Conditions: Mantle Cell Lymphoma Lymphoma, Mantle-Cell
Keywords: Mantle Cell Lymphoma Relapsed Mantle Cell Lymphoma Refractory Mantle Cell Lymphoma Lymphoma MCL
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 254
Healthy volunteers: no

Brief summary:
To evaluate the safety and efficacy of lenalidomide versus investigator choice in patients with relapsed or refractory mantle cell lymphoma.

Detailed description:
This research study is for patients who have relapsed or refractory mantle cell lymphoma following treatment such as radiotherapy, immunotherapy, chemotherapy, or radioimmunotherapy. Chemotherapy agents such as gemcitabine, cytarabine, chlorambucil, fludarabine, or the immunotherapeutic agent, rituximab, may be proposed. Thus, the aim is to search for new treatments that may improve the prognosis of patients with relapsed mantle cell lymphoma.

The present clinical study aims at determining if lenalidomide is safe and active in patients with mantle cell lymphoma who are refractory to their treatment or have relapsed once, twice or three times. Enrollment goal was met on March 7th 2013 and thus enrollment was stopped.

Arms:
arm 1: Lenalidomide arm 2: Investigators choice single agent - Chlorambucil, Rituximab, Cytarabine, Gemcitabine, Fludarabine

Interventions: intervention 1: Lenalidomide intervention 2: Investigators choice single agent
Intervention descriptions: intervention 1: For patients with a creatinine clearance of ≥ 60 mL/min: 25 mg daily x 21 days of a 28 day cycle until disease progression or unacceptable toxicity.

For patients who have a moderate renal insufficiency (creatinine clearance is ≥ 30 mL/min but \< 60mL/min: 10 mg daily x 21 days of a 28 day cycle (Cycles 1 and 2). After Cycle 2, if the patient remains free of Grade 3 or Grade 4 toxicity, the dose will be increased to 15 mg daily x 21 days of a 28 day cycle until disease progression or unacceptable toxicity. intervention 2: Investigators choice single agent - Chlorambucil, Rituximab, Cytarabine, Gemcitabine, or Fludarabine

Protocol document:
SAP_002.pdf: 
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 2, MULTICENTER, RANDOMIZED OPEN-LABEL STUDY TO DETERMINE 
THE EFFICACY OF LENALIDOMIDE (REVLIMID®) VERSUS INVESTIGATOR’S 
CHOICE IN PATIENTS WITH RELAPSED OR REFRACTORY MANTLE CELL 
LYMPHOMA
STUDY DRUG:
Lenalidomide/CC-5013
PROTOCOL NUMBER:
CC-5013-MCL-002
DATE FINAL:
26JUL2010
Date Amendment 1
18JUL2011
Prepared by:
Celgene International
Route de Perreux, 1
2017 Boudry, Switzerland
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
SUMMARY OF CHANGES FROM VERSION 1.1.................................................9
3.
INTRODUCTION..................................................................................................12
4.
OBJECTIVES ........................................................................................................13
5.
INVESTIGATIONAL PLAN .................................................................................14
5.1.
Overall Study Design and Plan ...............................................................................14
5.1.1.
Discussion of Study Design ....................................................................................14
5.2.
Study Endpoints .....................................................................................................15
5.3.
Stratification , Randomization and Blinding............................................................15
5.4.
Sample Size............................................................................................................16
5.5.
Changes to the Planned Protocol Analysis ..............................................................17
6.
GENERAL STATISTICAL CONSIDERATIONS .................................................18
6.1.
Reporting Conventions ...........................................................................................18
6.1.1.
Dates and partial dates imputation ..........................................................................18
6.1.2.
Calculations Using Dates........................................................................................19
6.1.3.
Calculation of Cycles..............................................................................................19
6.2.
Analysis Populations ..............................................................................................20
6.2.1.
Intent-to-Treat Population.......................................................................................20
6.2.2.
Full Analysis Set Population...................................................................................20
6.2.3.
Per Protocol Population ..........................................................................................20
6.2.4.
As treated Population..............................................................................................20
6.2.5.
Safety Population....................................................................................................20
7.
PATIENT DISPOSITION ......................................................................................22
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................23
8.1.
Demographics.........................................................................................................23
8.2.
Baseline Clinical Characteristics.............................................................................23
8.3.
Medical History......................................................................................................23
8.4.
Prior Therapy..........................................................................................................23
8.5.
Prior Medications ...................................................................................................24
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3.3


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
3
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................25
9.1.
Treatment Duration.................................................................................................25
9.2.
Cumulative Dose ....................................................................................................25
9.3.
Dose Intensity.........................................................................................................25
9.4.
Relative Dose Intensity...........................................................................................25
9.5.
Dose Modification..................................................................................................26
10.
CONCOMITANT MEDICATIONS .......................................................................28
11.
EFFICACY ANALYSIS ........................................................................................29
11.1.
General Statistical Methods ....................................................................................29
11.1.1.
Time to event endpoints..........................................................................................29
11.1.2.
Categorical endpoints .............................................................................................30
11.1.3.
Quality of Life endpoints........................................................................................30
11.2.
Expert Review of Disease Response .......................................................................30
11.3.
Analysis of Primary Efficacy Endpoint...................................................................31
11.4.
Analyses of Secondary Efficacy Endpoints.............................................................33
11.4.1.
Overall response rate ..............................................................................................33
11.4.2.
Duration of Response .............................................................................................33
11.4.3.
Tumor control rate..................................................................................................34
11.4.4.
Duration of Stable Disease......................................................................................34
11.4.5.
Time to progression (TTP)......................................................................................34
11.4.6.
Time to treatment failure (TTF)..............................................................................34
11.4.7.
Time to tumor response (TTR)................................................................................34
11.4.8.
Overall Survival (OS).............................................................................................34
11.5.
Subgroup Analysis..................................................................................................34
12.
SAFETY ANALYSIS ............................................................................................36
12.1.
Adverse Events.......................................................................................................36
12.2.
Clinical Laboratory Evaluations..............................................................................37
12.3.
Vital Sign Measurements........................................................................................37
12.4.
Physical Examination .............................................................................................37
12.5.
Electrocardiogram ..................................................................................................37
13.
QUALITY OF LIFE ANALYSIS...........................................................................38
13.1.
EORTC QLQ-C30..................................................................................................38
13.2.
Analysis of Quality of Life Scales...........................................................................40
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
4
14.
INTERIM ANALYSIS...........................................................................................41
14.1.
General Information................................................................................................41
14.2.
Statistical Approaches for Control of Alpha............................................................42
14.2.1.
Primary analysis .....................................................................................................42
14.2.2.
Interim analysis ......................................................................................................42
15.
REFERENCES.......................................................................................................43
16.
APPENDICES........................................................................................................44
16.1.
Date Imputation Guideline......................................................................................44
16.1.1.
Impute Missing AE/ Prior or Concomitant Medications Start Dates........................44
16.2.
Cycle derivation Guideline .....................................................................................45
16.3.
Endpoints derivation...............................................................................................48
16.4.
Laboratory Values ..................................................................................................49
16.5.
Tables and listings shells ........................................................................................65
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Confidence Intervals...............................................................................................16
Table 3:
InvC drug recommended dose.................................................................................26
Table 4:
Censoring Rules for Time to event (Progression and/or Death) Endpoints...............31
Table 5:
Method b: Censoring Rules for Time to event (Progression and/or Death) 
Endpoints sensitivity analysis .................................................................................32
Table 6:
Method c: Censoring Rules for Time to event (Progression and/or Death) 
Endpoints sensitivity analysis .................................................................................33
Table 7:
EORTC QLQ-C30 scores .......................................................................................38
Table 8:
Response percentage and 95% exact confidence interval ........................................41
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
AML
Acute Myelogenous Leukemia
BSA
Body surface area
CI
Confidence Interval
CR
Complete response
CRu
Complete response unconfirmed
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data monitoring committee
DOB
Date of birth
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
FAS
Full Analysis Set
GCP
Good Clinical Practice
HR
Hazard ratio
IC
Informed consent
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
InvC
Investigator’s choice
IRRC
Independent radiology review committee
ITT
Intent-to-treat
IVRS
Interactive voice response system
KM
Kaplan Meier
Len
Lenalidomide
MCL
Mantle Cell Lymphoma
MDS
Myelodysplastic syndrome
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
8
Abbreviation or 
Specialist Term
Explanation
MedDRA
Medical Dictionary for Drug Regulatory Activities
NCI-CTC
National Cancer Institute Common Toxicity Criteria
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PI
Principal Investigator
The investigator who leads the study conduct at an individual study center.  
Every study center has a principal investigator.
PP
Per protocol
PR
Partial response
QoL
Quality of Life
SAE
Serious adverse event
SAP
Statistical analysis plan
SCT
Stem Cell Transplant
SD
Stable disease
SDev
Standard deviation
SPM
Second Primary Malignancy 
TEAE
Treatment emergent adverse event
TTF
Time to treatment failure
TTP
Time to tumor progression
TTR
Time to response
WHO
World Health Organization
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
9
2.
SUMMARY OF CHANGES FROM VERSION 1.1
Section N°
Change
6.2 Analysis population
Additional analysis population “As treated population “ was 
added as supportive analysis
Rational :
Additional subgroup analysis to characterize treatment effect in 
addition to the primary analysis
11.1 General statistical 
methods
If any imbalances appear in the demographic or baseline 
characteristics variables considered as important predictive or 
prognostic factors to clinical outcomes, the variables will be 
analyzed as the stratification factors. They will be included as 
covariates in the Cox model to provide estimate of lenalidomide 
treatment effect adjusted for these factors and in the stratified 
log-rank test.
Rational: After the meeting held on 18 March 2011, DMC 
suggested that potential imbalance in some important key 
baseline characteristics could occur, therefore they need to be 
taken into account in the statistical analysis.
11.5 Subgroup analysis
Subgroup analyses will be conducted in an exploratory manner  
for the following endpoints PFS, ORR and OS in the following 
subgroups:
!
Number of prior treatment lines (with description of 
treatment regimens, including first line treatment and 
stem cell transplant)  (1 vs >1), (<2 vs ≥2), (<3 vs ≥3)
!
Number of relapses ( 1 vs > 1 relapses), (<2 vs ≥2 
relapses), (<3; ;≥3 relapses)
!
Any demographic or baseline characteristic 
considered as important prognostic factors with 
imbalance in two treatment arms.
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
10
Rational :
To accommodate request by DMC (after the meeting held on the 
18 March 2011), subgroup analyses will be conducted on 
important key baseline characteristics presenting an imbalance”.
Subgroup analyses will be restricted to PFS, ORR and OS
12.1 Adverse events
Second Primary Malignancy (SPM) will be summarized by 
frequency and 95% CI for the following categories: 
-
Invasive SPM including hematologic malignancies and 
solid tumor. Hematological malignancies will be 
subcategorized in B-cell lymphoma, AML, MDS and 
other
-
Non invasive SPM
Time to  first SPM will be analyzed using Kaplan Meier 
methods.
Incidence per 100 patient-year will also be calculated.
Rational :
Celgene has decided to include analysis on SPM to address 
patients safety, and to address concerns of any potential second 
primary malignancies from the EMA.
14.2 Statistical approaches 
to control the Alpha
14.2.1. Primary analysis 
.
The final PFS analysis will be conducted with an alpha level 
equal to 5% (two sided).
Reflecting a medical meaningful improvement, a p-value is 
above 0.05 and still below 0.10 will be considered as an 
acceptable trend.
14.2.2. Interim analysis 
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
11
No formal adjustment is needed. Interim analysis is run only for 
futility.
Rational:
After the meeting held on 18 March 2011, DMC members 
suggested that the current sample size may not be adequate to 
achieve study objectives. At this time there was no plan to 
increase the sample size due to near completion of enrollment.
16.4 Appendices
Update the conversion factors tables
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
12
3.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-5013-MCL-002 “A Phase 2, Multicenter, Randomized Open-Label Study To 
Determine The Efficacy Of Lenalidomide (REVLIMID®) Versus Investigator’s Choice In 
Patients With Relapsed Or Refractory Mantle Cell Lymphoma.” It contains definitions of 
analysis populations, derived variables and statistical methods for the analysis of efficacy and 
safety.
These analyses include one interim analysis for futility and one final analysis. Throughout this 
SAP, the treatment arms will be referred to as lenalidomide (Len) and Investigator’s choice 
(InvC).  The purpose of the SAP is to ensure the credibility of the study findings by specifying 
the statistical approaches to the analysis of study data prior to database lock for the final analysis. 
This SAP will be finalized and signed prior to the clinical database lock for the futility analysis. 
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.1.
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9.1


