement for a diagnosis of splenic marginal zone lymphoma 
(MZL) for patients who do not have a spleen specimen available during the 
screening period (Section 4.1.1).
As more MZL patients have been enrolled into the study, a few cases of splenic MZL 
patients who did not have spleen specimens were seen. It was decided to define the 
requirements for diagnosis for these patients within the protocol. 
The amendment also includes several other minor clarifications and corrections:
!
Revised to allow continuation of lenalidomide/placebo if rituximab is discontinued 
due to toxicity (Section 8.2.4.2).
!
Clarified that all patients MUST receive tumor lysis prophylaxis (Sections 9.3.1 and 
6.2.2.2).
!
Confirmed when end of treatment should occur: end of cycle 12, day 28. (Section 6.4)
!
The study rationale in Section 1.4 (Clinical Studies) was revised to include an 
updated reference for the recently published CALGB 50402 (Alliance) study along 
with the results. (Section 1.4, Section 17) A few deletions were made to the first 
sentence of section 1.3. 
!
Added Complete Response (CR) rate to the secondary objectives (Sections 2.2 and 
3.4).
!
Footnote 10 (table 1) and Section 8.2  were revised to reflect “there is no time 
window for study drug administration.”
!
Updated Sections 6.2.2.1,  6.2.2.2  and 6.2.2.3.2 with information from the MCL-002 
study that is now available.
!
Moved the last section of Section 8.2.3.1 (Requalification Criteria for Subsequent 
Treatment Cycles) up to Section 8.2.3 where it fits better.
!
Clarification of wording in second  paragraph of Section 8.2.4.1a.
!
Clarification of study medication in paragraph 2 and dose reduction occurring for 
concurrent adverse events (AEs) in last bullet of Section 8.2.4.1b.
!
Confirmed that no investigational or anticancer therapies other than lenalidomide or 
rituximab are allowed during the Treatment Period of the study (Section 9.2).
!
Added two paragraphs from the updated protocol template regarding Investigator 
Responsibilities (Section 13.2.)
!
Medical Monitor phone number was updated on page 2. 
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Lenalidomide (CC-5013)
Summary of Changes Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
3
CC-5013-NHL-007 Amendment 2 Final:  22 May 2014
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Update of Exclusion Criterion #21
The Exclusion Criterion #21 is being amended
 
) to complete the non-
inclusion criteria specifying that rituximab should not be administered in case of active, severe 
infections (for example, tuberculosis, septicaemia and opportunistic infection) in accordance 
with the recommendations of the Summary of Product Characteristics (SmPC) of the marketing 
authorisation (MA) of MabThera®.
A country specific protocol amendment is already available in France. The protocol has been
updated globally.
!
The surveillance and safety requirements should be followed as per the 
Rituximab package insert or SmPC
This protocol is also amended
 
that the 
female study subjects also need to be informed about the pregnancy prevention guidelines 
provided in the Rituximab/Mabthera SmPC (as long as the infertility is not definitely confirmed). 
Inclusion Criteria # 12 and #14 and Sections 8.2.2. and 11.4 are amended accordingly.
In Germany, the Inform Consent Document was updated. The protocol has been updated 
globally.
!
Revision to CT/MRI scan timing requirement after year 5 to one per year
This change was made based on investigator feedback and an attempt to avoid delaying 
treatment in the setting of aggressive lymphoma. This change was made based on Scientific 
Steering Committee discussion and approval.
!
Revision to exclusionary time period for prior malignancies and precision on the 
exceptions
This change is to decrease the exclusionary time period for prior malignancies from ≥ 10 to ≥ 5 
years. Basal cell carcinoma of the skin, squamous cell carcinoma of the skin are additional 
exceptions. These changes are to align this particular study with the rules agreed with Health 
authorities. 
!
Inclusion Criterion #7: Subjects with extranodal lesion are eligible 
Inclusion Criterion #7 and Section 6 were updated to clarify that subjects with extranodal lesion 
are eligible. This change was made based on Scientific Steering Committee discussion and 
approval.
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Lenalidomide (CC-5013)
Summary of Changes Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
4
CC-5013-NHL-007 Amendment 2 Final:  22 May 2014
!
HBV management 
A specific section was created to clarify the management of subjects at risk for HBV reactivation
(Section 9.3.3.). This change was made based on Scientific Steering Committee discussion and 
approval.
!
Exclusion Criterion #7
Subjects with a history of HCV, and who have received anti-viral treatment and who have no 
detectable HCV-RNA levels for at least 12 months are eligible. This change was made based on 
Scientific Steering Committee discussion and approval.
!
Clarify bone marrow biopsy requirement at screening and at response 
All subjects do not need BMB at screening, only in case of abnormal blood counts. The change 
in Sections 6.1. and 6.2.1.and inclusion criterion #10 was made based on Scientific Steering 
Committee discussion and approval.
!
Clarify study treatment continuation rules in case of lenalidomide or rituximab 
intolerance/ hypersensitivity 
These changes were made in Sections 8.2.3.1. and 8.2.3.2. were made based on investigator 
feedback and Scientific Steering Committee discussion and approval.
The amendment also includes several other minor clarifications and corrections:
!
Change of Celgene Medical Monitor
!
Updated and added new references
!
Clarification of the study design
!
Clarification of the Table of Events
!
Time window clarified the timing of procedure at Cycle 1 Day 1, 8, 15 and 22 
(±1 day), Cycles 2 to 5 Day 1 (±3 days) and Cycles 2 to 4 Day 15 (±1 day)
!
Clarification of FCBP and counseling procedures
!
Hematologic panel clarification, eosinophils and basophils added; WBC differential 
removed; urea” added.
!
Clarification and additional standard units.
!
Clarification to use prednisone or equivalent, prednisolone.
!
Added the possibility to contact the Medical Monitor or Steering Committee 
Members in case of equivocal progression
!
Inclusion Criterion # 8 clarification that subject will also need treatment if progressed
!
Inclusion Criterion # 10 was merged with Exclusion Criterion # 17 in order to have 
all screening laboratory values in one inclusion criterion.
!
Exclusion Criterion # 3, clarification for prednisolone
!
Exclusion Criterion # 5, administrative clarification 
!
Exclusion Criterion # 6, administrative clarification 
!
Administrative clarification of unblinding and discontinuation 
!
Clarification of growth factor and transfusion use
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Lenalidomide (CC-5013)
Summary of Changes Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
5
CC-5013-NHL-007 Amendment 2 Final:  22 May 2014
!
Statistical section clarification: correction of Intent-to-treat (ITT) population and 
Modified Intent-to-treat (mITT) population definitions. Endpoints definition added
!
Durable complete response rate (DCRR), complete response rate (CR) 
 
 definition and clarification
!
Clarification that histological transformations are not considered SPM
 
!
Clarification for Japan
!
Administrative correction of spelling, formatting errors, punctuation errors, and 
various abbreviations and acronyms were spelled out.
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
3
  CC-5013-NHL-007 Amendment 1 Final:  17 Jul 2013
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
The 2007 international working group (IWG) criteria for malignant lymphoma modified 
to allow the inclusion of extranodal disease as measurable disease will be utilized for 
efficacy determination to assess response and PFS.
Justification:
The current study will enroll follicular lymphoma (FL) and marginal zone lymphoma 
(MZL) patients. 
The 1999 IWG criteria state that only nodal disease is measurable disease. Patients with 
MZL often have extranodal disease without nodal disease and thus would be excluded. 
The 2007 IWG criteria (Cheson, 2007) allow assessment of extranodal disease as 
measurable disease.
With the aim to simplify the protocol, also allow inclusion of patients with only 
extranodal disease, and use one set of criteria which allows accurate assessment of
extranodal as well as nodal disease
 
Celgene will be using the 2007 IWG criteria in this study. This will 
allow inclusion and appropriate assessments of FL and MZL patients in this study. 
The amendment also includes several other clarifications and corrections
1. Updated the introduction section and the rationale with new available background 
information.
 
