Clinical trial NCT01996865
Conditions: Lymphoma, Non-Hodgkin
Keywords: Lymphoma, Mantle cell Lymphoma, Follicular Lymphoma, Marginal zone Lymphoma, Lenalidomide treatment, rituximab treatment, Non Hodgkins Lymphoma
Sponsor: Celgene
Start date: 2014-04-01; Completion date: 2024-09-17
Enrollment: 503 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL) are distinct histologic types of B-cell NHL. Lenalidomide is an immunomodulatory agent with direct and immune-mediated mechanisms of action, as well as clinical activity in NHL. Recent studies in frontline and relapsed/refractory NHL show high activity for lenalidomide plus rituximab (R2), supporting further study of this combination.

Detailed description:
MAGNIFY (NCT01996865) is a phase 3b, multicenter, open-label study of patients with grades 1-3b or transformed follicular lymphoma (FL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL) who received ≥1 prior therapy and had stage I-IV, measurable disease. \~500 patients are planned for enrollment in 12 cycles of R2 induction, with a projected \~314 patients with ≥SD after induction randomized (1:1) to two maintenance arms. Induction includes oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus IV rituximab 375 mg/m2, days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Patients are then randomized to maintenance lenalidomide 10 mg/day, d1-21/28, cycles 13-30, plus rituximab 375 mg/m2, day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (R2, Arm A), or rituximab alone (same schedule, Arm B). Patients receiving R2 maintenance after 18 cycles may continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (per patient and/or investigator discretion), until disease progression as tolerated. The primary endpoint is progression-free survival (per modified 1999 IWG criteria). Secondary endpoints include safety, overall survival, response rates, duration of response, and quality of life (exploratory). Patients will be followed for ≥5 years after the last patient initiated induction therapy. Enrollment in MAGNIFY began in March 2014; as of Jan 2016, 133 patients are enrolled.

Arms: arm 1: Induction Period (12 cycles): Lenalidomide 20mg (10 mg if creatinine clearance ≥ 30 mL/min but \< 60mL/min) by mouth (PO) daily (QD) on Days 1 to 21 of every 28-day cycle during cycles 1 through 12 and rituximab 375mg/m\^2 intraveneously (IV) every week in Cycle 1 on Days 1, 8, 15, and 22 and on Day 1 of every 28-day cycle during cycles 3, 5, 7, 9, and 11, followed by a Maintenance Period (lasting 18 Cycles) that includes Lenalidomide 10 mg PO QD on Days 1 to 21 of every 28-day cycle during cycles 13 to 30 and rituximab 375 mg/m\^2 IV on Day 1 of every 28-day cycle during cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 followed by an optional Maintenance Period (up to Progressive Disease) receiving Lenalidomide 10mg PO QD on Days 1 through 21 of every 28 day cycle until the disease progresses arm 2: Induction Period (12 Cycles): Lenalidomide 20 mg PO QD (10 mg if creatinine clearance ≥ 30 mL/min but \< 60 mL/min) on Days 1 to 21 of every 28-day cycle during cycles 1 to 12 and rituximab 375 mg/m\^2 IV every week in cycle 1 on Days 1, 8, 15, and 22 and on Day 1 of every 28-day cycle during cycles 3, 5, 7, 9, and 11, followed by a Maintenance Period for 18 Cycles that includes: Rituximab 375 mg/m\^2 IV on Day 1 of every 28-day cycle during cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29
Interventions: intervention 1: Lenalidomide intervention 2: Rituximab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Official Title of Study: 
A PHASE 3B RANDOMIZED STUDY OF LENALIDOMIDE (CC-5013) PLUS 
RITUXIMAB MAINTENANCE THERAPY FOLLOWED BY LENALIDOMIDE SINGLEAGENT 
MAINTENANCE VERSUS RITUXIMAB MAINTENANCE IN SUBJECTS WITH 
RELAPSED/REFRACTORY FOLLICULAR, MARGINAL ZONE OR MANTLE CELL 
LYMPHOMA 
The “MAGNIFY” Trial 
 
NCT Number: NCT01996865 
Document Date (Date in which document was last revised): 11 September 2022 
 
 
 


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
A PHASE 3B RANDOMIZED STUDY OF LENALIDOMIDE (CC-5013) PLUS 
RITUXIMAB MAINTENANCE THERAPY FOLLOWED BY LENALIDOMIDE SINGLE-
AGENT MAINTENANCE VERSUS RITUXIMAB MAINTENANCE IN SUBJECTS WITH
RELAPSED/REFRACTORY FOLLICULAR, MARGINAL ZONE OR MANTLE CELL 
LYMPHOMA
The “MAGNIFY” Trial
INVESTIGATIONAL PRODUCT (IP):
Lenalidomide (CC-5013)
PROTOCOL NUMBER:
CC-5013-NHL-008
COMPOUND NUMBER:
CC-5013 (BMS-986380)
ORIGINAL DATE FINAL:
27 August 2013
AMENDMENT 1 FINAL:
16 January 2014
AMENDMENT 2 FINAL:
24 February 2015
AMENDMENT 3 FINAL:
27 August 2019
AMENDMENT 4 FINAL:
03 November 2020
AMENDMENT 5 FINAL:
11 September 2022
EudraCT NUMBER:
NA
IND NUMBER:
060100
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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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:      
Title:        
 
Address:  86 Morris Ave., Summit, NJ, 07901, USA
Phone:     
E-mail:     
Contact Information:
Name:      
Title:        
Address:  86 Morris Ave., Summit, NJ, 07901, 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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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study site 
and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies.
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good Clinical 
Practices guidelines and agree to offer guidance throughout the study as needed.
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 5:
Considering the current rate of progression-free survival (PFS) events, which is slower than 
originally predicted, 
 the challenging follow-up of subjects in the 
context of the coronavirus disease 2019 pandemic,
 
191 PFS events
 
. The final analysis is now planned to be completed at 114 PFS events.
Upon confirmation of 114 PFS events, the remaining subjects on trial will be followed for 5 years
after the last subject has initiated induction therapy to meet the safety reporting requirements as 
outlined in the study.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 5
Section Number & Title
Description of Change
Brief Rationale
Title Page
Protocol Summary
Section 1.4: Lenalidomide
Added Bristol-Myers Squibb
Company (BMS) Compound Number 
CC-5013 (BMS-986380).
For clarification purposes.
Medical Monitor/Emergency Contact 
Information
Updated contact information for 
Medical Monitor/Emergency Contact.
 has transitioned off 
the study and 
 has taken over 
this role. 
Protocol Summary
Figure 1: Overall Study Design
Section 4.3: Study Duration
Table 1: Schedule of Study Assessments
Section 6.2.2: Second Primary 
Malignancies
Section 10.3: Sample Size and Power 
Considerations
Section 10.6.1: Primary Efficacy 
Endpoint
Updated to 114 progression-free 
survival (PFS) events instead of 191 
PFS events for the primary efficacy 
endpoint.
 
 
 
.
Protocol Summary
Section 4.3: Study Duration
Section 10.3: Sample Size and Power 
Considerations
Updated study duration period.
For clarification purposes to align with 
the extended study timeline.
Section 4.1.4: Randomization to 
Maintenance Treatment Period
Section 4.3: Study Duration
Added that all subjects who will be 
on treatment upon reaching 5 years 
after the last subject has initiated 
induction therapy
 
will continue the treatment 
and be followed up for safety 
purposes only.
For clarification purposes. Subjects will 
no longer be followed for efficacy upon 
reaching 114 PFS events, only safety 
purposes.
Section 4.1.6: Follow-up Period Upon 
Confirmation of 114 PFS Events
New section added.
This section has been included to clarify 
the required follow-up information to be 
collected after 114 PFS events are 
reached.
Section 4.1.6: Follow-up Period Upon 
Confirmation of 114 PFS Events
Section 6.2.2: Second Primary 
Malignancies
Added that 
 
 
.
To clarify visit frequency and duration of 
the follow-up period after the 
confirmation of 114 PFS events.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 5
Section Number & Title
Description of Change
Brief Rationale
Table 1: Schedule of Study Assessments

Added new column: 
 
 
.

Added footnote that upon 
confirmation of 114 PFS events 
achieved, no more computed 
tomography scans, 
 
response assessment, and 
subsequent anti-lymphoma 
therapies will be performed.
For clarification purposes of the required 
follow-up information to be collected 
after confirmation of 114 PFS events.
Table 1: Schedule of Study Assessments
Section 12.2: Study Discontinuation and 
Completion

Updated “At Treatment 
Discontinuation” column to “At 
Treatment 
Discontinuation/Completion.”

Updated section title and 
description of when subjects will 
be discontinued and off boarded 
from the study.
For clarification purposes of the required 
follow-up information to be collected 
after 114 PFS events are reached and 
timelines for discontinuation of subjects 
from the trial after 114 PFS events are 
reached.
Section 6.3: Efficacy Assessments
Added that scan results will be
assessed by the Investigator or 
qualified site personnel.
For clarification purposes as to who the 
assessor of scan results will be.
Section 6.3: Efficacy Assessments
Section 6.3.1: Subsequent 
Anti-lymphoma Therapy
 
Added that after confirmation of 114 
PFS events, no efficacy assessments 
will be conducted.
For clarification purposes of the required 
follow-up information to be collected 
after confirmation of 114 PFS events.
Section 10.3: Sample Size and Power 
Considerations
Added power calculation for 114 PFS 
events.
To provide additional information, ie 
power corresponding to the updated final 
analysis.
Section 10.6.2: Secondary Efficacy 
Endpoint
Added that overall survival (OS) rate 
will be collected for 5 years from the 
date of the last subject initiating 
induction therapy.
To support supplementary analysis of OS 
if needed.
Section 10.6.4: Analysis Methods
Updated the desired significance level 
for the Time-to-Event Endpoints.
To clarify that the significance level for 
the primary analysis needs to be adjusted 
due to the interim analysis.
Section 10.8: Interim Analysis
Added: “To ensure the overall 
1-sided type 1 error remains at 0.025, 
an appropriate amount of alpha will 
be spent for the interim analysis.”
To clarify that type 1 error for final 
analysis will be adjusted to preserve the 
overall type 1 error rate for the study.
All
Minor formatting and typographical 
corrections.
Minor, therefore, have not been 
summarized.
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Final: 11 Sep 2022
PROTOCOL SUMMARY
Study Title
A Phase 3b randomized study of lenalidomide (CC-5013, also known as BMS-986380) plus 
rituximab maintenance therapy followed by lenalidomide single-agent maintenance versus 
rituximab maintenance in subjects with relapsed/refractory follicular, marginal zone or mantle cell 
lymphoma.
Indication
Relapsed/refractory follicular lymphoma grades 1-3b, transformed follicular lymphoma, marginal 
zone lymphoma or mantle cell lymphoma.
Objectives
To compare the efficacy and safety of lenalidomide plus rituximab combination maintenance
therapy (for 18 cycles) followed by optional lenalidomide single-agent maintenance (to 
progression) versus rituximab single-agent maintenance (for 18 cycles) after 12 cycles of induction 
therapy with lenalidomide plus rituximab, in subjects with relapsed/refractory follicular lymphoma
grades 1-3b, transformed follicular lymphoma, marginal zone lymphoma or mantle cell 
lymphoma.
Study Design
This Phase 3b
multicenter, randomized, open-label study will enroll subjects with 
relapsed/refractory follicular lymphoma grades 1-3b, transformed follicular lymphoma, marginal 
zone lymphoma or mantle cell lymphoma. All subjects enrolled will receive 12 cycles of 
lenalidomide plus rituximab induction therapy. 
The study is designed to compare the efficacy and safety of two maintenance regimens following 
the induction therapy. Subjects who have stable disease (SD), partial response (PR), unconfirmed 
complete response (CRu) or complete response (CR) at the end of 12 cycles of induction therapy 
will be randomized to one of two maintenance arms: Arm A (experimental) or Arm B (control). 
Subjects randomized to Arm A will receive lenalidomide plus rituximab combination maintenance
therapy (for 18 cycles) followed by optional lenalidomide single-agent maintenance (to 
progression).  Subjects randomized to Arm B will receive rituximab single-agent maintenance (for 
18 cycles). 
Subjects will be stratified at time of randomization to the maintenance arm by histology, lines of 
anti-lymphoma therapy, and age.
The overall study design is described in Figure 1. The study is divided into a Screening Period, a 
Treatment Period (induction and maintenance), and a Follow-up Period. Approximately 
500 subjects are planned to be enrolled.
Upon giving written informed consent, a subject will enter the Screening Period and undergo safety 
and other assessments to determine eligibility for the study. All Screening assessments must be 
completed within 28 days prior to the subject initiating induction therapy.
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Subjects enter the Induction Treatment Period at the time they complete screening procedures and 
meet all eligibility criteria. Eligible subjects entering the Induction Treatment Phase will be 
enrolled using an Interactive Voice Response System (IVRS). The treatments will be given as 
described in detail in Section 8 and must begin no later than 1 week after enrollment in IVRS to 
receive induction therapy. Cycle length during induction and maintenance is 28 days.
Subjects may discontinue treatment earlier than described if they experience relapse or disease 
progression, unacceptable toxicity, or withdrawal of consent. All subjects who discontinue 
treatment or complete treatment will be followed for disease progression, subsequent 
anti-lymphoma therapy, and second primary malignancies (SPMs) for 5 years after the last subject 
has initiated induction therapy. Upon confirming 114 PFS events, all subjects who discontinue 
treatment or complete treatment will be followed for SPMs and overall survival for 5 years after 
the last subject has initiated induction therapy.
Assessments during the Screening, Treatment and Follow-up period are described in Table 1.
Efficacy determination for the primary endpoint will be based upon progression-free survival 
(PFS). See Section 10 for a description of the Statistical Analyses.
An independent external Data Monitoring Committee (DMC) will review safety data in an 
ongoing, periodic manner throughout the study. The frequency of DMC meetings will be 
documented in the DMC Charter.
The study will be conducted in compliance with Good Clinical Practices (GCPs).
Study Population
Subjects must have an investigator-assessed diagnosis of relapsed/refractory follicular lymphoma 
(FL) Grades 1, 2, 3a, or 3b(Gr 1-3b), transformed follicular lymphoma (tFL), marginal zone 
lymphoma (MZL), or mantle cell lymphoma (MCL), Stages I to IV, have been previously treated 
for their lymphoma with at least one prior line of therapy, have at least one measurable nodal or 
extranodal lesion by computed axial tomography (CT) or magnetic resonance imaging (MRI) scan, 
and have adequate bone marrow function, liver function, and renal function.
Length of Study
The expected accrual duration for 500 subjects is approximately 63 months. Subjects will receive
protocol-specified treatment until relapse or progression of disease, withdrawal of consent or 
unacceptable toxicity. The study duration to events for primary analysis is estimated to be 105
months. The duration of the entire study will be approximately 10 years (accrual period of 
approximately 5 years plus 5 years from last subject initiating induction therapy).
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 
 analyses, as pre-specified in the protocol and/or the Statistical 
Analysis Plan, whichever is the later date.
Study Treatments, please see Section 8.2 for details including dose adjustments for renal 
insufficiency
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Final: 11 Sep 2022

Induction Period (12 Cycles)
Lenalidomide 20 mg once daily on Days 1 to 21 of every 28-day Cycle AND rituximab 375 
mg/m2 intra-venous (IV) every week in Cycle 1 (Days 1, 8, 15, and 22) and Day 1 of every 
other Cycle (Cycle 3, 5, 7, 9, 11)
Followed by Maintenance Period

Arm A (Experimental arm):  Lenalidomide + rituximab (Maintenance) followed by optional 
lenalidomide (Maintenance)

Maintenance Period (18 Cycles)
Lenalidomide 10 mg once daily on Days 1 to 21 of every 28-day Cycle (Cycle 13 through 
30) AND rituximab 375 mg/m2 IV on Day 1 of every other Cycle up to Cycle 30 (Cycles 
13, 15, 17, 19, 21, 23, 25, 27, 29).
Followed by

Optional Maintenance Period (up to PD)
Lenalidomide 10 mg once daily on Days 1 to 21 of every 28-day Cycle. This treatment will 
be at the discretion of the subject and/or the investigator.
VERSUS

Arm B (Control arm):  Rituximab (Maintenance)