Lenalidomide/CC-5013
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Celgene International
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4.
OBJECTIVES
The objective of the statistical analyses will be to investigate the efficacy and safety of 
lenalidomide monotherapy in patients with relapsed or refractory mantle cell lymphoma.
Primary objective
!
To compare the progression free survival (PFS) of lenalidomide monotherapy versus 
investigator’s choice single agent in patients with mantle cell lymphoma (MCL) who 
are refractory to their regimen or have relapsed once, twice or three times..
Secondary objective
!
To determine the overall response rate (ORR) of lenalidomide monotherapy or 
investigator’s choice single agent in patients with relapsed or refractory MCL.
!
To evaluate the safety of lenalidomide monotherapy or investigator’s choice single 
agent in patients with relapsed or refractory MCL.
!
To determine the time to tumor progression (TTP), and overall survival (OS) of 
patients with relapsed or refractory MCL who have received treatment with 
lenalidomide or investigator’s choice single agent treatment.
!
To investigate the health-related quality of life (QoL) of patients treated with 
lenalidomide or investigator’s choice single agent treatment.
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
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5.
INVESTIGATIONAL PLAN
5.1.
Overall Study Design and Plan
This is a multicenter, randomized, open-label, comparative, active controlled phase II study to 
determine the efficacy and safety of single agent lenalidomide over a concurrent control group 
treated with an investigator’s choice monotherapy in patients with MCL who are refractory to 
their regimen or have relapsed once, twice or three times.
This multicenter study design aims to determine the PFS hazard ratio (HR) of lenalidomide over 
a single agent of investigator’s choice.
The investigator’s choice in the control arm comprises the monotherapy treatment with one of 
the following: chlorambucil, cytarabine, rituximab, fludarabine, or gemcitabine.  The 
investigator shall choose the single agent of choice in the control arm for each patient prior to 
randomization on to the study. Patients in the investigator’s choice arm will have the option to 
switch to lenalidomide at the time of progressive disease (cross over phase).
Patients will be stratified according to:
!
Time since diagnosis (< 3 years or ≥ 3 years)
!
Time since last treatment (< 6 months [refractory] or ≥ 6 months)
!
Prior stem cell transplant (yes or no).
This study will be conducted in four phases: 
1. A Screening Phase
2. An open label randomized Treatment Phase
3. A cross over phase (patients in the investigator’s choice Arm B only)
4. Follow-up phase.
5.1.1.
Discussion of Study Design
!
Duration of Treatment
Patients will be treated until progression in this study.  
!
Study Population
Patients with MCL who have relapsed once, twice or three times are being assessed to evaluate 
the efficacy of lenalidomide. There is no standard of care for such patients.
!
Blinding
The open-label option was chosen because the five alternatives therapies on the InvC arm are 
given either IV or orally.
!
Cross-over
Due to ethical concerns and based on the fact there is no alternative for patients on the InvC arm 
who progress the possibility to cross-over to Len is offered. It is clearly a source of bias in the 
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
15
analysis endpoints such as OS. Cross-over will not affect the primary endpoint (PFS) as it is 
allowed only after progression occurs.
5.2.
Study Endpoints
Following the implementation of Amendment #2 (dated 14 Dec 2009), PFS became the primary 
endpoint comparing PFS in patients who receive lenalidomide monotherapy versus 
investigator’s choice. Despite the change in the primary endpoint from ORR to PFS, there was 
no impact on the sample size calculation.
Primary
PFS is defined as the time from randomization to the first observation of disease progression or 
death due to any cause. If the patient has not progressed or died, PFS will be censored at the time 
of last completed assessment when the patient was known not to have progressed. Patients who 
receive a new treatment without documented progression will be censored at the last assessment 
date that the patient is known to be progression-free.
Secondary
!
ORR (complete response [CR], complete response unconfirmed [CRu], and partial 
response [PR]) will be assessed by a modification of the International Workshop 
Lymphoma Response Criteria (IWRC), which will hereafter be described as modified 
IWRC (Cheson,1999).
!
Duration of response
!
Duration of stable disease
!
Tumor control rate (Rates for CR, CRu, PR, and stable disease [SD])
!
Time to tumor progression (TTP)
!
Time to treatment failure (TTF)
!
Time to tumor response (TTR)
!
Overall survival (OS)
!
Safety
!
Quality of Life (EORTC QLQ-C30 questionnaire)
5.3.
Stratification , Randomization and Blinding
An Interactive Voice Response System (IVRS) will be utilized to ensure a 2:1 central 
randomization based on a permuted-block randomization method. Patients will be randomized 
according to the following stratification factors: Time since diagnosis (< 3 years or ≥ 3 years), 
Time since last treatment (< 6 months [refractory] or ≥ 6 months), Prior stem cell transplant (yes 
or no).
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Time since
Time since
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r no).


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
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5.4.
Sample Size
The main objective of the study changed to demonstrate the efficacy of lenalidomide over a 
single agent of investigator’s choice based on PFS.
The primary analysis for the study is to compare PFS between lenalidomide and investigator’s 
choice monotherapy. For the primary efficacy variable PFS, a hazard ratio (HR) of 1.7 leading to 
an improvement in median PFS from 2.5 months for the control arm to at least 4.25 months for 
lenalidomide is considered to be clinically relevant.
These assumptions are supported by recent data published in relapsed refractory MCL (Witzig et 
al. 2007 and Hess et al., 2009 ). 
With a hazard ratio of 1.7, full information necessary for a one-sided log rank test with an overall 
alpha of 0.025, to have 80% power, will be achieved when approximately 128 patients have 
progressed or died (PFS).
Initially, the sample size was calculated to estimate the ORR; however, it remains adequate to 
estimate PFS.
The sample size calculation is based on the width of the 95% confidence interval around a 
certain point estimate for ORR that is considered significant clinical activity.
Based on preliminary data, a response rate in the range of 30% to 40% can reasonably be 
expected.
A sample size equal to 100 allows the construction of a two sided 95% confidence interval with a 
width of 9% (one direction) for an expected proportion of 30%. 
The lower observed confidence interval limit would be about 21%, which is still considered to be 
clinically meaningful.
This sample size allows a width (one direction) of 9.6% for an expected proportion of 40% and 
9.3% for an expected proportion of 35% (Table 2).
Table 2:
Confidence Intervals
95% Two-Sided Confidence Intervals (N = 100)
Response rate
30%
35%
40%
CIa
0.214 – 0.400
0.257 – 0.452
0.303 – 0.503
a Exact confidence intervals based on the Clopper-Pearson method
Using a one group chi-square ( ∀2) test with a 0.050 two-sided significance level a sample size of 
100 patients will have 81% power to detect the difference between the Null hypothesis 
proportion of 20% and the alternative proportion of 32%.
No formal sample size calculation will be done for the control arm. With a 2:1 ratio 50 patients 
are needed in the control arm.
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
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17
Assuming that 10% of patients will be lost to follow up, 167 patients will need to be randomized.
5.5.
Changes to the Planned Protocol Analysis
Not applicable.
&(/*(1(35235,(7$5<,1)250$7,21


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Celgene International
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18
6.
GENERAL STATISTICAL CONSIDERATIONS
6.1.
Reporting Conventions
Summary tables, listings, and any supportive SAS output will include a “footer” of explanatory 
notes that will indicate, at a minimum, the following: 
!
Program source (e.g., SAS program name, including the path, that generates the output)
!
Data extraction date (e.g., the database lock date, run date).
!
Source listing(s) for the summary tables
The purpose of the data extraction date is to link the output to a final database, either active or 
archived, that is write-protected for replication and future reference.  An output date will also 
appear on each output page and will indicate the date the output was generated by the analysis 
program. Individual source listings will display all the relative values supporting the 
corresponding tables or figures.
6.1.1.
Dates and partial dates imputation
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9. datetime format in SAS) if complete dates are expected, 
for information (e.g: medical history, prior medications) dates can be reported in the YYYY-
MM-DD format.  Dates in the clinical database are classified into the categories of procedure 
dates, log dates, milestone dates, outcome dates, and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedures are 
performed.  They include the dates of laboratory testing, physical examinations, 
tumor scans, etc.  They should be present whenever data for a protocol-specified 
procedure is present and should only be missing when a procedure is marked as NOT 
DONE in the database.  Procedure dates will not be imputed.
!
Log Dates are dates recorded in case report form (CRF) data logs.  Specifically, they 
are the start and end dates for adverse events and concomitant 
medications/procedures.  They should not be missing unless an event or medication is 
marked as ongoing in the database.  Otherwise, incomplete log dates will be imputed 
according to the rules in Appendix 15.1 (eg, for duration or cycle assignment etc). 
However, in listings, log dates will be shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study termination, etc.  They should not be missing if the milestone occurs 
for a patient. They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc.  In most cases they are derived either from a milestone (eg, the 
survival date is derived from the death date), or a procedure date (eg, the progression 
date is derived from the date of the tumor scan that was used to determine progression
or from the date of clinical evaluation).  They may be subject to endpoint-specific 
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Lenalidomide/CC-5013
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Celgene International
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censoring rules if the outcome did not occur, but are not otherwise subject to 
imputation.
Dates recorded in comment fields will not be imputed or reported in any specific format.
6.1.2.
Calculations Using Dates
Calculations using dates (e.g., patient’s age or relative day after the first dose of study 
medication) will adhere to the following conventions: 
!
Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study medication (eg, 
lenalidomide) plus 1 day. The generalized calculation algorithm for relative day is as 
follows: STUDY DAY = [(TARGET DATE – DSTART) + 1] where DSTART = the 
start day of study drug.  Note that Study Day 1 is the first day of treatment of study 
drug.  Negative and zero study days are reflective of observations obtained during the 
baseline/screening period.  Note: in general, a partial date for the first date of study 
drug intake will not be imputed. All efforts should be made to avoid an incomplete 
study drug start date.
!
Age (expressed in days) is calculated: AGE = CONSENT – DATE of BIRTH + 1.  In 
practice, age will be transformed to years by dividing the difference by 365.25 days, 
then truncating.
o
The calculated age from the clinical database will be used preferentially. 
When not available, it will be permissible to use the calculated age from the 
CRF or IVRS
o
Partial birth date: impute missing day as 15th of the month; impute missing 
month as July; set missing age for missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS / 7.
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS / 30.4167.
6.1.3.
Calculation of Cycles
The start date of each treatment cycle will be calculated based on study drug exposure records 
for each patient. The start date of the first cycle will be the date when the patient receives any 
study drug.
The cycle will be derived following the algorithm given in Appendix 16.2. Rituximab drug has a 
cycle length of 56 days, whereas the other treatments have a 28 days schedule. Any 
programming should be adapted accordingly.
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Once the cycles are derived, they can be used to attribute adverse events to a specific cycle based 
upon the following rules: the start date of the adverse event should be included in a given cycle 
or if the start date does not fit in any defined cycle, the adverse event will be attributed to the 
previous cycle if the AE has started within 30 days after the end of the cycle.
6.2.
Analysis Populations
The primary efficacy analyses will be performed on the Intent-to-Treat (ITT) population for the 
primary and secondary endpoints. Sensitivity analyses will be conducted for the primary and 
secondary endpoints based on the Full Analysis Set (FAS) population.
The safety analyses will be conducted on the Safety population.
6.2.1.
Intent-to-Treat Population
The ITT population is defined as all patients who are randomized, independent of whether they 
received study treatment or not. The ITT population will be used for the primary efficacy 
analysis.
Patients will be analyzed according to the initial treatment to which they are assigned.
6.2.2.
Full Analysis Set Population
The FAS population includes all randomized patients that have received at least one single 
treatment dose with centrally confirmed histology of MCL as well as documented progression at 
entry.
6.2.3.
Per Protocol Population 
No per protocol population will be defined but major protocol violations will be reported.
Major protocol violations will be presented in data listing and summarized by categories in a 
table. Major protocol violations will be determined by careful medical review of the data prior to 
database lock and conduct of statistical analyses. Physician and clinical research scientist will be 
responsible to produce the final protocol violation file (formatted as a Microsoft Excel file) in 
collaboration with the clinical operation and the data management group. This file will include a 
description of the protocol violation and clearly identified whether or not this violation is 
considered as major or not.
6.2.4.
As treated Population
The As treated population  analysis set is defined as all randomized patients who receive at least 
two cycles of treatment regardless the treatment arm received.
This population will be used for exploratory analysis only.
6.2.5.
Safety Population
The Safety population or “All Treated Patients” analysis set is defined as all randomized patients 
who receive at least one dose of the study treatment (either lenalidomide or InvC).
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2.5.
2 5


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Drug exposure and all safety analyses (including AEs, labs and deaths) will be based on the 
Safety population. Patients will be analyzed according to the initial treatment actually received.