 
3. Summary section, Figure 1, study overview section, and assessment section (section 6) 
updated to be consistent with regards to:
a.
Response and PD data collected during next anti-lymphoma treatment
b. Duration for the submission of the pathology sample for central review
4. Reformatted Table 1, Schedule of study assessment to make it clear and more 
understandable.
5. Clarified that local HBV tests and tests done as part of standard of care will be acceptable. 
6. Updated the background and prophylaxis for VTE and also the definition of patients at risk
for VTE who will need prophylaxis.
7. Updated the background information for the tumor flare section. 
8. Clarification regarding use of steroid prophylaxis for rituximab cytokine release syndrome 
during treatment.
9. Updated the exclusion criterion #21 to include examples of conditions that would put patients 
under unacceptable risk such as coronary artery disease, congestive heart failure, pulmonary 
disease, chronic renal or immunological disease. 
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
4
  CC-5013-NHL-007 Amendment 1 Final:  17 Jul 2013
10. Updated Table 2 dose modification for lenalidomide or placebo to clarify the action required 
for rash and also include dose modification for Stevens-Johnson Syndrome or Toxic 
epidermal necrolysis. The footnote is updated to clarify that only TFR will be graded by NCI 
CTCAE version 3.0.
11. Updated treatment administration section (Section 8.2) to include definition of overdose.
12. Updated the Adverse event section to provide additional clarity regarding the SPMs and also 
severity/intensity grading according to CTCAE version 4.0.
13. Added ‘secondary endpoint’ title in Section 10.6
14. Provided clarification regarding the investigational product accountability and disposal and 
also provided additional information regarding monitoring.
15. Updated summary section and Section 4.0 to include definition of ‘end of trial’.
16. Updated the Table of Content and also corrected minor grammatical and formatting errors. 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
1
TITLE PAGE
STATISTICAL ANALYSIS PLAN
A PHASE 3, DOUBLE-BLIND RANDOMIZED STUDY TO COMPARE THE EFFICACY 
AND SAFETY OF RITUXIMAB PLUS LENALIDOMIDE (CC-5013) VERSUS RITUXIMAB 
PLUS PLACEBO IN SUBJECTS WITH RELAPSED/REFRACTORY INDOLENT
LYMPHOMA
STUDY DRUG:
CC-5013
PROTOCOL NUMBER:
CC-5013-NHL-007
DATE:
June 21, 2018
Prepared by:
Celgene Corporation
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-NHL-007
        Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION..................................................................................................10
3.
OBJECTIVES ........................................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................12
4.1.
Overall Study Design and Plan ...............................................................................12
4.1.1.
Study Population ....................................................................................................18
4.1.2.
Treatment Assignment............................................................................................18
4.1.3.
Screening Period.....................................................................................................19
4.1.4.
Treatment Period ....................................................................................................19
4.1.5.
Follow-up Period....................................................................................................20
4.2.
Study Endpoints .....................................................................................................20
4.3.
Stratification, Randomization, and Blinding............................................................21
4.4.
Sample Size............................................................................................................21
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................22
5.1.
Reporting Conventions ...........................................................................................22
5.1.1.
Dates Handling.......................................................................................................22
5.1.2.
Calculation Using Dates .........................................................................................23
5.2.
Analysis Populations ..............................................................................................23
5.2.1.
Intent-to-Treat Population (ITT) .............................................................................24
5.2.2.
Modified ITT (mITT) .............................................................................................24
5.2.3.
Safety Population....................................................................................................24
5.2.4.
Subgroup Analyses.................................................................................................24
6.
SUBJECT DISPOSITION......................................................................................27
7.
PROTOCOL DEVIATION/VIOLATIONS ............................................................28
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................29
8.1.
Demographics.........................................................................................................29
8.2.
Baseline Characteristics..........................................................................................29
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
3
8.3.
Medical History......................................................................................................30
8.4.
Prior Anti-lymphoma Therapy................................................................................30
8.5.
Prior Medications ...................................................................................................30
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................32
9.1.
Treatment Duration.................................................................................................32
9.2.
Cumulative Dose ....................................................................................................32
9.3.
Dose Exposure........................................................................................................32
9.4.
Average Dose .........................................................................................................32
9.5.
Dose Intensity.........................................................................................................32
9.6.
Relative Dose Intensity...........................................................................................33
9.7.
Dose Modification or Interruption or Reduction......................................................33
10.
CONCOMITANT MEDICATIONS/PROCEDURES AND NEXT 
ANTILYMPHOMA TREATMENT .......................................................................34
10.1.
Concomitant Medications .......................................................................................34
10.2.
Concomitant Procedures.........................................................................................34
10.3.
Next Antilymphoma Treatment...............................................................................34
11.
EFFICACY ANALYSES .......................................................................................35
11.1.
Analysis of Primary Efficacy Endpoint...................................................................35
11.1.1.
Sensitivity Analyses for PFS...................................................................................36
11.2.
Analyses of Secondary Efficacy Endpoints.............................................................37
11.2.1.
Overall Survival .....................................................................................................37
11.2.2.
Objective Response Rate ........................................................................................38
11.2.3.
Complete Response Rate ........................................................................................38
11.2.4.
Durable Complete Response Rate...........................................................................38
11.2.5.
Duration of Response .............................................................................................38
11.2.6.
Duration of Complete Response..............................................................................38
11.2.7.
Event-free Survival.................................................................................................39
11.2.8.
Time to Next Anti-lymphoma Treatment ................................................................39
11.4.
Subgroup Analysis of Efficacy Endpoints...............................................................41
12.
SAFETY ANALYSIS ............................................................................................42
12.1.
Adverse Events.......................................................................................................42
12.2.
Clinical Laboratory Evaluations..............................................................................44
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
4
12.3.
Vital Sign Measurements........................................................................................44
12.4.
Physical Examination, Pregnancy Testing and B symptoms....................................45
12.5.
ECOG Performance Status......................................................................................45
14.
INTERIM ANALYSIS...........................................................................................48
15.
REFERENCES.......................................................................................................49
16.
APPENDICES........................................................................................................50
16.1.
Date Imputation Guideline......................................................................................50
16.1.1.
Impute Missing Adverse Event / Prior or Concomitant Medications Start 
Dates ......................................................................................................................50
16.1.2.
Impute Missing Adverse Event / Prior or Concomitant Medications Stop 
Dates ......................................................................................................................50
16.1.3.
Impute Missing Disease Diagnosis Dates................................................................51
16.1.4.
Impute Missing Dates in Prior Anti-lymphoma Regimen........................................51
16.1.5.
Impute Missing Dates in Subsequent Antilymphoma Therapy: ...............................51
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Schedule of Study Assessments ..............................................................................13
Table 3:
Censoring Rules Used for the Primary Analysis of Progression-free Survival .........36
Table 4:
Censoring Rules Used for the Primary Overall Survival Analysis ...........................37
Table 5
Censoring rules for EFS..........................................................................................39
Table 6
Censoring rules for TTNLT....................................................................................40
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
6
SIGNATURE PAGE
SAP TITLE
A PHASE 3, DOUBLE-BLIND RANDOMIZED STUDY TO COMPARE THE 
EFFICACY AND SAFETY OF RITUXIMAB PLUS LENALIDOMIDE 
(CC-5013) VERSUS RITUXIMAB PLUS PLACEBO IN SUBJECTS WITH 
RELAPSED/REFRACTORY INDOLENT LYMPHOMA
SAP VERSION, DATE
Final Version, June 21, 2018
SAP AUTHOR
       
Printed Name and Title
Signature and Date
PROTOCOL TITLE
A PHASE 3, A PHASE 3, DOUBLE-BLIND RANDOMIZED STUDY TO 
COMPARE THE EFFICACY AND SAFETY OF RITUXIMAB PLUS 
LENALIDOMIDE (CC-5013) VERSUS RITUXIMAB PLUS PLACEBO IN 
SUBJECTS WITH RELAPSED/REFRACTORY INDOLENT LYMPHOMA
INVESTIGATIONAL 
PRODUCT
CC-5013
PROTOCOL NUMBER
CC-5013-NHL-007
PROTOCOL VERSION, 
DATE
Amendment 3, 21OCT2015
SIGNATURE 
STATEMENT
By my signature, I indicate I have reviewed this Statistical Analysis Plan (SAP) 
and find its contents to be acceptable.
Statistical Therapeutic Area Head
Signature
Printed Name
Date
Lead Clinical Research Physician / Clinical Research Physician
Signature
Printed Name
Date
Lead Product Safety Physician
Signature
Printed Name
Date
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation or specialist 
term
Explanation
AE
Adverse event
AML
Acute myelogenous leukemia 
APAC
Asia-Pacific region
ASCO
American Society of Clinical Oncology
ATC
Anatomical Therapeutic Chemical
BSA
Body surface area 
CI
Confidence interval
CIRS
Cumulative Illness Rating Scale
CMH
Cochran–Mantel–Haenszel
CR
Complete response
CrCl
Creatinine clearance
CRu
Complete response unconfirmed
CRF
Case Report Form
CT
Computed axial tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCRR
Durable complete response rate
DMC
Data Monitoring Committee
DoCR
Duration of complete response
DoR
Duration of response
DVT
Deep vein thrombosis
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EFS
Event-free survival 
EMEA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration
FL 
Follicular lymphoma
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
8
Table 1:
Abbreviations and Specialist Terms (Continued)
Abbreviation or specialist 
term
Explanation
GCPs
Good Clinical Practices
GCSF
Granulocyte colony-stimulating factor
GELF
Groupe D'Etude des Lymphomes Folliculaires
HP
Helicobacter pylori
IRC
Independent Review Committee
ITT
Intent to treat
IVRS
Interactive Voice Response System
IWG
International Working Group 
IWGRC
International Working Group Response Criteria
KM
Kaplan-Meier estimate
LDH
Lactate dehydrogenase
LLN
Lower limit of normal
MALT 
Mucosa-associated lymphoid tissue
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified intent to treat
MRI 
Magnetic resonance imaging
MZL
Marginal zone lymphoma
NCI 
National Cancer Institute 
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PE
Pulmonary embolism
PET
Positron emission tomography
PFS
Progression-free survival
 
PK
Pharmacokinetics
PR
Partial response
PT
Preferred term
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
9
Table 1:
Abbreviations and Specialist Terms (Continued)
Abbreviation or specialist 
term
Explanation
SAE
Serious adverse event
SAP
Statistical Aanalysis plan
SAS
Statistical Analysis System
SMQs
MedDRA queries 
SD
Stable disease
SOC
System organ class
SPM
Second primary malignancy
TEAE
Treatment-emergent adverse event
TFR
Tumor flare reaction
TTNLT
Time to next antilymphoma treatment
TTP
Time to progression
US
United States
ULN
Upper limit of normal
WHO
World Health Organization
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Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
10
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
study protocol CC-5013-NHL-007 “A Phase 3, Double-blind, Randomized Study to Compare 
the Efficacy and Safety of Rituximab Plus Lenalidomide (CC-5013) Versus Rituximab Plus 
Placebo in Subjects With Relapsed/Refractory Indolent Lymphoma”. It contains definitions of 
analysis populations, derived variables, and statistical methods for the analysis of efficacy and 
safety. The primary endpoint of the trial is PFS.
These analyses include one interim analysis for futility and one final analysis. Throughout this 
SAP, the treatment arms will be referred to as “experimental R2” for rituximab plus
lenalidomide arm and “control R” for rituximab plus placebo arm. The purpose of the SAP is to 
ensure the credibility of the study findings by specifying the statistical approaches to the analysis 
of study data prior to database lock for the final analysis. The final SAP which may include 
detailed data handling conventions will be signed off prior to the database lock for the study 
protocol specified futility analysis for progression-free survival (PFS). All statistical analyses 
detailed in this SAP will be conducted using SAS® Version 9.1.3 or higher.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
11
3.
OBJECTIVES
The primary objective of the study is:
!
to compare the efficacy of rituximab plus lenalidomide to rituximab plus placebo in 
subjects with relapsed/refractory indolent lymphoma
Efficacy determination will be based upon PFS as the primary endpoint, as assessed by the 
Independent Review Committee (IRC) using the 2007 International Working Group (IWG) 
response criteria (IWGRC) (Cheson, 2007) but without positron emission tomography (PET).
The secondary objectives of the study are:
!
to compare the safety of rituximab plus lenalidomide versus rituximab plus placebo
(no formal testing will be provided)
!
to compare the efficacy of rituximab plus lenalidomide versus rituximab plus placebo 
using other parameters of efficacy:
∀
durable complete response rate (DCRR), overall response rate (ORR), complete 
response rate (CR rate), duration of response (DoR) and duration of complete 
response (DoCR) by 2007 IWGRC without PET
∀
overall survival (OS), event-free survival (EFS), time to next anti-lymphoma 
treatment (TTNLT)
 