Maintenance Period (18 Cycles)
Rituximab 375 mg/m2 IV on Day 1 of every other Cycle up to Cycle 30 (Cycles 13, 15, 
17, 19, 21, 23, 25, 27, 29)
Overview of Efficacy Assessments
The International Working Group (IWG) 1999 response criteria (Cheson, 1999) for malignant 
lymphoma, modified to allow the inclusion of extranodal disease as measurable disease will be 
utilized for efficacy determination to assess response and progression. In addition to CT/MRI scan 
to assess disease, subjects with MZL involving the gastric area will undergo endoscopy as part of 
the response assessment.
The efficacy endpoints include:
1) Progression Free Survival (PFS)
2) Overall Survival (OS)
3) Improvement of Response (IOR)
4) Overall response rate (ORR)
including partial response (PR), complete response 
(CR)/complete response unconfirmed (CRu) and CR/CRu rate (CRR)
5) Duration of response (DOR), duration of CR/CRu (DOCR)
6) Time to next anti-lymphoma treatment (TTNLT)
7) Time to histological transformation (TTHT)
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Overview of Safety Assessments
Safety will be monitored throughout the study. Safety evaluations will include adverse event (AE) 
reporting, second primary malignancies (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. 
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 informed consent document (ICD) for 5 years 
from the date the last subject initiated induction therapy. 
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.
Once the 114 PFS events are confirmed, the follow-up period will continue for 5 years after the 
last subject has initiated induction therapy, and all subjects who are in the follow-up period will 
be deemed as completed and will be off boarded from the study 
.
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Final: 11 Sep 2022
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 5:...............................................6
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 5 ...................................6
PROTOCOL SUMMARY ..........................................................................................................8
TABLE OF CONTENTS..........................................................................................................12
LIST OF TABLES....................................................................................................................16
LIST OF FIGURES ..................................................................................................................17
1
INTRODUCTION..................................................................................................18
1.1
Follicular Lymphoma .............................................................................................18
1.1.1
Therapy in Relapsed/Refractory Follicular Lymphoma...........................................19
1.2
Mantle Cell Lymphoma ..........................................................................................20
1.2.1
Therapy in Relapsed/Refractory Mantle Cell Lymphoma ........................................21
1.3
Marginal Zone Lymphoma .....................................................................................21
1.3.1
Therapy in Relapsed/Refractory Marginal Zone Lymphoma ...................................22
1.4
Lenalidomide..........................................................................................................22
1.5
Preclinical Studies of Lenalidomide and Rituximab in Lymphoma .........................23
1.6
Clinical Studies of Single-Agent Lenalidomide and Rituximab plus 
Lenalidomide in FL, MZL, and MCL .....................................................................24
1.6.1
Follicular Lymphoma .............................................................................................24
1.6.2
Marginal Zone Lymphoma......................................................................................27
1.6.3
Mantle Cell Lymphoma...........................................................................................27
1.7
Lenalidomide as Maintenance Therapy...................................................................29
2
STUDY OBJECTIVES...........................................................................................31
2.1
Primary Objective...................................................................................................31
2.2
Secondary Objectives .............................................................................................31
...........................................................................................31
3
STUDY ENDPOINTS............................................................................................32
3.1
Primary Endpoint....................................................................................................32
3.2
Secondary Endpoints ..............................................................................................32
.........................................................................................32
4
OVERALL STUDY DESIGN ................................................................................33
4.1
Study Design ..........................................................................................................33
4.1.1
Screening Period ....................................................................................................33
4.1.2
Induction and Maintenance Period.........................................................................33
4.1.3
Enrollment in Induction Treatment Period..............................................................33
4.1.4
Randomization to Maintenance Treatment Period...................................................34
4.1.5
Follow-up Period....................................................................................................34
4.1.6
Follow-up Period Upon Confirmation of 114 PFS Events.......................................34
4.2
Study Design Rationale ..........................................................................................34
4.3
Study Duration .......................................................................................................38
4.4
End of Trial ............................................................................................................38
5
TABLE OF EVENTS.............................................................................................39
6
PROCEDURES......................................................................................................45
6.1
Study Entry.............................................................................................................45
6.1.1
Informed Consent Document...................................................................................45
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6.1.2
Inclusion and Exclusion Criteria ............................................................................45
6.1.3
Demographic Data .................................................................................................45
6.1.4
Lymphoma and Complete Medical History .............................................................45
6.1.5
Bone Marrow Biopsy ..............................................................................................45
6.1.6
Endoscopy and Gastric Biopsy ...............................................................................46
6.1.7
Central Nervous System Lymphoma........................................................................46
6.1.8
Lenalidomide Dosing - Creatinine Clearance (Cockcroft-Gault Estimation)...........46
6.1.9
12-Lead Electrocardiogram....................................................................................46
6.1.10
Hepatitis B..............................................................................................................46
6.2
Safety Assessments.................................................................................................47
6.2.1
Adverse Events .......................................................................................................47
6.2.2
Second Primary Malignancies ................................................................................47
6.2.3
Birth Control and Lenalidomide Counseling...........................................................47
6.2.4
Study Drug Return/Accountability ..........................................................................48
6.2.5
Prior and Concomitant Medications, Procedures and Hospitalizations...................48
6.2.6
Physical Examination .............................................................................................48
6.2.7
Eastern Cooperative Oncology Group (ECOG) Performance Status.......................48
6.2.8
B Symptoms............................................................................................................48
6.2.9
Vital Signs ..............................................................................................................48
6.2.10
Clinical Laboratory Safety Tests.............................................................................48
6.2.10.1
Hematology ............................................................................................................49
6.2.10.2
Serum Chemistry ....................................................................................................49
6.2.10.3
Thyroid Stimulating Hormone.................................................................................50
6.2.11
Assessments for Tumor Flare..................................................................................50
6.2.12
Assessments for Tumor Lysis ..................................................................................51
6.2.13
Deep Vein Thrombosis............................................................................................52
6.2.13.1
Deep Vein Thrombosis in Multiple Myeloma...........................................................52
6.2.13.2
Deep Vein Thrombosis in Non-Hodgkin Lymphoma................................................53
6.3
Efficacy Assessments .............................................................................................54
6.3.1
Subsequent Anti-lymphoma Therapy.......................................................................55
.................................................55
..............................................................................................................55
7
STUDY POPULATION.........................................................................................57
7.1
Number of Subjects and Sites .................................................................................57
7.2
Inclusion Criteria....................................................................................................57
7.3
Exclusion Criteria...................................................................................................58
8
DESCRIPTION OF STUDY TREATMENTS........................................................61
8.1
Description of Investigational Product(s)................................................................61
8.2
Treatment Administration and Schedule .................................................................61
8.2.1
Lenalidomide Therapy............................................................................................62
8.2.2
Rituximab Therapy .................................................................................................62
8.2.3
Lenalidomide Therapy in Maintenance...................................................................63
8.2.4
Dose Modification or Interruption ..........................................................................63
8.2.4.1
Overdose ................................................................................................................63
8.2.4.2
Dose Modification or Interruption for Lenalidomide...............................................63
8.2.4.3
Dose Reduction Levels Based on Lenalidomide Starting Dose ................................68
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8.2.4.4
Dose Reduction Levels Based on Lenalidomide Maintenance Starting Dose ...........69
8.2.4.5
Dose Adjustment for Rituximab...............................................................................70
8.3
Method of Treatment Assignment...........................................................................70
8.4
Packaging and Labeling..........................................................................................70
8.5
Investigational Product Accountability and Disposal ..............................................70
8.6
Investigational Product Compliance........................................................................71
9
CONCOMITANT MEDICATIONS AND PROCEDURES....................................72
9.1
Permitted Concomitant Medications and Procedures...............................................72
9.1.1
Tumor Flare Reaction Treatment............................................................................72
9.1.2
Thromboembolism Prophylaxis...............................................................................72
9.1.3
Growth Factors ......................................................................................................72
9.2
Prohibited Concomitant Medications and Procedures..............................................73
9.3
Required Concomitant Medications and Procedures................................................73
9.3.1
Tumor Lysis Syndrome Prophylaxis........................................................................73
9.3.2
Rituximab Premedication........................................................................................73
10
STATISTICAL ANALYSES..................................................................................74
10.1
Overview................................................................................................................74
10.2
Study Population Definitions ..................................................................................74
10.3
Sample Size and Power Considerations...................................................................75
10.4
Background and Demographic Characteristics........................................................76
10.5
Subject Disposition.................................................................................................76
10.6
Efficacy Analysis....................................................................................................76
10.6.1
Primary Efficacy Endpoint......................................................................................76
10.6.2
Secondary Efficacy Endpoint..................................................................................76
..............................................................................78
10.6.4
Analysis Methods....................................................................................................79
10.7
Safety Analysis.......................................................................................................79
10.8
Interim Analysis .....................................................................................................80
10.9
Other Topics...........................................................................................................80
11
ADVERSE EVENTS..............................................................................................81
11.1
Monitoring, Recording and Reporting of Adverse Events .......................................81
11.2
Evaluation of Adverse Events.................................................................................81
11.2.1
Seriousness.............................................................................................................81
11.2.2
Severity / Intensity ..................................................................................................83
11.2.3
Causality ................................................................................................................83
11.2.4
Duration.................................................................................................................84
11.2.5
Action Taken...........................................................................................................84
11.2.6
Outcome .................................................................................................................84
11.3
Abnormal Laboratory Values..................................................................................84
11.4
Pregnancy...............................................................................................................84
11.4.1
Females of Childbearing Potential .........................................................................85
11.4.2
Male Subjects .........................................................................................................85
11.5
Reporting of Serious Adverse Events......................................................................85
11.5.1
Safety Queries ........................................................................................................86
11.6
Expedited Reporting of Adverse Events..................................................................86
12
DISCONTINUATIONS .........................................................................................88
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12.1
Treatment Discontinuation......................................................................................88
12.2
Study Discontinuation and Completion...................................................................88
13
EMERGENCY PROCEDURES.............................................................................89
13.1
Emergency Contact.................................................................................................89
13.2
Emergency Identification of Investigational Products .............................................89
14
REGULATORY CONSIDERATIONS...................................................................90
14.1
Good Clinical Practice............................................................................................90
14.2
Investigator Responsibilities ...................................................................................90
14.3
Subject Information and Informed Consent.............................................................90
14.4
Confidentiality........................................................................................................91
14.5
Protocol Amendments.............................................................................................91
14.6
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................91
14.7
Ongoing Information for Institutional Review Board / Ethics Committee................92
14.8
Closure of the Study ...............................................................................................92
15
DATA HANDLING AND RECORDKEEPING.....................................................93
15.1
Data/Documents .....................................................................................................93
15.2
Data Management...................................................................................................93
15.3
Record Retention....................................................................................................93
16
QUALITY CONTROL AND QUALITY ASSURANCE........................................95
16.1
Study Monitoring and Source Data Verification......................................................95
16.2
Audits and Inspections............................................................................................95
17
PUBLICATIONS ...................................................................................................96
18
REFERENCES.......................................................................................................97
19
APPENDICES......................................................................................................107
...................................................107
19.2
Appendix B:  Ann Arbor Staging..........................................................................110
19.3
Appendix C:  Performance Status Criteria.............................................................111
19.4
Appendix D:  CAIRO - BISHOP DEFINITION OF TUMOR LYSIS 
SYNDROME .......................................................................................................112
19.5
Appendix E:  Response Criteria for NHL..............................................................113
19.5.1
Tumor Assessment by 1999 IWG Criteria for NHL................................................113
19.5.2
Additional Response Assessment in Gastric MALT subjects with Radiological 
Response of at Least a PR by 1999 IWG Criteria..................................................113
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LIST OF TABLES
Table 1:
Schedule of Study Assessments..............................................................39
Table 2:
Dose Modification for Lenalidomide ......................................................64
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........................................................................................68
Table 4:
Dose Modification Steps for Subjects Initiating Treatment at 10 
mg Daily on Days 1 to 21, Every 28 Days ..............................................69
Table 5:
Dose Reduction Steps for Adverse Events Related to Study Drug 
for Subjects Initiating Maintenance Treatment at 10 mg Daily on 
Days 1 to 21, Every 28 Days...................................................................69
Table 6:
Tumor Assessment by 1999 IWG Criteria ............................................113
Table 7:
GELA Histological Scoring System for Evaluation of Gastric 
MALT lymphoma.................................................................................114
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................37
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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 adverse event profile of the 
Investigational Product (IP).
The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
applicable regulatory requirements.
1.1
Follicular Lymphoma
Follicular lymphoma is one of the most common low-Grade non-Hodgkin lymphomas (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, 2011). Follicular lymphoma typically 
follows an indolent course with a median overall survival (OS) of 7 to 10 years. Although FL 
initially responds well to treatment it is characterized by recurrent relapses or progressions with 
progressively shorter intervals in between treatments (Salles, 2007). Transformation to diffuse 
large B-cell lymphoma (DLBCL) and other aggressive lymphoma occurs at a rate of approximately 
2% to 3% per year (Bastion, 1997).
The classification of FL has evolved through major changes over the past century.  The Revised 
European American lymphoma (REAL) classification and the World Health Organization (WHO) 
classification proposed the terms, follicle center cell lymphoma, follicular Grade 1, 2, 3a, and 3b.  
Differences in molecular genetics and clinical behavior suggest that FL Grade 3a is an indolent 
disease and 3b is an aggressive disease.  Investigation of the cellular microenvironment of FL has 
provided interesting insights into prognosis, and the interaction between tumor cells and the 
microenvironment may determine overall clinical behavior (Vaidyanathan, 2014).
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. The 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-Céligny, 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 host immune response in this disease.
A pivotal event in the natural history of FL is histological transformation to more aggressive 
malignancies, most commonly diffuse large B-cell lymphoma (DLBCL).  The reported frequency 
of higher grade FL transformation varies significantly, ranging from 10% to 60% of patients.  
Immunophenotypic and genetic features suggest that Grade 3b FL may be similar to de novo 
DLBCL, however, most clinical studies have not shown a survival difference between Grade 3a 
versus 3b FL.  Transformation is defined as pathologically demonstrated and clonally confirmed 
progression of FL Grades 1, 2, 3a to DLBCL or other high grade morphology; progression from 
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FL Grades 1 and 2 to FL Grade 3a is not considered histologic transformation, but a common 
progression event during the course of therapy (Vaidyanathan, 2014).
1.1.1
Therapy in Relapsed/Refractory Follicular Lymphoma
There is no standard treatment for patients with relapsed/refractory FL. Treatment options include 
radiation, single-agent or combination chemotherapy, single-agent
rituximab, idelalisib, 
rituximab-containing chemotherapy regimens such as BR (bendamustine, rituximab), fludarabine 
plus rituximab, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), 
R-CVP (rituximab, cyclophosphamide, vincristine, prednisone), R-FCM (rituximab, fludarabine, 
cyclophosphamide, mitoxantrone), and radioimmunotherapy or autologous/allogeneic stem cell 
transplant in some selected patients (NCCN guidelines, 2015; Gopal, 2014; Ghielmini, 2013). 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 United States of America (USA), Europe and many other countries 
for treatment of relapsed or refractory FL as a 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 single-agent rituximab in relapsed/refractory FL or other low-grade NHL 
patients, and three multicenter single-arm studies have led to regulatory approval in the USA, 
Europe and other countries (McLaughlin, 1998; Piro, 1999; Davis, 2000a). In some countries, the 
approved number of rituximab doses is four or eight. A recent update of the results from the Swiss 
Group for Clinical Cancer Research (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 an additional 4 maintenance doses every 2 months reported a durable 
response with 35% of responders still in remission at 8 years. 
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, 2004; Van Oers, 2010). Rituximab 
maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months 
with observation. 
The combination of rituximab and bendamustine, an alkylating agent approved in the USA, Europe 
and many other countries for the treatment of rituximab refractory iNHL showed a response rate 
of 90% and a 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 a 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 
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rituximab in relapsed indolent NHL demonstrated a 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).
Other recent efforts have been made to find novel regimens for the treatment of relapsed follicular 
lymphoma that do not contain cytotoxic agents. Such efforts include combinations 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), 
interferons (Davis, 2000b; Sacchi, 2001) granulocyte macrophage colony-stimulating factor 
(GM-CSF) (Cartron, 2008) and IL-12 (Ansell, 2002). 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 a 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).
More recently, idelalisib has been added to the treatment options for relapsed refractory FL (Gopal, 
2014) and the FDA has approved idelalisib as a single agent for use in the treatment of patients 
with follicular lymphoma who have received at least 2 prior systemic therapies. 
The treatment approach for subjects with transformed follicular lymphoma is often individualized, 
as there are no randomized studies in the modern era to guide practice. These patients are often 
excluded from clinical trial participation, therefore there is a paucity of objective data guiding 
optimal management. The literature suggests patients treated with rituximab-containing 
chemotherapy can experience significantly better overall survival compared with other published 
retrospective cohorts of patients treated with chemotherapy alone, who have 5-year OS rates of 
20% to 30%, and median survival ranging between 1 and 2 years.  However, patients receiving 
dose intensification and consolidation seem to have improved outcomes (Casulo, 2014). 
Novel agents have been reported in transformed follicular lymphoma, including a phase 2 study 
using lenalidomide, an immunomodulatory agent, showing an overall response rate of 57%, with 
median response duration of over 1 year in patients with transformed follicular lymphoma 
(Czuczman, 2011). Other drugs inhibiting novel targets, such as Aurora Akinase (alisertib), Bruton
tyrosine kinase (ibrutinib), the delta isoform of phosphatidylinositol 3-kinase (idelalisib), and the 
BCL2 protein (GDC-0199/ABT199), currently being studied in both indolent and aggressive
lymphomas have the potential to significantly impact patients with transformed follicular 
lymphoma (Casulo, 2014). 
1.2
Mantle Cell Lymphoma
Mantle cell lymphoma is a distinct subtype within B-cell type lymphoma originating from the 
mantle zone of the lymph node and is characterized by the overexpression of a member of the 
cyclin D family. Tumors with overexpression of cyclin D1 are associated with the 
t(11;14)(q13;q32) chromosomal translocation (Fernàndez, 2005). In rare cases, overexpression of 
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other cyclin D members is seen (Fu, 2005). MCL accounts for approximately 5% to 10% of all 
lymphomas and usually affects men over the age of 60.
Histologically, the MCL cells appear small with features similar to indolent lymphomas. For this 
reason, MCL was often grouped in the category of indolent lymphoma. However, the discovery of 
a characteristic chromosomal translocation involving the cyclin D1 gene, resulting in its 
unregulated overexpression, led to an improved ability to diagnose MCL and recognition that MCL 
had clinical behavior similar to aggressive lymphomas and has one of the poorest survival rates 
among the lymphomas.
1.2.1
Therapy in Relapsed/Refractory Mantle Cell Lymphoma
For the treatment of patients with newly diagnosed MCL, the National Comprehensive Cancer 
Network (NCCN) NHL guidelines and the recent European Society for Medical Oncology 
(ESMO) consensus suggest that rituximab should be part of any induction chemotherapy regimen 
and also that rituximab maintenance should be offered to all patients responding to frontline
R-chemotherapy (NCCN guidelines, 2015; Dreyling, 2013a). Most physicians have used 
rituximab-containing multi-agent chemotherapy regimens such as R-CHOP, R-HyperCVAD, 
R-DHAP or R-FCM, often supplemented with autologous transplantation for consolidation upon
completion of first-line therapy in younger patients.
Following initial chemotherapy, almost all patients experience relapse of their disease. In subjects 
with MCL who have relapsed after initial therapy, few effective treatment options are available. 
Currently, three agents have received FDA approval for use in this setting. Single agent 
bortezomib was approved in December 2006 for patients who received at least one prior therapy 
based on results from a single-arm trial.  The reported objective response rate (ORR) in 155 
patients was 31%, including 8% of patients achieving a complete remission (CR + CRu), median 
duration of response (DOR) was 9.3 months, and a median overall survival (OS) was 23.5 months 
(Goy, 2009; Velcade PI, 2014). Lenalidomide was approved in July 2013 for patients whose 
disease relapsed or progressed after two prior therapies, one of which included bortezomib. Single-
agent lenalidomide approval was based on results from a single-arm trial (n = 134) resulting in an 
ORR of 26% that included 7% of patients who achieved a CR/CRu and median DOR of 16.6 
months (Revlimid PI, 2014; Goy, 2013). More recently, single-agent ibrutinib was approved for 
MCL after one prior therapy based on results from a single-arm trial (n = 111) resulting in an ORR 
of 68% that included 21% of patients achieving a CR, and median DOR 17.5 months with OS not 
yet reached (Imbruvica PI, 2014; Wang, 2013a).
1.3
Marginal Zone Lymphoma
Marginal Zone Lymphoma is a distinct histology within the category of B-cell lymphomas, 
constituting approximately 8% of NHLs. 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 (NMZL). Although these subtypes of B-cell 
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lymphoma share morphologic, immunophenotypic and genetic characteristics, there are also 
important differences in their frequency, clinical presentation, and pathogenesis.
Extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue 
(MALT-lymphoma) is most common and accounts for 8% of all newly diagnosed lymphomas 
(Isaacson, 2008) and for approximately 70% of all MZLs; splenic MZL accounts for 
approximately 20% 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 Sjögren 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, 2011). In early stage disease, 
treatment of the underlying infection is the treatment of choice.
Splenic MZL patients present with an enlarged spleen, as well as 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 have lymph node-based disease without involvement of the spleen or 
extranodal sites. The molecular pathogenesis of nodal MZL is not understood.
1.3.1
Therapy in Relapsed/Refractory Marginal Zone Lymphoma
In patients who have relapsed after initial treatment, rituximab alone or in combination with 
cytotoxic agents is often used. Advanced stage disease and relapsed disease requiring systemic 
treatment is managed like follicular lymphoma - rituximab with or without chemotherapy, being 
the preferred option (NCCN guidelines, 2015; Dreyling, 2013a). Nodal MZL is also treated like
follicular lymphoma, although no studies of large series have been published so far in this type of 
MZL.
Combination therapy with rituximab and fludarabine is a very active treatment as the initial 
systemic treatment for patients with extranodal MALT lymphoma (Salar, 2009). Treatment of 
splenic MZL patients with rituximab (either alone or in combination with chemotherapy) has 
shown a high response rate (Bennett, 2010).
1.4
Lenalidomide
Lenalidomide is the lead member of a proprietary series of drugs with immunomodulatory and 
other properties, referred to as the IMiD®s class of compounds, and is also sometimes referred to 
as CDC-501 and CC-5013 (also known as BMS-986380), as well as the registered name 
REVLIMID®. 
Lenalidomide offers potential benefit over 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 
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multiple mechanisms of action in vitro, which act to produce both anti-inflammatory 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 Tumor Necrosis Factor alpha (TNF-α)
inhibitory, T-cell costimulatory, and antiangiogenic activities (Galustian, 2004).
Lenalidomide is approved in the USA for the treatment of patients with MCL whose disease has 
relapsed or progressed after two prior therapies, one of which included bortezomib. Lenalidomide 
is also approved in the USA for the treatment of patients with transfusion-dependent anemia due 
to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or 
without additional cytogenetic abnormalities and in the EU for the treatment of patients with 
transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes 
associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are 
insufficient or inadequate. Lenalidomide is also approved worldwide, in combination with 
dexamethasone, for the treatment of patients with multiple myeloma who had been treated with at 
least one prior therapy. Lenalidomide is being investigated as a treatment for various hematologic 
and oncologic indications.
1.5
Preclinical Studies of Lenalidomide and Rituximab in Lymphoma
Lenalidomide is an immunomodulatory agent that has both direct tumoricidal and 
immunomodulatory activities that are likely important for its clinical activity in the treatment of 
various hematologic malignancies. This activity is at least in part mediated by an 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 been shown to augment 
ADCC mainly by increasing CD16 expression on NK cells (Zhang, 2009). In a murine NHL 
model, lenalidomide induced a significant increase in the recruitment of NK cells to tumor sites 
resulting in enhanced anti-tumor activity of rituximab (Reddy, 2007). 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 follicular lymphoma (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). Lenalidomide treatment induced actin 
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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 the rituximab-lenalidomide 
combination described in this clinical trial protocol.
1.6
Clinical Studies of Single-Agent Lenalidomide and Rituximab plus 
Lenalidomide in FL, MZL, and MCL
1.6.1
Follicular Lymphoma
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 a 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 the previous therapy. ORR was 23% (10 of 43), including a 7% complete response (CR) or 
unconfirmed (CRu) rate. Twenty-seven percent (6 of 22) of patients with follicular lymphoma 
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% Confidence Interval 
(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).
In 2011,Witzig et al published the results of an international multi-center single-arm phase 2 trial 
(Witzig, 2011). This trial aimed to demonstrate the safety and efficacy of lenalidomide in patients 
with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma 
(MCL), follicular grade 3 lymphoma (FL-3), or transformed lymphoma (TL). Two hundred and 
seventeen patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13% 
(29/217) complete remission (CR), 22% (48/217) partial remission, and 21% (45/217) with stable 
disease. The ORR for FL-3 was 42% (8/19) with CR/CRu rate of 11%. The ORR for TL was 45% 
(15/33) with CR/CRu rate of 21%. In this trial patients with TL achieved median PFS of 5.4 months 
with median duration of response (DOR) of 12.8 months. In patients with FL-3, median PFS was 
8.9 months and median DOR was not achieved at time of publication. The most common adverse 
events were myelosuppression with grade 4 neutropenia and thrombocytopenia in 17% and 6% of 
subjects, respectively.
Leonard et al (Leonard, 2012) reported results from a randomized Phase 2 clinical trial conducted 
by the US cooperative group Cancer and Leukemia Group B (CALGB) evaluating 
rituximab-lenalidomide combination therapy versus single-agent lenalidomide in patients with 
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recurrent FL who had prior therapy with rituximab alone or in combination, and with a time to 
progression of ≥ 6 months from last rituximab dose. Ninety-four patients were enrolled to receive 
either lenalidomide (N = 45) or lenalidomide and rituximab combined (N = 44). Baseline 
characteristics included median age 63 (range, 34 to 85) and intermediate- or high-risk FLIPI (60% 
of patients). Grade 3 or 4 AEs were similar in both arms (49% lenalidomide, 52% lenalidomide 
and rituximab combination) with 9% of patients experiencing Grade 4 events in both arms. The 
most common Grade 3 or 4 events were neutropenia (16% lenalidomide, 19% lenalidomide and 
rituximab combination), fatigue (9% lenalidomide, 14% lenalidomide and rituximab 
combination), and thrombosis (16% [7 patients] lenalidomide, 4% [2 patients] lenalidomide and 
rituximab combination, p = 0.158). The treatment regimen was completed in 33% (lenalidomide) 
and 59% (lenalidomide and rituximab combination) of patients, with the difference due to more 
progressions or non-responders in the lenalidomide alone group. In both arms about 19% of 
patients discontinued therapy early due to adverse events (AEs) and relative dose intensity was 
over 80%. Objective response rates were 49% (13% CR) for lenalidomide and 75% (32% CR) for 
lenalidomide plus rituximab. With a median follow-up of 1.5 years (range, 0.1 to 3.6 years), 
median event free survival (EFS) was 1.2 years (lenalidomide) and 2.0 years (lenalidomide and 
rituximab).
The results of this study are further supported by findings from two smaller single institution 
studies reported by Dutia et al (Dutia, 2010) and Ahmadi et al (Ahmadi, 2011). Dutia et al (Dutia, 
2010) conducted a clinical trial of the combination of rituximab and lenalidomide in 16 patients 
with relapsed/refractory indolent lymphoma. Of the 16 patients, 13 had FL. In this subset of FL 
patients, the ORR was 85% and CR/CRu was achieved in 5 patients (38%). Ahmadi et al (Ahmadi, 
2011) reported the results from a Phase 2 trial of lenalidomide-dexamethasone-rituximab (Cohort 
1) and lenalidomide-rituximab (Cohort 2) in patients with indolent B-cell or mantle cell 
lymphomas refractory to rituximab. Patients received two 28-day treatment Cycles of either 
lenalidomide 10 mg daily and dexamethasone 8 mg once weekly or lenalidomide 10 mg daily. 
After assessment of response, all patients received rituximab 375 mg/m2 weekly for 4 doses 
starting with Cycle 3. Lenalidomide-dexamethasone or lenalidomide therapy continued with the 
addition of rituximab. Of the 45 patients enrolled, the histologies were follicular (n = 28), mantle 
cell (n = 11), small lymphocytic (n = 4), and marginal zone (n = 2) lymphomas. Of the 35 patients 
completing both parts of the treatment regimen, the response rate was 60% and the CR rate was 
34%.
The combination of lenalidomide and rituximab in patients with grade 3 FL and transformed 
lymphoma has also been studied (Wang, 2013).  In this phase 2 trial, 45 patients with relapsed or 
refractory DLBCL (n = 32), transformed lymphoma (n = 9) or grade 3 follicular lymphoma (n = 
4) who had received 1 to 4 prior lines of treatment were given 20 mg oral lenalidomide on Days 
1–21 of each 28-day cycle, and intravenous rituximab (375 mg/m2) weekly during Cycle 1. Grade 
3/4 hematological toxicities included neutropenia (53%), lymphopenia (40%), thrombocytopenia 
(33%), leukopenia (27%) and anemia (18%), with a median follow-up time of 29.1 months (range,
14.7–52.0 months). The ORR was 33%; median response duration was 10.2 months. Median PFS 
and OS were 3.7 and 10.7 months, respectively. In this trial, patients with transformed lymphoma
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achieved an ORR of 56% (5/9) and CR rate of 33%, median PFS of 4.3 months with OS of 11.5 
months. Patients with grade 3 follicular lymphoma achieved an ORR of 25% (1/4) (all PR), median 
PFS of 2.0 months and median OS of 25.6 months.
The rituximab plus lenalidomide combination has also been studied as frontline therapy in FL. In 
2013, Martin et al (Martin, 2013) reported the results of a phase 2 clinical trial of rituximab-
lenalidomide combination given for 12 months in previously untreated FL, grades 1 through 3a,
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 375 mg/m2 intravenous 
(IV) weekly x 4 in Cycle 1 and on Day 1 of Cycle 4, 6, 8, and 10. Sixty-five patients were enrolled. 
Three patients did not receive protocol treatment and were removed from analyses. The median 
age of the remaining 62 patients was 53 years; 49% were male; and 63% had a FLIPI score >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 higher toxicity in > 5% of patients 
included fatigue (25%), infusion reaction (17%), upper respiratory infection (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%). At the time 
of the presentation, of the 57 evaluable subjects, the ORR was 93% (72% CR), with a median time 
to CR of 10 weeks. Complete responses were not associated with FLIPI score, grade, or presence 
of bulky disease. At a median follow-up of 1.6 years, 7/57 evaluable patients had progressed; 2 
stopped after 1 to 2 cycles due to toxicity, and 2 achieved best response of CR.
More recently, Fowler et al. (Fowler, 2014) published the results of a phase 2 study evaluating the 
efficacy and safety of rituximab-lenalidomide in patients with untreated, Stage III/IV, indolent 
NHL, including FL grades 1,2, small lymphocyctic lymphoma, and MZL. A total of 110 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; those subjects with a 
clinical benefit could continue up 12 cycles. Response was assessed after every 3 cycles using the 
IWG (Cheson, 1999) criteria.  The median age was 58 years (range, 34 to 84), 53% of patients 
were male, and 103 patients were evaluable for response. Among all evaluable patients, the overall 
response rate was 90%. Complete responses were attained in 65 (63%) of patients, 28 patients 
(27%) had a PR. Among the subset of patients with follicular lymphoma, 40 of 46 evaluable 
patients (87%) attained a CR/CRu. As part of an 
, pre-and post-treatment 
positron emission tomography (PET) scans were obtained and available for 45 patients.  Forty-
four were PET-positive prior to therapy; after treatment, 42 (93%) patients were PET-negative. 
Median PFS for all patients was 53.8 months. The median PFS had not been reached at a median 
follow-up of 40.6 months for patients with FL. The most common Grade 3/4 AEs reported were 
neutropenia (35%), muscle pain (9%), rash (7%), pulmonary symptoms (5%), fatigue (5%), 
thrombosis (5%), and thrombocytopenia (4%). Six patients were removed from treatment due to 
AEs but were eligible for survival assessment.
The RELEVANCE study (NCT01476787) is a Phase 3, randomized two-arm comparison 
sponsored by the LYSARC cooperative group and designed to evaluate the effect of the combined 
treatment of lenalidomide and rituximab in controlling the FL disease and also increase the length 
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of response compared to the available standard combination chemotherapy treatment for FL (1000 
patients). The study consists of Arm A = R-CHOP or R-CVP or R-bendamustine; Arm B = 
R-lenalidomide. A total of 1030 patients were randomly assigned to receive rituximab (R) plus 
lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The median follow-up 
was 37.9 months. The rate of confirmed or unconfirmed complete response at 120 weeks was 
similar in the two groups: 48% (95% CI, 44 to 53) in the R–lenalidomide group and 53% (95% 
CI, 49 to 57) in the R–chemotherapy group (P = 0.13) per central review. The interim 3-year rate 
of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. 
A higher percentage of patients in the R–chemotherapy group had Grade 3 or 4 neutropenia (32% 
versus 50%) and febrile neutropenia of any grade (2% versus 7%), and a higher percentage of 
patients in the R–lenalidomide group had Grade 3 or 4 cutaneous reactions (7% versus 
1%)(Morschhauser, 2018).
1.6.2
Marginal Zone Lymphoma
Data in MZL has also been reported. Recent data (ORR of 61%) suggested for the first time the 
activity of single-agent lenalidomide in MALT lymphoma with manageable side effects 
(Kiesewetter, 2012). In a separate Phase 2 study, the combination of lenalidomide and rituximab 
was administered for 6 cycles (12 cycles for responders) and was studied in previously untreated 
patients (Fowler, 2014). In this study, among the 27 patients with MZL, ORR was 89% with 67% 
CR. Two patients had an improvement in response (PR to CR) after completing therapy.  In 
patients with MZL, median PFS was 53.8 months, 3-year PFS was 87%, and 3-year OS was 100%.
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, thrombopenia grade 1 in three patients and anemia grade 1 in one patient. Other 
adverse events reported were mild fatigue (n = 5), pruritus (n = 6, one patient grade 3), 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).
1.6.3
Mantle Cell Lymphoma
Patients with MCL who relapse after an initial response or do not respond to first-line treatment 
have a poor prognosis (Goy, 2011). With single-agent lenalidomide, response rates of 53% and 
35% were seen respectively in patients with MCL and relapsed or refractory aggressive 
lymphomas (Habermann, 2009; Wiernik, 2008). The Celgene sponsored MCL-001, “Emerge”
study demonstrated rapid and durable efficacy of single-agent lenalidomide in MCL subjects who 
relapsed or progressed after or were refractory to bortezomib. These results in heavily pretreated 
MCL patients (with a median of 4 prior treatments) support single-agent lenalidomide in patients 
with relapsed or refractory MCL after bortezomib (Goy, 2013). Considering the results from 
various Phase 2 studies (38% to 50% in response rates), the NCCN guidelines and the recent 
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ESMO consensus suggested that lenalidomide may be considered in advanced relapses, as toxicity 
seems to be manageable with some moderate myelotoxicity. Median PFS, under continuous 
medication, may be extended 6 to 9 months (Dreyling, 2013b). A study has reported that 25% of 
patients with SD at initial evaluation improved with more prolonged treatment, suggesting that a 
more prolonged schedule of therapy might be beneficial when administering lenalidomide
(Wiernik, 2008).
The combination of lenalidomide and rituximab has also been reported in MCL (Wang, 2012). 
Fourteen patients have participated in the Phase 1 segment and 38 in the Phase 2 segment of the 
trial. During Phase 1, the dose of lenalidomide was gradually increased from 10 to 25 mg with the 
standard dose of rituximab administered weekly x4 during Cycle 1 only. Due to a number of 
toxicities and even a death in Cycle 2 with the highest dose, the dose of 20 mg of lenalidomide 
was finally adopted for Phase 2. Treatment in both phases continued until disease progression, 
stem-cell transplantation, or severe toxicity. Median age of patients was 66 years, and they had
received previously a median of two treatment lines. All patients had already been treated with 
rituximab. During the study a dose reduction was necessary for half of the patients. In terms of 
efficacy, among 44 patients, 57% had an overall response:  36% had a CR and 20% had a PR. The 
median response duration was 18.9 months (95% CI was 17.0 months to not reached [NR]). The 
median PFS was 11.1 months (95% CI was 8.3 to 24.9 months), and the median OS was 24.3 
months (19.8 months to NR). Interestingly, five of 14 patients who had received bortezomib 
treatment before enrollment achieved an overall response.
More recently Ruan et al. (Ruan, 2014) reported mature results from an ongoing multi-center phase 
2 trial evaluating the combination of lenalidomide plus rituximab as initial treatment for patients 
with MCL followed by lenalidomide plus rituximab as maintenance therapy. Thirty-eight subjects 
with previously untreated MCL were enrolled at 4 centers.  During the induction phase, 
lenalidomide was administered at 20 mg daily on Days 1-21 of a 28-day cycle for a total of 12 
cycles, with dose escalation to 25 mg daily if tolerated.  Standard dose rituximab was administered 
weekly x 4 during Cycle 1, then once every other cycle, for a total of 9 doses.  During the 
maintenance phase, which started with Cycle 13, lenalidomide was administered at 15 mg daily 
on Days 1-21 of a 28-day cycle, with rituximab maintenance once every other cycle until 
progression of disease.  Treatment was generally well tolerated with expected side effects.  Grade 
3-4 hematologic toxicities included neutropenia (47% in total, 42% with induction, 24% with 
maintenance), thrombocytopenia (13%) and anemia (8%).  Grade 3-4 non-hematologic toxicities 
including rash (26%), tumor flare (11%), serum sickness associated with rituximab (8%) and 
fatigue (8%) were reported during induction phase only. At time of reporting, median follow-up 
was 26 months (range, 5-38 months) the ORR for all evaluable patients was 89% with 58% CR 
and 31% PR.  Median time to objective response was 2.8 months, with median time to CR achieved 
at 11 months.  Median progression-free survival and duration of response had not been reached.  
The 2-year PFS rate is estimated at 85%.  Neither MIPI score nor Ki67 index correlated with 
response.  Quality of life parameters were maintained or improved during treatment by FACT-
Lym analysis.
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1.7
Lenalidomide as Maintenance Therapy
Thalidomide and lenalidomide have been incorporated into the treatment paradigm of newly 
diagnosed and relapsed multiple myeloma (MM), as well as maintenance therapy (Munshi, 2013).
Three recent trials support the use of lenalidomide maintenance therapy in MM. Lenalidomide at 
a 10 mg maintenance dose is highly active in MM (Palumbo, 2012; Attal, 2012; McCarthy, 2012;
Boccadoro, 2013), confirming the improvement in the time to progression in all three trials and 
one showing an improvement in survival. At a median follow-up of 30 months, PFS was 
significantly prolonged in patients administered lenalidomide maintenance therapy following 
melphalan, prednisone, and lenalidomide induction therapy (MPR+R) (31 months) compared with 
those who received MPR or MP induction therapy only (14 months, p < 0.001 or 13 months, p < 
0.001, respectively) (Palumbo, 2012). The trial by Attal demonstrated that PFS was 41 months 
with lenalidomide and 23 months with placebo maintenance. In the McCarthy study, the median 
time to progression, post-transplant, was 46 months with lenalidomide maintenance versus 
 in the placebo group (p < 0.001). The trial by the “Gruppo Italiano Malattie 
EMatologiche Dell'Adulto” (GIMEMA) reported that patients who were given lenalidomide 
maintenance therapy had a significantly higher PFS (37 versus 26 months) and OS (75% vs. 58%) 
than those with no maintenance (Boccadoro, 2013).
Lenalidomide is being studied as
maintenance therapy in lymphoma (NCT01122472;
NCT01415752; NCT01216683; NCT01476787).
The REMARC study (NCT01122472) is a Phase 3, randomized, double-blind, placebo-controlled 
study sponsored by the LYSARC cooperative group and Celgene, and is designed to explore the 
effect of 2-year maintenance therapy with lenalidomide versus placebo on PFS in DLBCL patients 
(621 planned) responding to induction therapy with R-CHOP. A total of 650 patients were 
randomly assigned. At the time of the primary analysis (December 2015), with a median follow-
up of 39 months from random assignment, median PFS was not reached for lenalidomide 
maintenance versus 58.9 months for placebo (hazard ratio, 0.708; 95% CI, 0.537 to 0.933; P = 
0.01). The result was consistent among analyzed subgroups (eg, male versus female, age-adjusted 
International Prognostic Index 0 or 1 versus 2 or 3, age younger than 70 versus ≥70 years), 
response (PR versus CR) after R-CHOP, and positron emission tomography status at assignment 
(negative versus positive). With longer median follow-up of 52 months (October 2016), overall 
survival was similar between arms (hazard ratio, 1.218; 95% CI, 0.861 to 1.721; P = 0.26). The 
most common Grade 3 or 4 adverse events associated with lenalidomide versus placebo 
maintenance were neutropenia (56% versus 22%) and cutaneous reactions (5% versus 1%), 
respectively (Thieblemont, 2017).
The NCT01415752 study (E1411 study; Eastern Cooperative Oncology Group [ECOG] and 
National Cancer Institute [NCI]) is a Phase 2, randomized, four-arm study designed to evaluate 
the efficacy of rituximab together with bendamustine and bortezomib compared to rituximab and 
bendamustine, followed by rituximab alone or with lenalidomide in older MCL patients (332 
planned). Arm A = rituximab+ bendamustine followed by rituximab consolidation (RB → R); 
Arm B = rituximab + bendamustine + bortezomib followed by rituximab consolidation (RBV→ 
R); Arm C = rituximab + bendamustine followed by lenalidomide + rituximab consolidation (RB 
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→ LR) or Arm D = rituximab + bendamustine + bortezomib followed by lenalidomide + rituximab 
consolidation (RBV → LR).
The NCT01216683 study (2408 study; ECOG) is a Phase 2, randomized, three-arm comparison 
studying bendamustine and rituximab together with or without bortezomib followed by rituximab 
with or without lenalidomide in patients with follicular lymphoma. It consists of Arm A = 
rituximab+ bendamustine followed by rituximab consolidation (RB → R); Arm B = rituximab + 
bendamustine + bortezomib followed by rituximab consolidation (RBV→ R); Arm C = rituximab 
+ bendamustine followed by lenalidomide + rituximab consolidation (RB → LR).
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2
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of the study is to compare the efficacy of lenalidomide plus rituximab 
combination maintenance therapy (for 18 cycles) followed by optional lenalidomide single-agent 
maintenance (to progression) versus rituximab single-agent maintenance (for 18 cycles) after 12 
cycles of induction therapy with lenalidomide plus rituximab, in subjects with relapsed/refractory 
FL grades 1-3b, transformed FL, MZL or MCL. Efficacy determinations will be based upon PFS 
as the primary endpoint, using a modification of the IWG 1999 criteria (Cheson, 1999).
2.2
Secondary Objectives
The secondary objectives of the study are:

To compare the safety of lenalidomide plus rituximab combination maintenance therapy (for 
18 cycles) followed by optional lenalidomide single-agent maintenance (to progression) versus 
rituximab single-agent maintenance (for 18 cycles) after 12 cycles of induction therapy with 
lenalidomide plus rituximab.

To compare other parameters of efficacy (OS, IOR, ORR, CRR, DOR, DOCR, TTNLT, 
TTHT) of lenalidomide plus rituximab combination maintenance therapy (for 18 cycles) 
followed by optional lenalidomide single-agent maintenance (to progression) versus rituximab 
single-agent maintenance (for 18 cycles) after 12 cycles of induction therapy with lenalidomide 
plus rituximab.
All efficacy assessments will be assessed using a modification of the IWG 1999 criteria (Cheson, 
1999) to allow the inclusion of extranodal disease as measurable disease.
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3
STUDY ENDPOINTS
All efficacy assessments will be made using a modification of the IWG 1999 criteria to allow the 
inclusion of extranodal disease as measurable disease (Cheson, 1999).
3.1
Primary Endpoint

PFS
3.2
Secondary Endpoints

OS

IOR

ORR

CRR

DOR

DOCR

TTNLT

TTHT

Safety
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4
OVERALL STUDY DESIGN
4.1
Study Design
This Phase 3b randomized study is designed to compare the efficacy and safety of lenalidomide 
plus rituximab combination maintenance therapy (for 18 cycles) followed by optional 
lenalidomide single-agent maintenance (to progression) versus rituximab single-agent 
maintenance (for 18 cycles) after 12 cycles of induction therapy with lenalidomide plus rituximab
in subjects with relapsed/refractory FL grades 1-3b, transformed follicular lymphoma, MZL or
MCL. The overall study design is described in Figure 1. The study is divided into the Screening
Period, Treatment Period, and Follow-up Period. Approximately 500 subjects are planned to be 
enrolled.
All efficacy assessments will be based on local radiology and appropriate clinical assessment using 
a modification of the IWG 1999 criteria (Cheson, 1999). The Cheson criteria (1999) were modified 
to allow the inclusion of extranodal disease as measurable disease. Evaluation of a PR allowing
inclusion of sites of dominant extranodal disease (still requiring a 50% or greater decrease in the 
sum of the perpendicular diameters of measurable sites of disease) is adopted in this clinical trial 
since extranodal involvement is common in MZL and MCL. A similar modification to the Cheson 
criteria has been adopted in other MCL studies (Fisher, 2006; Kane, 2007). For subjects with MZL 
involving the gastric area, results of endoscopy will be included in the assessment of response.
An independent external DMC will review ongoing safety data throughout the study. The 
frequency of DMC meetings will be described in the DMC Charter.
The study will be conducted in compliance with GCP.
4.1.1
Screening Period
Upon giving written informed consent, the subject will enter the Screening Period to determine 
eligibility. All Screening assessments must be completed within 28 days prior to enrollment in 
IVRS to receive induction therapy. During the Screening Period, the subject will undergo safety 
and other assessments to determine eligibility for the study and undergo enrollment into the trial.
Subject eligibility will be based on investigator assessment of the pathologic diagnosis. 
4.1.2
Induction and Maintenance Period
4.1.3
Enrollment in Induction Treatment Period
The subject will be enrolled into the Induction Treatment Period once all required screening
assessments have been performed and the subject meets all eligibility criteria. Eligible subjects 
entering the Induction Treatment Period will be enrolled using an Interactive Voice Response 
System (IVRS). The Induction Treatment Period will start on Day 1 of the first cycle (C1D1). The 
lenalidomide plus rituximab induction treatment will be given as described in detail in Section 8
and must begin no later than 1 week after enrollment in IVRS to receive induction therapy. 
Subjects will receive induction treatment, and be evaluated for efficacy, and safety assessments 
for 12 Cycles or until relapse or progression of disease, withdrawal of consent, or unacceptable 
toxicity. The local laboratory will be used for the analysis of hematology and serum chemistry. 
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Clinical decisions and dose modifications during the study can be based on these results (see 
Section 6.2.10).
4.1.4
Randomization to Maintenance Treatment Period
After 12 cycles of lenalidomide plus rituximab induction therapy, subjects achieving CR/CRu, PR 
or having SD will be randomized to enter the maintenance period. During the maintenance period, 
subjects randomized to Arm B will receive rituximab (only) administered for 18 Cycles. Subjects 
randomized to Arm A will receive lenalidomide plus rituximab treatment for 18 Cycles and then 
lenalidomide until relapse or progression of disease. Lenalidomide (only) treatment in Arm A will 
be given per subject and/or physician discretion as described in detail in Section 8 and must begin 
no later than 1 week after the last cycle of rituximab plus lenalidomide. Subjects randomized under 
previous protocol (version 16 January 2014) who achieve a response of SD or better at the end of 
the Induction Treatment Period will remain in their originally assigned arm of maintenance 
therapy.
All subjects (in both Induction and Maintenance Treatment Periods) receive treatment as described 
unless they withdraw consent from treatment, experience unacceptable toxicities or have disease 
progression. Once subjects discontinue or complete treatment, they enter the follow-up period. All 
enrolled subjects will be followed for disease progression using the schedule described in Table 1. 
Subjects who progress before the end of planned treatment will enter the Follow-up Period. 
Determination of disease progression will be based on investigator assessment. All subjects who 
discontinue the protocol-specified treatment early for any reason without documented evidence of 
disease progression will also be followed in the Follow-up Period.
All subjects who will be on treatment upon reaching 5 years after the last subject has initiated 
induction therapy 
 will continue the treatment and will be followed up for 
safety purposes only.
4.1.5
Follow-up Period
Upon completion or discontinuation of the protocol-specified treatment, subjects will enter the 
Follow-up Period. In the Follow-up Period, all subjects will be followed for survival, time to next 
lymphoma treatment, and SPMs for 5 years after the last subject has initiated induction therapy 
unless they withdraw consent from the study, die or are lost to follow-up. Subjects whose disease 
has not yet progressed will also be followed for disease progression.
 