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7.
PATIENT DISPOSITION
All patients enrolled/randomized will be included in the analyses listed below. Patient 
disposition will be summarized for the following analysis populations by initial dosing regimen:
!
ITT Population
!
FAS Population
!
Safety Population.
A separate listing will be provided for patients not randomized.
The number of patients who will cross-over will be also displayed.
The primary reasons for ending study treatment will be collected on the CRF and will be 
summarized for all randomized patients using the following categories:
!
Adverse events
!
Disease progression
!
Withdrew consent
!
Lost to follow-up
!
Death
!
Protocol violation
!
Other.
The primary reasons for study discontinuation in all randomized patients will also be collected 
on the CRF and summarized using the categories outlined above.
The number of patients who will enter the follow-up phase with or without progression will be 
displayed.
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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics and baseline characteristics will be summarized for the ITT 
population. Baseline clinical characteristics are defined as the latest data collected on or before 
day 1 (or randomization day in case day 1 is missing). When there are retested values, the retest 
values will be used for the analysis. Individual patient listings will be provided to support the 
tables.
Baseline characteristics will be summarized for the FAS population if the ITT and FAS 
populations differ by ≥ 10% in size.
8.1.
Demographics
Age, baseline weight, height, and body surface area (BSA) will be summarized descriptively by 
treatment group. Age is calculated based on the date of birth at the date of informed consent.
Body surface area (BSA) will be calculated, using the formula:
BSA (m²) = ( [Height(cm) x Weight(kg) ]/ 3600 )½      Mosteller formula
Baseline body mass index (BMI) will be calculated, using the formula:
BMI (kg/m²) = baseline weight / (height²) with weight expressed in kg and height in m.
The BMI will be summarized, and the frequency counts of the different categories (< 20, 20 to 
< 25, 25 to < 30, and ≥30) will be displayed.
Age categories (< 65, ≥65) and race will be summarized with frequency counts.
Baseline ECOG and baseline ECG (normal/abnormal) will be summarized with frequency 
counts.
8.2.
Baseline Clinical Characteristics
Time from initial diagnosis to the first study treatment, and time from the latest disease 
progression to the first study treatment, will be calculated in months and summarized 
descriptively.
Histological diagnosis (investigator’s assessment and confirmed histology) will be summarized.
8.3.
Medical History
A summary of medical history will be presented by MedDRA system organ class (SOC).  A 
similar summary will be generated for the concomitant disease (currently active medical history 
events).
8.4.
Prior Therapy 
Frequency tabulations of the number of patients with at least one prior therapy and the different 
types of previous therapies (chemotherapies, immunotherapies, Stem cell transplant (SCT)
separating autologus from allogenic if possible, radiation, and so on) will be given.
descript
descriptive
formed 
form
con
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Mosteller fo
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expressed 
expressed 
of the
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.4.4


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8.5.
Prior Medications
Prior medications are defined as medications that were started before the start of the study 
treatment (whether or not ended before the start of the study treatment). Prior medications that 
continue into study treatment period will be also reported as concurrent therapy.  Frequency 
tabulations of the number of patients with at least one prior medication and the different types of 
prior medications will be provided.
&(/*(1(35235,(7$5<,1)250$7,21


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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
Duration of treatment is the total number of days on treatment (date of last dose – date of first 
dose + 1).  For patients ongoing in the treatment phase of the study on the cut-off date for the 
final analysis, the cut-off date will be used as the date of last dose.
The treatment duration (weeks) is defined as: 
[(The study treatment end date) – (the first study drug start date) + 1] / 7
Summary statistics will be provided for treatment duration by treatment group. 
An additional table will be created for all treated patients, displaying number of patients by cycle 
and the treatment arm.
Days Dosed is the total number of days study drug was taken, adjusted for any treatment 
interruptions.  Days dosed will be calculated by cycle and overall.
Cycles Dosed is the total number of treatment cycles during which a patient took study drug.
Average Number of Days dosed per cycle is calculated as days dosed (overall) divided by 
cycles dosed.
9.2.
Cumulative Dose
Overall Cumulative dose is the total dose received during the treatment period.
Cumulative dose will be calculated separately for lenalidomide or InvC.  The cumulative dose 
during the treatment is defined as the sum of all doses taken across the treatment period (in 
milligrams).
Cumulative dose at each cycle is calculated as the total dose received up to and including the 
current cycle.  
9.3.
Dose Intensity
Dose intensity during the treatment is defined as the cumulative dose divided by treatment 
duration. Dose intensity will be calculated separately for lenalidomide and for InvC single agents
separately.  
The dose intensity per cycle is calculated as the overall cumulative dose divided by the number 
of cycles dosed. 
9.4.
Relative Dose Intensity
Relative dose intensity is the dose intensity divided by the planned dose intensity:
!
For lenalidomide the planned dose intensity is 25 mg/per 28 days.
!
For InvC single agents:
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Lenalidomide/CC-5013
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Table 3:
InvC drug recommended dose
Investigator’s choice
mg/m2
days
q days
max # cycles
Chlorambucil PO
40 (total monthly 
dose)
Split over 3-10 
days
28
until PD or 
toxicity
Rituximab IV
375
1, 8, 15, 22
56#
until PD or 
toxicity
Cytarabine IV
1000 -2000 once 
or twice per day
1, 2
28
6
Gemcitabine IV
1000
1, 8, 15
28
6
Fludarabine IV
25
1-5
28
6
Fludarabine PO
40
1-5
28
6
IV = intravenous; PD = progressive disease; PO = oral; q = days, repeated; y = years.
# Rituximab (single agent) is to be repeated every 56 days after Day 56 (given only on day 1 of every 56 days cycle).
For the prevention of cytokine release syndrome associated with the treatment of Rituximab ≤125 mg of 
methylprednisolone or equivalent are accepted on C1D1.
Descriptive statistics (n, mean, SD, median, max, min) of treatment duration, cumulative dose, 
dose intensity and relative dose intensity will be presented by treatment arm.
9.5.
Dose Modification
Dose reduction overall is the number and percent of patients with at least one dose reduction 
during the treatment period.  Dose reduction by cycle is the number and percent of patients with 
only one (patients with one dose reduction) or more than one (number of patients with two or 
more dose reductions) during a given cycle.
In order for a patient to have two or more dose reductions, study drug must have been reduced 
for one or more days, followed by another period of one or more days during which study drug 
dosing was reduced.
Dose interruption overall is the number and percent of patients who interrupted treatment with 
study drug for one or more days at least once during the treatment period.  Dose interruption by 
cycle is the number and percent of patients with only one (patients with one dose interruption) or 
more than one (number of patients with two or more dose interruptions) during a given cycle.  In 
order for a patient to have two or more dose interruptions, study drug must have been stopped for
one or more days, followed by dosing for one or more days, followed by another period of one or 
more days during which study drug dosing was stopped. 
Time to first dose reduction/interruption for patients with at least one dose 
reduction/interruption, is the time in days elapsed from the date of first dose of treatment to the 
date that first dose reduction/interruption occurred.
Interval between dose reduction/interruptions is the time from the start of the first dose 
reduction/interruption to the start of the second dose reduction/interruption.
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Time to fir
educti
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Dose reduction/interruption will be summarized by Intitial dosing regimen group. Summaries 
include patients who have at least one dose reduction/interruption, time to first dose 
reduction/interruption. Additional descriptive statistics will include first and second dose 
reduction/interruption due to AE, duration of first and second dose reduction/interruption due to 
AE and interval between first and second dose reduction/interruption due to AE.
&(/*(1(35235,(7$5<,1)250$7,21


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10.
CONCOMITANT MEDICATIONS
Concomitant mediations are defined as non-study medications that are started after the start (start 
included) but before the end of the study treatment, or started before the start of the study 
treatment and ended or remain ongoing during the study treatment.
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations.  The Anatomical Therapeutical Chemical (ATC) coding scheme of the World Health 
Organization (WHO) will be used to group medications into relevant categories for these 
tabulations.
&(/*(1(35235,(7$5<,1)250$7,21
h h 


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11.
EFFICACY ANALYSIS
All efficacy evaluations will be conducted using the ITT population. Supportive analysis of the 
primary and key secondary efficacy endpoints using the FAS population will be conducted for 
the final analysis.  Statistical comparisons will be made between lenalidomide and InvC.
11.1.
General Statistical Methods
11.1.1.
Time to event endpoints
Kaplan-Meier (KM) survival analysis will be performed (unadjusted for the stratification 
variables). The resulting survival estimates will be presented graphically for selected endpoints. 
The median, 25th and 75th percentile time-to-event data will be presented with 95% CIs (if they 
exist) unadjusted by strata and within strata for the primary endpoint only.  
The numerical difference (and CI of the difference) in the median, 25th and 75th percentiles 
between lenalidomide and InvC will be presented for the unstratified analysis.
In addition, the event rates at specific time-points will be computed, along with the standard 
errors (Greenwood’s formula; Klein, 1997), based on which the event rates at specific timepoints 
can be compared if necessary. 
The groups will be compared using the stratified log-rank test in order to assess superiority.
The stratified Cox proportional hazard regression models will be used to estimate the hazard 
ratios (HR) and associated 95% CIs for the HRs. 
If any imbalances appear in the demographic or baseline characteristics variables considered as 
important predictive or prognostic factors to clinical outcomes, the variables will be analyzed as 
the stratification factors. They will be included as covariates in the Cox model to provide 
estimate of lenalidomide treatment effect adjusted for these factors and in the stratified log-rank 
test.
More detailed methods (for example exploring additional covariates such as age) will be 
investigated as a robustness check and may also be presented. 
Underlying model assumptions will be investigated for the analysis of the PFS endpoint using 
diagnostic statistics and graphical methods and, if necessary, an alternative analysis technique 
may be used.
Any changes in methodology will be documented in the clinical study report (CSR), including 
the rationale for use.  The proportional hazards assumption will be assessed by graphical display 
of the log-log survival distribution function versus the log event time for each treatment group.  
&(/*(1(35235,(7$5<,1)250$7,21
ratificat
atificatioion
r selected e
r selected e
d with 95%
with 
only
only.  
, 25th and 
25th and 
atified anal
atified a
omputed, a
mputed, 
hich the ev
hich the e
lolog-
g-rank te
rank t
ssio
ssion mo
mode
de
he HRs.
he HRs.
emographi
emograph
ostic factors
ostic facto
hey
ey will
will
y
b
l e
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e treatmen
ailed meth
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igated as a 
nderlying m
nderlying m
didiagnosti
agnosti
may be
may be


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The censoring distributions of the treatment groups will be assessed for possible differences 
using KM methods.  
KM curves will be displayed graphically by treatment group.  Additionally, reasons for 
censoring will be summarized (n, percent) for the TTP, PFS, and OS endpoints.
Individual survival time information and mortality data will be provided in patient data listings. 
In order to evaluate the effect of cross-over on overall survival a Mantel-Byar approach will be 
used. The estimation of the control arm without cross-over and the mixed arm (lenalidomide arm 
and cross-over patients) will be estimated. A weighted log rank test or Wilcoxon test will be used 
to take into account the effect of cross-over.
Multivariate models will be used to identify those baseline and prognostic factors (eg absolute 
leukocyte count, time from diagnosis, number of prior therapies and any other variables 
suggested in the literature prior to the analysis) most predictive of response (Colett, 1991).
11.1.2.
Categorical endpoints
Categorical analyses will be based on the Fisher exact test.  Sensitivity analyses will be 
performed using the Cochran-Mantel-Haenszel test with the stratification factors as strata.  The 
p-values will be presented.  The null hypothesis is that incidence is equal for both treatment 
arms, the alternative hypothesis being that incidence is not equal.
The probability of response rates will be estimated using the proportion of patients with 
responses with exact two-sided 95% confidence intervals.
The response rate in the cross-over portion of patients in Arm B will be analyzed in a descriptive 
manner.
11.1.3.
Quality of Life endpoints
The EORTC QLQ-C30 will be analyzed using change from baseline and percentage of change 
from baseline according to the functional scores and the recommendations in the EORTC scoring 
manual. Statistical tests could be performed in an exploratory manner.
The EORTC Reference Data Manual will also be used to descriptively check comparability 
between patients in our trial and with other comparable populations.
Mann-Whitney tests for simple comparison and longitudinal data modeling techniques (ie Proc 
mixed in SAS) will be used to analyze QoL scores.
Patients who drop out of the study without being evaluated for QoL will be counted as 
non-responders. Responses from patients after they receive other anti-cancer treatments will be 
treated as non responders.
An update of the time to events endpoints and overall survival will be done at the end of the 
follow up. No adjustment for multiplicity will be applied.
11.2.
Expert Review of Disease Response
The independent review committee (IRC) is composed of two external independent radiologists 
(with an additional radiologist adjudicator in the event of a tie) and a hematologist/oncologist.  
The IRC will perform a blinded, independent assessment of radiological response (including 
&(/*(1(35235,(7$5<,1)250$7,21
m
used 
use
abso
bsolut
lute
iables
ables
let
lett, 1991
t, 199
25
)
y y analyses w
analyses 
cat
c ioion fafactc
e is equal fo
e is equal f
qual
qual.
the propor
he prop
als.
als
entnts in Arm
s in Ar
zed using c
zed usin
ctional sco
sco
e performe
e performe
a Manual
a Manual
rial and wi
rial and w
for simple
for simple
ill be used 
ill be used 
drop out o
drop out o
nders. Resp
ders. Resp
as non resp
as non resp
update of t
update of t
follo
llow up. N
w up. 
2