 
 
 
 
 
 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
        Celgene Corporation
Confidential and Proprietary
12
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This Phase 3 multicenter, double-blind, randomized study is designed to evaluate the efficacy 
and safety of rituximab plus lenalidomide versus rituximab plus placebo. The overall study 
design is described in Figure 1. The study is divided into the Screening Period, Treatment Period, 
and Follow-up Period. It is planned to randomize 350 subjects.
Upon giving written informed consent, the subject enters the Screening Period to determine 
eligibility. All Screening assessments must be completed within 28 days prior to randomization.
During the Screening Period, the subject will undergo safety and other assessments to determine 
eligibility for the study and undergo randomization to either the experimental arm (rituximab 
plus lenalidomide) or control arm (rituximab plus placebo) in a 1:1 ratio.
The subject will enter the Treatment Period once the subject has fulfilled the required 
assessments in the Screening Period and has been randomized. The treatments will be given as 
described in detail in the study protocol Section 8, and must begin as soon as possible after 
randomization but no later than 1 week after randomization. The subjects will receive study 
protocol-specified treatments for a maximum of 12 cycles or until relapse or progression of 
disease, withdrawal of consent, or unacceptable toxicity. All randomized subjects will be 
assessed for disease progression (PD) and OS during the study using the schedule described in 
the study protocol. This includes all subjects who discontinue the study protocol-specified 
treatment or the study early for any reason without documented evidence of clinical and/or 
radiological disease progression.
Upon completion or early discontinuation of the study protocol-specified treatments (study 
protocol Section 8), all subjects will enter the Follow-up Period. In the Follow-up Period, 
subjects will be followed for disease progression, subsequent anti-lymphoma therapy 
 
, development of any second primary malignancies (SPMs) and OS.
The Schedule of Study Assessments are is listed in Table 2.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
13
Table 2:
Schedule of Study Assessments
Procedure
Screening
(Day -28
to Day -1)
Treatment Period 12 Months
At 
Treatment
Discontinuation 
or
Completion
Follow-up
Cycles 1 to 12:
Every
Cycle
Day 1
(±3 days)
Additional Assessments
If no PD
then follow
the CT 
scan 
assessment 
schedule6 or 
otherwise 
specified
If progressed
then
every 6
months
(±2 weeks)
Cycle 1
Days 1, 8, 15, 
22 (±1 day)
Cycles 2
to 5 
Day 1 
(±3 days)
Cycle 1
Days 1, 8, 
15
(±1 day)
Cycles 2  
to 4
Day 15
(±1 day)
Cycle 4 &
Cycle 7  
Day 1
(± 3 days)
Cycle 10
Day 1
(±3 days)
Informed Consent
X
-
-
-
-
-
-
-
-
-
Inclusion/Exclusion Criteria
X
-
-
-
-
-
-
-
-
-
Complete Medical History
X
-
-
-
-
-
-
-
-
-
CNS Lymphoma Evaluation
X
-
-
-
-
-
-
-
-
-
Creatinine Clearance
(Cockcroft-Gault 
estimation)
X
-
-
-
-
-
-
-
-
-
12-Lead ECG
X
-
-
-
-
-
-
-
-
-
HBV Screening
X
-
-
-
-
-
-
-
-
-
FFPE Tumor Specimen1
X
-
-
-
-
-
-
-
-
-
Eastern Cooperative 
Oncology Group (ECOG) 
Performance Status
X
X
-
-
-
-
-
X
X12
-
Vital Signs2
X
X
-
-
-
-
-
X
-
-
Hematology 3
X
X
-
X
X
-
-
X
X12
-
Serum Chemistry3
X
X
-
X
X
-
-
X
X12
-
Serum Immunoglobulin 
(IgG, IgA, IgM)
X
-
-
-
-
-
X
-
-
-
Thyroid Stimulating 
Hormone (TSH)
X
-
-
-
-
X
X
-
-
-
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
14
Table 2:
Schedule of Study Assessments (Continued)
Procedure
Screening
Treatment Period 12 Months
Follow-up
(Day -28
to Day -1)
Cycles 1 to 
12:
Every
Cycle
Day 1
(±3 days)
Additional Assessments
At 
Treatment
Discontinuation
or
Completion
If no PD
then follow
the CT 
scan 
assessment 
schedule6 or 
otherwise 
specified
If progressed
then
every 6
months
(±2 weeks)
Cycle 1
Days 1, 8, 15, 
22 (±1 day)
Cycles 2
to 5 
Day 1 
(±3 days)
Cycle 1
Days 1, 8, 
15
(±1 day)
Cycles 2to 
4
Day 15 
(±1 day)
Cycle 4 &
Cycle 7 
Day 1
(± 3 days)
Cycles 10
Day 1
(±3 days)
Tumor Flare and Tumor 
Lysis Assessments4
-
-
-
X
-
-
-
-
-
-
Pregnancy Testing - for 
FCBP with Regular or No 
Menstrual Cycles
Once between 
Days -10 to -14, and 
within 24h prior to 
C1D1
Weekly during first 28 days; every cycle on Day 1 thereafter
X
-
-
Pregnancy Testing - for 
FCBP with Irregular 
Menstrual Cycles
Once between 
Days -10 to -14, and 
within 24h prior to 
C1D1
Weekly during first 28 days; every cycle on Days 1 and 14 thereafter
X
-
-
Birth Control and 
Lenalidomide 
Counseling5
Once between Days
-10 to -14
X
-
-
-
-
-
X
-
-
Distribute Lenalidomide
Counseling Sheet5
X
X
-
-
-
-
-
X
-
-
Adverse Events
X
After signing the informed consent document through 28 days after last dose.
Assessment of Second 
Primary Malignancy 
(SPM)6
X
After signing the informed consent document up to and including a follow-up period of up to 5 years from the date of the last subject 
randomized
Prior/Concomitant 
Medications/ Procedures / 
Record Hospitalizations
X
After signing the informed consent document through 28 days after last dose.
Physical Examination
X
X
-
-
-
-
-
X
X12
-
B Symptoms
X
X
-
-
-
-
-
X
X12
-
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
15
Table 2:
Schedule of Study Assessments (Continued)
Procedure
Screening
Treatment Period 12 Months
Follow-up
(Day -28
to Day -1)
Cycles 1 to 
12:
Every
Cycle
Day 1
(±3 days)
Additional Assessments
At 
Treatment
Discontinuation 
or
Completion
If no PD
then follow
the CT 
scan 
assessment 
schedule6 or 
otherwise 
specified
If progressed
then
every 6
months
(±2 weeks)
Cycle 1
Days 1, 8, 15, 
22 (±1 day)
Cycles 2
to 5 
Day 1 
(±3 days)
Cycle 1
Days 1, 8, 
15
(±1 day)
Cycles 2 to 
4
Day 15 
(±1 day)
Cycle 4 &
Cycle 7  
Day 1
(± 3 days)
Cycles 10
Day 1
(±3 days)
CT or MRI of Neck, Chest, 
Abdomen and Pelvis
and
Response Assessment 7
X
Years 1-3: Every 12 weeks (± 1 week)
Year 4: Every 16 weeks (± 1 week)
Year 5: Every 6 months (± 2 weeks)
Years onwards: Every year (± 3 weeks) and up to PD
-
Bone Marrow Biopsy
X9
For subjects with radiological CR/CRu and conditions as defined in protocol section 6.2.1
Upper Gastrointestinal 
Endoscopy and Gastric 
Biopsy10
X
Years 1: Cycle 7 Day 1 (± 2 weeks); After cycle 12 (+ 2 months)
Year 2-3: Every 6 months (± 2 weeks)
Year 4 onwards: Every year (± 2 weeks) and up to PD or CR
-
Dispense Study Drug11
-
X
-
-
-
-
-
-
-
-
Rituximab11
-
-
X
-
-
-
-
-
-
-
Study Drug Return/
Accountability
-
X
-
-
-
-
-
X
-
-
Subsequent Anti-Lymphoma 
Therapie
 
-
-
-
-
-
-
-
X
-
X
Note:  Safety assessments (including labs) must be performed prior to dosing at each treatment visit.
C1D1: Cycle 1 Day 1; CBC: Complete blood count; CNS: Central nervous system; CRF: Case report form; CT: Computed tomography; ECG: 
Electrocardiogram; FCBP: females of childbearing potential; FFPE: Formalin-fixed paraffin embedded; HBV: Hepatitis B virus; MRI: magnetic resonance 
imaging; 
TLS: Tumor lysis syndrome; TSH: Thyroid stimulating hormone. 
1.
If an FFPE tumor block cannot be sent, one hematoxylin and eosin (H and E) stained slide and 10 unstained slides or 11 unstained slides will be acceptable.
2.
Vital signs include weight, height (only at Screening), blood pressure, temperature, and pulse.
3.
If Screening labs are drawn within 1 week before receipt of study drug on Cycle 1 Day 1, they do not need to be repeated on C1D1.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
16
4.
The site should make every effort to contact the subject on Day 5 (± 1 day) of the first cycle to inquire about the subject’s condition and to make sure that 
he/she is continuing with TLS prophylaxis measures by keeping hydrated and taking the TLS prophylaxis as instructed (see protocol section 9.3.1 for more 
details).
5.
All subjects enrolled into this study must conform to all aspects of the lenalidomide pregnancy prevention risk management plan (standalone document, see 
study protocol Section 18.6).  
6.
Medical history of any prior cancer other than the disease under study will be reported and, in addition, SPMs will be monitored as events of interest and must 
be reported as serious adverse events (SAE) regardless of the treatment arm the subject is in. This includes any second primary malignancy, regardless of 
causal relationship to study drug[s], occurring at any time for the duration of the study, from the time of signing the Informed consent (ICD) up to and 
including the follow-up period and until 5 years after the last subject randomized.  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 second primary malignancy must be provided at the time of reporting as a serious 
adverse event (eg, any confirmatory histology or cytology results, X-ray reports, CT scan reports, etc.).
7.
Efficacy assessment to be performed until progression or relapse. See study protocol Section 6.2.1 for more details.
 