4.1.6
Follow-up Period Upon Confirmation of 114 PFS Events
 
SPMs for 5 years after the last subject has 
initiated induction therapy unless the subject withdraws from the study, dies, or is lost to follow-up.
4.2
Study Design Rationale
Follicular lymphoma, marginal zone or mantle cell lymphoma are distinct histologic types within
the broad category of B-cell NHL according to the World Health Organization (WHO)
classification (Harris, 2008). For FL, this histology is further divided into Grades - Grades 1 to 3
34
1.0
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930192439
1.0
v
Approved
1.0
v


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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 into Grades 3a and 3b.
Grade 3a versus 3b distinction has implications for treatment decisions, since Grade 3b FLs are 
clinically more similar to more aggressive lymphomas, with more infiltration of large cells. Grade
3a is typically treated as an indolent lymphoma, while Grade 3b is treated as an aggressive 
lymphoma with similar outcome. 
A pivotal event in the natural history of FL is histological transformation to more aggressive 
malignancies, most commonly diffuse large B cell lymphomas (DLBCL) or other high-grade 
morphologies. In this process a more virulent subclonal population of cells emerge, typically 
associated with the loss of the follicular growth pattern, a rapidly progressive clinical course 
refractory to treatment, and short survival (commonly of less than 2 years). Although one of the 
earliest descriptions of FL transformation was reported more than 65 years ago, this biological 
process and clinical event still remains incompletely understood without a standard treatment 
approach (Lossos, 2011).  Despite heterogeneities in the biology and treatment practices between 
FL, transformed lymphoma, MZL, and MCL, it is important to note that in advanced stage disease 
and in relapsed disease, the clinical behavior and treatments are very similar among the lymphomas 
that are being studied in this clinical trial. These similarities, for example, are reflected in the 
nearly identical treatment guidelines for the management of advanced stage FL versus advanced 
stage MZL (NCCN guidelines, 2015; Dreyling, 2013a). For this reason, FL and MZL are studied 
together in this clinical trial.
Rituximab is approved in many countries for the treatment of relapsed/refractory low-grade NHL 
or FL. “Low-grade” is a term based on the Working Formulation (Robb-Smith, 1982) that included 
lymphomas with indolent behavior solely on their histologic appearance. In recent years low-grade 
lymphoma has been replaced by the term “indolent.” Clinically, “low-grade” lymphoma can be 
used interchangeably with “indolent lymphoma.”
Subsequent to this initial rituximab approval, the treatment of relapsed/refractory low-grade NHL
has evolved so that multiple options are now available. Thus, rituximab has become the backbone 
of combination therapy. As discussed in Section 1.6 the lenalidomide-rituximab regimen has been 
reported to be active in FL, transformed FL, MZL and MCL (Leonard, 2012; Fowler, 2014; Wang, 
2012; Wang 2013). As mentioned in Section 1.7, lenalidomide is highly active as a single agent in 
FL, MCL, and MZL and as a maintenance agent in myeloma. There are ongoing trials studying 
lenalidomide maintenance therapy in lymphoma. Thus, in summary, sufficient evidence exists that 
the combination of rituximab plus lenalidomide is a useful combination to study in FL, MZL, and 
MCL, where no single standard of care is available.
The current study is a Phase 3b, multicenter, randomized, open-label study designed to compare 
the efficacy and safety of lenalidomide plus rituximab combination maintenance therapy (for 18 
cycles) followed by optional lenalidomide single-agent maintenance (to progression) versus 
rituximab single-agent maintenance (for 18 cycles) after 12 cycles of induction therapy with 
lenalidomide plus rituximab in subjects with relapsed/refractory FL, transformed FL, MZL, or
MCL. It is anticipated that with a longer duration of lenalidomide we will observe a longer duration 
35
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
of response with minimal added toxicities. The multicenter nature of the study provides assurance 
that the results are likely to have general applicability.
Subjects are required to have measurable disease and to have frequent periodic disease assessments 
for an accurate assessment of PFS, the primary endpoint of this study. Because extranodal disease 
is common in MCL and MZL, the Cheson criteria (Cheson, 1999) will be modified to allow
inclusion of sites of dominant extranodal disease as measurable disease, as has been previously 
used in a mantle cell lymphoma study (Fisher, 2006; Kane, 2007). The use of this established tool 
will ensure that data across centers are evaluated consistently and also allow for comparison to 
historical data. For assessment of MZL, endoscopy has been added to the efficacy assessment. In 
addition, in this clinical trial, these criteria exclude the use of PET scan, which is less established 
as an indicator of disease activity in indolent lymphoma compared to aggressive lymphoma. 
The primary endpoint of PFS is an accepted measure of clinical benefit.
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 version 3.0.
Monitoring for certain events (see Section 6.2 for details), including TFR, tumor lysis syndrome
(TLS), and venous and arterial thromboembolic events (VTE and ATE) will be performed along 
with safety assessments routinely conducted in investigational studies of hematologic 
malignancies. Prophylaxis for thromboembolic events is strongly recommended for subjects who 
are at risk for thromboembolic events (TE). Thromboembolic events, TFR and TLS will be 
recorded as AEs.
Second primary malignancies will be monitored as events of interest and should be included as 
part of the assessment of adverse events throughout the course of the study. Investigators are to 
report any second primary malignancies as serious adverse events regardless of causal relationship 
to IP (study drug), occurring at any time for the duration of the study, from the time of signing the 
ICD for 5 years from the date the last subject initiates induction therapy.
36
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Approved
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v


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
Figure 1:
Overall Study Design
Screening Period
Induction Period
Maintenance Period
Follow Up Period
12 Cycles
18 Cycles
up to PD
Day -28 to 0
If CR/CRu, PR or SD 
response 
after 
induction:
Arm A
Arm B
a Treatment must begin no later than 1 week after completing enrollment in IVRS to receive induction therapy.
b All enrolled subjects are followed for disease progression using the same schedule described in Table 1. This includes subjects who discontinue the protocol-
specified treatment or the study early for any reason without documented evidence of PD or relapse.
c Upon confirmation of 114 PFS events, subjects will be followed up for survival and SPM as detailed in the follow-up section. See Section 4.1.6.
Follow-up visitb,c
-For all subjects, data
on disease progression
(PD) or relapse (if
appropriate), time to
next 
anti-lymphoma
therapy, and second
primary malignancies
will be collected for
5 years after the last
subject has
initiated
induction therapy.
Stratification;
Randomization
[1:1]
Screening 
Eligibility & 
informed 
consent 
document 
signature
Rituximab (375 mg/m2)
on Day 1 of Cycles 13,
15, 17, 19, 21, 23, 25, 
27, and 29.
Lenalidomide 10 
mgc
On Days 1-21 
every 28 days
At discretion of 
subject and/or 
investigator
Lenalidomide
20 mg if CrCl ≥60mL/min
10 mg if CrCl ≥30 but 
<60mL/min
On Days 1-21 of Cycles
1 to 12a
Rituximab (375 mg/m2)
Weekly [Days 1, 8, 15, 22] in 
Cycle 1 and then on Day 1 of 
Cycles 3, 5, 7, 9, and 11
Lenalidomide 10 mg
On Days 1-21 of Cycles 
13 to 30
Rituximab (375 mg/m2)
on Day 1 of Cycles
13, 15, 17, 19, 21, 23, 
25, 27, and 29.
37
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930192439
1.0
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Approved
1.0
v


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
4.3
Study Duration
The expected accrual duration is approximately 63 months. Subjects will receive protocol-
specified treatment until relapse or progression of disease, withdrawal of consent or unacceptable 
toxicity. The study duration to events for primary analysis is estimated to be 105 months. Subjects 
will be followed for disease progression, survival, subsequent anti-lymphoma therapy and SPMs. 
Upon confirmation of 114 PFS events, subjects will be followed for survival and SPMs for 5 years 
after the last subject has initiated induction therapy. All subjects who will be on treatment upon 
reaching 5 years after the last subject has initiated induction therapy 
 will 
continue the treatment and will be followed up for safety purposes only.
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 
, as pre-specified in the protocol and/or the Statistical 
Analysis Plan, whichever is the later date.
38
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Approved
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v


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
5
TABLE OF EVENTS
Table 1:
Schedule of Study Assessments
PROCEDUREa
Screening
Period
Every 
Cycle
Day 1
Induction &
Maintenance 
Periods
(± 3 days)
Induction Period
Maintena
nce
Period
At 3 cycles
(84 days after 
C1D1) (±2 
weeks)
At 6 cycles
(168 days after 
C1D1)(±2 
weeks)
Every 6 cycles 
(168 days)
(±2 weeks) up
to 5 years then 
Annually
(± 3 weeks)b
At
Treatment
Discontinu
ation/
Completio
n
Follow-up
 
 
 
Cycle 1
Cycles
2 & 3
Cycles
3, 5, 7, 
9 & 11
Cycles
5 & 9
Cycle
7
Cycle
10
Cycles
13, 15, 17, 
19, 21, 23, 
25, 27 
& 29
If no PD 
then follow 
the CT 
scan 
assessment 
scheduleb
 
 
Days
-28 to -1
Up to PD 
for 
Arm A
Or up to 30
cycles for
Arm B
Day 1
(± 3 
days)
Day 
8 & 
15
(± 1 
day)
Day
22
Day 
15
(± 1 
day)
Day 1
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 days)
Informed Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/Exclusion 
Criteria
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographic Data
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Lymphoma and 
Complete Medical 
History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Central Nervous 
System Lymphoma 
Evaluation
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Creatinine 
Clearance
(Cockcroft-Gault 
Estimation)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
12-Lead 
Electrocardiogram
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
HBV Screeningc
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
39
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930192439
1.0
v
Approved
1.0
v


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
Table 1:
Schedule of Study Assessments
PROCEDUREa
Screening
Period
Every 
Cycle
Day 1
Induction &
Maintenance 
Periods
(± 3 days)
Induction Period
Maintena
nce
Period
At 3 cycles
(84 days after 
C1D1) (±2 
weeks)
At 6 cycles
(168 days after 
C1D1)(±2 
weeks)
Every 6 cycles 
(168 days)
(±2 weeks) up
to 5 years then 
Annually
(± 3 weeks)b
At
Treatment
Discontinu
ation/
Completio
n
Follow-up
 
 
 
Cycle 1
Cycles
2 & 3
Cycles
3, 5, 7, 
9 & 11
Cycles
5 & 9
Cycle
7
Cycle
10
Cycles
13, 15, 17, 
19, 21, 23, 
25, 27 
& 29
If no PD 
then follow 
the CT 
scan 
assessment 
scheduleb
 
 
)
Days
-28 to -1
Up to PD 
for 
Arm A
Or up to 30
cycles for
Arm B
Day 1
(± 3 
days)
Day 
8 & 
15
(± 1 
day)
Day
22
Day 
15
(± 1 
day)
Day 1
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 days)
Safety Assessments
Adverse Events
From signing ICD and until 28 days after the last dose
Assessment of 
Second Primary 
Malignancyd
From signing ICD and up to and including the Follow-up Period (5 years from last subject initiating induction treatment)
Pregnancy Test 
(FCBP Only)e
X
X
X
X
X
-
-
-
-
-
-
-
Xf
-
-
-
Birth Control/ 
Lenalidomide 
Counseling
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Distribute 
Lenalidomide 
Counseling Sheet
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior/ Concomitant 
Medications/
Procedures/ 
Hospitalizations 
From signing of ICD until 28 days after last dose of treatment
-
Physical 
Examination
X
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
40
1.0
Approved
930192439
1.0
v
Approved
1.0
v


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
Table 1:
Schedule of Study Assessments
PROCEDUREa
Screening
Period
Every 
Cycle
Day 1
Induction &
Maintenance 
Periods
(± 3 days)
Induction Period
Maintena
nce
Period
At 3 cycles
(84 days after 
C1D1) (±2 
weeks)
At 6 cycles
(168 days after 
C1D1)(±2 
weeks)
Every 6 cycles 
(168 days)
(±2 weeks) up
to 5 years then 
Annually
(± 3 weeks)b
At
Treatment
Discontinu
ation/
Completio
n
Follow-up
 
 
 
Cycle 1
Cycles
2 & 3
Cycles
3, 5, 7, 
9 & 11
Cycles
5 & 9
Cycle
7
Cycle
10
Cycles
13, 15, 17, 
19, 21, 23, 
25, 27 
& 29
If no PD 
then follow 
the CT 
scan 
assessment 
scheduleb
 
 
Days
-28 to -1
Up to PD 
for 
Arm A
Or up to 30
cycles for
Arm B
Day 1
(± 3 
days)
Day 
8 & 
15
(± 1 
day)
Day
22
Day 
15
(± 1 
day)
Day 1
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 days)
Eastern 
Cooperative 
Oncology Group 
(ECOG) 
Performance 
Status
X
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
B Symptoms
X
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
Vitals Signs
X
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
Hematology 
Laboratory Testsg
X
X
-
X
-
X
-
-
-
-
-
-
X
-
-
-
Serum Chemistry 
Laboratory Testsg
X
X
-
X
-
X
-
-
-
-
-
-
X
-
-
-
Thyroid 
Stimulating 
Hormoneg,n (TSH)
X
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
Tumor Flare and 
Tumor Lysis 
Assessments
h
-
-
X
X
-
-
-
-
-
-
-
-
-
-
-
-
41
1.0
Approved
930192439
1.0
v
Approved
1.0
v


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
Table 1:
Schedule of Study Assessments
PROCEDUREa
Screening
Period
Every 
Cycle
Day 1
Induction &
Maintenance 
Periods
(± 3 days)
Induction Period
Maintena
nce
Period
At 3 cycles
(84 days after 
C1D1) (±2 
weeks)
At 6 cycles
(168 days after 
C1D1)(±2 
weeks)
Every 6 cycles 
(168 days)
(±2 weeks) up
to 5 years then 
Annually
(± 3 weeks)b
At
Treatment
Discontinu
ation/
Completio
n
Follow-up
 
 
 
Cycle 1
Cycles
2 & 3
Cycles
3, 5, 7, 
9 & 11
Cycles
5 & 9
Cycle
7
Cycle
10
Cycles
13, 15, 17, 
19, 21, 23, 
25, 27 
& 29
If no PD 
then follow 
the CT 
scan 
assessment 
scheduleb
 
 
Days
-28 to -1
Up to PD 
for 
Arm A
Or up to 30
cycles for
Arm B
Day 1
(± 3 
days)
Day 
8 & 
15
(± 1 
day)
Day
22
Day 
15
(± 1 
day)
Day 1
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 days)
Efficacy Assessments
CT with contrast or 
MRI of Neck, 
Chest, Abdomen 
and Pelvis
X
-
-
-
-
-
-
-
-
-
-
Xo
-
X
-
-
Bone Marrow 
Biopsyi
X
Only if nodal CR and bone marrow involvement at baseline
Endoscopy/Gastric 
Biopsyj
Xj
Repeat twice within 3 months of CR/CRu by IWG criteria
Response 
Assessment
-
-
-
-
-
-
-
-
-
-
-
Xo
-
X
-
-
Subsequent Anti-
Lymphoma 
Therapies
-
-
-
-
-
-
-
-
-
-
-
-
Xo
-
X
-
Survival
-
-
-
-
-
-
-
-
-
-
-
-
-
X
X
X
Treatment
Tumor lysis 
prophylaxisl
-
-
X
X
-
-
-
-
-
-
-
-
-
-
-
-
42
1.0
Approved
930192439
1.0
v
Approved
1.0
v


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
Table 1:
Schedule of Study Assessments
PROCEDUREa
Screening
Period
Every 
Cycle
Day 1
Induction &
Maintenance 
Periods
(± 3 days)
Induction Period
Maintena
nce
Period
At 3 cycles
(84 days after 
C1D1) (±2 
weeks)
At 6 cycles
(168 days after 
C1D1)(±2 
weeks)
Every 6 cycles 
(168 days)
(±2 weeks) up
to 5 years then 
Annually
(± 3 weeks)b
At
Treatment
Discontinu
ation/
Completio
n
Follow-up
 
 
 
Cycle 1
Cycles
2 & 3
Cycles
3, 5, 7, 
9 & 11
Cycles
5 & 9
Cycle
7
Cycle
10
Cycles
13, 15, 17, 
19, 21, 23, 
25, 27 
& 29
If no PD 
then follow 
the CT 
scan 
assessment 
scheduleb
 
 
Days
-28 to -1
Up to PD 
for 
Arm A
Or up to 30
cycles for
Arm B
Day 1
(± 3 
days)
Day 
8 & 
15
(± 1 
day)
Day
22
Day 
15
(± 1 
day)
Day 1
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 
days)
Day 1
(± 3 days)
Administer 
Rituximabm
-
-
X
X
X
-
X
-
-
-
X
-
-
-
-
-
Study Drug Return/
Accountability
-
X
-
-
-
-
-
-
-
-
-
-
X
-
-
-
Arm A:  Experimental arm; Arm B:  Control arm; CR:  Complete Response; CRF:  Case Report Form; CT:  Computed Tomography; C1D1: Cycle 1 Day 1; FCBP:  
Females of childbearing potential; HBV:  Hepatitis B Virus; ICD:  Informed Consent Document; MRI:  Magnetic Resonance Imaging; MZL:  Marginal Zone 
Lymphoma; PD:  Progressive Disease; PR:  Partial Response; SAE:  Serious Adverse Event; IP:  Investigational Product; IWG:  International Working Group; 
SOC: Standard of Care
a See Section 6 for details on the procedures.
b Efficacy assessments to be performed until progression, relapse or initiation of new anti-lymphoma therapy. See Section 6.3 for details.
c Eligibility for the study is based on the local HBV tests including if performed as standard of care within 4 weeks prior to enrollment in IVRS to receive induction 
therapy.
d 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. 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 for 5 years from the date the last subject initiates induction treatment. Events of second primary malignancy are to 
be reported using the SAE report form and must be considered an “Important Medical Event” if no other seriousness criteria apply; these events must also be 
documented in the appropriate page(s) of the CRF and the 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-rays, CT scans, etc.).
43
1.0
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930192439
1.0
v
Approved
1.0
v


Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
e For females of childbearing potential only. All FCBP enrolled into this study must conform to all aspects of the lenalidomide Pregnancy Prevention Plan 
(standalone document). A local laboratory will be used for all pregnancy testing, including the Screening tests (see Section 6.2.3 and 7.2). 
f All FCBP must have pregnancy tests at treatment discontinuation and at Day 28 following lenalidomide discontinuation. For FCBP with irregular menstrual 
cycles pregnancy tests will be conducted weekly during the 4 weeks of treatment, and then every 14 days through 28 days following the last dose of lenalidomide. 
Refer to Section 6.2.3.
g 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 (see Section 6.2.10).
Hematology and serum chemistry labs should be done before administration of study drugs; when these are required on these visits per above table the allowed 
window periods will be as follow: Day 1 (-3 days) of every treatment cycle, Day 8 (-1 day) and Day 15 (-1 day).
h 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 if necessary and as instructed (see Section 9.3.1)
i Bone marrow biopsy is required at Screening (for staging). A bone marrow biopsy conducted as SOC within 24 weeks prior to enrollment in IVRS to receive 
induction therapy may be used for Screening. During the study bone marrow biopsy is required only if the subjects had positive bone marrow at Screening and 
has otherwise fulfilled the criteria for a nodal CR. See more details in Section 6.1.5. 
j
Only for subjects with MZL involving gastric area. Subjects will have a repeat gastric biopsy for histological evaluation if the subject has fulfilled the IWG 
criteria for response of at least a CR/CRu. See more details in Section 6.1.6.
l
All subjects at risk for TLS should receive TLS prophylaxis (allopurinol, rasburicase or equivalent as per institutional guidelines) and be well hydrated (orally) 
during the first week of the first cycle or as clinically indicated. To monitor for TLS, 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. See more details in Section 9.3.1.
m See Section 8 for more details regarding treatment administration. Possible time windows mentioned do not concern treatment schedule. Initiation of induction 
treatment should begin no later than 1 week after completion of enrollment in IVRS to receive induction therapy
n Thyroid stimulating hormone will be assessed at Screening and end of induction treatment or treatment discontinuation and thereafter as clinically indicated 
during the maintenance treatment period.
o Upon confirmation of 114 PFS events, CT scans, 
, response assessment, and subsequent anti-lymphoma therapies will no longer be required to be 
completed.
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
6
PROCEDURES
Subjects will be screened for protocol eligibility during a period of no more than 28 days prior to 
enrollment in IVRS to receive induction therapy (the Screening period) as outlined in the Schedule 
of Study Assessments.  Procedures conducted as standard of care may be used to meet the 
requirements of this study provided they meet the description and timeline specified in the 
protocol.
Cycle definition:  defined in this study as lenalidomide Cycle; 21 days treatment + 7 days rest 
period = 28 days total.
6.1
Study Entry
6.1.1
Informed Consent Document
The subject must approve and sign the ICD prior to undergoing any study-related Screening
assessments
6.1.2
Inclusion and Exclusion Criteria
The subject’s eligibility (inclusion and exclusion criteria) must be evaluated during the Screening
Period prior to enrollment in IVRS to receive induction therapy (see Section 7.2 and 7.3).
6.1.3
Demographic Data
The demographic data will include (but not be limited to) the subject’s initials, date of birth, age, 
gender, and race/ethnic origin. The demographic profile will be recorded in the source documents 
and case report form (CRF).
6.1.4
Lymphoma and Complete Medical History 
A medical history will be obtained by the investigator or qualified designee within 4 weeks prior 
to the first day of treatment. Medical history judged as relevant to the study and to the safety of 
the study subject will be recorded in the source documents and CRF.
Eligibility for FL grades 1-3b, transformed FL, MZL and MCL subjects will be based on local 
pathology review. For MCL confirmation of Cyclin D1 expression or the presence of the t(11;14) 
translocation is recommended. Diagnosis based on core biopsy is acceptable, but diagnosis based 
on fine needle aspiration is not considered acceptable pathologic data for entry into this study.
6.1.5
Bone Marrow Biopsy
Bone marrow biopsy is required at Screening (for staging). A recent bone marrow biopsy 
conducted within 24 weeks of Cycle 1 Day 1, is acceptable as the Screening biopsy. If no such 
recent bone marrow biopsy is available, then a repeat biopsy will be required prior to enrollment 
in IVRS to receive induction therapy. During the treatment period (induction or maintenance) of 
the study, a bone marrow biopsy is required only if the subject had positive bone marrow at 
Screening and has otherwise fulfilled the criteria for a nodal CR. The bone marrow procedure 
should be performed within 28 days after the criteria for radiological CR have otherwise been met.
The biopsy may be unilateral or bilateral at the discretion of the investigator.
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
6.1.6
Endoscopy and Gastric Biopsy
Subjects with MZL involving the gastric area will undergo endoscopy as part of the response 
assessment. Histological evaluation for subjects with MZL involving the gastric area (for staging) 
based on endoscopy and gastric biopsy (from stomach, duodenum, and gastroesophageal junction 
and from any abnormal-appearing site) is required during Screening. A recent histological 
evaluation, conducted within 12 weeks prior to C1D1, is acceptable as the Screening assessment. 
If no such recent evaluation is available, then gastric repeat biopsy and histological evaluation will 
be required for subjects with MZL involving the gastric area prior to enrollment in IVRS to receive 
induction therapy.
Subjects with MZL involving the gastric area will have a repeat gastric biopsy for histological 
evaluation if the subject has fulfilled the IWG criteria for response of at least a CR/CRu. For 
subjects achieving radiological CR/CRu, a biopsy performed at two separate time points within 3 
months after the criteria for CR/CRu were first met is required to confirm response. Histological 
evaluation of the gastric biopsy will be performed by the local pathologist. The Groupe d' Etude 
des Lymphomes de l' Adulte (GELA) grading system (Copie-Bergman, 2003; Copie-Bergman, 
2012) is suggested to be used in the pathologic assessment. 
6.1.7
Central Nervous System Lymphoma
Subjects with current or past Central Nervous System (CNS) lymphoma involvement are excluded 
from the study. Subjects with suspicion of CNS involvement must undergo neurologic evaluation 
and CT or MRI of brain and a lumbar puncture to exclude active CNS disease.
6.1.8
Lenalidomide Dosing - Creatinine Clearance (Cockcroft-Gault 
Estimation)
To determine the dose of lenalidomide on C1D1, the Cockcroft-Gault estimation of creatinine 
clearance (CrCl) will be assessed at Screening by the local laboratory utilizing actual body weight
(Cockcroft, 1976; Luke, 1990; Griggs, 2012) and will be recorded in the source documents and 
CRF. See also Section 6.2.10.
CrCl (mL/min) = (140 – age) (weight [kg]) / 72 (serum creatinine [mg/dL]); for females, the 
formula is multiplied by 0.85. 
6.1.9
12-Lead Electrocardiogram
12-lead electrocardiogram (ECG) is performed at Screening and as clinically indicated thereafter.
6.1.10
Hepatitis B
Hepatitis B Screening is required for all subjects and includes hepatitis B surface antigen (HBsAg), 
hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs). See exclusion 
criterion # 6 (Section 7.3) for further details. Eligibility for the study is based on the local HBV 
tests including if performed as standard of care within 4 weeks prior to enrollment in IVRS to 
receive induction therapy.
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
6.2
Safety Assessments
Serial assessments of safety will be performed as outlined in the Schedule of Study Assessments 
(Table 1).
Time to histological transformation will be measured based on documentation of histological 
transformation as assessed by the investigator. The date of the histology/pathology report will be 
used as the date of transformation. In case of clinical suspicion of transformation, including rapid 
disease progression, unexpected changes in “B” symptoms or rapidly increasing lactate 
dehydrogenase (LDH), a biopsy should be performed. In this clinical trial, histological 
transformation will be considered disease progression.
Subjects who relapse or progress will continue to be followed for SPMs for 5 years from the date 
of the last subject initiates induction therapy.
6.2.1
Adverse Events
Adverse events will be assessed and hospitalizations recorded from the signing of the informed 
consent form up to 28 days after the last dose of treatment with the exception of Second Primary 
Malignancies, see Section 6.2.2 below.
6.2.2
Second Primary Malignancies
Second primary malignancies are new cancers that are diagnosed in patients following a prior
diagnosis of a first cancer. For the MAGNIFY trial, the primary (first) cancer is follicular grades 
1-3b, transformed FL, marginal zone, or mantle cell lymphoma. Second primary malignancies will 
be monitored as events of interest and should be included as part of the assessment of adverse 
events throughout the course of the study. Investigators are to report any second primary 
malignancies as serious adverse events regardless of causal relationship to IP (study drug), 
occurring at any time for the duration of the study, from the time of signing the ICD for 5 years 
from the date the last subject initiates induction therapy.
 
6.2.3
Birth Control and Lenalidomide Counseling
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 all females of childbearing potential (FCBP)1 two pregnancy tests must be performed 
prior to the first dose of study drug: one test during Screening period (10 to 14 days prior to the 
first dose of lenalidomide) and one test within 24 hours prior to the first dose of lenalidomide. See 
the Pregnancy Prevention Plan for more details (standalone document).
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted on Day 1 of every lenalidomide treatment Cycle. All subjects must also be counseled 
against sharing lenalidomide and donating blood during and within 28 days of discontinuing 
                                                       
1 Female of child-bearing potential definition: a female who: 1) has achieved menarche at some point, 2) has not 
undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea 
following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months).
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
protocol-specified therapy. Pregnancy tests for all FCBP will be performed weekly during the first 
Cycle, every 28 days (Day 1 of every Cycle) during treatment, at study discontinuation, and at Day 
28 following study drug discontinuation. Additionally, for FCBP with irregular menstrual cycles 
pregnancy tests will be conducted weekly during the first 4 weeks of treatment and then every 14 
days through 28 days following the last dose of lenalidomide. See the Pregnancy Prevention Plan 
for more details.
6.2.4
Study Drug Return/Accountability
The reconciliation of capsules will be done at the beginning of each Cycle and at treatment 
discontinuation. See Sections 8.4, 8.5, and 8.6 for more details.
6.2.5
Prior and Concomitant Medications, Procedures and Hospitalizations
Relevant prior and concomitant medications, procedures and hospitalizations will be collected 
from signing of informed consent through 28 days after the last dose of investigational product, 
and will be recorded in the source documents.
6.2.6
Physical Examination
The subject must have a physical examination performed within 4 weeks prior to the first day of 
treatment. The physical examination assessments should be repeated at the beginning of each 
Cycle, at treatment discontinuation and at any additional times as deemed necessary by the 
investigator. Investigators are required to report any clinically significant abnormal findings as 
AEs.
6.2.7
Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG performance status (see Appendix C) will be measured within 2 weeks prior to the first day 
of treatment. ECOG status will also be measured at treatment discontinuation. Investigators are 
to report any clinically significant abnormal findings as AEs.
6.2.8
B Symptoms
The B symptom assessment is to be performed at Screening, at treatment discontinuation, and at 
any additional times as deemed necessary by the investigator.
B symptoms are fever (>38°C), night sweats, and weight loss greater than 10% within the prior 
6 months.
6.2.9
Vital Signs
Vital signs including height (at Screening only), weight, blood pressure, pulse, and temperature 
will be measured at the beginning of each Cycle, at treatment discontinuation and at designated 
times thereafter. Investigators are required to report any clinically significant abnormal findings 
as AEs.
6.2.10
Clinical Laboratory Safety Tests
The local laboratory will perform hematology and chemistry testing of Screening and on-study 
subject blood samples. Their results will be the basis for safety endpoint calculations. 
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
If Screening labs are drawn within 1 week before receipt of study drug on C1D1, they do not need 
to be repeated on C1D1.
Clinical laboratory safety tests will include hematology, serum chemistry, and thyroid stimulating 
hormone (TSH) assessment according to standard laboratory procedures. 
The principal investigator (PI) or medically-qualified designee will review and assess all clinical 
laboratory data. The laboratory reports should be initialed and dated by the PI or medically 
qualified designee, and the clinical significance of any abnormal laboratory results should be 
indicated. Abnormal laboratory results may be repeated to rule out laboratory errors. Any 
clinically-significant abnormal laboratory result should be reported as an AE and should be 
followed to resolution (ie, it returns to baseline or becomes clinically insignificant).
Additional clinical safety laboratory evaluations should be performed if judged clinically 
appropriate by the investigator or medically qualified designee, or if the ongoing review of the 
data suggests that a more detailed assessment of clinical laboratory safety evaluations is warranted.
6.2.10.1
Hematology
Hematology laboratory tests will include hemoglobin, hematocrit, white blood cell (WBC) count,
absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and platelet count. Any 
circulating abnormal cells (tumor cells) will also be recorded as the absolute count.
Hematology laboratory tests should be done before administration of study drugs; when these are 
required on these visits per Schedule of Study Assessments (Table 1), the allowed window periods
will be Day 1 (-3 days) of every treatment cycle, Day 8 (-1 day) and Day 15 (-1 day). Hematology 
tests will be required during the Screening Visit and Day 1 of every treatment Cycle (induction 
and maintenance period), Days 8 and 15 of Cycle 1, Day 15 of Cycles 2 and 3, and at treatment 
discontinuation.
Complete blood count (CBC), ANC, ALC and platelet count will be recorded in the CRF.
6.2.10.2
Serum Chemistry
Serum chemistry will include total protein, albumin, calcium, phosphorous, glucose, uric acid, 
total bilirubin, alkaline phosphatase, aspartate aminotransferase (AST) or serum glutamic 
oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT) or serum glutamic pyruvate 
transaminase (SGPT), sodium, potassium, chloride, blood urea nitrogen, creatinine, and LDH.
Serum chemistry laboratory tests should be done before administration of study drugs; when these 
are required on these visits per Schedule of Study Assessments (Table 1), the allowed window 
periods will be on Day 1 (-3 days) of every treatment cycle, Day 8 (-1 day) and Day 15 (-1 day).
Serum chemistry tests will be required during Screening and Day 1 of every treatment Cycle
(induction and maintenance period), Days 8 and 15 of Cycle 1, Day 15 of Cycles 2 and 3, and at 
treatment discontinuation.
Calcium, phosphorus, uric acid, potassium, creatinine, total bilirubin, AST, ALT and LDH will be 
recorded in the CRF.
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
6.2.10.3
Thyroid Stimulating Hormone
Thyroid stimulating hormone (TSH) will be assessed at Screening and end of induction treatment 
or treatment discontinuation and thereafter as clinically indicated during the maintenance treatment
period.  Results of TSH testing will be recorded in the CRF.
6.2.11
Assessments for Tumor Flare
Tumor flare assessments are conducted in Cycle 1 on Days 1, 8, and 15 (±1 day), and when 
clinically indicated thereafter.
Tumor flare reaction (TFR) is defined in the NCI-CTCAE version 3.0 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 non-Hodgkin 
lymphoma (NHL) (Witzig, 2009), TFR has also been reported at a lower rate in NHL patients 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 in subjects with CLL. 
Manifestations include 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 of lenalidomide and 
occurs within the first 2 to 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 to 2 weeks with or without intervention (Witzig, 2009).
The experience with tumor flare in Celgene-sponsored studies of single agent lenalidomide in NHL 
is summarized. Over 400 subjects with relapsed or refractory aggressive or indolent non-Hodgkin 
lymphoma have received lenalidomide in four Phase 2 clinical studies. These 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 non-Hodgkin lymphoma, 49 subjects with relapsed/refractory aggressive NHL, and 
217 subjects with relapsed/refractory aggressive NHL, respectively. These protocols suggested 
that any subject who experienced TFR during the first 1 to 2 weeks of Cycle 1 may be treated 
symptomatically with non-steroidal anti-inflammatory drugs (NSAIDS). TFR occurred in 4 
subjects in the NHL-001 study (Grade 1 [n = 1] and Grade 2 [n = 3]), in none in the NHL-002 
study; and in 7 of 217 subjects in the NHL-003 study (Grade 1 [n = 2], Grade 2 [n = 2 and Grade
3 [n = 3]). In a recent study evaluating lenalidomide as single agent in subjects with MCL (n =
134) who relapsed or progressed after or were refractory to bortezomib, TFR was reported in 13 
subjects (10%) (Goy, 2013).
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
In a single-center, open-label Phase 2 investigator-initiated study, Ahmadi et al evaluated the use 
of lenalidomide, dexamethasone, and rituximab (Cohort 1) versus lenalidomide plus rituximab 
(Cohort 2) in subjects with relapsed or refractory indolent B-cell or MCL resistant to rituximab 
(Ahmadi, 2011). Tumor flare was reported in 12 (5 in Cohort 1 and 7 in Cohort 2) of the 45 subjects 
(MCL and FL).
It is important to note that the increased lymphadenopathy seen in TFR may mimic PD. 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 the 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. 
6.2.12
Assessments for Tumor Lysis
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).
The experience with tumor lysis syndrome in Celgene-sponsored studies of single agent 
lenalidomide in NHL is summarized below. Three 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
study), 49 subjects with 
relapsed/refractory aggressive NHL (NHL-002 study), and 217 subjects with relapsed/refractory 
aggressive NHL (NHL-003 study). All three studies suggested that subjects receive tumor lysis 
prophylaxis (allopurinol or equivalent) and be well hydrated during the first 7 days of lenalidomide 
administration in the first Cycle or as clinically indicated. Grade 1 TLS occurred in 1 of the 309 
(0.3%) subjects receiving lenalidomide. There was one subject with findings consistent with 
laboratory evidence of TLS in the MCL-001 study, a Phase 2 clinical trial of single agent 
lenalidomide in subjects with MCL (Goy, 2013).
In an investigator-initiated study, a single-center, open-label Phase 2 study, Dutia et al evaluated 
the use of lenalidomide and rituximab in subjects with relapsed or refractory indolent B-cell NHL 
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
(Dutia, 2010). Two of the first four 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 recommended that subjects at risk for TLS receive prophylaxis 
(allopurinol, rasburicase, or equivalent as per institutional guidelines) during the first week of the 
first Cycle or as clinically indicated (see Section 9.3.1 for more information).
Tumor lysis syndrome assessments are conducted in Cycle 1 on Days 1, 8 (± 1 day), and 15 (± 1 
day), and when clinically indicated thereafter. 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 (if subject is at risk) as instructed (see Section 9.3.1 for more details).
Severity grading for TLS should follow the Cairo-Bishop Grading System for TLS (Appendix D)
rather than using the CTCAE version 4.03.
6.2.13
Deep Vein Thrombosis
6.2.13.1
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 single-agent lenalidomide. A significantly 
increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) has been observed 
in patients with multiple myeloma who were treated with lenalidomide and dexamethasone therapy 
(Revlimid PI, 2014).  Clinical data in multiple myeloma patients treated with lenalidomide 
suggests that concomitant administration of gluco-corticosteroids or erythropoietin can increase 
the thrombotic risk. Male gender and smoking history have also been reported to increase the risk 
of VTE in myeloma patients treated with lenalidomide (Leleu, 2011).
In the two pivotal randomized studies (MM-009 and MM-010) a significantly increased risk of 
DVT and PE was seen in subjects with multiple myeloma who were treated with REVLIMID® 
(lenalidomide) in combination with dexamethasone (Celgene, 2014). In these pivotal trials for 
REVLIMID® (lenalidomide) in subjects with multiple myeloma receiving lenalidomide plus 
dexamethasone, deep venous thrombosis and pulmonary embolism were reported in the 
lenalidomide plus dexamethasone arm at a rate of 7.4% and 3.7% of subjects respectively, 
compared to 3.1% 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 that thromboembolic events were significantly higher in subjects treated with 
lenalidomide/dexamethasone in the absence of prophylactic use of an anticoagulant (p < 0.001) 
(Dimopoulos, 2009). The effect of adding erythropoietin to lenalidomide/dexamethasone 
demonstrated a higher, but not statistically significant rate of thrombosis in the erythropoietin 
group, 18% versus 10% for the lenalidomide/dexamethasone group without the addition of 
erythropoietin (p = 0.14) (Weber, 2007). The ECOG trial (E4A03) evaluated lenalidomide 25 mg 
on Days 1 to 21 plus high-dose dexamethasone 40 mg on Days 1 to 4, 9 to 12, and 17 to 20 of a 
28-day Cycle (RD) versus lenalidomide plus low-dose dexamethasone 40 mg on Days 1, 8, 15,
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
and 22 (Rd) in subjects with newly-diagnosed multiple myeloma. Overall, 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.
More recently, Palumbo et al. (Palumbo, 2012) published results from an international multi-center 
phase 3 pivotal trial in patients administered lenalidomide maintenance therapy following 
melphalan, prednisone, and lenalidomide induction therapy (MPR+R) versus. patients receiving
MPR or MP induction therapy only. In this trial, the incidence of Grade 3 or 4 deep-vein 
thrombosis was 3% in the lenalidomide-containing induction treatment groups of the trial and 1% 
in the control group treated with melphalan-prednisone induction. During the maintenance phase 
of MPR-R, the incidence of new or worsened grade 3 or 4 adverse events was low (0 to 6%). Deep-
vein thrombosis was reported in 2 patients (2%) in the MPR-R group and 1 (1%) in the MPR 
group;
6.2.13.2
Deep Vein Thrombosis in Non-Hodgkin Lymphoma
Factors known to increase thrombotic risk in cancer patients in general, not necessarily those 
receiving lenalidomide, include the underlying disease, family history, age, obesity, 
immobilization, hormonal therapy, central venous catheter, recent DVT, doxorubicin and other 
factors (Zhou, 2010; Park, 2012; Lyman, 2013).
Venous thromboembolism including DVT and PE, has been reported in patients during treatment 
for NHL generally, 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 lymphoma (HG-NHL) 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.
In lenalidomide clinical trials, DVT and PE were reported in 7 (2.6%) and 6 (2.2%) of 266 subjects 
with relapsed or refractory aggressive NHL receiving lenalidomide in clinical studies NHL-002 
and NHL-003 (Wiernik, 2008; Witzig, 2011) and in 5 (4%) and 3 (2%) of 134 subjects with 
relapsed or refractory MCL receiving lenalidomide in the clinical study MCL-001 (Goy, 2013). 
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 was required for subjects considered to be high risk of developing DVT in NHL-003. In the 
recent CALGB study evaluating lenalidomide plus rituximab versus lenalidomide single agent 
therapy in relapsed FL subjects (N = 89), thrombosis was reported in 2 (4%) of 44 subjects in the 
lenalidomide plus rituximab arm versus 7 (16%) of 45 subjects in the lenalidomide arm (Leonard, 
2012). In a study evaluating lenalidomide plus rituximab in relapse refractory MCL subjects (n =
44), three thromboembolic events were reported (2 [5%] grade 3; 1 [5%]  Grade 4) after 379 Cycles
of lenalidomide plus rituximab (Wang, 2012).
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Final: 11 Sep 2022
It cannot be excluded 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 strongly recommended 
that all subjects at risk receive anti-thrombotic prophylaxis, and all subjects will be closely 
monitored for VTE, see Section 9.1.2.
6.3
Efficacy Assessments
Radiological assessments for efficacy will be CT scan or MRI, to confirm the presence of 
measurable disease of > 1.5 cm in the transverse diameter at baseline. A CT is to be performed 
with contrast unless it is medically contraindicated. The regions to be imaged can be the neck, 
chest, and abdomen/pelvis, as well as any other regions clinically indicated for tumor imaging. 
The same imaging modality and regions for lesion evaluation at Screening must be consistently 
used throughout the study. CT/MRI scan performed for the purpose of standard of care may be 
used as the Screening CT scan if it is obtained within 8 weeks prior to C1D1.
All CT or MRI scan assessments will be determined from first dose date and will follow the 
counting of the dosing Cycles (ie, 1 cycle = 28 days). It is critical that the same modality used at 
Screening be used throughout the study for each subject. The scans must be performed:

At 3 cycles after C1D1 (84 days ± 2 weeks) 

At 6 cycles after C1D1 (168 days ± 2 weeks)

then every 6 cycles (168 days ± 2 weeks) for 5 years

and annually (± 3 weeks) thereafter until disease progression, relapse, or initiation of new anti-
lymphoma therapy

After the confirmation of the 114 PFS events, no efficacy assessments will be conducted
A subject with positive bone marrow at Screening will have a repeat bone marrow biopsy to 
confirm radiological CR only if the subject has otherwise fulfilled the criteria for a nodal CR; this 
bone marrow biopsy should be performed within 28 days after the criteria for CR have otherwise 
been met.
In addition to CT/MRI scan to assess disease, subjects with MZL involving the gastric area will 
undergo endoscopy as part of the response assessment. Subjects will have a repeat gastric biopsy 
for histological evaluation if the subject has fulfilled the IWG criteria for response of at least a 
CR/CRu. Histological evaluation will be performed by local pathologies laboratories using the 
GELA grading system (Copie-Bergman, 2003; Copie-Bergman, 2012; see also Section 6.1.6).
All enrolled subjects are followed for PD or relapse using the schedule described in Table 1.This 
includes subjects who discontinue treatment for any reason without documented evidence of PD 
or relapse. Subjects who start a new anti-lymphoma therapy without evidence of PD or relapse 
will not be followed by radiological assessments.
Since the study endpoint is PFS based on CT, 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.
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Final: 11 Sep 2022
The radiological assessments (CT or MRI) and other assessments will be made according to a 
modification of the IWG 1999 criteria (Cheson, 1999), which are considered the primary method 
of response assessment. Scan results will be assessed by the Investigator or qualified site 
personnel. The modifications to the Cheson 1999 criteria are:

Allow the inclusion of extranodal disease as measurable disease, as long as they fulfill all other 
requirements of measurable disease, including >1.5 cm in the longest transverse diameter. 