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assessment of Stable Disease [SD] and Progressive Disease [PD]), as well as reviewing the 
tumor response data and the dates of disease progression for each patient.
For further details please refer to Central Radiology Manual.
No central review will be performed for the patients who crossed over after progression.
11.3.
Analysis of Primary Efficacy Endpoint
PFS is defined as the time from randomization to the first observation of disease progression or
death due to any cause. If the patient has not progressed or died, PFS will be censored at the time 
of last completed assessment when the patient was known not to have progressed. Patients who 
will receive a new treatment without documented progression will be censored at the last 
assessment date that the patient is known to be progression-free. These rules are based on FDA 
guidance for cancer trial endpoints (FDA guidance, 2007).
Table 4:
Censoring Rules for Time to event (Progression and/or Death) Endpoints
Situation
Date of Progression or Censoring
Situation 
Outcome
No baseline assessments
Randomization
Censored
Progression documented
First adequate assessment determined by 
central review
Progressed
No progression
Date of last adequate assessment with 
evidence of no progression
Censored
Study discontinuation for reasons other 
than disease progression or death
Date of last adequate assessment with 
evidence of no progression
Censored
New anti-lymphoma / non-protocol 
treatment started prior to progression
Date of last adequate assessment with 
evidence of no progression prior to the start of 
new anti-lymphoma treatment
Censored
Death before first PD assessment while on 
study
Date of death
Progressed
Death between adequate assessment visits
Date of death
Progressed
Progression after an extended lost-to-
follow-up time (two or more missed 
assessments)
Date of last adequate assessment with 
evidence of no progression
Censored
PD = progressive disease.
See details in Appendix 15.3.
As additional robustness checks of the primary endpoint and censoring definition, the time to 
event analysis will be repeated for the ITT population using the following modified definitions of 
PFS:
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fter an exten
fter an exten
ime (two or 
me (two or 
ents)
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time
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ast 
ed on FDA
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Date of l
Date of
eviden
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35
23
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23
23
23
2
ssment whi
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3
quate asses
quate asses
1(
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(/*
progressive 
progressive 
e details in
details in A


Lenalidomide/CC-5013
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!
Using the investigator assessment instead the IRC central review 
!
Considering progression or death under a new anti-lymphoma treatment as an event 
(Table 4)
!
Considering Death or progression after an extended lost-to-follow-up time (two or 
more missed assessments) as an event (Table 5)
!
One using the earliest progression date either in investigator set or IRC set.
Table 5:
Method b: Censoring Rules for Time to event (Progression and/or Death) 
Endpoints sensitivity analysis
Situation
Date of Progression or Censoring
Situation 
Outcome
No baseline assessments
Randomization
Censored
Progression documented
First adequate assessment determined by 
central review
Progressed
No progression
Date of last adequate assessment with 
evidence of no progression
Censored
Study discontinuation for reasons other 
than disease progression or death
Date of last adequate assessment with 
evidence of no progression
Censored
New anti-lymphoma / non-protocol 
treatment started prior to progression
First adequate assessment determined by 
central review
Progressed
Death before first PD assessment while on 
study
Date of death
Progressed
Death between adequate assessment visits 
Date of death
Progressed
Progression after an extended lost-to-
follow-up time (two or more missed 
assessments) 
Date of last adequate assessment with 
evidence of progression
Progressed
PD = progressive disease.
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ath) 
th)
Situa
Situa
Ou
O
50
25
2
etermined b
etermined
1
e assessmen
e assessme
rogression
rogression
5<
adequate ass
adequate ass
of no progre
of no progr
$5
adequate as
dequate a
ntral review
ntral review
(7
Date of de
Date o
5
23
visits
visits
Da
D
23
23
23
23
stst-to
to-
missed 
missed 
52
(
2


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Table 6:
Method c: Censoring Rules for Time to event (Progression and/or Death) 
Endpoints sensitivity analysis
Situation 
Date of Progression or Censoring 
Outcome 
No baseline assessment 
Randomization 
Censored 
Progression documented between scheduled visits 
As defined for the main analysis 
Progressed 
No progression 
Date of last visit with adequate 
assessment 
Censored 
Investigator claim of clinical progression 
Scheduled visit (or next scheduled 
visit if between visits) 
Progressed 
Treatment discontinuation for toxicity or other 
reason 
Date of last visit with adequate 
assessment 
Censored 
New anticancer treatment started with no claim of 
progression 
Date of last visit with adequate 
assessment 
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessment visits or after 
patient misses one assessment visit 
Date of death 
Progressed 
Progression after an extended lost-to-follow-up time 
(two or more missed assessments) 
Last visit with adequate assessment 
Censored 
PD = progressive disease.
11.4.
Analyses of Secondary Efficacy Endpoints
The secondary endpoints will be analyzed in an exploratory manner (see details in 
Appendix 15.3).
11.4.1.
Overall response rate
The Overall response rate will include best response of CR, CRu, or PR. The modified IWRC 
will be used and response assessed by CT scan/MRI every 56 days (± 7 days) for the first 
6 months and then every 90 days ± 15 days thereafter.
Patients who discontinue before any post-randomization efficacy assessments will be considered 
to be non-responders.
11.4.2.
Duration of Response
Duration of response will be measured from the time of initial response (at least PR) until 
documented tumor progression or death. Patients who do not progress at the time of analysis will 
be censored at the last assessment date that the patient is known to be progression-free. Patients 
who will receive a new treatment without documented progression will be censored at the last 
assessment date that the patient is known to be progression-free. 
This analysis will be restricted to the subgroup of responding patients.
&(/*(1(35235,(7$5<,1)250$7,21
,2
ored 
ored
,2
,2
7,2
Progresse
Progresse
$7
50
Ce
C
50
50
50
50
dequate
dequate
2
1)
th
< ,1
st visit with 
visit wit
$5
(7
Efficacy 
Efficac
nalyzed 
lyzed in a
n
nse rate
e rate
ate will inc
ate will inc
ponse asse
onse asse
en every
n every 90
90
y
discont
discontinu
inu
responders
sponders
2.2.
Dur
Du
Durati
Duration of
on o
docum
documen
ce


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11.4.3.
Tumor control rate
Rates for CR, CRu, PR, and SD.
CR/CRu/PR/SD will be determined using the modified IWRC (Cheson, 1999).
11.4.4.
Duration of Stable Disease
SD is defined as less than PR but is not progressive disease or relapsed disease.
Duration of SD will be calculated as the time from the first evidence of SD to documented 
disease progression or documented response or death. Patients who do not progress or respond at 
the time of analysis will be censored at the last assessment date that the patient is known to be 
progression-free. Patients who will receive a new treatment without documented progression will 
be censored at the last assessment date that the patient is known to be progression-free. 
This analysis will be restricted to the subgroup of SD patients.
11.4.5.
Time to progression (TTP)
TTP will be defined as the time from randomization until objective tumor progression. TTP will 
not include deaths. Patients without progression at the time of analysis will be censored at the 
last assessment date that the patient is known to be progression-free. Patients who will receive a 
new treatment without documented progression will be censored at the last assessment date that 
the patient is known to be progression-free. Deaths due to progression of disease will be 
considered as an event.
11.4.6.
Time to treatment failure (TTF)
TTF is defined as the time from the first dose of study drug to discontinuation of treatment for 
any reason, including disease progression, treatment toxicity or death. Patients who will be on 
drug or complete the treatment according to the protocol will be censored at the last date of drug 
intake.
11.4.7.
Time to tumor response (TTR)
This analysis will be restricted to the subgroup of responding patients.  Time to tumor response 
(TTR) will be defined as the time from randomization until initial response (CR, CRu, PR) if it 
has been confirmed.
11.4.8.
Overall Survival (OS)
OS will be defined as the time from randomization until death from any cause. Patients alive or 
lost to follow up at the time of analysis will be censored at the last date the patient was known to 
be alive.
11.5.
Subgroup Analysis
Subgroup analyses will be conducted in an exploratory manner for the following endpoints PFS, 
ORR and OS in the following subgroups:
!
Time since diagnosis (< 3 years or ≥ 3 years)
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ond at 
nd at 
to be
o be
ression wil
ession wil
free.
ree.
umor pro
mor progr
gr
lysis will b
ysis will b
free. Patie
free. 
ored at the 
ored at the
o progressio
progressio
e of study
e of study d
treatment 
treatment 
ng to the pr
g to the p
ponse (TT
onse (TT
cted to the 
ed to the
s the time f
s the time
rall Surviv
rall Surviv
defined
defined as
a
llow up at
w up a
ve
ve.
11.5.
11.5
ubgro
ubgro


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!
Time since last treatment (<6 months [refractory] or ≥ 6 months)
!
Prior stem cell transplant (yes or no)
!
Age and gender 
!
MCL International Prognostic Index (MIPI) score at initial time of diagnosis 
!
Number of prior treatment lines (with description of treatment regimens, including 
first line treatment and stem cell transplant)  (1,> 1), (<2;≥2), (<3; ;≥3)
!
Ki-67 index (as defined by Determann, 2008) labeling in the original pathology 
specimen at diagnosis, if available at time or at time of relapse
!
Absolute lymphocyte count at baseline (< 800/mm3 or ≥ 800/mm3)
!
Time since last rituximab to cycle 1 day 1 (< 230 days or ≥ 230 days)
!
Prior regimens received.
!
Number of relapses ( 1 vs > 1), (<2 vs ;≥2 relapses), (<3; ;≥3 relapses)
!
Any demographic or baseline characteristic considered as important prognostic 
factors with imbalance in two treatment arms.
In addition any other possible prognostic factors may be used as exploratory analyses.
The methods described in previous sections will be used for each subgroup separately.
&(/*(1(35235,(7$5<,1)250$7,21
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as importan
as import
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d as explo
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for each 


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12.
SAFETY ANALYSIS
The purpose of this section is to define the safety parameters for the study. All summaries of 
safety data will be conducted using the Safety population. 
12.1.
Adverse Events
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version 12.0. The intensity of AEs will be graded according to the
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version 3.0 (same as protocol).
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on 
or after the first treatment of the study medication and within 30 days after the last dose. TEAEs,
TEAEs leading to study medication discontinuation, TEAEs leading to dose 
reduction/interruption, TEAEs related to study medication and treatment-emergent serious 
adverse events (SAEs) will be summarized by system organ class and preferred term for each 
treatment group. A summary of TEAEs with NCI CTCAE grade 3 or higher and most frequent 
preferred terms will also be provided.
If a patient experiences the same preferred term multiple times then the patient will be counted 
only once and by greatest severity.
Listings for the corresponding summary tables will be presented separately.
For the cross-over patients, any adverse events starting after the start of the drug will be assigned 
to lenalidomide even if the event has started within 30 days after the InvC end date. Additional 
summary tables will be provided for these TEAEs (cross-over lenalidomide).
Analysis of TEAEs of special interest, time to TEAEs of special interest will be presented. 
TEAEs of special interest will be defined using standardized MedDRA Queries (SMQs). The 
SMQ will be selected based on the Risk Management Plan (RMP) and the internal expertise on 
the drug and the disease.
Second Primary Malignancy (SPM) will be summarized by frequency and 95% CI for the 
following categories:
-
Invasive SPM including hematologic malignancies and solid tumor. Hematological 
malignancies will be subcategorized in b cell lymphoma, AML, MDS and other
-
Non invasive SPM
Time to onset to first SPM will be analyzed using Kaplan Meier methods.
Incidence per 100 patient-year will also be calculated.
&(/*(1(35235,(7$5<,1)250$7,21
AE
AE)
worsening o
worsening
last dose. T
ast dose
em
emergent
ergent s
pref
preferred te
erred 
f
or hig
higher 
her an
es then the
es then the
e presented
e presented
arting after
arting afte
ithin 30
hin 30 da
da
EAEs
EAE (cro
(cro
time to
me to TE
TEA
fined using
fined usin
e Risk Man
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gnancy
gnancy (SP
(SP
y
s:
e SPM incl
e SPM in
gnancies w
gnancies w
Non invasiv
invasi
me to onse
me to onset
Incidence
Incidence