 
9. Bone marrow biopsy is required at Screening (for staging) only for subjects with abnormal CBC.  See study protocol Sections 6.1 and 6.2.1 for more details.
10.Upper gastrointestinal endoscopy including biopsies (from stomach, duodenum, gastroesophageal junction and from any abnormal-appearing site) is required 
only in subjects with gastric mucosa-associated lymphatic tissue (MALT) lymphoma. See study protocol Sections 6.1 and 6.2.1 for more details.
11.See study protocol Sections 8.1 and 8.2 for more details regarding treatment administration. There is no window for study drug administration.
12.During Follow-up, at same time as the CT/MRI scan evaluation and every 6 months (± 2 weeks) after year 5 (see protocol section 6.4).
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
17
Efficacy determination for the primary endpoint will be based upon PFS as determined by the 
IRC. 
An independent external Data Monitoring Committee (DMC) will review ongoing safety data 
throughout the study according to DMC charter.
The study will be conducted in compliance with Good Clinical Practices (GCPs).
Figure 1:
Overall Study Design
Screening Period
   
Treatment Period a
    
Follow-up Period  
        
0.5 years                             2 years
CrCl = creatinine clearance; ICD = informed consent document; FL = follicular lymphoma; 
MZL = marginal zone lymphoma; PD = progressive disease.
a Treatment must begin as soon as possible after randomization but no later than 1 week after randomization.
b 10 mg if CrCl ≥ 30 mL/min but < 60 mL/min; 20 mg if CrCl ≥ 60 mL/min.
c Cycle defined as Lenalidomide / Placebo cycle of 28 days (21 days treatment and 7 days rest period)
d All randomized subjects are followed for disease progression and overall survival using the same schedule 
described in Table 1. This includes patients who discontinue the protocol-specified treatment or the study 
early for any reason without documented evidence of PD or relapse.
ICD
Signature 
Screening, 
Eligibility
Stratification
-Previous rituximab 
treatment
-Time since last anti-
lymphoma therapy 
-FL / MZL
Randomizationa
350 subjects
[1:1]
Follow-up visit d
- for up to 5 years from 
last subject randomized
- for the following: 
progressive disease 
(PD) / relapse, overall 
survival, subsequent 
antilymphoma therapies 
 and 
second primary 
malignancies
LENALIDOMIDE
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375 mg/m2
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on Day 1 of Cycles c 2 to 5
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10 mg or 20 mg b
On Days 1-21 of Cycles c 1 to 12
RITUXIMAB
375 mg/m2
Weekly [Days 1, 8, 15, 22] in Cycle c 1 and then
on Day 1 of Cyclesc 2 to 5
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
18
4.1.1.
Study Population
The study population includes relapsed and refractory indolent lymphoma subjects who:
!
must have an investigator-assessed diagnosis of relapsed/refractory indolent 
lymphoma, defined in this clinical trial as grade 1, 2 or 3a follicular lymphoma or 
marginal zone lymphoma, 
!
must have been previously treated for their lymphoma with systemic therapy 
(chemotherapy, immunotherapy, or chemoimmunotherapy), 
!
must be refractory to or have relapsed after their last treatment, 
!
must have received at least 2 previous doses of rituximab and must not be 
rituximab-refractory (as of study protocol Amendment 3), and
!
must have at least one measurable lesion by computed axial tomography (CT) or 
magnetic resonance imaging (MRI) scan, and must have adequate bone marrow 
function, liver function and renal function.
Definitions:
!
Relapsed lymphoma: relapsed after initial response of CR to prior therapy.
!
Progressive lymphoma: PD after initial response of PR or stable disease (SD) to the 
prior therapy.
!
Refractory lymphoma: subject who received a non-rituximab containing systemic
therapy and who experienced the best response of PD to this therapy.
!
Rituximab-refractoriness: 
∀
did not respond (at least a PR) to rituximab or R-chemoregimen therapy and/or
∀
time to disease progression < 6 months after last rituximab dose.
!
Rituximab-sensitive marginal zone lymphoma (MZL) or FL:
∀
Responded (at least a PR) to rituximab or rituximab-chemoregimen therapy and
∀
Time to disease progression ≥ 6 months after last rituximab dose
4.1.2.
Treatment Assignment
It is planned to randomize 350 subjects in a 1:1 rate to experimental arm (175 subjects) or 
control arm (175 subjects):
Experimental Arm (Experimental R2): rituximab plus lenalidomide
!
Rituximab, 375 mg/m2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 
22) and on Day 1 of every 28-day cycle from Cycles 2 through 5,
plus
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
19
!
Lenalidomide, 20 mg once daily on Days 1 through 21 every 28 days up to 12 cycles. 
Control Arm (Control R): rituximab plus placebo
!
Rituximab, 375 mg/m2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 
of every 28-day cycle from Cycles 2 through 5,
plus 
!
Placebo (identical matched capsule), once daily on Days 1 through 21 of every 
28-day cycle up to 12 cycles.
4.1.3.
Screening Period
Upon giving written informed consent, the subject will enter the Screening Period to determine 
eligibility (the Screening Period timing begins on the day [Day −28] the first study procedure is 
performed after the subject has provided written informed consent). All screening assessments 
must be completed within 28 days prior to randomization. During the Screening Period, the 
subject will undergo safety and other assessments to determine eligibility for the study and 
undergo randomization to either the experimental arm (rituximab plus lenalidomide) or control 
arm (rituximab plus placebo).
Subject eligibility will be based on investigator assessment of the pathologic diagnosis.
However, subject’s disease diagnosis will be assessed retrospectively by central pathology to 
confirm the FL or MZL diagnosis. Thus, the investigator must confirm that archival formalin-
fixed paraffin embedded (FFPE) tumor or lymph node tissue specimen exists during the 
Screening Phase. If an archival specimen is not available for submission, then a rebiopsy is 
required prior to randomization. All tumor specimens must be sent to the central pathology 
laboratory, preferably during the screening period and no later than 8 weeks after randomization. 
Confirmation of FL or MZL by the central pathologist is not required for entry into the study.
4.1.4.
Treatment Period
The Treatment Period begins with Cycle 1 Day 1 dosing of the therapy drugs and must begin as 
soon as possible after randomization but no later than 1 week after randomization. The subjects 
will receive protocol-specified treatments and efficacy and safety assessments for a maximum of 
12 cycles, or until relapse or progression of disease, withdrawal of consent, or unacceptable 
toxicity. A central laboratory will be used for the analysis of hematology and serum chemistry.
Clinical decisions and dose modifications during the study can be based on local laboratory 
results.
All randomized subjects will be followed for disease progression and OS using the same 
schedule as described in protocol’s Schedule of Study Assessments. This includes all subjects 
who discontinue the protocol-specified treatment or the study early for any reason without 
documented evidence of disease progression. A subject’s withdrawal from the 
protocol-specified treatment for disease progression will be based upon investigator assessment. 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
20
4.1.5.
Follow-up Period
The Follow-up Period begins upon study treatment completion or discontinuation. 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 anti-lymphoma / 
salvage therapy (chemotherapy, stem cell transplants, radiotherapy, etc.). In the Follow-up 
Period, the subjects will be followed for disease progression, OS, subsequent anti-lymphoma 
therapies, 
 
 and SPMs. The Follow-up period ends when subjects complete the 5 year 
follow up after the last subject has been randomized. 
4.2.
Study Endpoints
Progression free survival (PFS), best overall response including ORR, CR rate, durable CR rate, 
and DOR will be assessed per2007 IWGRC (Cheson, 2007) by IRC assessments. Investigator 
assessments will also be provided for sensitivity analyses. In addition to CT/MRI scan to assess 
response and progression, subjects with gastric MALT lymphoma will also undergo endoscopy 
as part of response assessment.
All following endpoints are further defined in Section 11.1
.
The protocol-specified primary efficacy endpoint is:
!
Progression-free survival (PFS)
The protocol-specified secondary endpoints are:
!
Overall survival (OS)
!
Durable complete response rate (DCRR)
!
Overall response rate (ORR)
!
Complete response rate (CR)
!
Duration of response (DoR)
!
Duration of complete response (DoCR)
!
Event-free survival (EFS)
!
Time to next anti-lymphoma treatment (TTNLT)
!
Safety (type, frequency, and severity of adverse events [AEs], and relationship of 
AEs to study drug or comparator)
 