> 2.0 cm bone marrow biopsy length is not required if the biopsy sample is considered adequate 
for assessment by the investigator.

Gastric MALT subjects are required to undergo an additional evaluation of endoscopy and 
gastric biopsy at 2 time points within 3 months of radiologic evaluation demonstrating 
CR/CRu.

PET scan is not considered part of the response criteria. 
A similar modification to include extranodal disease as a measurable disease has been used 
previously (Fisher, 2006; Kane, 2007). The additional assessments – clinical assessments, bone 
marrow biopsy assessments, and endoscopic assessments (including biopsy) – are considered 
confirmatory to the initial CT scan findings. Bone marrow assessments are considered in the 
response assessment only in subjects with bone marrow involvement in the baseline bone marrow 
biopsy. Endoscopic biopsy and evaluation of the biopsy findings are required for confirmation of 
response only in subjects with an investigator-assessed pathologic diagnosis of MZL involving the
gastric area. 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.
Subjects who relapse or progress will continue to be followed for TTNLT and survival for 5 years 
from the date of the last subject initiating induction therapy.
6.3.1
Subsequent Anti-lymphoma Therapy
In the Follow-up Period, 
for subsequent anti-
lymphoma therapy. The date of first documented administration of a new anti-lymphoma treatment 
regimens following discontinuation from the study treatment will be recorded. After the 
confirmation of 114 PFS events, there will be no assessment of subsequent anti-lymphoma therapy.
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Final: 11 Sep 2022
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
7
STUDY POPULATION
Subjects must have an investigator-assessed diagnosis of Grade 1, 2,3a, 3b FL, transformed FL, 
MZL, or MCL Stage I to IV, must have been previously treated for their lymphoma, must be 
refractory or must have relapsed after their last treatment, must have at least one measurable nodal 
or extranodal lesion by CT or MRI scan, and must have adequate bone marrow function, liver 
function and renal function.
7.1
Number of Subjects and Sites
Approximately 500 subjects in the USA are planned to be enrolled in this study. Celgene 
Corporation will select approximately fifteen (15) sites within Germany. Subject enrollment will 
include approximately 50 subjects in Germany collectively.
7.2
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1) Males and females ≥ 18 years old at the time of signing the informed consent document
2) Histologically confirmed FL (Grade 1, 2, 3a, or 3b), transformed FL, MZL, or MCL by WHO 
2008 classification (Jaffe, 2009) as assessed by the investigator or local pathologist
3) Must have been previously treated with at least one prior treatment for lymphoma including 
radiotherapy, chemotherapy, immunotherapy, chemoimmunotherapy, or novel agent.
4) Must have documented relapsed, refractory or PD after last treatment 
a) Relapsed lymphoma:  defined as subject who relapsed after initial response of CR to prior 
therapy
b) Progressive lymphoma:  defined as subject who progressed after initial response of PR or 
SD to the prior therapy
c) Refractory lymphoma:  defined as subjects who received therapy and who experienced a 
best response of PD
d) Subjects with gastric MALT lymphoma and evidence of H. pylori infection must have 
documented non-response to antibiotic therapy as judged by a minimum follow-up of 12 
months after successful H. pylori -eradication
e) Subjects who are rituximab-refractory (defined as a subject who experienced a best 
response of PD or SD to treatment with rituximab or a rituximab-containing regimen OR 
a response (PR or CR) lasting fewer than 6 months following the last rituximab dose) are 
eligible
5) Bi-dimensionally measurable disease on cross sectional imaging by CT or MRI with at least 
one lesion > 1.5 cm in the transverse diameter, as defined by a modification of the IWG 1999 
criteria (Cheson, 1999; see Section 6.3). Measurable disease cannot be previously irradiated
6) Must be in need of treatment for relapsed or refractory disease as assessed by the investigator
7) Performance status < 2 on the ECOG scale (Appendix C)
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8) All females of childbearing potential (FCBP)2 must:
a) Have two negative pregnancy tests as verified by the study doctor prior to starting study 
therapy. She must agree to ongoing pregnancy testing during the course of the study, and 
after end of study therapy. This applies even if the subject practices true abstinence3 from 
heterosexual contact
b) Either commit to true abstinence3 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), and for 28 days after discontinuation of study therapy
9) Male subjects must:
a) Must practice true abstinence3 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
10) 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 drug 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 study drug discontinuation
11) Understand and voluntarily sign an informed consent document prior to any study-related 
assessments/procedures being conducted
12) Able to adhere to the study visit schedule and other protocol requirements
7.3
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1) Presence or history of CNS involvement by lymphoma
2) Any medical condition (other than the underlying lymphoma) that requires chronic steroid use
3) Subjects taking corticosteroids during the last 1 week prior to C1D1, unless administered at a 
dose equivalent to < 20 mg/day of prednisone (over this week)
4) Major surgery (excluding lymph node or bone marrow biopsy) within 28 days prior to signing 
informed consent
                                                       
2 See definition in 6.2.3. 
3 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the patient. (Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception).
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
5) Systemic therapy within 28 days prior to Day 1 dosing or use of the following prior to Day 1 
dosing:
a) Antibody agents within 4 weeks
b) Radioimmunotherapy within 3 months
6) Seropositive for or active viral infection with hepatitis B virus (HBV):  

HBsAg positive

HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral DNA
Note:  Subjects who are HBsAg negative, anti-HBs positive, and/or anti-HBc positive, but 
viral DNA negative are eligible

Subjects who are seropositive because of HBV vaccination are eligible (HBV surface 
antibody positive, HBV core antibody negative, and HBV surface antigen negative)
7) Known seropositive for or active infection with hepatitis C virus (HCV), including positive 
HCV RNA
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 (rituximab)
11) Prior history of invasive malignancies, other than FL, transformed FL, MZL or MCL unless 
the subject has been free of the disease for ≥ 5 years. Exceptions include a history of previously 
treated:
a) Localized non-melanoma skin cancer
b) Carcinoma in situ of the cervix
c) Carcinoma in situ of the breast
d) Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
12) Prior use of lenalidomide
13) Known allergy to thalidomide
14) Neuropathy > Grade 2
15) Subjects who are at a risk for a thromboembolic event and are not willing to take VTE 
prophylaxis
16) Any of the following laboratory abnormalities during Screening period:
a) Absolute neutrophil count (ANC) < 1.5 x 109/L unless secondary to bone marrow 
involvement by lymphoma as demonstrated by recent bone marrow aspiration and bone 
marrow biopsy
b) Platelet count <75 x 109/L unless secondary to bone marrow involvement by lymphoma 
as demonstrated by recent bone marrow aspiration and bone marrow biopsy
c) Hemoglobin < 8.0 g/dL (5 mmol/L) unless secondary to bone marrow involvement by 
lymphoma as demonstrated by recent bone marrow aspiration and bone marrow biopsy
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
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
e) Total bilirubin > 2.0 mg/dl (34 µmol/L) except in cases of Gilberts Syndrome and 
documented liver or pancreatic involvement by lymphoma
f)
Creatinine clearance of < 30 mL/min
17) Uncontrolled intercurrent illness including, but not limited to:
a) Uncontrolled diabetes mellitus as assessed by the investigator
b) Chronic symptomatic congestive heart failure (Class III or IV of the New York Heart 
Association Classification for Heart Disease
c) Unstable angina pectoris, angioplasty, stenting, or myocardial infarctions within 6 months
d) Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or 
asymptomatic sustained ventricular tachycardia. Subjects with controlled atrial fibrillation 
that is asymptomatic are eligible.
18) Any significant medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form and participating in the study
19) Any condition including the presence of laboratory abnormalities, that places the subject at 
unacceptable risk if he/she were to participate in the study
20) Any condition that confounds the ability to interpret data from the study
21) Pregnant or lactating females
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
8
DESCRIPTION OF STUDY TREATMENTS
8.1
Description of Investigational Product(s)
Investigational products in this study are lenalidomide and rituximab.
Celgene Corporation will supply lenalidomide 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg capsules 
for oral administration. Subjects will receive treatment with lenalidomide for 21 days per Cycle.
Study drug will be packaged in bottles containing study capsules for days 1 - 21 of every 28 day 
Cycle.
Commercially available intravenous (IV) formulation of rituximab may be used. 
In Germany, Celgene Corporation will supply both lenalidomide capsules and rituximab
intravenous formulation as investigational products.
8.2
Treatment Administration and Schedule
Eligible subjects entering the Induction Treatment Phase will be enrolled using an Interactive 
Voice Response System (IVRS). Subjects entering the Maintenance Phase will be randomized 
using the IVRS into one of two arms (experimental or control) in a 1:1 ratio. Randomization will 
be stratified as described in Section 8.3. Subjects randomized under previous protocol (version 16 
January 2014) who achieve a response of SD or better at the end of the Induction Treatment Period 
will remain in their originally assigned arm of maintenance therapy.
Study Treatments, please see Sections 8.2.1 and 8.2.2 for details

Induction Period (12 Cycles)
Lenalidomide 20 mg (10 mg if creatinine clearance ≥ 30 mL/min but < 60 mL/min) once daily 
on Days 1 to 21 of every 28-day Cycle for Cycles 1 to 12 AND rituximab 375 mg/m2 every 
week in Cycle 1 (Days 1, 8, 15, and 22) and Day 1 of every 28-day Cycle for Cycles 3, 5, 7, 9, 
and 11
Followed by Maintenance Period

Arm A (Experimental arm):  Lenalidomide + rituximab (Maintenance) followed by optional 
lenalidomide (Maintenance)

Maintenance Period (18 Cycles)
Lenalidomide 10 mg once daily on Days 1 to 21 of every 28-day Cycle for Cycles 13 to 30 
AND rituximab 375 mg/m2 on Day 1 of every 28-day Cycle for Cycles 13, 15, 17, 19, 21, 
23, 25, 27, and 29
Followed by

Optional Maintenance Period (up to PD)
Lenalidomide 10 mg once daily on Days 1 to 21 of every 28-day Cycle up to PD. This 
treatment will be at the discretion of the subject and the investigator. 
VERSUS
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022

Arm B (Control arm):  Rituximab (Maintenance)

Maintenance Period (18 Cycles)
Rituximab 375 mg/m2 on Day 1 of every 28-day Cycle for Cycles 13, 15, 17, 19, 21, 23, 
25, 27, and 29
Induction treatment must begin no later than 1 week after enrollment in IVRS to receive induction 
therapy. The Treatment Period for each subject starts with first intake of study drug, which is 
defined as Day 1 of Cycle 1.
8.2.1
Lenalidomide Therapy
Lenalidomide dosing will be based on a subject’s creatinine clearance calculated using the 
Cockcroft-Gault formula and actual body weight. This calculation will be performed at Screening
by the local laboratory utilizing actual body weight. 

Subjects who have a creatinine clearance ≥ 60 mL/min will receive oral lenalidomide at a dose 
of 20 mg once daily on Days 1 to 21 in each 28-day Cycle. A minimum 7-day rest period 
following the 21 days of dosing is mandatory regardless of the allowed visit windows.

Subjects who have moderate renal insufficiency (creatinine clearance ≥ 30 mL/min but < 60 
mL/min) will receive a lower starting dose of lenalidomide of 10 mg once daily on Days 1 to 
21 of the 28-day Cycle in Cycle 1 and in Cycle 2. A minimum 7-day rest period following the 
21 days of dosing is mandatory regardless of allowed visit windows. 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.

Subjects who have renal insufficiency (creatinine clearance < 30 mL/min) are to be excluded 
from the study.
Lenalidomide should be taken at approximately the same time every day. There is no requirement 
for taking lenalidomide with or without food, or with or without certain types of foods or liquids. 
If a subject misses a dose of lenalidomide 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 postdose;
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.
Lenalidomide may be administered until disease progression; therefore, there is no need to “make 
up” a missed dose due to a transient toxicity. If a delay for toxicity occurs during planned treatment 
days, subjects should skip those days and either restart drug immediately after the toxicity resolves
or finish the mandatory seven-day rest period, as appropriate. If a delay for toxicity extends the 
rest period beyond 7-days, the next dose of drug should begin a new Cycle.
8.2.2
Rituximab Therapy
The planned dose of rituximab is 375 mg/m2 every week in Cycle 1 (Days 1, 8, 15, and 22) and 
on Day 1 of every other 28-day Cycle up to 30 Cycles (3, 5, … 29). Premedication should be 
administered (see Rituximab PI and Section 9.3.2). The infusion should be according to 
instructions in the package insert and institutional guideline.
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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 information for further information on rituximab therapy including 
guidance on pregnancy restrictions.
8.2.3
Lenalidomide Therapy in Maintenance
The planned dose of lenalidomide during the Maintenance Therapy Period is 10 mg once daily on 
Days 1 to 21 of a 28-day Cycle. A minimum 7-day rest period following the 21 days of dosing is 
mandatory regardless of allowed visit windows.

Subjects who have undergone dose reduction for adverse events during the Induction Period 
(first 12 Cycles) and are receiving lenalidomide at a dose less than 10 mg will continue at their 
current dose during maintenance. No dose increase will be permitted.
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 
drug(s) causing the toxicity.
8.2.4.1
Overdose
Overdose as defined for this protocol, refers to lenalidomide and rituximab. On a per dose basis, 
an overdose is defined as the following amount over the protocol-specified dose of these drugs 
assigned to a given subject, regardless of any associated adverse events or sequelae:
Per oral
any amount over the protocol-specified dose
Intravenous
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. 
See Section 11.1 for the reporting of adverse events associated with overdose.
8.2.4.2
Dose Modification or Interruption for Lenalidomide
The dose of lenalidomide for each subject will be interrupted and modified following toxicity as 
described in Table 2. Refer to Table 3 and Table 4 (and Table 5 for the maintenance period) for 
dose reduction instructions for study drug; the dose may also be reduced for reasons in addition to 
those listed in Table 2 per investigator discretion. If a dose is reduced, re-escalation is not permitted
unless discussed with Celgene Medical Monitor.
If a subject experiences an AE that requires a dose interruption, the subject cannot be re-started on 
study drug 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 [and Table 5 for the maintenance period] for the actual dose) for the 
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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 for that
next Cycle once the AE has resolved and the requirements detailed below have been met.
The new Cycle of treatment may begin on the scheduled Day 1 of the next Cycle once a 7-day rest 
period has occurred and if:

The ANC is ≥ 1,000 cells/mm³ (1.0 x 109/L).

The platelet count is ≥ 50,000 cells/mm³ (50 x 109/L).

Lenalidomide-related allergic reaction or hypersensitivity not requiring discontinuation has
resolved to ≤ Grade 1 severity.

Any other lenalidomide-related AE not requiring discontinuation has resolved to ≤Grade 2 
severity.
If these conditions are not met on Day 1 of a new Cycle, the subject will be evaluated at least once 
every seven days and a new Cycle of study drug will not be initiated until the toxicity has resolved 
as described above. If a new Cycle is delayed for more than 28 consecutive days (counting begins 
following the mandatory 7-day rest period), the Medical Monitor must be notified. The treatment 
can be resumed according to the treating physician and could be discussed with the Medical 
Monitor.
The study assessments should remain in line with dosing days (the actual number of days that 
lenalidomide plus rituximab has been administered) but the tumor assessments will be determined 
from C1D1 and will follow the counting of the dosing Cycles, ie, 28-day cycles.
Table 2:
Dose Modification for Lenalidomide
NCI CTCAE
Toxicity Gradea
ACTION REQUIRED
Grade 3 neutrophil count 
decreased (neutropenia)
(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 [50 x 109/L])

Hold (interrupt dose)

Follow CBC weekly

If thrombocytopenia resolves to ≤ Grade 2 restart at next lower 
dose level
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Table 2:
Dose Modification for Lenalidomide
NCI CTCAE
Toxicity Gradea
ACTION REQUIRED
Rash
Grades 1-2

Determine the causative study drug(s)

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

Dermatology evaluation

Consider supportive measuresb
Desquamating (blistering) rash
Any Gradec

Discontinue lenalidomide

Dermatology evaluation

Consider supportive measuresb
Stevens-Johnson Syndrome or 
Toxic epidermal necrolysis

Discontinue lenalidomide

Dermatology evaluation
Allergic reaction or 
hypersensitivity
Grade 2

Determine the causative study drug(s)

Hold (interrupt) dose. Follow at least every seven days

When the toxicity resolves to ≤ Grade 1 restart at next lower 
dose level
Grades 3-4

Discontinue lenalidomide
Constipation
Grades 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
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.
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
Table 2:
Dose Modification for Lenalidomide
NCI CTCAE
Toxicity Gradea
ACTION REQUIRED
Tumor Flare Reaction (TFR)a
Grades 1-2

Continue lenalidomide, maintain dose level

At the investigator’s discretion may initiate therapy with 
NSAIDs, limited duration corticosteroids, and/or narcotics
Grades 3-4

Hold (interrupt dose) and initiate therapy with NSAIDs, 
corticosteroids, and/or narcotics

When symptoms resolve to ≤ Grade 1, restart at same dose 
level for the rest of the Cycle
Laboratory TLS or Grade 1 TLS

Continue lenalidomide (maintain dose), or at the investigator’s 
discretion, continue lenalidomide 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
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
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
Table 2:
Dose Modification for Lenalidomide
NCI CTCAE
Toxicity Gradea
ACTION REQUIRED
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 at the same dose

If hyperthyroidism confirmed and alternative etiologies 
eliminated, restart lenalidomide dosing at next lower dose
Liver Functiond
ALT Grade 2 
( >3 - 5 x ULN)
and
Total bilirubin Grade 1
(> ULN - 1.5 x ULN)

Continue study drug:  re-test at next scheduled visit

No dose modification
ALT ≥ 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, perform weekly 
testing of liver functions during that Cycle and then decrease 
the dose by one level when recovered (returned to baseline)
Cairo-Bishop Toxicity Grade (see Appendix D)
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
Notes:  AE:  Adverse Event; ALT:  alanine aminotransferase; ASCO:  American Society of Clinical Oncology ; CBC:  
Complete Blood Count; ESMO:  European Society for Medical Oncology; G-CSF:  Granulocyte Colony-Stimulating 
Factor; GM-CSF:  Granulocyte-Macrophage Colony-Stimulating Factor; LLN:  lower limit of normal; NCI CTCAE:  
National Cancer Institute Common Terminology Criteria for Adverse Events; NSAID:  non-steroidal anti-
inflammatory drugs; PO:  Per Oral; QAM:  every morning; QPM:  every evening; TFR:  Tumor Flare Reaction; TLS:  
Tumor Lysis Syndrome; TSH:  Thyroid stimulating hormone; ULN:  upper limit of normal.
a AEs are Graded using the NCI CTCAE vrsion 4.03; however TFR will be graded using NCI CTCAE version 3.0.
Severity grading for TLS should follow the Cairo-Bishop Grading System for TLS (Appendix D) (not CTCAE 
version 4.03).
b Suggested supportive measures - 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 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 of the lenalidomide treatment.
c In cases of Grade 4 or desquamating rash, prompt dermatologic evaluation with skin biopsy is strongly 
recommended.
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
d For subjects with Gilberts Syndrome or liver involvement by lymphoma, dose reductions should be made in 
consultation with the Medical Monitor.
8.2.4.3
Dose Reduction Levels Based on Lenalidomide Starting Dose
The daily dose of lenalidomide 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.
Note, rituximab dosing should continue as per protocol even if lenalidomide has been discontinued 
due to toxicity.
Subjects who cannot tolerate the lowest applicable dose level are to be discontinued from the 
Treatment Phase.
For subjects with a starting dose of 20 mg 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 (a decrement of 5 mg; refer to Table 3) at the next treatment Cycle if toxicity requiring dose 
modifications (as in Section 8.2.4.2) 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 (Days 1 to 21 of 28 days)
in Cycle 1 and 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

The daily oral dose of study drug may be reduced successively by one level in response to an 
event of toxicity as described in Table 2
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 unless discussed with medical 
monitor.
b Subjects who cannot tolerate Dose Level 4 are to be discontinued from the Treatment Period of the study.
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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 Day Cycles
Level -1
a
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 to 21 of each 28 day Cycle at the discretion of the treating physician from 
Cycle 3 onwards.
a, b Once the dose is escalated to 15 mg once daily for 21 days every 28 days, the 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 unless discussed with medical monitor.
c, d Subjects who cannot tolerate Dose Level 3 are to be discontinued from the Treatment period of the study.
8.2.4.4
Dose Reduction Levels Based on Lenalidomide Maintenance Starting 
Dose
The daily dose of lenalidomide in maintenance may be reduced successively by one level from the 
starting dose. There will be no more than one dose level reduction from one Cycle to the next 
unless otherwise permitted after consultation with the medical monitor. No dose (re)escalation is 
permitted at any time.
Subjects who cannot tolerate the lowest applicable dose level are to be discontinued from the 
Treatment Phase.
The daily oral dose of study drug shall be reduced by one level (refer to Table 5) at the next 
treatment Cycle if toxicity requiring dose modifications (as in Section 8.2.4.2; Table 2) has 
occurred during the previous treatment Cycle.
Table 5:
Dose Reduction Steps for Adverse Events Related to Study Drug for 
Subjects Initiating Maintenance Treatment at 10 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)
10 mg daily on Days 1-21, every 28 days
Level 2a
5 mg daily on Days 1-21, every 28 days
Level 3a
2.5 mg daily on Days 1-21, every 28 days
Level 4a, b
2.5 mg every other day on Days 1-21, every 28 days
a Once a subject's dose has been reduced, no dose re-escalation will be permitted unless discussed with medical 
monitor.
b Subjects who cannot tolerate Dose Level 4 are to be discontinued from the Treatment Phase of the study.
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
8.2.4.5
Dose Adjustment for Rituximab
The dose of rituximab will be interrupted and modified according to the clinical practice of the 
investigator’s institution, and in line with the approved prescribing information, including 
administration, warnings, precautions, contraindications, and adverse reactions, as applicable.
In case a dose is missed during the Cycle because of toxicity, it will not be rescheduled. In case of 
delay in the start of the next Cycle due to toxicity, rituximab of the next Cycle will be postponed 
until the AE has resolved, at which point the next Cycle is started.
8.3
Method of Treatment Assignment
Enrollment into the Induction Treatment Period will occur in the Screening Period, once all the 
required Screening procedures have been completed and subject meets all eligibility criteria, and 
all required data have been submitted to the IVRS/ Interactive Web Response System (IWRS)
system. Upon completion of 12 cycles of induction therapy and achieving a response of PR or 
CR/CRu or having SD, the maintenance treatment will be randomly assigned using the IVRS.
Subjects randomized under previous protocol (version 16 January 2014) who achieve a response 
of SD or better at the end of the Induction Treatment Period will remain in their originally assigned 
arm of maintenance therapy.