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12.2.
Clinical Laboratory Evaluations
Clinical laboratory values will be graded according to NCI CTCAE version 3.0 for applicable 
tests (see appendix 15.5 for details on standardization of the laboratory values). Frequency 
distributions for shift from baseline in severity grade to most extreme post-baseline value will be 
displayed in cross-tabulations for the whole study period for each treatment. Normal ranges will 
be used to determine the categories if High, Low, and Normal for lab tests that have no severity 
grade.  Listings of clinical laboratory data with abnormal flags will be provided by patients and 
tests. 
12.3.
Vital Sign Measurements
For vital signs, shift from baseline to worst during the treatment in below, within and above the 
normal ranges will be displayed in cross-tabulations for each treatment. Summary statistics (N, 
Mean, SDev, Median, Minimum, and Maximum) of observed and change from baseline values 
will be presented.
12.4.
Physical Examination
Shift tables regarding the evolution of the spleen, liver, lymphadenopathy will be displayed by 
treatment groups.
Presence or absence of lymphoma symptoms will be summarized by visit and treatment groups.
12.5.
Electrocardiogram
The overall ECG interpretation will be summarized by presenting the number and percentage of 
patients with ‘Normal’, ‘Abnormal, not clinically significant’, and ‘Abnormal, clinically 
significant’ by treatment. Shift from baseline to worst during the treatment in the overall ECG 
interpretation will be displayed in cross-tabulations for each treatment.
&(/*(1(35235,(7$5<,1)250$7,21
d above the
d above the
y statist
statisticics (
s
m baseline v
baseline
nopathy
opathy wi
w
y
marized by 
rized by
zed by
zed by pres
pres
y
ally signifi
ally signifi
ne to w
ne to wors
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tabulat
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13.
QUALITY OF LIFE ANALYSIS
13.1.
EORTC QLQ-C30
QoL instrument: EORTC QLQ-C30 (see attachment 21.9)
The version 3.0 of the EORTC QLQ-C30 is a 30-item scale. The EORTC QLQ-C30 is composed 
of both multi-item scales and single-item measures. These include five functional scales, three 
symptom scales, a global health status / QoL scale, and six single items (Table 7).
Table 7:
EORTC QLQ-C30 scores
FUNCTIONAL 
SCALES
(15 QUESTIONS)
SYMPTOM SCALES
(7 QUESTIONS)
SINGLE ITEMS
(6 QUESTIONS)
GLOBAL QUALITY 
OF LIFE
(2 QUESTIONS)
PHYSICAL
(ITEMS 1 TO 5)
FATIGUE 
(ITEMS 10, 12, 18)
CONSTIPATION
(ITEM 16)
GLOBAL QOL
(ITEMS 29, 30)
ROLE
(ITEMS 6, 7)
PAIN
(ITEMS 9, 19)
DIARRHEA
(ITEM 17)
COGNITIVE
(ITEMS 20,25)
NAUSEA /
VOMITING
(ITEMS 14, 15)
SLEEP
(ITEM 11)
EMOTIONAL
(ITEMS 21 TO 24)
DYSPNEA
(ITEM 8)
SOCIAL
(ITEMS 26, 27)
APPETITE
(ITEM 13)
FINANCIAL
(ITEM 28)
All of the scales and single-item measures range in score from 0 to 100. A higher scale score 
represents a higher level of well being and better ability of daily functioning. A 10-point change 
in the scoring is considered to be meaningful change in QoL (Osoba, 1998).
Thus a high score for a functional scale represents a high/healthy level of functioning; a high 
score for the global health status/QoL represents a high QoL, but a high score for a symptom 
scale/item represents a high level of symptomatic problems.
Data collection and timing
Questionnaires must be filled out by the patient at 6 pre-specified time points (see below) when 
the patient comes for a scheduled visit. They will be handed out by a nurse or the treating 
physician/investigator, and ideally are collected again soon after the patient has filled it out.
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Patients will be asked to complete the questionnaire as completely and accurate as possible. The 
average time to complete the questionnaire is around 10to 15 minutes. The reasons for not 
completing the questionnaire will be recorded.
QoL will be assessed at 6 time points:
!
at screening/baseline (within 7 days prior to randomization)
!
after cycle 2 (C3D1)
!
after cycle 4 (C5D1)
!
after cycle 6 (C7D1)
!
after cycle 8 (C9D1)
!
and at time of discontinuation from treatment.
A ± 7 days time window will be allowed.
Compliance & Missing data
During the study compliance will be investigated at each time point. The compliance rate will be 
descriptively compared between the two arms. 
In the case that a patient still on study has not filled in the questionnaire, no more than ± 7 days 
delay is accepted.
The rate of compliance will be assessed after 40, 80, and 120 patients enrolled.
Missing data will be reported as recommended in the EORTC scoring manual (Fayers, 2002).
Scales scores: if at least 50% of the items have been answered, the scale scores will be 
calculated according to the standard equations given on the manual (any items with missing 
values will be ignored). In other cases, scores will be set to missing.
Single-item measures: the score will be set to missing.
Statistical considerations
No calculation in terms of sample size will be performed based on changes in QoL.
In the absence of more specific hypothesis, the global score will be used as the primary QoL 
outcome and physical functional score and fatigue item will be used as secondary outcomes.
Expectations are that the global score and the physical functional score are improved by 
lenalidomide. The fatigue item may be worse initially under lenalidomide, but improve in mid 
and long term in responding patients due to tumor control compared to control arm with shorter 
response duration
A difference of 10 points between the two arms is considered as clinically significant.
Derivation
For all scales, the Raw Score, RS, is the mean of the component items:
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For functional scales:
For symptom scales / items and Global health status / QoL:
Range is defined as the difference between the maximum possible value of RS and the minimum 
possible value, eg, most items are quoted from 1 to 4, the range is equal to 3.
13.2.
Analysis of Quality of Life Scales
The EORTC QLQ-C30 will be analyzed using change from baseline and percentage of change 
from baseline according to the functional scores and the recommendations in the EORTC scoring 
manual. Statistical tests could be performed in an exploratory manner.
The EORTC Reference Data Manual will also be used to descriptively check comparability 
between patients in our trial and with other comparable populations.
Mann-Whitney tests for simple comparison and longitudinal data modeling techniques (ie Proc 
mixed in SAS) will be conducted to analyze QOL scores.
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14.
INTERIM ANALYSIS
14.1.
General Information
An independent external Data Monitoring Committee (DMC) will review on an ongoing basis 
safety data throughout the study and efficacy for futility at a pre-defined time point. Specifics are 
outlined in the DMC charter. Summaries of safety information will be prepared for Data 
Monitoring Committee (DMC) review. The first safety analysis will occur after the first 
40 patients have received at least 2 cycles of treatment or have discontinued prior to completing 
2 cycles.  The second safety analysis, as well as an efficacy analysis for futility, will occur after 
80 patients complete 2 cycles or withdraw before completing 2 cycles. A third safety analysis 
will occur after 120 patients complete 2 cycles or withdraw before completing 2 cycles.
The futility analysis will be conducted when approximately 80 patients complete 2 cycles or 
withdraw before completing 2 cycles (around 54 patients in the lenalidomide arm) on 
investigator and central assessment.
The DMC will conduct an analysis for futility on PFS and ORR. No specific stopping rules will 
be given to the DMC for the PFS; the following rules might be used for ORR.
Based on a 95%CI approach, if the upper bound is below than 20% in the lenalidomide arm, the 
DMC should recommend stopping the trial. 
Table 8:
Response percentage and 95% exact confidence interval 
FREQUENCY 
OF RESPONSE
BINOMIAL 
PROPORTION 
P
EXACT LOWER
CL, BINOMIAL
PROPORTIONA
EXACT UPPER
CL, BINOMIAL
PROPORTIONA
1
1.8519
0.04687
9.8915
2
3.7037
0.45173
12.7472
3
5.5556
1.16068
15.3885
4
7.4074
2.05510
17.8933
5
9.2593
3.07528
20.3002
6
11.1111
4.18838
22.6313
7
12.9630
5.37430
24.9012
8
14.8148
6.61976
27.1198
9
16.6667
7.91544
29.2941
10
18.5185
9.25455
31.4297
CI = confidence interval.
a Exact confidence intervals based on the Clopper-Pearson method.
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Lenalidomide/CC-5013
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14.2.
Statistical Approaches for Control of Alpha
14.2.1.
Primary analysis
The final PFS analysis will be conducted with an alpha level equal to 5% (two sided).
Reflecting a medical meaningful improvement, a p-value is above 0.05 and still below 0.10 will 
be considered as an acceptable trend.
14.2.2.
Interim analysis 
No formal adjustment is needed. Interim analysis is run only for futility.
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Celgene International
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43
15.
REFERENCES
Cheson 1999 – please add complete reference
Collett, D. Modelling Binary Data. 1991; London: Chapman & Hall. 
Collett, D. Modelling Survival Data in Medical Research Second Edition. 2003; London: 
Chapman & Hall.
Determann O et al.; European Mantle Cell Lymphoma Network and the German Low Grade 
Lymphoma Study Group.Ki-67 predicts outcome in advanced-stage mantle cell lymphoma 
patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the 
European MCL Network and the German Low Grade Lymphoma Study Group. Blood. 2008 Feb 
15; 111(4):2385-7.
Fayers PM, Weeden S, Curran D on behalf of the EORTC Quality of Life Study Group.  EORTC 
QLQ-C30 Reference Values.  In:  EORTC, 1998.  ISBN:  2-930064-11-0.
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. 
FDA , May2007 
Hess G, et al., Phase III Study to Evaluate Temsirolimus Compared With Investigator’s Choice 
Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma. J Clin Oncol 
27:3822-3829.
Klein J.P, Moeschberger ML. Survival Analysis: Techniques for Censored and Truncated Data, 
1997; New York: Springer-Verlag.
Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 
22;317(17):1098 (letter) 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J.  Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16(1):139-44.
Stead ML, Brown JM, Velikova G, Kaasa S, Wisloff F, Child JA, et al.  Development of an 
EORTC questionnaire module to be used in health-related quality-of-life assessment for patients 
with multiple lymphoma.  European Organization for Research and Treatment of Cancer Study 
Group on Quality of Life.  Br J Haematol 1999 Mar;104(3):605-11.
Witzig TE, Reeder CB, Polikoff J, et al. Initial Results from an International Study in 
Relapsed/Refractory Aggressive Non-Hodgkin s Lymphoma to Confirm the Activity, Safety and 
Criteria for Predicting Response to Lenalidomide Monotherapy. Blood (ASH Annual Meeting 
Abstracts), Nov 2007; 110: 2572.
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of f the
od. 2008 F
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udy
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Group
y
ancer Drugs
ancer Drug
pared Wi
pared W th
i h
e Cell Lym
 Cell Lym
chniques fo
hniques
y Surface A
Surface A
y
B, Pater J. 
, Pater J. 
J Clin Onc
J Clin On
a G, Kaasa 
a G, Kaasa 
le to be use
le to be use
 European 
 Europe
fe. 
fe. Br J H
Br J H
r CB, Polik
CB, Polik
ctory
ctory Agg
Agg
y
r
Predicting R
Predicting R
), Nov 2007
Nov 200