 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
21
 
 
4.3.
Stratification, Randomization, and Blinding
The randomization procedure will be accomplished by a validated interactive voice response 
system (IVRS), using the method of randomly permuted block within strata, stratified by the 
following: 
!
previous rituximab treatment (yes; no), 
!
time since last anti-lymphoma therapy (≤ 2; > 2 years), and 
!
disease histology (FL; MZL).
4.4.
Sample Size
The basis for the power and sample size determination will be a test of the equality of the overall 
time-to-event (ie, PFS) curves between experimental and control treatment groups using a 
stratified log-rank test. The primary efficacy endpoint is PFS. To fulfill the primary objective of 
the study, it must be shown that the experimental arm is superior to the control arm on the 
primary endpoint at one-sided α = 0.025 level. It is hypothesized that the median PFS is 
17.6 months in the experimental arm and 11 months in the control arm (corresponding hazard 
ratio [HR] of 0.625, assume that FL and MZL subjects have the same median PFS). For 90% 
power to detect this difference with 1-sided α = 0.025, a total of 193 PFS events will be required.
Based on the rate of accrual anticipated in this study, and annual dropout rate of 5%, it is planned 
to randomize a total of approximately 350 subjects in a 1:1 ratio to the 2 treatment arms and the 
study duration to reach the PFS events is expected to be 43 months.
Sample size and power were calculated using the East® Version 5.4 software system (Cytel Inc, 
675 Massachusetts Avenue, Cambridge, MA 02139; http://www.cytel.com).
&&,
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
22
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
Summary tables, listings, and any supportive SAS output will include a “footer” of explanatory 
notes that will indicate, at a minimum, the following: 
!
Program source (eg, SAS program name, including the path, that generates the 
output) and
!
Data extraction date (eg, the database lock date, run date)
The purpose of the data extraction date is to link the output to a final database, either active or 
archived, that is write-protected for replication and future reference. An output date will also 
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.
5.1.1.
Dates Handling
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9. datetime format in SAS unless specified otherwise).
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, tumor scans, etc. They should 
be present whenever data for a protocol-specified procedure are 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 dates recorded in CRF data logs. Specifically, they are the start and 
end dates for adverse events 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 16.1 (eg, for duration or cycle assignment, etc). However, in listings, log 
dates will be shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
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 are not otherwise subject to imputation.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
23
!
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
(see Section 5.1.2 below). 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
5.1.2.
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: 
!
For all safety analyses, study days on or after the start day of study drug will be 
calculated as the difference between the date of interest and the first date of dosing of 
study medication (eg, rituximab or lenalidomide, whichever is earlier) plus 1 day; 
study days before the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study medication. Note that 
Study Day 1 is the first day of treatment of study drug. There is no day zero, and 
negative study days are reflective of observations obtained during the 
baseline/screening period. All effort should be made to avoid incomplete study drug 
start date. 
!
For all efficacy analyses, time-to-event days for efficacy endpoints will be calculated 
as the difference between the date of interest and the randomization date plus 1 day.
!
Age (expressed in days) is calculated as follows: 
AGE = DATE of RANDOMIZATION – DATE of BIRTH + 1.
!
If the date of randomization is not available (ie, screen failure), then the date of 
informed consent is used. In practice, age will be transformed to years by dividing the 
difference by 365.25 days, then truncating.
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
!
WEEKS = DAYS / 7.
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
!
MONTHS = DAYS / 30.4375
5.2.
Analysis Populations
The primary efficacy analyses will be performed on the Intent-to-treat (ITT) population for the
primary and secondary endpoints. Primary and secondary endpoints will also be analyzed for the 
modified Intent-to-treat (mITT) population. Sensitivity analyses will be conducted for the 
primary and secondary endpoints based on the ITT population. All ITT and mITT analyses will 
be based on randomized treatment groups.
Safety analyses will be conducted only on the Safety population.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
24
5.2.1.
Intent-to-Treat Population (ITT)
The 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 ITT (mITT)
The mITT population is defined as all randomized subjects who have received at least 1 dose of 
study medication, have confirmed diagnosis of relapsed/refractory FL or MZL by central 
pathology review except SMZL which was based on local pathology assessment, and have 
baseline (Screening) and at least one post baseline tumor assessment for efficacy.
The efficacy analysis will also be performed on the mITT population as supportive evidence
and/or sensitivity analysis. Subjects will be analyzed according to the treatment arm to which
they are initially assigned
5.2.3.
Safety Population
The safety population is defined as all subjects who have received at least one dose of study 
medication.
The safety population will be used for all safety analysis. Subjects will be analyzed according to 
the treatment which they initially received.
5.2.4.
Subgroup Analyses
In addition to analyses that include the ITT population, PFS (primary endpoint per 2007 
IWGRC) and ORR (per 1999 IWGRC) will be performed for subgroups to compare treatments 
within stratification factors: previous rituximab treatment (yes; no), time since last anti-
lymphoma therapy (≤ 2; > 2 years); histology (FL; MZL). Separate efficacy analyses for FL and 
MZL subjects will be also performed. For these stratification factors, data collected by CRF will 
be used in subgroup analyses.
Subgroup analyses may also be performed on other important factors such as demographic and 
baseline characteristics as needed:
!
Age (< 65; ≥ 65 years)
!
Sex (male; female)
!
Race (White; Other Races)
!
Region (the United States [US], the European Union [EU], Asian-Pacific Region and 
Brazil[Other])
!
FLIPI (  >=3 ; <3) for FL subjects only;
!
Number of prior anti-lymphoma regimens (1 ; >1) ; 
!
Ann Arbor Stage at Enrollment (I-II; III-IV)
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!


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
25
!
Prior Rituximab containing chemotherapy regimen (Yes or No)
!
Refractory to last prior regimen (Yes; No)
!
High tumor burden perGELF, (Salles et al., Lancet 2010, 377:42-51 ) (Yes; No)
!
Chemoresistant (<PR or PD <=6 months from last chemotherapy, Yes; No)
!
Unfit for Chemotherapy (defined by Age>=70, or if 60-69 years old AND CrCL<60 
mL/min or ECOG PS>=2, Yes; No)
Definitions:
!
Prior Rituximab containing chemotherapy regimen (Yes; No):
Prior rituximab containing chemotherapy regimen requires that rituximab AND one 
or more chemotherapeutic agents are used in the same regimen (at least one regimen, 
no requirement on which line the regimen is used).
!
High tumor burden (Yes; No): 
High tumor burden condition is met when a subject meets at least one of the 
following criteria at baseline:
 A nodal or extranodal (except spleen) mass >7cm in greater diameter  
 Involvement of at least 3 nodal or extra-nodal sites (each with a diameter greater 
than 3 cm) 
 Symptomatic splenomegaly (>16 cm) 
 Compression syndrome (ureteral, orbital, gastrointestinal) 
 Pleural or peritoneal serous effusion (irrespective of cell content) 
 B-symptoms
 Any one of the following:

hemoglobin < 10g/dL (6.25 mmol/L) 

absolute neutrophil count (ANC) < 1.5 x 109 /L 

platelets <100 x 109/L 
 Baseline Lactate dehydrogenase (LDH) > upper limit of normal (ULN)
!
Chemoresistant (Yes; No):
Chemoresistant criteriaon is met when a subject meets one of the either conditions 
below:
 the best overall response to last chemotherapy treatment is SD or PD 
 the best overall response to last chemotherapy treatment is PR, CRu, or CR, but 
progression occurs within 6 months after completion of treatment
!
Unfit for Chemotherapy (Yes; No):
Subjects who are unfit for chemotherapy meet one of the either conditions below:
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below
below:



Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
26
 age ≥70;
 if age ≥ 60 and age < 70, with at least one of the following: 

CrCl is ≥30 mL/min AND < 60mL/min

ECOG Performance Status ≥ 2.
The planned subgroup analyses may not be performed on the population with insufficient 
number of subjects or insufficient information.
&&,
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
27
6.
SUBJECT DISPOSITION
For all enrolled subjects, subject disposition will be tabulated using frequency and percent.
Subject disposition includes the number of subjects in the following populations by treatment 
arm: ITT, mITT, and safety populations.
Primary reasons for discontinuation from each study treatment will be collected on the CRF and 
will be listed in subject data listings as well as summarized, using frequency and percent, for all 
randomized subjects including the following categories:
!
Adverse event(s)
!
PD or relapse
!
Withdrawal of consent
!
Death
!
Lost to follow-up
!
Protocol violation
!
Other
for each study drug and overall treatment. 
Number of subjects who are ongoing in treatment, number of subjects who are ongoing in 
follow-up, and number of subjects who completed treatment (maximum of 12 cycles) will also 
be tabulated.
Number and percent of subjects who entered the follow-up phase with or without progression
will be summarized. Primary reasons for study discontinuation will be collected on the CRF and 
will be listed in subject data listings as well as summarized, using frequency and percent, for all 
randomized subjects including the following categories:
!
Withdrawal of consent
!
Death
!
Lost to follow up
!
Protocol violation
Duration of study participation, defined as from date of randomization to date of discontinuation
of the study (or the date of last visit), will be summarized. 
Subject listings will be provided for randomized subjects, subjects discontinued from treatment, 
subjects discontinued from study, and subjects who are excluded with the reason. The screen 
failures will be tabulated by unmet inclusion/exclusion criteria. A summary tabulation will be 
provided for subjects enrolled by study center and country/region.
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r of subjec
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pro ded
ded