Subjects will undergo randomization in a 1:1 ratio to either Arm A (maintenance therapy as 
rituximab plus lenalidomide followed by optional lenalidomide) or Arm B (maintenance 
therapy as rituximab). The randomization procedure will be accomplished by a validated 
interactive voice response system (IVRS/IWRS).

Randomized subjects will be stratified by:

Histology (FL (grades 1-3b and transformed FL) versus MZL versus MCL)

Lines of anti-lymphoma therapy (≤ 2 vs. > 2 lines)

Age (< 65 vs. ≥65 years)
8.4
Packaging and Labeling
Lenalidomide will be packaged in bottles and each bottle will contain 21 capsules.
The label(s) for IP will include sponsor name, address and telephone number, the protocol number, 
IP name, dosage form and strength (where applicable), amount of IP per container, lot 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.
In Germany, rituximab intravenous formulation packaging and label will be provided as 
investigational product.
8.5
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.
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
Celgene (or designee) will review with the investigator and relevant site personnel the process for 
Investigational Product return, disposal, and/or destruction including responsibilities for the site 
vs. Celgene (or designee).
8.6
Investigational Product Compliance
For the oral medication lenalidomide, 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, the reconciliation of capsules will be done at the beginning of each Cycle and at 
treatment discontinuation.
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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 prescription and over-the-counter medications, treatments and therapies 
which are related to an adverse event or are clinically relevant from 28 days prior to the start of 
the study drug through the last dose of study drug must be recorded on the appropriate page of the 
CRF.
9.1.1
Tumor Flare Reaction 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 in 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. The 
decision by the investigator to take prophylactic measures should be made carefully after an 
assessment of an individual subject’s underlying risk factors.
As reference information, for subjects receiving lenalidomide in open-label trials, it is strongly 
recommended that subjects with VTE risk receive either aspirin (70 – 325 mg PO 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 International Normalized Ratio [INR] of 2.0). 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
Growth factors (e.g., G-CSF, erythropoietin) 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 administered during the Screening Period to 
increase a subject’s blood values in order to meet entry criteria and are not to be administered 
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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 or equivalent) is 
prohibited during the Treatment Phase. For subjects receiving systemic corticosteroids at doses 
above 20 mg/day (prednisone 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 or equivalent) are allowed for the treatment of TFR 
at any time, for rituximab cytokine release syndrome prophylaxis with each rituximab infusion on 
Cycle 1 Day 1, 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.
9.3
Required Concomitant Medications and Procedures
9.3.1
Tumor Lysis Syndrome Prophylaxis
All subjects at risk for TLS should receive TLS prophylaxis (allopurinol, rasburicase or equivalent 
as per institutional guidelines) and be well hydrated (orally) during the first week of the first Cycle 
or as clinically indicated. Hydration levels should be adjusted according to age and clinical status. 
To monitor for TLS, the subjects will have 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 per investigator discretion. Any 
subject contact that is made on Day 5 (± 1 day) should be documented in the subject’s medical 
record, and any AEs that are discovered should be captured on the CRF. TLS will be assessed by
the Cairo-Bishop Grading system (see Appendix D).
9.3.2
Rituximab Premedication
Premedication consisting of acetaminophen and an antihistamine should be administered before 
each rituximab infusion (see package insert). 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 and infusion rate should be applied 
as recommended by the manufacturer/current guidelines.
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
10
STATISTICAL ANALYSES
10.1
Overview
The objective of the statistical analyses is to compare the efficacy and safety of lenalidomide plus 
rituximab combination maintenance therapy (for 18 cycles) followed by optional lenalidomide 
single-agent maintenance (to progression) versus rituximab single-agent maintenance (for 18 
cycles) after 12 cycles of induction therapy with lenalidomide plus rituximab in subjects with 
relapsed/refractory follicular lymphoma grades 1-3b, transformed follicular lymphoma, marginal 
zone lymphoma, or mantle cell lymphoma.
All statistical analyses specified in this protocol will be conducted using SAS® version 9.2 or 
higher.
10.2
Study Population Definitions
The following three populations, defined as below, will be used in the analysis.
Intent-to-treat (ITT) population:  The ITT population is defined as all subjects who are 
randomized and have received at least one dose of maintenance therapy.
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 Intent-to-treat (mITT) population:  The mITT population is defined as all subjects 
who satisfy the following conditions:
1) are randomized
2) have received at least one dose of maintenance therapy
3) have confirmed diagnosis of relapsed/refractory FL grades 1-3b, transformed FL, MZL, or 
MCL
4) have SD, PR or CR/CRu after completing induction therapy
5) have at least one tumor assessment for efficacy after beginning of maintenance therapy
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 drug, including induction therapy. The safety population will be used for all safety 
analyses. For safety analysis of the maintenance period, subjects will be analyzed according to the 
treatment that they actually received.
Induction Efficacy Population: The Induction Efficacy Population is defined as all subjects who 
meet all of the criteria for eligibility into the study.
 
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
10.3
Sample Size and Power Considerations
The main objective of the study is to demonstrate the efficacy of lenalidomide plus rituximab
maintenance therapy followed by the optional lenalidomide single-agent maintenance versus the 
rituximab single-agent maintenance. The primary endpoint is PFS, which is defined as the time 
from the first dose date of maintenance therapy to objective disease progression or death from any 
cause, whichever occurs first.
To fulfill the primary objective of the study, it must be shown that the experimental arm (Arm A)
is superior to the control arm (Arm B) on the primary endpoint at a one-sided α = 0.025 level. It is 
hypothesized that the median PFS from the first dose date of maintenance therapy is 
in 
Arm A and 
 in Arm B for FL (grades 1-3b and transformed FL) and MZL subjects, and 
that the median PFS from the first dose date of maintenance therapy is 
 in Arm A and 
 in Arm B for MCL subjects (about 10% are MCL subjects) (corresponding to a hazard 
ratio of 
 for all histologies). The sponsor may make a determination to close entry to one or 
more histologies if enrollment is skewed or oversubscribed. For 80% power to detect this 
difference with a one-sided α = 0.025, a total of 191 PFS events that happen after the first dose 
date of maintenance therapy would have been required.
Based on the rate of accrual anticipated in this study, and an annual dropout rate of 5%, it was 
planned to enroll a total of 500 subjects to the induction treatment phase. It was projected that
approximately 314 subjects would have been randomized at a ratio of 1:1 into the two maintenance 
treatment arms based on an estimated response rate of the induction therapy (Wang, 2012; 
Leonard, 2012). It was expected that the 191 PFS events that occur after the first dose date of 
maintenance therapy would have been available in about 57 months from the first dose date of 
maintenance therapy, and the total study duration from the beginning of induction period would 
have been about 69 months.
 
. The primary efficacy endpoint is planned 
now at 114 PFS events. The expected accrual duration for 500 subjects is approximately 
63 months. The study duration to events for primary analysis is estimated to be 105 months. The 
duration of the entire study will be approximately 10 years (accrual period of approximately 
5 years plus 5 years from last subject initiating induction therapy).
Assuming a hazard ratio (HR) of 
, the power is about 57.9%. If HR is 20% better than 
originally assumed, ie, HR = 0.533, the power would be 92%.
Sample size was calculated using the East® Version 6.5 software system (Cytel Inc., 675
Massachusetts Avenue, Cambridge, MA 02139, http://www.cytel.com).
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
10.4
Background and Demographic Characteristics
All subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race, histology, and other categorical variables will be provided using 
frequency tabulations. Medical history data will be summarized using frequency tabulations by 
system organ class and preferred term.
10.5
Subject Disposition
Subject disposition (analysis population allocation, randomization status, discontinuation of 
treatment, primary reason for early treatment discontinuation, discontinuation of study, and 
primary reason for early study discontinuation) will be summarized using frequency and 
percentage for all enrolled subjects. A summary of subjects enrolled by site will be provided. 
Protocol deviations will be summarized using frequency tabulations.
10.6
Efficacy Analysis
All efficacy analyses will be performed on the ITT population. Efficacy analyses will also 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.
10.6.1
Primary Efficacy Endpoint
Progression-free Survival
The primary efficacy endpoint for the study is PFS, which is defined as the time from the first dose 
date of maintenance therapy to objective disease progression or death from any cause, whichever 
occurs first. The PFS events will be determined using a modification of the IWG 1999 criteria
(Cheson, 1999). 
Subjects who did not experience disease progression and who did not die before the clinical data 
cut-off date will be censored at the time of the last visit with adequate response assessment when 
the subjects were known not to have progressed. Subjects who received new anticancer therapy 
without objective disease progression will be censored at the date of the last radiological 
assessment prior to the new anticancer therapy.
The primary efficacy endpoint will be compared between the two treatment arms when 114 PFS 
events that happen after the first dose date of maintenance therapy are observed. 
10.6.2
Secondary Efficacy Endpoint
Secondary efficacy endpoints will include OS, IOR, ORR, CRR, DOR, DOCR, TTNLT and 
TTHT.
Overall Survival
The OS is defined as the time between the first dose date of maintenance therapy and death from 
any cause.  Subjects who complete the study and are still alive at the time of the clinical data cutoff 
date will be censored at the last visit date or the last contact date, whichever is later.  Subjects who 
were lost to follow-up prior to the clinical data cut-off date will also be censored at the time of the
last contact.
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Final: 11 Sep 2022
Overall survival information will be collected for 5 years from the date of the last subject initiating 
induction therapy. The additional OS data may be analyzed as supplementary information. No 
formal hypothesis testing will be performed post the final primary endpoint analysis.
Improvement of Response
Improvement of response is defined as the proportion of subjects who have improved their tumor 
response during the maintenance phase, that is, the proportion of subjects who are converted from 
PR at the end of induction period to CR/CRu as best response, and subjects who are converted 
from SD at the end of induction period to PR or better as best response during the maintenance 
phase.
Overall Response Rate
Overall response will be analyzed in two aspects. The overall response rate at the end of 18 cycles 
of maintenance therapy is defined as the proportion of subjects with a response of at least PR 
(including CR, Cru, and PR) by the end of 18 cycles of maintenance therapy and prior to any 
treatment change. 
In addition, best ORR, defined as the proportion of subjects with a best response of at least PR 
(including CR, CRu and PR) after the first dose date of maintenance therapy and prior to any 
treatment change, will also be presented.
Complete Response Rate
Complete response will also be analyzed in two aspects. The complete response rate at the end of 
18 cycles of maintenance therapy is defined as the proportion of subjects with a response of at 
least CRu (including CR and CRu) by the end of 18 cycles of maintenance therapy and prior to 
any treatment change. 
In addition, best CRR, defined as the proportion of subjects with a best response of at least CRu 
(including CR and CRu) after the first dose date of maintenance therapy and prior to any treatment 
change, will also be presented.
Duration of Response
Duration of response is defined only for subjects who have achieved PR or better after the first 
dose date of maintenance therapy and prior to any treatment change. It is calculated as the time 
from the initial response (at least PR) after the first dose date of maintenance therapy and prior to 
treatment change to documented disease progression or death.
Subjects who have not progressed or died at the time of the clinical data cutoff date will be 
censored at the last assessment showing no progression.  Subjects who change treatment without 
evidence of disease progression will be censored at the last assessment showing no progression 
prior to treatment change.
Duration of Complete Response
Duration of complete response is defined only for subjects who have achieved CR/CRu after the 
first dose date of maintenance therapy and prior to any treatment change. It is calculated as the 
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
time from the initial response (at least CRu) after the first dose date of maintenance therapy and 
prior to treatment change to documented disease progression or death.
Subjects who have not progressed or died at the time of the clinical data cutoff date will be 
censored at the last assessment showing no progression.  Subjects who change treatment without 
evidence of disease progression will be censored at the last assessment showing no progression 
prior to treatment change.
Time to Next Anti-lymphoma Treatment
Time to next anti-lymphoma treatment is defined as the time from the first dose date of 
maintenance therapy to the time of first documented administration of new anti-lymphoma 
therapy. Subjects without new treatment therapy will be censored at the last visit. 
Time to Histological Transformation
Time to histological transformation is defined as the time from the first dose date of maintenance 
therapy to the time of histological transformation as measured based on documentation of 
histological transformation (as assessed by the investigator). In case of clinical suspicion of 
transformation, including rapid disease progression, unexpected changes in “B” symptoms or 
rapidly increasing LDH, a biopsy should be performed. In this clinical trial, histological 
transformation will be considered disease progression. This endpoint will not be calculated for 
subjects randomized with transformed Follicular Lymphoma (tFL).
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10.6.4
Analysis Methods
Time-to-Event Endpoints
For the time-to-event endpoints, the Kaplan-Meier estimates of the survival function will be 
calculated and graphically presented. The stratified log-rank test will be performed to evaluate 
treatment efficacy. The experimental arm will be declared superior if the 2-sided p-value from the 
stratified log-rank test is less than or equal to the desired significance level in favor of the 
experimental arm. The un-stratified log-rank test will be performed as sensitivity analysis.  
Hazard ratio with two-sided 95% confidence interval (CI) will be estimated using the Cox 
proportional hazards model. 
Binary Endpoints
The binary endpoints such as IOR will be summarized in frequency and percentage.  The stratified 
Cochran-Mantel-Haenszel (CMH) test will be performed to evaluate treatment efficacy. The un-
stratified CMH test will be performed as sensitivity analysis.
10.7
Safety Analysis
Safety analyses will be based on all subjects in the safety population, and will be analyzed by the 
induction period, maintenance period, and follow-up period.
Study drug exposure will be summarized, including duration of study drug, total dose taken, and 
dose reductions.
Adverse events, vital sign measurements, clinical laboratory measurements, and concomitant 
medications will be summarized.
AEs will be coded according to Medical Dictionary for Drug Regulatory Activities (MedDRA) 
and classified using the National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE version 4.03, except for tumor flare, which will be assessed using version 3.0). 
The incidence rates of AEs will be tabulated by system organ class and preferred term. The 
incidence of AEs will also be tabulated by severity within each system organ class and preferred 
term.  The most severe grade of each preferred term for a subject will be utilized for summaries of 
AEs by NCI CTCAE grade.
Subsets of AEs to be summarized include AEs, suspected treatment-related AEs, and AEs that 
result in withdrawal of investigational product.
AEs of interest include SPM, VTE, ATE, TLS, and TFR. All AEs with corresponding attributes 
will be displayed in a by-subject listing. Adverse events leading to death or to discontinuation from 
treatment, events classified as CTCAE Grade 3 or higher, suspected treatment-related events, and 
SAEs will also be displayed in separate by-subject listings.
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Laboratory data will be summarized according to the CTCAE severity grade.
10.8
Interim Analysis
A formal interim analysis for futility only is planned to examine the overall response rate to 
induction therapy, which is defined as the proportion of subjects whose response at the end of 
induction period is at least PR (including CR, CRu and PR). It will be conducted with the first 50
efficacy evaluable subjects by the end of the Induction Period. Efficacy evaluable subjects are 
defined as subjects who have had the scheduled response assessment at 12 months, or progressed 
or died before the end of the Induction Treatment Period. If the lower limit of the 95% confidence 
interval for overall response rate during the induction period in these 50 subjects is less than 30% 
then the trial might be stopped for futility.
Since this interim analysis is only to evaluate the induction therapy, it has no impact on the number 
of events we need for the maintenance period, sample size, or alpha.
Considering the current PFS event rate and estimated timing of final analysis, one nonbinding 
interim analysis for patients in the maintenance phase is planned at 50% of information (95 PFS 
events) for both superiority and futility. The date of occurrence of the 95th PFS event will be used 
as data cut-off date for the analysis.  This interim analysis will be conducted by an external 
independent statistician, while the study team will remain blinded.
The study may be stopped early for futility if the observed hazard ratio (HR) is > 1.154, based on 
Gamma (-8) family (Hwang, Shih, and DeCani, 1990), ie, in favor of the control arm, and/or if 
recommended by the DMC based on the safety profile of this combination regimen. The stopping 
boundary for superiority based on O’Brien Fleming Analog (Lan & DeMets, 1983) is hazard ratio
≤0.546, if the observed HR cross the superiority boundary in favor of the proposed treatment, the 
trial may stop and claim the superiority. To ensure the overall 1-sided type 1 error remains at 0.025, 
an appropriate amount of alpha will be spent for the interim analysis.
 
 
The DMC will review the efficacy and safety data from these analyses and communicate 
recommendations to the sponsor who may use the recommendations in a risk/benefit analysis.
10.9
Other Topics
Not applicable.
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11
ADVERSE EVENTS
11.1
Monitoring, Recording and Reporting of Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, 
including laboratory test values (as specified by the criteria in Section 11.3), regardless of etiology. 
Any worsening (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 adverse event should be reported as separate 
terms. See Section 8.2.4.1 for more details.
All subjects will be monitored for AEs during the study. Assessments may include monitoring of 
any or all of the following parameters:  the subject’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or findings from other tests and/or
procedures.
All AEs will be recorded by the investigator from the time the subject signs informed consent until 
28 days after the last dose of IP and those SAEs made known to the investigator at any time 
thereafter that are suspected of being related to IP. AEs and serious adverse events (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.
Note that 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).
11.2
Evaluation of Adverse Events
A qualified investigator will evaluate all adverse events as to:
11.2.1
Seriousness 
A serious adverse event (SAE) is any AE occurring at any dose that:

Results in death;

Is life-threatening (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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Final: 11 Sep 2022
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 for 
5 years from the date the last subject initiates induction therapy. Events of second primary 
malignancy are to be reported using the SAE report form and must be considered an “Important 
Medical Event” if no other seriousness 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 or an elective procedure for a pre-existing condition unrelated to the 
studied indication, which has not worsened from baseline.

Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
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11.2.2
Severity / Intensity
For both AEs and SAEs, the investigator must assess the severity / intensity of the event.
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE, Version 4.03). However, TFR will be graded using NCI CTCAE version 
3.0. Severity grading for TLS should follow the Cairo-Bishop Grading System for TLS (Appendix 
D) rather than using the CTCAE v4.03.
AEs that are not defined in the NCI CTCAE should be evaluated for severity / intensity according 
to the following scale:

Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required.

Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required.

Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible.

Grade 4 = Life threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable.