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16.
APPENDICES
16.1.
Date Imputation Guideline
16.1.1.
Impute Missing AE/ Prior or Concomitant Medications Start Dates
Missing day and month
!
If the year is same as the year of first day on study medication, then the day and month of the start date of study medication 
will be assigned to the missing fields
!
If the year is prior to the year of first day on study medication, then December 31 will be assigned to the missing fields.
!
If the year is after the year of first day on study medication, then January 1 will be assigned to the missing fields.
Missing day only 
!
If the month and year are same as the year and month of first day on study medication, then the start date of study medication 
will be assigned to the missing day.
!
If the month and year are before the year and month of first day on study medication, then the last day of the month will be 
assigned to the missing day.
!
If the month and year are after the year and month of first day on study medication, then the first day of the month will be 
assigned to the missing day.
!
If the stop date is non-missing and the imputed start date is after the stop date, the start date will be imputed by the stop date. 
Missing day, month, and year
Included as TEAE
Incomplete Stop Date: If the imputed stop date is before the start date then the imputed stop date will be equal to the start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dose date of study medication, then the day and month 
of the last dose date will be assigned to the missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dose date of double-blind study medication, then 
December 31 will be assigned to the missing fields. 
!
If the year of the incomplete stop date is after the year of the last dose date of study medication, then January 1 will be 
assigned to the missing fields.
Missing day only 
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before the
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date is the
signed to th
signed to th
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!
If the month and year of the incomplete stop date are the same as the month and year of the last dose date of study medication, 
then the day of the last dose date will be assigned to the missing day. 
!
If the month and year of the incomplete stop date are before the month and year of the last dose date of the study medication, 
then the last day of the month will be assigned to the missing day. 
!
If the month and year of the incomplete stop date are after the month and year of the last dose date of study medication, then 
the first day of the month will be assigned to the missing day.
16.2.
Cycle derivation Guideline
Subjects on Rituximab treatment have cycles of 56 days in duration past cycle 1. Cycle 2 day 1 will in fact correspond to day 56.
Programming need to be adapted accordingly.
eCRF 
pages 
completi
on
C1D1
C2D1
C3D1
C4D1
C5D1
C6D1
C7D1
days on 
study
1
28
56
84
112
140
168
Tumor 
assessme
nt
X
X
X
Rituxim
ab cycles
C1D1
C2D1
C3D1
C4D1
A cycle is defined as follows:
A new cycle is defined when the delay between the previous drug start date and the current start date is lower or equal to -26.
del <=-26 and del=lag1(SDRSTDT)-SDRSTDT;
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If the data do not fulfill the previous condition, a cumulative duration (dur = Σ SDRENDT –SDRSTDT + 1) is calculated (including 
the previous record) to take into account the fact that several drug modifications could have appeared during one cycle.  If the 
cumulative duration does not exceed 28 days, there is no new cycle.
data drugcyl;
set drug_n;
by pt EXSTDT;
retain prevcum cumdur 0;
** Difference between the previous and current record;
del=lag1(EXSTDT)-EXSTDT;
** Duration for one record;
dur=EXENDT -EXSTDT+1;
** Interval between the previous end date and the start of the current cycle;
inter=lag1(EXENDT) -EXSTDT;
** Duration of the previous record ;
prevdur=lag1(dur);
**Initialization of the variable for the first drug record for any new patients;
if first.pt then do;del=.;prevdur=.;prevcum=0;inter=.;cumdur=dur;end;
** Condition for a new cycle;
if del <=-26 then  cycle=1;
if dur>=21 then  cycle=1;
if prevdur>=21 then cycle=1;
if cycle=1
then if .<del<=-21 then  do;cumdur=dur;prevcum=0;end;
else  do;cumdur=dur;prevcum=0;end;
** If condition not fulfilled, calculation of the cumulative duration including the previous duration;
skip:if cycle ne 1 then do;
cumdur=cumdur+dur;
prevcum=prevcum+del;
end;
if cumdur>=28 or prevcum<=-28  then do;cycle=1;
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cumdur=0;prevcum=0;
goto skip;
end;
run;
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16.3.
Endpoints derivation
Efficacy evaluation window:
All efficacy assessments will be taken into account if they are occurred after the randomization date 
to the end the study, for patients who do not stop study medication and not start other non study anti-cancer therapy;
Best response
Best response is defined as best efficacy benefit response during the “window” for efficacy evaluation.
PFS:
PFS = PFS Ending Date – PFS Starting Date + 1
Starting date: the randomization date
Ending date: the earliest date among the following 4 events during the “window” for efficacy evaluation:
a. Death;
b. The earlier assessment date for the cycle with overall response is PD or Relapse; 
c. Study discontinue due to Disease progression specified; 
d. Treatment discontinue due to Disease progression specified;
For patients who have more than 1 consecutive missing regular assessments right before the earliest of the four events date and this 
non-assessed period last more than 118 days (this length is study-dependent),  then, the date of last adequate assessment indicating no 
progression before the date will be used, and the PFS will be censored.
If patients who do not have any of the 4 events listed above, then ending date is defined as the latest CT/MRI date for target or non-
target lesion that indicating no progression, if patients do not have such response, they will be censored at the day after the 
randomization date.
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Duration of response (DoR)
DoR = Ending Date – Starting Date + 1
Starting date: The date of the first occurrence of CR, CRu or PR during the Window for efficacy evaluation
Ending date: the earliest date among the following 4 events during the “window” for efficacy evaluation:
a. Death;
b. The earlier assessment date for the cycle with overall response is PD or Relapse; 
c. Study discontinue due to Disease progression specified; 
d. Treatment discontinue due to Disease progression specified;
For patients who have more than 1 consecutive missing regular assessments right before the earliest of the four events date and this 
non-assessed period last more than 118 days,  then, the last adequate at least PR or better response assessment date before the date will 
be used, and the DoR will be censored.
If patients who do not have any of the 4 events listed above, then ending date is defined as the latest CT/MRI date for target or non-
target lesion with at least PR or better response after the DoR start date, if patients do not have such response, they will be censored at 
the day after the 1st response date
16.4.
Laboratory Values
The following calculations need to be performed for all patients in treatment arms A and B.  The lab values will be standardized using 
the normal range values collected in the eCRF.
Step 1:  Assign an upper (ULN) and lower (LLN) normal range value to each analyte at each visit collected by merging the ranges 
collected in the datasets labrng. Use the labseq variable to assign the appropriate normal ranges to a value.
  If the ranges could not be assigned then use the default SI ranges after the conversion of the value..
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Convert any raw lab values to the unit that corresponds to the normal range values as necessary.  These converted (if necessary) or 
raw (if conversion not needed) lab values and their associated ULN and LLN values will be referred to as the “base” values in the 
calculations given in Step 2. 
Step 2:  Convert all base values (lab, ULN, and LLN values) to the standardized units given in Table 1 below.  The standardized units 
are the units associated with the normal ranges to be used for mapping the lab value to a standardized value.  Calculations in Step 3 are 
based on these converted lab and normal range values (referred to as converted values). 
Hematology
Test
Normal 
Range Unit
Conversion 
Factor
SI Unit
Females
Male
Low
High
Low
High
Red Blood Cell 
Count (RBC)
10^6/uL
X 1 
1012/L
3.9
5.2
4.4
5.8
10^3/uL
÷ 1000
1012/L
3.9
5.2
4.4
5.8
10^9/L
X 1000
1012/L
3.9
5.2
4.4
5.8
10^12/L
X 1
1012/L
3.9
5.2
4.4
5.8
k/uL or K/micl
÷ 1000
1012/L
3.9
5.2
4.4
5.8
10^6/mm^3 or 
10^6mm^3
x 1
1012/L
3.9
5.2
4.4
5.8
10^6/cumm
X 1
1012/L
3.9
5.2
4.4
5.8
10^12/L
X 1
1012/L
3.9
5.2
4.4
5.8
M/uL or M/micL
X 1
1012/L
3.9
5.2
4.4
5.8
M/mL
÷ 1000
1012/L
3.9
5.2
4.4
5.8
Hemoglobin
g/dL
x 0.62058
mmol/liter
7.4
9.9
8.1
11.2
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35
35
35,
35,
5,
5,
35
35235
52
x 1
35
35
35
35
35
35
35
( 3
( 3
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/mL
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g/
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
51
g/L
x 0.062058
mmol/liter
7.4
9.9
8.1
11.2
mmol/liter
X 1
mmol/liter
7.4
9.9
8.1
11.2
mmol/L
X 1
mmol/liter
7.4
9.9
8.1
11.2
Hematocrit
18-44 years
% 
X 0.01
fraction of red blood cells
0.35
0.45
0.39
0.49
L/L
X1
fraction of red blood cells
0.35
0.45
0.39
0.49
Proportion of 1.0
X 1
fraction of red blood cells
0.35
0.45
0.39
0.49
45-64 years
%
X 0.01
fraction of red blood cells
0.35
0.47
0.39
0.5
L/L
X1
fraction of red blood cells
0.35
0.47
0.39
0.5
Proportion of 1.0
X 1
fraction of red blood cells
0.35
0.45
0.39
0.49
65-74 years
%
X 0.01
fraction of red blood cells
0.35
0.47
0.37
0.51
L/L
X1
fraction of red blood cells
0.35
0.47
0.37
0.51
Proportion of 1.0
X 1
fraction of red blood cells
0.35
0.45
0.39
0.49
Platelets
10^3/uL
X 1
109/L
130
400
130
400
10^9/L
X 1
109/L
130
400
130
400
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$7,2
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7,2
$7
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$7
$7
$7
$7
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
52
k/uL or k/micL
X 1
109/L
130
400
130
400
cells/mcL
÷ 1000
109/L
130
400
130
400
10^3/mm^3
X 1
109/L
130
400
130
400
thous/mm^3
X 1
109/L
130
400
130
400
1000cumm
X 1
109/L
130
400
130
400
10^9/L
X 2
109/L
130
400
130
400
mm^3
0.001
109/L
130
400
130
400
k/mL
÷ 1000
109/L
130
400
130
400
White Blood Cells
10^3/uL
X 1
109/L
4.5
11.0
4.5
11.0
10^9/L
X 1
109/L
4.5
11.0
4.5
11.0
k/uL or k/micL
X 1
109/L
4.5
11.0
4.5
11.0
cells/mcL
÷ 1000
109/L
4.5
11.0
4.5
11.0
10^3/mm^3
X 1
109/L
4.5
11.0
4.5
11.0
thous/mm^3
X 1
109/L
4.5
11.0
4.5
11.0
1000cumm
X 1
109/L
4.5
11.0
4.5
11.0
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7,2
7,2
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400
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0$
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25
40
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
53
mm^3
0.001
109/L
4.5
11.0
4.5
11.0
k/mL
÷ 1000
109/L
4.5
11.0
4.5
11.0
Absolute basophils
10^3/uL
X 1
109/L
0.0
0.2
0.0
0.2
10^9/L
X 1
109/L
0.0
0.2
0.0
0.2
k/uL or k/micL
X 1
109/L
0.0
0.2
0.0
0.2
cells/mcL
÷ 1000
109/L
0.0
0.2
0.0
0.2
10^3/mm^3
X 1
109/L
0.0
0.2
0.0
0.2
thous/mm^3
X 1
109/L
0.0
0.2
0.0
0.2
1000cumm
X 1
109/L
0.0
0.2
0.0
0.2
mm^3
0.001
109/L
0.0
0.2
0.0
0.2
k/mL
÷ 1000
109/L
0.0
0.2
0.0
0.2
Absolute 
eosinophils
10^3/uL
X 1
109/L
0.0
0.44
0.0
0.44
10^9/L
X 1
109/L
0.0
0.44
0.0
0.44
k/uL or k/micL
X 1
109/L
0.0
0.44
0.0
0.44
cells/mcL
÷ 1000
109/L
0.0
0.44
0.0
0.44
10^3/mm^3
X 1
109/L
0.0
0.44
0.0
0.44
thous/mm^3
X 1
109/L
0.0
0.44
0.0
0.44
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
54
1000cumm
X 1
109/L
0.0
0.44
0.0
0.44
mm^3
0.001
109/L
0.0
0.44
0.0
0.44
k/mL
÷ 1000
109/L
0.0
0.44
0.0
0.44
Absolute 
lymphocytes
10^3/uL
X 1
109/L
1
4.8
1
4.8
10^9/L
X 1
109/L
1
4.8
1
4.8
k/uL or k/micL
X 1
109/L
1
4.8
1
4.8
cells/mcL
÷ 1000
109/L
1
4.8
1
4.8
10^3/mm^3
X 1
109/L
1
4.8
1
4.8
thous/mm^3
X 1
109/L
1
4.8
1
4.8
1000cumm
X 1
109/L
1
4.8
1
4.8
mm^3
0.001
109/L
1
4.8
1
4.8
k/mL
÷ 1000
109/L
1
4.8
1
4.8
Absolute 
monocytes
10^3/uL
X 1
109/L
0
0.8
0
0.8
10^9/L
X 1
109/L
0
0.8
0
0.8
k/uL or k/micL
X 1
109/L
0
0.8
0
0.8
cells/mcL
÷ 1000
109/L
0
0.8
0
0.8
10^3/mm^3
X 1
109/L
0
0.8
0
0.8
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
55
thous/mm^3
X 1
109/L
0
0.8
0
0.8
1000cumm
X 1
109/L
0
0.8
0
0.8
mm^3
0.001
109/L
0
0.8
0
0.8
k/mL
÷ 1000
109/L
0
0.8
0
0.8
Absolute 
neutrophils
10^3/uL
X 1
109/L
1.8
7
1.8
7
10^9/L
X 1
109/L
1.8
7
1.8
7
k/uL or k/micL
X 1
109/L
1.8
7
1.8
7
cells/mcL
÷ 1000
109/L
1.8
7
1.8
7
10^3/mm^3
X 1
109/L
1.8
7
1.8
7
thous/mm^3
X 1
109/L
1.8
7
1.8
7
1000cumm
X 1
109/L
1.8
7
1.8
7
mm^3
0.001
109/L
1.8
7
1.8
7
k/mL
÷ 1000
109/L
1.8
7
1.8
7
MCV
μm^3
X 1.00
fl
78
102
78
100
fl
X 1.00
fl
78
102
78
100
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7,2
7,2
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50$
0.8
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$7
$7
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5<
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09/L
$5
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35
35
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
56
Chemistry
Test
Normal 
Range Unit
Conversion 
Factor
SI Unit
Females
Male
Low
High
Low
High
Sodium
mmol/L
X 1.00
mmol/liter
135
145
135
145
mEq/L
X 1.0
mmol/liter
135
145
135
145
Potassium
mmol/L
X 1.00
mmol/liter
3.5
5.1
3.5
5.1
mEq/L
X 1.0
mmol/liter
3.5
5.1
3.5
5.1
Chloride
mmol/L
X 1.00
mmol/L
95
108
95
108
mEq/L
X 1.0
mmol/L
95
108
95
108
Creatinine
mg/dL
X 88.4
umol/liter
53
97
62
105
mg/L
X 8.84
umol/liter
53
97
62
105
mmol/L
X 1085.409
umol/liter
53
97
62
105
umol/L
X 1
umol/liter
53
97
62
105
Glucose
mg/dL
x 0.05551
mmol/liter
3.9
6.1
3.9
6.1
&(
pri
prietet
35235,(7$5<,1)250$7,21
25
25
250
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High
25
25
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25
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25
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7$
7$
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235
235
mm
35
35
2
352
352
4
52
52
52
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84
35
35
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mg/dL
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
57
mmol/L
X 1
mmol/liter
3.9
6.1
3.9
6.1
g/L
x 5.551
mmol/liter
3.9
6.1
3.9
6.1
g/dL
X 55.51
mmol/liter
3.9
6.1
3.9
6.1
BUN
mg/dL
x 0.357
mmol/liter
2.9
8.9
2.9
8.9
g/L
x 35.7
mmol/liter
2.9
8.9
2.9
8.9
mmol/L
1
mmol/liter
2.9
8.9
2.9
8.9
Albumin
g/dL
x 10
g/liter
31
43
31
43
g/L
1
g/liter
31
43
31
43
g/%
X 10
g/liter
31
43
31
43
mg/dL
X 0.01
g/liter
31
43
31
43
Calcium (serum)
mg/dL
x 0.25
mmol/liter
2.1
2.6
2.1
2.6
mg/L
x 0.025
mmol/liter
2.1
2.6
2.1
2.6
mEq/l
0.5
mmol/liter
2.1
2.6
2.1
2.6
mmol/L
X 1
mmol/liter
2.1
2.6
2.1
2.6
Phosphorus
mg/dL
X 0.323
mmol/L
0.81
1.45
0.81
1.45
mg/L
x 0.0323
mmol/L
0.81
1.45
0.81
1.45
&(
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mg/L
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g/liter
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52
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
58
mmol/L
1
mmol/L
0.81
1.45
0.81
1.45
Alkaline 
Phosphatase
units/L 
X0.01667
ukat/L
0.50
2.00
0.50
2.00
U/L
X0.01667
ukat/L
0.50
2.00
0.50
2.00
IU/L
X0.01667
ukat/L
0.50
2.00
0.50
2.00
mU/ml or mU/mL
X0.01667
ukat/L
0.50
2.00
0.50
2.00
ukat/L
X 1
ukat/L
0.50
2.00
0.50
2.00
ALT (SGPT)
units/L
X0.01667
ukat/L
0.17
0.68
0.17
0.68
U/L
X0.01667
ukat/L
0.17
0.68
0.17
0.68
IU/L
X0.01667
ukat/L
0.17
0.68
0.17
0.68
mU/ml or mU/mL
X0.01667
ukat/L
0.17
0.68
0.17
0.68
ukat/L
X 1
ukat/L
0.17
0.68
0.17
0.68
AST (SGOT)
units/L
X0.01667
ukat/L
0.17
0.51
0.17
0.51
U/L
X0.01667
ukat/L
0.17
0.51
0.17
0.51
IU/L
X0.01667
ukat/L
0.17
0.51
0.17
0.51
mU/ml or mU/mL
X0.01667
ukat/L
0.17
0.51
0.17
0.51
ukat/L
X 1
ukat/L
0.17
0.51
0.17
0.51
Total Bilirubin
mg/dL
x 17.1
umol/liter
0
17
0
17
mg/L
x 1.71
umol/liter
0
17
0
17
umol/L or mkmol/L
X 1
umol/liter
0
17
0
17
&(
pri
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
59
g/dL
X17100
umol/liter
0
17
0
17
Lactate 
Dehydrogenase 
(LDH)
12-60 years
units/L
X0.01667
ukat/L
1.8
3.4
1.8
3.4
U/L
X0.01667
ukat/L
1.8
3.4
1.8
3.4
ukat/L
x1
ukat/L
1.8
3.4
1.8
3.4
mU/ml or mU/mL
X0.01667
ukat/L
1.8
3.4
1.8
3.4
IU/L
X0.01667
ukat/L
1.8
3.4
1.8
3.4
> 60 years
units/L
X0.01667
ukat/L
1.8
3.5
1.8
3.5
U/L
X0.01667
ukat/L
1.8
3.5
1.8
3.5
ukat/L
x1
ukat/L
1.8
3.5
1.8
3.5
mU/ml or mU/mL
X0.01667
ukat/L
1.8
3.5
1.8
3.5
IU/L
X0.01667
ukat/L
1.8
3.5
1.8
3.5
Total protein
g/dL
X 10
g/liter
64
83
64
83
g/L
X 1
g/liter
64
83
64
83
Uric acid
18-60 years
umol/L or mkmol/L
÷ 1000
mmol/L
0.13
0.39
0.26
0.45
mg/L
x 0.00595
mmol/L
0.13
0.39
0.26
0.45
mmol/L
1
mmol/L
0.13
0.39
0.26
0.45
mg/dL
X 0.0595
mmol/L
0.13
0.39
0.26
0.45
> 60 years
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
60
umol/L or mkmol/L
÷ 1000
mmol/L
0.2
0.43
0.25
0.47
mg/L
x 0.00595
mmol/L
0.2
0.43
0.25
0.47
mmol/L
1
mmol/L
0.2
0.43
0.25
0.47
mg/dL
X 0.0595
mmol/L
0.2
0.43
0.25
0.47
TSH
Test
Normal 
Range Unit
Conversion 
Factor
SI Unit
Females
Male
Low
High
Low
High
TSH
uU/mL
X 1
mU/L
0.32
5
0.32
5
uU/L
÷ 1000
mU/L
0.32
5
0.32
5
mU/L
X 1
mU/L
0.32
5
0.32
5
mIU/L
X 1
mU/L
0.32
5
0.32
5
MIU/mL
X 1
mU/L
0.32
5
0.32
5
uUI/ML or μUI/ML or 
microUI/ML
X 1
mU/L
0.32
5
0.32
5
mME/L
mU/L
0.32
5
0.32
5
MU/ML
X 1
mU/L
0.32
5
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
61
MCU/ml
X1 
mU/L
0.32
5
0.32
5
mIE/L
X1
mU/L
0.32
5
0.32
5
UIU/mL
X 1
mU/L
0.32
5
0.32
5
Free T3
ng/dL
X 15.4
pmol/L
4.0
7.4
4.0
7.4
ng/L
X 1.54
pmol/L
4.0
7.4
4.0
7.4
nmol/L
X 1000
pmol/L
4.0
7.4
4.0
7.4
pg/mL 
X1.54
pmol/L
4.0
7.4
4.0
7.4
pg/dL
X 0.0154
pmol/L
4.0
7.4
4.0
7.4
pmol/L
X 1
pmol/L
4.0
7.4
4.0
7.4
Free T4
ug/dL
X 12870
pmol/L
10.3
23.0
10.3
23.0
nmol/L
X 1000
pmol/L
10.3
23.0
10.3
23.0
pg/mL 
X 1.287
pmol/L
10.3
23.0
10.3
23.0
ng/dL
X 12.87
pmol/L
10.3
23.0
10.3
23.0
ng/L
X 1.287
pmol/L
10.3
23.0
10.3
23.0
pmol/L
X 1
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10.3
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
62
Step 3:  Determine, for each (converted) lab value, if it is within the (converted) normal range and assign a flag indicating where the 
value falls relative to the upper and lower limits of normal (eg, low (below lower limit normal), normal, or high (above upper limit 
normal).
Step 4:  Determine p, the value to be used for mapping the converted lab value to a standardized value as follows:
a)  If the converted lab value is within converted normal range then
        