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
28
7.
PROTOCOL DEVIATION/VIOLATIONS
Protocol deviations/violations are identified and assessed by the clinical research physician or 
designee following company standard operational procedure. The protocol violations will be 
summarized by treatment arm in the ITT population. 
Protocol deviations will be summarized using frequency tabulations and listed under individual 
subject listings with no derivation as this information is from the clinical trial monitoring system.
A by-subject listing of subjects with protocol violations and deviations in the ITT population will 
be provided. 
&&,
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ill
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
29
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics and baseline characteristics will be carried out for the ITT 
population and the mITT population. Baseline is defined as the last measurement prior to or on
the date of the first dose of any study medication (or the last measurement prior to or on the date 
of randomization in case the first dose date is missing). When there are retested values, the retest 
value that is the closest to and prior to or on the first dose date will be used for the analysis. 
Individual subject listings will be provided to support the summary tables. 
Summary statistics (mean, standard deviation, median, minimum, and maximum) will be 
provided for variables measured on a continuous scale, e.g., age, height, and weight. The 
frequency distribution (n, %) will be provided for those variables measured on a nominal scale.
8.1.
Demographics
Subjects’ age, height, weight, and other baseline characteristics (e.g., baseline vital signs and 
selected safety laboratory values) will be summarized using descriptive statistics, while sex, and 
other categorical variables (e.g., age categories <65; ≥65 years, reasons to start the treatment, 
reasons for considering rituximab monotherapy), baseline electrocardiogram (ECG)
interpretation, baseline Eastern Cooperative Oncology Group (ECOG) performance status, will 
be provided using frequency tabulations.
8.2.
Baseline Characteristics
The following items will be summarized by treatment arm.
!
Body surface area (BSA)
!
Histology (FL, MZL) 
!
Grade (1,2, 3a) for FL subjects
!
Follicular Lymphoma International Prognostic Index (FLIPI) category: High (≥3), 
Intermediate (2), Low (0,1) for FL subjects
!
Number of prior antilymphoma regimens: 1,>1
!
Subtype for MZL subjects (exrtranodal MZL, nodal MZL, splenic MZL)
!
Stage at initial diagnosis
!
Stage at enrollment 
!
Bulky disease (yes, no)              
!
Patients whose first relapse/progression documented within 2 years of initial 
diagnosis (yes, no)
!
Creatinine clearance (ml/min) and its categories (≥30 mL/min and <60 ml/min, ≥60 
ml/min)
!
Baseline B symptom present (yes, no)
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prior antily
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
30
!
Lactate dehydrogenase (LDH): Elevated, Normal
!
Bone marrow involved (Yes, No)
!
Ann Arbor Stage (1-2; 3-4 )
!
Early relapse for FL subjects (Yes; No)
!
Prior Rituximab containing chemotherapy regimen (Yes or No)
!
Refractory to last prior regimen (Yes; No)
!
High tumor burden (GELF) (Yes; No)
!
Chemoresistant (Yes; No)
!
Chemotherapy eligible (Yes; No)
!
Unfit for Chemotherapy (Yes; No)
8.3.
Medical History
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) Version 20.0 or later. 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) in descending order of frequency by SOC, and then within each 
SOC by descending order of PT by the rituximab plus lenalidomide treatment group. 
By-subject listings will display medical history including all relevant data collected on the CRF.
8.4.
Prior Anti-lymphoma Therapy 
Prior anti-lymphoma drugs will be summarized using frequency tabulations by preferred name 
(World Health Organization [WHO] dictionary term, Version March 2018 or later). A summary 
of last prior anti-lymphoma drugs (i.e., drugs included in the anti-lymphoma regimen prior to 
study entry) will also be produced.
Number of prior radiation therapies, best response to prior radiation therapies, prior 
transplantation, and best responses to prior transplantation, number of prior systemic anticancer 
therapies, time from the last therapy, best response to last systemic anticancer therapies, best 
response to each line of prior systemic anticancer therapy will be summarized accordingly.
8.5.
Prior Medications
Prior medications are defined as medications that were started before the start of the study 
treatment (regardless whether medications ended before the start of the study treatment or not). 
Prior medications that continue into study treatment period will also be reported as concomitant
therapy.
All prior medications will be summarized in frequency tabulations. The Anatomical Therapeutic
Chemical (ATC) coding scheme of the WHO dictionary term (Version March 2018 or later) will 
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r Regul
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will 
nical data.
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by M
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summari
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
31
be used to group medications into relevant categories for these tabulations. The frequencies will 
be summarized by ATC level 1 term and preferred name (PN) in descending order of frequency 
by ATC level 1 term, and then within each ATC level 1 term by descending order of PN by the 
rituximab plus lenalidomide treatment group. 
&&,
CCI