Grade 5 = Death - the event results in death.
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This criterion is not the same as “serious” which is based 
on subject/event outcome or action criteria associated with events that pose a threat to a subject’s 
life or functioning.
Seriousness, not severity, serves as a guide for defining regulatory obligations.
11.2.3
Causality 
The investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means a causal relationship of the adverse event to IP 
administration is unlikely or remote, or other medications, 
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event.
Suspected:
Means there is a reasonable possibility that the administration 
of IP caused the adverse event.  ‘Reasonable possibility’ means 
there is evidence to suggest a causal relationship between the IP 
and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
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If an event is assessed as suspected of being related to a comparator, ancillary or additional IP that 
has not been manufactured or provided by Celgene, please provide the name of the manufacturer 
when reporting the event.
11.2.4
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.
11.2.5
Action Taken
The investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(e.g., discontinuation, interruption, or reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event.
11.2.6
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered or death (due to the 
SAE).
11.3
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of IP dose, or any other therapeutic intervention; 
or

is judged to be of significant clinical importance, eg, one that indicates a new disease process 
and/or organ toxicity, or is an exacerbation or worsening of an existing condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion need 
to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (e.g., record thrombocytopenia rather than decreased platelets).
11.4
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject or partner of a male 
subject are immediately reportable events.
In the event of a pregnancy occurring in a female subject of childbearing potential or female partner 
of a male subject, Celgene will follow up with the clinical investigator each trimester of pregnancy 
and for 1 year following the birth of the infant (if applicable). Please reference the pregnancy 
information consent (permission) forms for data collection for additional information.
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Final: 11 Sep 2022
11.4.1
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated β human chorionic gonadotropin 
[βhCG] or a positive pregnancy test regardless of age or disease state) of a female subject occurring 
while the subject is on lenalidomide, or within 28 days of the subject’s last dose of lenalidomide, 
are considered immediately reportable events. Lenalidomide is to be discontinued immediately 
and the subject instructed to return any unused portion of the IP to the investigator. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form. The exposure of any pregnant female (e.g., caregiver or pharmacist) 
to lenalidomide, is also an immediately reportable event.
The female subject should be referred to an obstetrician-gynecologist, preferably one experienced 
in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (e.g., spontaneous abortion), the investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the seriousness
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 6.2.2). 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 
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
for 5 years from the date the last subject initiates induction therapy. Events of second primary 
malignancy are to be reported using the SAE report form and must be considered an “Important 
Medical Event” if no other seriousness 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.).
The investigator is required to ensure that the data on these forms is accurate and consistent.  This 
requirement applies to all SAEs (regardless of relationship to IP) that occur during the study (from 
the time the subject signs informed consent until 28 days after the last dose of IP), and any SPM 
occurring at any time during the study including follow-up period (if applicable) or any SAE made 
known to the investigator at anytime thereafter that are suspected of being related to IP. SAEs 
occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug Safety 
as soon as these become available. Any follow-up data should be detailed in a subsequent SAE 
Report Form, or approved equivalent form, and sent to Celgene Drug Safety.
Where required by local legislation, the investigator is responsible for informing the IRB/EC of 
the SAE and providing them with all relevant initial and follow-up information about the event. 
The investigator must keep copies of all SAE information on file including correspondence with 
Celgene and the IRB/EC.
11.5.1
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail. The response time is expected to be no more than five (5) business 
days.  Urgent queries (e.g., missing causality assessment) may be handled by phone.
11.6
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to lenalidomide based on the investigator Brochure.
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.
Celgene or its authorized representative shall notify the investigator of the following information:

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.
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.
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The investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC (See Section 15.3 for record retention information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
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12
DISCONTINUATIONS
12.1
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product:

Adverse event(s)

PD or relapse

Subject withdrawal (subject no longer wants to receive study drug, but is willing to have 
additional data collected)

Withdrawal of consent (both from treatment and study, including release of further subject
data)

Death

Lost to follow-up

Protocol violation

Lack of efficacy

The completion of study treatment (the completion of 30 Cycles for subjects in arm B) as per 
protocol
The reason for discontinuation should be recorded in the CRF and in the source documents.
12.2
Study Discontinuation and Completion
The following events are considered sufficient reasons for discontinuing a subject from follow-up 
in the study:

Screen failure

Withdrawal of consent (including release of further subject data).

Death

Lost to follow-up

Protocol violation

Lack of efficacy
The reason for discontinuation should be recorded in the CRF and in the source documents.
Once the 114 PFS events are confirmed, the follow-up period will continue for 5 years after the 
last subject has initiated induction therapy, and all subjects who are in the follow-up period will 
be deemed as completed and will be off boarded from the study
.
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13
EMERGENCY PROCEDURES
13.1
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/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. 
13.2
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
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14
REGULATORY CONSIDERATIONS
14.1
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, and 
investigator abide by Good Clinical Practice (GCP), as described in International Conference on 
Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
14.2
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in the 
local regulations. Celgene staff or an authorized representative will evaluate and approve all 
investigators who in turn will select their staff.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions. 
The investigator should maintain a list of Sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties.
The investigator is responsible for keeping a record of all subjects who sign an informed consent 
document and are screened for entry into the study. Subjects who fail Screening must have the 
reason(s) recorded in the subject’s source documents.
The investigator is responsible for documentation of every procedure and assessment required by 
this protocol in a source document to be maintained by the site.  Some procedures or assessments 
required in this study may be considered standard of care.  These must be captured in the source 
document as well.
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.
14.3
Subject Information and Informed Consent
The investigator must obtain informed consent of a legal representative prior to any study-related 
procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study and 
of the informed consent process should be recorded in the study subject’s source documents 
including the date. The original informed consent document signed and dated by the study subject 
and by the person consenting the study subject prior to the study subject’s entry into the study, 
must be maintained in the investigator’s study files and a copy given to the study subject. In 
addition, if a protocol is amended and it impacts on the content of the informed consent, the 
informed consent document must be revised. Study subjects participating in the study when the 
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amended protocol is implemented must be re-consented with the revised version of the informed 
consent document. The revised informed consent document signed and dated by the study subject 
and by the person consenting the study subject must be maintained in the investigator’s study files 
and a copy given to the study subject.
14.4
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in compliance 
with ICH and other local regulations (whichever is most stringent). Celgene requires the 
investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent document, it is the responsibility of the investigator to obtain 
such permission in writing from the appropriate individual.
14.5
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor. Amendments will be submitted to the IRB/EC for written approval.
Written approval must be obtained before implementation of the amended version occurs. The 
written signed approval from the IRB/EC should specifically reference the investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC for 
information purposes.
14.6
Institutional Review Board/Independent Ethics Committee Review and 
Approval
Before the start of the study, the study protocol, informed consent document, and any other 
appropriate documents will be submitted to the IRB/EC with a cover letter or a form listing the 
documents submitted, their dates of issue, and the site (or region or area of jurisdiction, as 
applicable) for which approval is sought. If applicable, the documents will also be submitted to 
the authorities in accordance with local legal requirements.
IP can only be supplied to an investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. Formal 
approval by the IRB/EC should mention the protocol title, number, amendment number (if 
applicable), study site (or region or area of jurisdiction, as applicable), and any other documents 
reviewed. It must mention the date on which the decision was made and must be officially signed 
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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 informed consent document 
should also be revised.
The investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.
14.7
Ongoing Information for Institutional Review Board / Ethics Committee
If required by legislation or the IRB/EC, the investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible.

Periodic reports on the progress of the study.

Deviations from the protocol or anything that may involve added risk to subjects.
14.8
Closure of the Study
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (e.g., IRB/EC, regulatory authorities, etc.). At termination and 
investigator’s discretion, subjects who had been receiving lenalidomide without unacceptable 
toxicities and have not met the criteria for withdrawal may continue to receive open-label 
lenalidomide provided by the Sponsor.
In addition, the investigator or Celgene has the right to discontinue a single site at any time during 
the study for medical or administrative reasons such as:

Unsatisfactory enrollment.

GCP noncompliance.

Inaccurate or incomplete data collection.

Falsification of records.

Failure to adhere to the study protocol.
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15
DATA HANDLING AND RECORDKEEPING
15.1
Data/Documents
The investigator must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the investigational product are complete, accurate, filed and retained. 
Examples of source documents include: hospital records; clinic and office charts; laboratory notes; 
memoranda; subject’s diaries or evaluation checklists; dispensing records; recorded data from 
automated instruments; copies or transcriptions certified after verification as being accurate copies; 
microfiche; x-ray film and reports; and records kept at the pharmacy, and the laboratories, as well 
as copies of CRFs or CD-ROM.
15.2
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene SOPs. This data 
will be electronically verified through use of programmed edit checks specified by the clinical 
team. Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary. Resolutions to these issues will be reflected in the 
database. An audit trail within the system will track all changes made to the data.
15.3
Record Retention
Essential documents must be retained by the investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. The investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer. Essential documents include, but are not limited to, the following:

Signed informed consent documents for all subjects.

Subject identification code list, Screening log (if applicable), and enrollment log.

Record of all communications between the investigator and the IRB/EC.

Composition of the IRB/EC.

Record of all communications between the investigator, Celgene, and their authorized 
representative(s).

List of Sub-investigators and other appropriately qualified persons to whom the investigator 
has delegated significant study-related duties, together with their roles in the study, curriculum 
vitae, and their signatures.

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.).

All other documents as listed in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial).
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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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Final: 11 Sep 2022
16
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative for 
compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after the 
study. 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 on-site 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.
16.2
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance unit 
exists within Celgene.  Representatives of this unit will conduct audits of clinical research activities 
in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice guidelines 
and regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for audits 
and inspections by IRB/IECs, regulatory authorities (e.g., FDA, EMA, Health Canada) and 
company authorized representatives. The investigator should make every effort to be available for
the audits and/or inspections. If the investigator is contacted by any regulatory authority regarding 
an inspection, he/she should contact Celgene immediately.
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17
PUBLICATIONS
The results of this study 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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Final: 11 Sep 2022
18
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the 
multicenter phase 2 PINNACLE study. Ann. of Oncol. 2009; 20:520-5.
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of Clinical Oncology. Appropriate chemotherapy dosing for obese adult patients with cancer:  
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monotherapy produces a high response rate in patients with relapsed or refractory mantle cell 
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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19
APPENDICES
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19.2
Appendix B:  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 (AJCC, 1997). Non Hodgkin’s lymphoma.
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19.3
Appendix C:  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
Source:  Oken, 1982.
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19.4
Appendix D:  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; TLS:  Tumor Lysis Syndrome.
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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19.5
Appendix E:  Response Criteria for NHL
19.5.1
Tumor Assessment by 1999 IWG Criteria for NHL
Table 6:
Tumor Assessment by 1999 IWG Criteria
Response Category 
Physical 
Examination 
Lymph Nodes 
Lymph Node 
Masses 
Bone Marrow 
CR 
Normal 
Normal 
Normal 
Normal 
Cru 
Normal 
Normal 
Normal 
Indeterminate 
Normal 
Normal 
>75% decrease 
Normal or 
indeterminate 
PR 
Normal 
Normal 
Normal 
Positive 
Normal 
≥50% decrease 
≥50% decrease 
Irrelevant 
Decrease in 
liver/spleen 
≥50% decrease 
≥50% decrease 
Irrelevant 
SD
Less than PR but is not PD nor relapsed disease 
Relapse or PD 
Enlarging 
liver/spleen; new 
sites 
New or increased 
New or increased 
Reappearance 
Normal for lymph nodes is defined as follows:
Lymph nodes and nodal masses < 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm 
before therapy.
Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before 
treatment must have decreased to < 1 cm in their greatest transverse diameter after treatment, or 
by more than 75% in the sum of the products of the greatest diameters (SPD)
Indeterminate bone marrow is defined by increased number or size of aggregates without 
cytological or architectural atypical
19.5.2
Additional Response Assessment in Gastric MALT subjects with 
Radiological Response of at Least a PR by 1999 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 6.1.6). The histological scoring will be based on the GELA histological scoring system 
(Table 7). Final response assessment in subjects with gastric MALT will incorporate the IWG 
criteria as well as the histological findings.
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Table 7:
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)
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 investigations 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 
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Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
CC-5013-NHL-008 Amendment 5
Final: 11 Sep 2022
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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EDMS Doc. Number: 25143199 - 20129465
Lenalidomide (CC-5013)
Summary of Changes CC-5013-NHL-008
Celgene Corporation
Confidential and Proprietary
3
CC-5013-NHL-008 Amendment 4 Final: 03 November 2020
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Considering the current progression free survival (PFS) event rate, which is slower than 
originally predicted (approximately 60 PFS events as of August 2020), the challenging follow-up 
of subjects in the context of the COVID-19 pandemic, and estimated timing of final analysis, one 
nonbinding interim analysis for patients in the maintenance phase is planned at 50% of 
information (95 PFS events) for both superiority and futility. This analysis will enhance formal 
benefit/risk assessment for subjects continuing on treatment. The date of occurrence of the 95th
PFS event will be used as data cut-off date for the analysis.  This interim analysis will be
conducted by an external independent statistician, while the study team will remain blinded.
The study may be stopped early for futility if the observed hazard ratio (HR) is > 1.154, based on 
Gamma (-8) family (Hwang, Shih, and DeCani, 1990), ie, in favor of the control arm, and/or if 
recommended by the data monitoring committee (DMC) based on the safety profile of this 
combination regimen. The stopping boundary for superiority based on O’Brien Fleming Analog 
(Lan & DeMets, 1983)  is hazard ratio  ≤0.546, if the observed HR cross the superiority 
boundary in favor of the proposed treatment, the trial may stop and claim the superiority, 
reflecting a one-sided p-value < 0.002.
The stopping rule for superiority will occur if the observed hazard ratio HR is ≤0.54.
Revised Section: Section 10.8
Additional Updates

Study team changes resulted in updates in the medical monitor and emergency
contact information.
Revised Section: Medical Monitor / Emergency Contact Information.
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EDMS Doc. Number: 24042759 - 20129465
Lenaldomide (CC-5013)
Summary of Changes CC-5013-NHL-008
Celgene Corporation
Confidential and Proprietary
3
CC-5013-NHL-008 Amendment 3 Final: 27 August 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Incorporation of information communicated per Protocol Addendum for Germany
A protocol addendum dated 22 Jun 2017 was issued to address aspects of the protocol that are 
adapted in order to comply with laws and drug regulations applicable in Germany. These 
changes are now incorporated in the current global protocol amendment.

Number of Subjects and Sites
Celgene will select fifteen (15) sites within Germany.  Subject enrollment of approximately 
50 subjects is planned in Germany collectively from sites listed in the clinical trial 
application at submission to regulatory authorities. 
Revised Section: Section 7.1 

Description of Investigational Product(s) 
This is to clarify that for Germany, Celgene will supply both lenalidomide capsules and 
rituximab intravenous formulation as investigational products (IPs).
Revised Section: Section 8.1 

Packaging and Labeling in Germany
This is to clarify that for Germany, rituximab intravenous formulation packaging and label 
will be provided as an IP.
Revised Section: Section 8.4
Clarification of the Efficacy Assessments frequency
This is to clarify that schedule of tumor assessment would follow cycles rather than calendar 
months, to ensure that all subjects have a tumor assessment performed as required by protocol, 
prior to randomization. Additionally, clarification added that efficacy assessment should be 
performed until progression, relapse or initiation of new anti-lymphoma therapy. 
Revised sections: Section 5 Table of Events, Section 6.3, Section 8.2 
Clarification of the collection window for laboratory samples
The protocol now includes a clarification for the window for collection of hematology and serum 
chemistry samples as communicated to the sites in the administrative change letter dated 11 May
2018 as well as a site communication sent on 18 Jun 2018. This is in line with the update of the 
protocol in Germany following the request from the German health authority, BfArM on 23 Jul
2018.
Revised sections: Section 5 Table of Events, Section 6.2.
Update to clinical background information on lenalidomide

Addition of results of the RELEVANCE and REMARC trials
Revised section: Section 1.6.1, Section 1.7, Section 18
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EDMS Doc. Number: 24042759 - 20129465
Lenaldomide (CC-5013)
Summary of Changes CC-5013-NHL-008
Celgene Corporation
Confidential and Proprietary
4
CC-5013-NHL-008 Amendment 3 Final: 27 August 2019
Additional Updates

Study team changes resulted in updates in the medical monitor and emergency 
contact information.
Revised Sections: Section medical monitor and emergency contact information.

Minor editorial and formatting changes (eg, consistency of acronym use throughout 
the document per Celgene Style Guide, spelling, grammatical error corrections, etc.) 
were also made throughout the document.
Revised sections: Section 1.6, Section 1.7, Section 7.3

Grading of tumor flare reaction and tumor lysis syndrome clarified
Revised sections: Section 6.2,  Section 8.2

Number of sites revised per current status for German sites
Revised sections: Section 7.1

Description of IP updated
Revised section: Section 8.1

Update of evaluation and reporting of adverse events per current guidelines
Revised section: Section 11

Update of birth control and pregnancy language per Celgene standard language
Revised sections: Section 6.2, Section 11.4
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EDMS Doc. Number: 20130385 - 20129465
Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
Confidential and Proprietary
3
CC-5013-NHL-008  Amendment 2 FINAL 24 February 2015
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Modification of Randomization Timepoint
The primary purpose of this protocol amendment is to change the timing of randomization  from 
prior to induction therapy to prior to maintenance therapy. This is due to feedback received from 
external experts in statistical analysis and institutional review boards regarding the statistical 
section of the previous protocol to ensure the validity of statistical comparison between two 
maintenance treatment groups.
Section 10.6 of  the previous protocol defined the primary endpoint as PFS from randomization 
(prior to induction therapy) until PD/Death. However, since all patients receive the same 
induction therapy prior to maintenance therapy, comparing PFS from induction therapy between 
both arms is not suitable as a primary endpoint for the trial. Also, the intent to treat (ITT) 
population is defined as the primary population. This included all patients who did not proceed to 
maintenance therapy, yet the events occurring during induction therapy were not to be included 
in the primary endpoint analysis of the previous protocol.
Furthermore, since only patients achieving Partial Response or better at the end of the induction 
treatment were allowed to continue to maintenance, it is possible that the maintenance arms 
would not be balanced per randomization stratification factors in the previous protocol.
Changing the timing of randomization from prior to induction (as per previous protocol) to prior 
to maintenance allows for PFS from the timepoint of randomization to maintenance to be 
statistically viable as a primary endpoint. 
It is important to note that the treatment used in the induction phase of the clinical trial remains 
experimental as it is not an approved regimen. As a result, data will continue to be collected on 
subjects during the induction phase of the trial in much the same manner as per the previous
version of the protocol (Protocol Amendment1 16 Jan 2014). The change of randomization 
timepoint bring this study design in line with similar trials that seek to determine the treatment 
effect of a maintenance regimen in a patient population receiving a common induction regimen
(eg., PRIMA trial published by Salles, et al., Lancet 2011, as referenced in the protocol). 
Modification of Inclusion/Exclusion Criteria
One goal of this study is to gain experience with the lenalidomide plus rituximab regimen in 
subjects who represent the population seen in a range of clinical practice settings in the United 
States. Feedback from participating sites advised slight modifications to the inclusion/exclusion 
criteria to be more representative of this disease population. These modifications are as follows:
For the inclusion criteria:

ECOG  < 2 (previous protocol) will be changed to ECOG  ≤2.

Simplify prior treatment language to include a broader range of treatments (including 
novel agents)

Allow inclusion of patients with grade 3b and transformed follicular lymphoma 
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EDMS Doc. Number: 20130385 - 20129465
Lenalidomide (CC-5013)
Protocol CC-5013-NHL-008
Celgene Corporation
Confidential and Proprietary
4
CC-5013-NHL-008  Amendment 2 FINAL 24 February 2015
For the exclusion criteria:

Neuropathy > grade 1 (previous protocol) will be changed to Neuropathy > grade 2.

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. Carcinoma in situ of the breast, and incidental histological 
finding of prostate cancer (TNM stage of T1a or T1b) have been added as
exceptions. These changes are to align this particular study with the rules agreed 
upon with Health authorities.
Lenalidomide monotherapy maintenance changed to optional
In the previous version of the protocol (Protocol Amendment 1 16 Jan 2014) patients were to 
continue lenalidomide single agent maintenance after completing 18 cycles of 
lenalidomide + rituximab maintenance with lenalidomide monotherapy maintenance until 
disease progression. Due to feedback from participating sites and their experience in treating 
patients with maintenance therapy, the protocol amendment will make this component of 
treatment optional at the discretion of the physician and/or patient.
Revision to Secondary Endpoints and Interim Analyses
As this trial is a maintenance trial, and patients randomized to the maintenance treatment period 
must have a minimum response of stable disease, it is important to analyze whether there is an 
improvement in response with prolonged maintenance treatment. As a result, Improvement of 
Response was added as a secondary endpoint.
Due to different durations of treatment in the maintenance phase, Time to Treatment Failure 
(TTF) may be biased as an endpoint. The control arm (Arm B) maintenance treatment is defined 
as 18 cycles with Rituximab whereas the experimental Arm A has the option to continue 
treatment with lenalidomide single agent until progression of disease. As a result, TTF has been 
removed as a secondary endpoint.
In the previous protocol (Protocol Amendment 1 16 Jan 2014), there were four planned interim 
analyses. This is now reduced to a single interim analysis for futility of the induction treatment 
regimen. 
 
These major changes as well as minor changes in language have been made throughout multiple 
sections of the protocol.
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Lenalidomide (CC-5013) 
Summary of Changes CC-5013-NHL-008 
Celgene Corporation 
Confidential and Proprietary 
3 
CC-5013-NHL-008  Amendment 1 Final 16 January 2014 
1. 
JUSTIFICATION FOR AMENDMENT 
Significant changes included in this amendment are summarized below: 
 Addition of Overall Survival as a secondary endpoint. 
 Changes in the pregnancy restriction language to reflect the Rituximab Prescribing 
information. 
The amendment also includes several other minor clarifications and corrections: 
 Changes to Schedule of activities including correction/deletion of footnotes,  Deletion of 
certain procedures at specific timepoints: 
o Modification of frequency of QoL questionnaire to collect data required for this 
IIIb study. 
o Deletion of footnote re: ECOG status assessment timing. 
o Broadening window allowed for scans to allow them to be completed at scheduled 
visits. 
 Statement added to Procedures section reflecting ability to use standard of care 
procedures to meet the requirements of the study if they meet the description and timeline 
specified in the protocol.   
 Statements added to reflect data that will be collected in the CRF, Source Document 
and/or Adverse Event pages. 
 Statement that local labs will be used for the study, and which lab results will be captured 
in the CRF. 
 Correction of typographical errors, or grammar. 
 Modification of the timepoints ECOG performance status will be assessed. 
 Correction of numbers in statistical section . 
 
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