            p = (lab value – LLN value) / (ULN value – LLN value)
b) If the converted lab value is less than converted LLN then
            p = lab value / LLN value
c) If the converted lab value is greater than converted ULN then
            p = lab value / ULN value
Step 5:  Use the value of p calculated in Step 4 and the standardized ULN and LLN values
a)  If the converted lab value is within normal range then
        
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
63
SLV = p(sULN value – sLLN value) + sLLN
b) If the converted lab value is less than LLN then
SLV = p( sLLN value)
c) If the converted lab value is greater than ULN then
SLV = p( sULN value)
Step 6: Use the SLV and the sLLN and sULN to assign the NCI-CTC grade and for summary statistics in all tables.  
Example calculations for standardizing lab values to the standard normal ranges
Patient X at CxD1 visit:
SGPT = 22 UI/L
Step 1:  normal range
LLN = 7 UI/L
ULN = 40 UI/L
Step 2:
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
64
Since the conversion factor for converting UI/L to U/L is 1.0, the converted values associated with unit=U/L remain the same as the
original values.
converted SGPT = 22 U/L
converted LLN = 7 U/L
converted ULN = 40 U/L
Step 3: 
Value of 22 U/L is within the normal range.
Normal range flag = N
Step 4:  Calculate p for 22 U/L based on formula a):
p = (lab value – LLN value) / (ULN value – LLN value)
   = (22 – 7) / (40 – 7)
   = 15 / 33
   = 0.45
Step 5:  Calculate SLV for p = 0.45 and sLLN = 6 U/L and sULN = 35 U/L.  
SLV = p(sULN value – sLLN value) + sLLN
        = 0.45(35 – 6) + 6
        = 19.2 U/L
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
65
Step 6:  NCI-CTC grade = 0, since the value is within normal limits.
16.5.
Tables and listings shells
The presented shells are not exhaustive.
Non efficacy Tables
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
66
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.1.1
Subject Disposition
Treatment A
Treatment B
Total
n
(%)[a]
n
(%)[a]
n
(%)[a]
Analysis Populations
Safety [b]
xx (xx)
xx (xx)
xx (xx)
Intent-to-treat
(ITT)[c]
xx (xx)
xx (xx)
xx (xx)
Subjects discontinued from study
xx (xx)
xx (xx)
xx (xx)
Primary reason for discontinuation from the study
Adverse event
xx (xx)
xx (xx)
xx (xx)
Lack of therapeutic effect/PD
xx (xx)
xx (xx)
xx (xx)
Subject withdrew consent
xx (xx)
xx (xx)
xx (xx)
Subject lost to follow-up
xx (xx)
xx (xx)
xx (xx)
Death
xx (xx)
xx (xx)
xx (xx)
Protocol violation
xx (xx)
xx (xx)
xx (xx)
Other
xx (xx)
xx (xx)
xx (xx)
Total number of subjects who completed study
xx (xx)
xx (xx)
xx (xx)
[a] Percents are based on the safety population.
[b] Define the safety population.
[c] Define the ITT population.
Order of appearance of treatment groups: Lowest dose of Celgene drug to Highest dose, active control and placebo.
Bolded sections are optional.
Program path: 
Data source: DISPO
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xx (xx)
xx (xx)
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(xx)
x (xx)
(xx)
xx (xx)
xx (xx)
xx (xx)
x (xx)
xx (x
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xx
xx
3
: Lowest d
Lowest d