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
32
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.
9.1.
Treatment Duration
Treatment duration (months) of a drug is defined as: 
[(end date of the study drug – (start date of the study drug) + 1] / 30.4375.
The start date of study drug is defined as the first dosing date of the study drug;
The end date of a study drug is the latter one of the last dose date of the study drug and the Day 28 
of the last cycle for the study drug, or death date, whichever occurs first, i.e. Min ( Max (the last 
dose date of the study drug, Day 28 of the last cycle for the study drug), death date). 
Summary statistics will be provided for treatment duration for rituximab and 
lenalidomide/placebo separately. Total number of cycles in treatment phase will be tabulated by 
treatment arm. 
9.2.
Cumulative Dose 
Cumulative dose will be calculated separately for rituximab and lenalidomide/placebo.
Cumulative dose during the treatment is defined as the sum of all doses taken across the 
treatment period.
9.3.
Dose Exposure 
Dose exposure will be calculated separately for rituximab and lenalidomide/placebo. Dose 
exposure for lenalidomide/placebo is defined as the total number of actual days on drug during 
the treatment phase. Dose exposure for rituximab is defined as the total number of actual doses
received during the treatment phase.
9.4.
Average Dose 
Average dose will be calculated separately for rituximab and lenalidomide/placebo. For 
lenalidomide/placebo, average dose will be calculated as the cumulative dose divided by dose 
exposure in days. For rituximab, average dose will be the total actual dose received divided by 
total number of actual doses received.
9.5.
Dose Intensity 
Dose intensity will be calculated separately for rituximab and lenalidomide/placebo. Dose 
intensity during the treatment period is defined as the cumulative dose divided by treatment 
duration for lenalidomide/placebo (mg/week) and for rituximab(mg/m2/week) separately.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
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9.6.
Relative Dose Intensity 
Relative dose intensity is dose intensity divided by planned dose intensity.
!
For lenalidomide/placebo, the planned dose intensity is the first 21 days of 20 mg/day
(10 mg/day if moderate renal impairment) every 28 days.
!
For rituximab, the planned dose intensity is 375 mg/m2 at Days 1, 8, 15 and 22 of 
Cycle 1, and then Day 1 of 375 mg/m2 for the Cycles 2 through 5.
9.7.
Dose Modification or Interruption or Reduction
Dose modification will be summarized by assigned treatment group and study medication. Time 
to first dose reduction/interruption for subjects with at least 1 dose reduction/interruption is the 
time in days elapsed from the date of first dose of treatment to the date that first dose 
reduction/interruption occurred.
Dose interruption is defined as the number and percent of subjects who interrupted treatment 
with study drug for 1 or more days at least once during the treatment period due to AE or any 
other reasons.
Dose reduction is defined as a subject is taking less than 95% of baseline assigned treatment for 
lenalidomide/placebo during the treatment period due to AE or any other reasons.
Summaries include subjects who have at least one dose reduction, time to first dose reduction, 
subjects who have at least one dose reduction due to AE, time to first dose reduction due to AE. 
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dose reduc
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
34
10.
CONCOMITANT MEDICATIONS/PROCEDURES AND NEXT 
ANTILYMPHOMA TREATMENT
10.1.
Concomitant Medications
Concomitant mediations are defined as non-study medications that are started after the initiation 
but before the end of the study treatment + 28 days, or started before the initiation of the study 
treatment and ended or remain ongoing up to the end of the study treatment + 28 days. 
All concomitant treatments documented during the treatment period will be summarized in 
frequency tabulations. The ATC coding scheme of the WHO dictionary term will be used to 
group medications into relevant categories for these tabulations. The frequencies will be 
summarized by ATC level 1 term and PN in descending order of frequency by ATC level 1 term, 
and then within each ATC level 1 term by descending order of PT by the rituximab plus 
lenalidomide treatment group. 
By-subject listings will be provided for all prior and concomitant medications and therapies
taken during the trial.
10.2.
Concomitant Procedures
The CRF page records procedure, date, and indication. These procedures will be coded using 
MedDRA Version 20.0 or higher. A frequency summary of subjects by concomitant procedures 
summarized in frequency tabulations by high level term and preferred term by treatment arm for 
the ITT Population.
Concomitant procedures will be identified as procedures or surgeries that occurred after or on the 
date of first dose of any study drug until 28 days after the last dose of any study drug.
10.3.
Next Antilymphoma Treatment
Subsequent antilymphoma treatment and next antilymphoma chemotherapy will be summarized 
by ATC level 1 term and preferred name for the safety population, respectively. Details of 
subsequent antilymphoma treatment will be presented in subject data listings.
.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
35
11.
EFFICACY ANALYSES
All efficacy analyses will be performed on the ITT population. Key efficacy analyses will be 
performed on the mITT population as supportive evidence and to assess robustness of efficacy 
findings. Subjects will be analyzed according to randomized treatment group.
The primary endpoint PFS per 2007  IWGRC and ORR per 1999 IWGRC will also be analyzed 
by subgroups.
All stratified analyses will be based on CRF data
For time-to-event data, Kaplan-Meier (KM) survival analyses will be performed (unadjusted for 
the stratification variables). Number and percent of subjects censored will be provided. 
Kaplan-Meier product limit method will be used to estimate the survivorship function for all 
time-to-event endpoints (eg, PFS, OS, EFS, etc). Event rates at specific time points will be 
estimated from KM curves. Medians together with 2-sided 95% confidence intervals (CIs) will 
be provided. The confidence interval will be constructed using log-log transformation. 
The resulting survival estimates will be presented graphically for selected endpoints.
The stratified (by stratification factors: previous rituximab treatment [yes, no]), time since last 
antilymphoma therapy [≤2, >2 years], histology [FL, MZL]) )) Cox proportional hazard 
regression models will be used to estimate the HRs and associated 95% CIs for the HRs.
For categorical data, CMH test with the stratification factors as strata will be used. The p-values 
will be presented. The probability of rates will be estimated using the proportion of subjects with 
responses with exact 2-sided 95% CIs.
11.1.
Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint is PFS assessed by the IRC using 2007 IWGRC but without PET 
imaging. In addition to CT/MRI scan to assess response and progression, subjects with gastric 
MALT lymphoma will also undergo endoscopy as part of response assessment.
Progression-free survival is defined as the time from date of randomization into the study to the
first observation of documented disease progression or death due to any cause, whichever occurs 
first.
The primary endpoint will be compared between the 2 treatment arms when approximately
193 IRC assessed PFS events after applying appropriate censoring rules are achieved. KM
estimates of PFS will be provided. Kaplan-Meier product limit method will be used to estimate 
the survivorship function for PFS. PFS rates at specific time points will be estimated from KM
curves. Medians together with 2-sided 95% CIs will be provided. The resulting PFS estimates 
will be presented graphically.
The stratified (with all 3 stratification factors: previous rituximab treatment [yes, no], time since 
last anti-lymphoma therapy [≤2, >2 years], histology [FL,MZL]) log-rank test will be used to 
assess superiority of the experimental arm.
The experimental arm will be declared superior if the one-sided p-value from a stratified 
log-rank test is < 0.025 in favor of the experimental arm. 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
36
Conventionally, the hazard ratio with 2-sided 95% CI will be estimated using the Cox 
proportional hazards model with Efron method for handling a tie.
The primary PFS analysis will be performed for the ITT population following the censoring rules 
in Table 3 (based on FDA guidance [FDA, 2007]).
Table 3:
Censoring Rules Used for the Primary Analysis of Progression-free Survival 
Situation
Date of Event or Censoring
Outcome
Death before first PD assessment while on study
Date of death
Event
Death between adequate assessment visits
Date of death
Event
Progression documented
Date of earliest assessment which 
revealed progression determined by 
IRC
Event
Death or progression after more than 1
consecutively missed scheduled visits
Date of last adequate assessment which 
revealed no progression
Censored
No baseline assessment
Randomization
Censored
No progression, nor death
Date of last adequate assessment with
evidence of no progression by IRC
Censored
Study discontinuation for any reason other than 
death or disease progression 
Date of last adequate assessment with
evidence of no progression by IRC
Censored
Non-protocol new antilymphoma treatment 
started prior to progression/death
Date of last adequate assessment with
evidence of no progression by IRC
before the start of new antilymphoma 
treatment
Censored
IRC = Independent Review Committee; PD = progressive disease.
Source: FDA, 2007.
11.1.1.
Sensitivity Analyses for PFS
In order to evaluate the robustness of the primary PFS analysis, several sensitivity analyses will
be performed;
1. IRC assessed PFS is analyzed per European Medicines Agency (EMA) guideline (EMA,
2013). All progressions and deaths are considered as events, regardless of whether they 
occurred after initiating next anti-lymphoma treatment or after 2 or more missed 
scheduled assessments. Subjects alive and for whom an objective disease progression had 
not been observed are censored at last assessment date that the subject is known to be 
progression-free. Other censoring rules specified in Table 3 Table 3 are still followed.
2. PFS is analyzed based on investigator assessment using FDA censoring rule.
3. PFS is analyzed based on investigator’s assessment using censoring rule following EMA 
guidance.
4. PFS is analyzed based on IRC’s assessment per 1999 IWGRC (Cheson, 1999) using 
censoring rule following FDA guidance.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
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The primary analyses for PFS will also be performed on mITT population.
11.2.
Analyses of Secondary Efficacy Endpoints
Secondary endpoints will be analyzed without controlling α as there are no key secondary 
endpoints declared. All secondary efficacy endpoints will be analyzed in the ITT population.
Secondary endpoints will also be analyzed in the mITT population.
All secondary efficacy endpoints will be analyzed at the time when the final primary endpoint 
PFS is due for analysis.
11.2.1.
Overall Survival
Overall survival is calculated as the time from randomization to death from any cause. Overall 
survival will be censored at the last date that the subject was known to be alive for subjects who 
were alive at the time of analysis and for subjects who were lost to follow-up before death was 
documented.
Kaplan-Meier estimates of OS will be provided. Survival rates at specific time points will be
estimated from KM curves. Medians together with 2-sided 95% CIs will be provided. The 
resulting OS estimates will be presented graphically. In addition, this OS will also be 
summarized after 5 years from the last subject randomized date.
Censoring rules used for the OS analysis are shown in Table 4.
Table 4:
Censoring Rules Used for the Primary Overall Survival Analysis
Situation
Date of Progression or Censoring
Outcome
Death prior to or on the 
cutoff date
Date of death
OS event
No death prior to or on the 
cutoff date
Date of last known alive
Censored
Last date known alive is defined as the last valid date of subject assessment prior to or on the 
data cutoff date in the clinical database. For subjects who have withdrawn consent during the 
study, the last date known alive will be the date of consent withdrawal from the study. For all 
other subjects, the last date known alive will be derived by searching through all valid 
assessment dates in all study datasets to identify the last valid subject assessment date available 
for each subject.  
If the last valid subject assessment date available is on or prior to the data cutoff date, it is used 
as the last date known alive. 
If the last valid subject assessment date available is after the data cutoff date, the data cut-off 
date is used as the last date known alive.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
38
11.2.2.
Objective Response Rate
Objective response rate is defined as the proportion of subjects with best response of at least PR 
during the trial without administration of new anti-lymphoma therapy.
The number and percent of subjects with CR/PR will be tabulated by treatment arm. A stratified 
CM test to adjust for the stratification factors will be performed and p-value will be provided for 
ORR.
11.2.3.
Complete Response Rate
Complete response rate is defined as the proportion of subjects with best response of CR during 
the study by administration of new anti-lymphoma therapy.
The number and percent of subjects with CR will be tabulated by treatment arm. A stratified 
CMH test to adjust for the stratification factors will be performed and p-value will be provided 
for CR rate.
11.2.4.
Durable Complete Response Rate
Durable complete response is defined as the proportion of subjects that stay in CR for at least 
1 year, ie, have duration of CR no less than 1 year (>=48 weeks).
The number and percent of subjects with durable complete response will be tabulated by 
treatment arm. A stratified CMH test to adjust for the stratification factors will be performed and 
p-value will be provided for DCRR.
11.2.5.
Duration of Response
This analysis will be restricted to responding subjects.
Duration of response is defined as from the time from of initial response (at least PR) until
documented disease progression or death. Subjects who do not progress at the time of analysis
will be censored at the last assessment date that the subject is known to be progression-free.
Subjects who receive a new treatment without documented progression will be censored at the 
last assessment date that the subject is known to be progression-free prior to the start of the new 
treatment.
Kaplan-Meier estimates of DoR will be provided. Kaplan-Meier product limit method will be 
used to estimate the survivorship function for DoR. Durable response rates at specific time points 
will be estimated from KM curves. Medians together with 2-sided 95% CIs will be provided. A
stratified log-rank test will be performed and p-value will be provided.
11.2.6.
Duration of Complete Response
This analysis will be restricted to subjects with CR.
Duration of complete response is defined as from the time from of initial CR until documented 
disease progression or death. Subjects who do not progress at the time of analysis will be 
censored at the last assessment date that the subject is known to be progression-free. Subjects 
who receive a new treatment without documented progression will be censored at the last 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
39
assessment date that the subject is known to be progression-free prior to the start of the new 
treatment.
Kaplan-Meier estimates of DoCR will be provided. Kaplan-Meier product limit method will be
used to estimate the survivorship function for DoCR. Complete response rates at specific time 
points will be estimated from KM curves. Medians together with 2-sided 95% CIs will be 
provided. A stratified log-rank test will be performed and p-value will be provided.
11.2.7.
Event-free Survival
Event-free survival (EFS) is defined as the time from date of randomization to date of first 
documented progression, relapse, institution of new anti-lymphoma treatment (chemotherapy, 
radiotherapy or immunotherapy) or death from any cause. Responding subjects and subjects who 
are lost to follow up will be censored at the last date known alive. Censoring rules of for EFS are 
summarized in Table 5.
Kaplan-Meier estimates of EFS will be provided. Kaplan-Meier product limit method will be 
used to estimate the survivorship function for EFS. EFS rates at specific time points will be
estimated from KM curves. Medians together with 2-sided 95% CIs will be provided. A stratified 
log-rank test will be performed and p-value will be provided.
Table 5
Censoring rules for EFS
Situation
Date of EFS
Outcome
Death 
Date of death
Event
Progression
Date of progression
Event
Death or progression after more than 
one missed visit
Date of death or date of progression
Event
New antilymphoma therapy started 
after first progression
Date of progression
Event
New antilymphoma therapy started 
prior to first progression
Date of the first administration of the 
antilymphoma therapy
Event
New antilymphoma therapy started 
without prior or subsequent 
progression
Date of the first administration of the 
antilymphoma therapy
Event
No baseline tumor assessment
Randomization
Censored
No progression, no new antilymphoma 
therapy, nor death, 
Last day known alive
Censored
11.2.8.
Time to Next Anti-lymphoma Treatment
Time to next anti-lymphoma treatment (TTNLT) is defined as the time from date of 
randomization to date of first documented administration of a new anti-lymphoma treatment 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
40
(including chemotherapy, radiotherapy, radioimmunotherapy or immunotherapy). Censoring 
rules for TTNLT are provided in Table 6.
Table 6
Censoring rules for TTNLT
Situation
Date of TTNLT
Outcome
Death without any new anti-
lymphoma treatment
Date of death
Censored
Administration of any new 
antilymphoma treatment 
(chemotherapy, radiotherapy, radio-
immunotherapy, immunotherapy)
Date of  first administration of the treatment
Event
No Death or new administration of 
any new antilymphoma treatment
Last day know alive
Censored
Kaplan-Meier estimates of TTNLT will be provided. Event rates at specific time points will be
estimated from KM curves. Medians together with 2-sided 95% CIs will be provided. A stratified 
log-rank test will be performed and p-value will be provided.
 
 
 
 
 
 
 
 
 
 
 
 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
41
 
 
 
 
 
 
 
11.4.
Subgroup Analysis of Efficacy Endpoints
In addition to analyses that include all evaluated subjects, selected analyses will be performed to 
compare treatments within the subgroups defined in Section 5.2.4. Forest plots for subgroup
analyses will be provided for selected endpoints. 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
42
12.
SAFETY ANALYSIS
All subjects who receive at least one dose of study drug will be included in the safety analyses.
12.1.
Adverse Events
Adverse events will be coded according to the MedDRA Version 20.0 or higher. The intensity of 
AEs will be graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) Version 4.03, except for tumor flare reaction (TFR) which will 
be graded using the NCI-CTCAE Version 3.0.
The following preferred terms under system organ class 'Investigations' are reclassified into the 
new System Organ Class 'Blood and lymphatic system disorders' and are collapsed into different 
preferred terms respectively: 'Granulocyte count decreased','Granulocytopenia' and 'Neutrophil 
count decreased' are collapsed to 'Neutropenia'; 'Hyperchromic anaemia', 'Hypochromic 
anaemia', 'Hypoplastic anaemia', 'Haemoglobin decreased', 'Red blood cell count decreased', 
'Anaemia macrocytic', 'Anaemia megaloblastic','Microcytic anaemia','Normochromic normocytic 
anaemia', 'Anaemia of chronic disease' and 'Anaemia of malignant disease' are collapsed to 
'Anemia'; 'Platelet count decreased' is collapsed to 'Thrombocytopenia'.
A treatment-emergent adverse events (TEAEs) are is defined as any AE occurring or worsening 
on or after the first treatment of the study medication and within 28 days after the last dose date 
of any study drug. 
The frequency of TEAEs will be summarized by MedDRA SOC and PT in descending order of 
frequency by SOC, and then within each SOC by descending order of PT by the rituximab plus 
lenalidomide treatment group. If a subject experienced the same PT multiple times then the 
subject will be counted only once within the particular PT and by greatest severity. All TEAEs 
will be summarized by SOC, PT and Cycle of Onset will be summarized.
The following TEAEs will be summarized by SOC and PT for each treatment group: TEAEs 
leading to study medication discontinuation, TEAEs leading to dose reduction, TEAEs leading to 
dose interruption, TEAEs related to study medication, serious TEAEs, serious TEAEs related to 
study medication, serious TEAEs leading to study medication discontinuation, NCI-CTCAE 
Grade 3 or and 4 TEAEs, Grade 3 orand 4 TEAEs leading to study medication discontinuation, 
Grade 5 TEAEs and AEs of special interest.
Adverse events of special interest (except for SPMs) will be defined using standardized 
MedDRA Queries (SMQs), sub-SMQ, SOC, HLT or list of preferred terms that are selected by 
internal expertise based on the drug and the disease.
Adverse events of special interest include:
!
Neutropenia
!
Infection
!
Thrombocytopenia
!
Bleeding
!
Cardiac arrhythmias
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
43
!
Cardiac failure
!
Ischemic heart disease (including myocardial infarction)
!
Arterial thromboembolism (ATE) events
!
Venous thromboembolism (VTE) events
!
Mixed thromboembolism
!
Renal failure
!
Peripheral neuropathy
!
Diarrhea 
!
Constipation
!
Cutaneous reactions
!
Hypersensitivity 
!
Angioedema
!
Hepatic disorders
!
Tumor lysis syndrome
!
Tumor flare reaction
!
Teratogenicity
!
Interstitial lung disease (interstitial pneumonitis)
For each AESI, the incidence rate per 100 person-years along with 95% confidence interval will 
be provided. Total person-year of an AESI is defined as the total time to onset for subjects with 
any AE in the AESI category plus the total follow-up time for all other subjects. The confidence 
interval will be constructed using exact method with F distribution (Ulm, 1990).
Treatment-emergent adverse events, TEAEs with NCI-CTCAE Grade 3 or 4, and serious TEAEs 
will be descriptively summarized within subgroups defined by the following variables:
!
Sex (Male, Female)
!
Age group (<65, ≥65 years)
!
Number of prior anti-lymphoma regimens (≤ 1,> 1)
!
CrCl at baseline (< 60 mL/min, ≥60 mL/min)
!
Race (White, Other Races)
!
Ann Arbor stage at enrollment (I-II, III-IV)
!
Region (US, EU and Other). 
Deaths during treatment period (ie, after the first treatment of the study medication and within 
28 days after last dose date of any study drug) and during the follow up stage (after the treatment 
period) will be tabulated by treatment arm for the safety population.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
44
The number and percentage of subjects with SPMs will be tabulated by treatment group for the 
following categories:
!
All SPMs (invasive and non-invasive SPMs)
!
All invasive SPMs (hematologic and solid tumor SPMs)
!
All hematologic SPMs 
!
All solid tumor SPMs
!
All non-invasive SPMs (non-melanoma skin cancers)
Hematologic malignancies will be subcategorized into B-cell malignancies, acute myelogenous 
leukemia (AML), myelodysplastic syndrome (MDS), MDS to AML and other hematologic 
malignancies.
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.
The number and percentage of subjects with SPMs who died and those who did not die will be 
tabulated by SPM category. Follow up time for all surviving subjects in the safety population 
will be summarized.
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 1 new malignancy within an SPM category, the onset of the earliest SPM will be used. Time 
to onset will be summarized descriptively by treatment group 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 were defined as the total time to onset for subjects with any SPM in the SPM 
category plus the total follow-up time for all other subjects.
Incidence rate per 100 person-years will be calculated for each treatment arm and SPM category. 
Confidence intervals will be provided. 
12.2.
Clinical Laboratory Evaluations
Clinical laboratory values will be graded according to NCI CTCAE Version 4.0 for applicable 
tests. Shift from baseline to worst severity grade observed during the treatment will be displayed 
by treatment. Normal ranges will be used to determine the categories if High, Low, and Normal 
for lab tests that have no severity grade.
Listings of clinical laboratory data with abnormal flags will be provided by subject and test. 
12.3.
Vital Sign Measurements
Vital signs will be presented in a listing, within and above the normal ranges, will be displayed 
in the listing for each treatment. Normal ranges are defined as follows:
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
45
!
Systolic BP
Normal (90 through 119 mmHg, inclusive)
!
Diastolic BP
Normal (60 through 79 mmHg, inclusive)
!
Body Temperature
Normal (36.1 through 37.8°C, inclusive)
!
Pulse
Normal (60 through 100 bpm, inclusive)
12.4.
Physical Examination, Pregnancy Testing and B symptoms
The physical examinations will be summarized by each visit.
Pregnancy testing results for female subjects of childbearing potential will be summarized by 
visit.
For B symptoms, shift from Baseline to post baseline assessment will be tabulated.
12.5.
ECOG Performance Status
Shift from baseline during study in ECOG performance status will be displayed for each 
treatment.
Scores for ECOG performance status are: 0 = fully active; 1 = restricted activity but ambulatory;
2 = ambulatory but unable to carry out work activities; 3 = capable of only limited self-care;
4 = completely disabled; 5 = death.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
46
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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Celgene Corporation
Confidential and Proprietary
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
48
14.
INTERIM ANALYSIS
One interim analysis is planned at 50% of information (96 events) for futility only. An external 
IRC will review all the disease progression events at the time of interim and final analyses. For 
the interim analysis, the date of the approximate 96th event, as determined by the IRC, will be 
used as the data cutoff date. The results of the interim analysis will be reviewed by the 
independent external DMC.
A conditional power approach is used for futility analysis; if the interim analysis shows less than 
25% conditional power for success, the trial may stop for futility. 
A stratified log-rank test of IRC reviewed PFS data with censoring rule listed as primary analysis 
will be performed on the ITT population at the Interim analysis, and its p-value will be compared 
with the futility boundary. 
The 25% conditional power is equivalent to a one-sided p-value of 0.579 under the design hazard 
ratio without binding. If the one-sided p-value is ≤ 0.579 at the interim analysis, the trial should 
continue until the required 193 PFS events in the ITT population are observed.
If the one-sided p-value is > 0.579 at the interim analysis, 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 can continue, if so desired, to the final analysis for efficacy without inflating the Type 1 
error or losing power.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
Confidential and Proprietary
49
15.
REFERENCES
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, et al.  Report of an international 
workshop to standardize response criteria for non-Hodgkins lymphomas. J Clin Oncol 1999; 
17:1244
Cheson B, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J 
Clin Oncol. 2007; 25: 579-86.
EMA Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man
(CHMP/EWP/205/95 Rev.4): methodological considerations for using progression-free survival 
(PFS) or disease-free survival (DFS) in confirmatory trials (EMA/CHMP/27994/2008/Rev.1). 
2013.
FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, FDA/CDER/CBER. May 2007. 
Salles G et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular 
lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised 
controlled trial.  Lancet , 2011; 377: 42 – 51.
 
 
Ulm K. (1990) A simple method to calculate the confidence interval of a standardized mortality 
ratio. American Journal of Epidemiology, 131(2):373-375.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
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50
16.
APPENDICES
16.1.
Date Imputation Guideline
16.1.1.
Impute Missing Adverse Event / Prior or Concomitant Medications Start Dates
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.
Missing month with non-missing year
!
If the year is same as the year of 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 prior to the year of first day on study medication, then 31 December  
will be assigned to the missing fields.
!
If the year is after the year of first day on study medication, then 01 January  will be 
assigned to the missing fields.
Missing day only 
!
If the month and year are same as the year and month of 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 before the year and month of 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 after the year and month of first day on study medication, 
then the first day of the month will be assigned to the missing day.
Missing year
!
Not imputed. Included as TEAE.
16.1.2.
Impute Missing Adverse Event / Prior or Concomitant Medications Stop Dates
If the imputed stop date is before the start date then the imputed stop date will be equal to the 
start date.
Missing month with non-missing year
!
If the year of the incomplete stop date is the same as the year of the last dose date of 
study medication, then the day and month of the last dose date will be assigned to the 
missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dose date of 
study medication, then 31 December will be assigned to the missing fields. 
!
If the year of the incomplete stop date is after the year of the last dose date of study
medication, then January 1 will be assigned to the missing fields.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-NHL-007
Celgene Corporation
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51
Missing day only 
!
If the month and year of the incomplete stop date are the same as the month and year 
of the last dose date of study medication, then the day of the last dose date will be 
assigned to the missing day. 
!
If the month and year of the incomplete stop date are before the month and year of 
the last dose date of the study medication, then the last day of the month will be 
assigned to the missing day. 
!
If the month and year of the incomplete stop date are after the month and year of the 
last dose date of study medication, then the first day of the month will be assigned to 
the missing day.
Missing year
!
Not imputed. 
16.1.3.
Impute Missing Disease Diagnosis Dates
!
For partial diagnosis dates, January will be assigned to the missing month; and the 
first day of the month will be assigned to the missing day.
16.1.4.
Impute Missing Dates in Prior Anti-lymphoma Regimen
!
For each prior anti-lymphoma regimen, the regimen start/stop date, will be collected. 
If the day of any date is missing, then the first day of the non-missing month will be 
assigned to the missing day; if month or year of the date is missing, then the date will 
not be imputed and treated as missing.
16.1.5.
Impute Missing Dates in Subsequent Antilymphoma Therapy:
!
Patients will be allowed to take other anti-lymphoma therapy after discontinuation
from the study. The anti-lymphoma therapy start/stop date will be collected. If the 
day of any date is missing, then the last day of the non-missing month will be 
assigned to the missing day; if day and month are both missing, then 31 December of 
the non-missing year will be assigned to the missing day. If the imputed date is later 
than the last date known alive, the last date known alive will be used.
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