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
67
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.1.2
Demographic and Baseline Characteristics - (Safety Population)
Treatment A
Treatment B
Overall
(N=XX)
(N=XX)
(N=XX)
Age (years)
   n                                                                  xx                       xx                     xx
   Mean                                                               xx                       xx                     xx
   SD                                                                 xx                       xx                     xx
   Median                                                             xx                       xx                     xx
   Min, Max                                                         xx, xx                   xx, xx                 xx, xx
Age category                                                       n  (%)                 n  (%)                   n  (%)
   <65                                                            xx  (xx)               xx  (xx)                 xx  (xx)
   >=65                                                             xx  (xx)               xx  (xx)                 xx  (xx)
   Missing                                                         xx  (xx)               xx  (xx)                 xx  (xx)
Sex                                                                 n  (%)                 n  (%)                   n  (%)
   Male                                                            xx  (xx)               xx  (xx)                 xx  (xx)
   Female                                                          xx  (xx)               xx (xx)                 xx  (xx)
   Missing                                                         xx  (xx)               xx  (xx)                 xx  (xx)
Race [a]                                                            n  (%)                 n  (%)                   n  (%)
   White                                                           xx  (xx)               xx  (xx)                 xx  (xx)
   Black                                                           xx  (xx)               xx  (xx)                 xx  (xx)
   Asian/Pacific Islander                                          xx  (xx)               xx  (xx)                xx  (xx)
   Other                                                           xx  (xx)               xx  (xx)                 xx  (xx)
   Missing                                                         xx  (xx)               xx  (xx)                 xx  (xx)
BMI (units)[b]
   N                                                                 xx                     xx                       xx
   Mean                                                              xx                     xx                       xx
   SD                                                                xx                     xx                       xx
   Median                                                            xx                     xx                       xx
   Min, Max                                                        xx, xx                 xx, xx                   xx, xx
[a]
Percents may add up to more than 100% since subjects were allowed to select more than one Race.  (Add this footnote ONLY if 
percents add up to >100%.)
[b]
Order of appearance of treatment groups: Lowest dose of Celgene drug to Highest dose, active control and placebo.
Bolded sections are optional.
Program path: 
Data source: DEMO 
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
68
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.1.3
                              Medical History - Number (%) of Subjects by Treatment Group - (Safety Population)
Treatment A
Treatment B
Total
   (N=XX)
  (N=XX)
(N=XX)
System organ class/Preferred term [a]
n  (%)
n  (%)
n  (%)[b]
Metabolism and nutrition disorders
xx (xx)
xx (xx)
xx
(xx)
Haemochromatosis
xx (xx)
xx (xx)
xx
(xx)
Diabetes mellitus NOS
xx (xx)
xx (xx)
xx
(xx)
Hyperlipidaemia NOS
xx (xx)
xx (xx)
xx
(xx)
Hypercholesterolaemia
xx (xx)
xx (xx)
xx
(xx)
Diabetes mellitus non-insulin-dependent
xx (xx)
xx (xx)
xx
(xx)
Hyperuricaemia
xx (xx)
xx (xx)
xx
(xx)
Gout
xx (xx)
xx (xx)
xx
(xx)
Haemosiderosis
xx (xx)
xx (xx)
xx
(xx)
Hypokalaemia
xx (xx)
xx (xx)
xx
(xx)
Glucose tolerance impaired
xx (xx)
xx (xx)
xx
(xx)
Hyperglycaemia NOS
xx (xx)
xx (xx)
xx
(xx)
Hypertriglyceridaemia
xx (xx)
xx (xx)
xx
(xx)
Hyponatraemia
xx (xx)
xx (xx)
xx
(xx)
Lactose intolerance
xx (xx)
xx (xx)
xx
(xx)
Obesity
xx (xx)
xx (xx)
xx
(xx)
Vitamin B12 deficiency
xx (xx)
xx (xx)
xx
(xx)
Anorexia
xx (xx)
xx (xx)
xx
(xx)
Appetite decreased NOS
xx (xx)
xx (xx)
xx
(xx)
Dehydration
xx (xx)
xx (xx)
xx
(xx)
Dyslipidaemia
xx (xx)
xx (xx)
xx
(xx)
Fluid retention
xx (xx)
xx (xx)
xx
(xx)
Hyperkalaemia
xx (xx)
xx (xx)
xx
(xx)
Hyperproteinaemia
xx (xx)
xx (xx)
xx
(xx)
Hypoalbuminaemia
xx (xx)
xx (xx)
xx
(xx)
Hypomagnesaemia
xx (xx)
xx (xx)
xx
(xx)
Impaired fasting glucose
xx (xx)
xx (xx)
xx
(xx)
Metabolic acidosis NOS
xx (xx)
xx (xx)
xx
(xx)
[a]  Medical History terms are coded using the MedDRA dictionary (indicate the version of the dictionary used).  System organ 
classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical).  Multiple occurrences of the same preferred 
term from a patient are counted only once within each treatment group.   Order of appearance of treatment groups: Lowest dose of 
Celgene drug to Highest dose, active control and placebo.
Program path: 
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
69
Celgene Corporation                                                                                          Page xx of xx
Protocol:                                                                                                    DB (Interim) Lock Date:
Table 14.1.4
Prior Medications – Number (%) of Subjects by Treatment Group (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A                Treatment B             Total
ATC3 Classification/                                                  (N=XX)                    (N=XX)                (N=XX)
Preferred Name[a]                                                    n   (%)                   n   (%)                n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one prior medication              
xx  (xx)                  xx  (xx)               xx  (xx)
PLATELET AGGREGATION INHIBITORS EXCL. HEPARIN                           xx  (xx)                  xx  (xx)               xx  (xx)
ACETYLSALICYLIC ACID                                                 xx  (xx)                  xx  (xx)               xx  (xx)
CLOPIDOGREL SULFATE                                                  xx  (xx)                  xx  (xx)               xx  (xx)
            ASPIRINE                                                             xx  (xx)                  xx  (xx)               xx  (xx)
ANAGRELIDE                                                           xx  (xx)                  xx  (xx)               xx  (xx)
CLOPIDOGREL                                                          xx  (xx)                  xx  (xx)               xx  (xx)
AGGRENOX                                                             xx  (xx)                  xx  (xx)               xx  (xx)
ASA                                                                  xx  (xx)                  xx  (xx)               xx  (xx)
ASPIRIN PROTECT                                                      xx  (xx)                  xx  (xx)               xx  (xx)
IRON CHELATING AGENTS                                                   xx  (xx)                  xx  (xx)               xx  (xx)
DEFEROXAMINE                                                         xx  (xx)                  xx  (xx)               xx  (xx)
DEFEROXAMINE MESILATE                                                xx  (xx)                  xx  (xx)               xx  (xx)
DEFERIPRONE                                                          xx  (xx)                  xx  (xx)               xx  (xx)
DESFERAL                                                             xx  (xx)   
xx  (xx)               xx  (xx)
OTHER PLAIN VITAMIN PREPARATIONS                                        xx  (xx)                  xx  (xx)               xx  (xx)
VITAMIN E                                                            xx  (xx)                  xx  (xx)               xx  (xx)
PYRIDOXINE                                                           xx  (xx)                  xx  (xx)               xx  (xx)
VITAMIN B                                                           xx  (xx)                  xx  (xx)               xx  (xx)
TOCOPHEROL                                                           xx  (xx)                  xx  (xx)               xx  (xx)
VITAMIN B6                                                           xx  (xx)                  xx  (xx)               xx  (xx)
OPTOVIT                                                              xx  (xx)                  xx  (xx)               xx  (xx)
PROTON PUMP INHIBITORS                                                  xx  (xx)                  xx  (xx)               xx  (xx)
OMEPRAZOLE                                                          xx  (xx)                  xx  (xx)               xx  (xx)
PANTOPRAZOLE                                                         xx  (xx)                  xx  (xx)               xx  (xx)
ESOMEPRAZOLE                                                        xx  (xx)                  xx  (xx)               xx  (xx)
LANSOPRAZOLE                                                         xx  (xx)                  xx  (xx)               xx  (xx)
ACIPHEX                                                              xx  (xx)                  xx  (xx)               xx  (xx)
PREVACID                                                             xx  (xx)                  xx  (xx)               xx  (xx)
NEXIUM                                                               xx  (xx)                  xx  (xx)               xx  (xx)
RABEPRAZOLE SODIUM                                                   xx  (xx)                  xx  (xx)               xx  (xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] ATC3 classification and preferred name are based on WHODD (coding dictionary) (indicate the version of the dictionary used).
Program path: 
Data source:  CONMEDS
&(/*(1(35235,(7$5<,1)250$7,21
x of xx
 of xx
Interi
Inter m) L
 
—————————
—————————
ent B      
B    
X)         
         
  (%)    
  (%)   
——————————
—————————
    xx  (x
   xx  
       xx
       xx
         
      
          
     
          
          
          
     
         
         
)         
      
xx)        
x)    
(xx)      
(xx)     
xx  (xx)  
xx  (xx
 xx  (xx)
 xx  (xx)
   xx  (x
   xx  
     xx  
     xx  
       xx 
      xx
         
        
          
         
         
        
         
      
          
        
         
         
         
        
         
       
          
       
         
         
         
        
         
       
          
         
——————————
—————————
preferred
preferred


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
70
Celgene Corporation                                                                                          Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
            Table 14.1.5
Concomitant Medications – Number (%) of Subjects by Treatment Group (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A                Treatment B              Total
ATC3 Classification/                                                 (N=XX)                    (N=XX)                 (N=XX)
Preferred Name[a]                                                    n   (%)                   n   (%)                n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one concomitant medication                       xx  (xx)                  xx  (xx)               xx  (xx)
ANILIDES                                                                xx  (xx)                  xx  (xx)               xx  (xx)
ACETAMINOPHEN                                                        xx  (xx)                  xx  (xx)               xx  (xx)
TYLENOL                                                              xx  (xx)                  xx  (xx)               xx  (xx)
PARACETAMOL                                                          xx  (xx)                  xx  (xx)               xx  (xx)
ACETAMINOPHEN W/HYDROCODONE BITARTRATE                               xx  (xx)                  xx  (xx)               xx  (xx)
NYQUIL                                                               xx  (xx)                  xx  (xx)               xx  (xx)
EXCEDRIN /USA/                                                       xx  (xx)                  xx  (xx)               xx  (xx)
    GALENIC /ACETYLSAL.ACID/CAFFEINE/PARACET                             xx  (xx)                  xx  (xx)               xx  (xx)
VICODIN                                                              xx  (xx)                  xx  (xx)               xx  (xx)
ACETAMINOPHEN W/OXYCODONE                                            xx  (xx)                  xx  (xx)               xx  (xx)
GOODYS POWDERS                                                       xx  (xx)                  xx  (xx)               xx  (xx)
HYDROCODONE W/ACETAMINOPHEN                                          xx  (xx)                  xx  (xx)               xx  (xx)
THOMAPYRIN                                  
xx  (xx)                  xx  (xx)               xx  (xx)
TYLENOL ALLERGY SINUS                                                xx  (xx)                  xx  (xx)               xx  (xx)
VICKS DAYQUIL                                                        xx  (xx)                  xx  (xx)               xx  (xx)
FLUOROQUINOLONES                                                        xx  (xx)                  xx  (xx)               xx (xx)
CIPROFLOXACIN                                                        xx  (xx)                  xx  (xx)               xx  (xx)
LEVOFLOXACIN                                                         xx  (xx)            
xx  (xx)               xx  (xx)
LEVAQUIN                                                             xx  (xx)                  xx  (xx)               xx  (xx)
GATIFLOXACIN                                                         xx  (xx)                  xx  (xx)               xx  (xx)
MOXIFLOXACIN                                                         xx  (xx)                  xx  (xx)               xx  (xx)
TAVANIC                  
xx  (xx)                  xx  (xx)               xx  (xx)
TEQUIN                                                               xx  (xx)                  xx  (xx)               xx  (xx)
       AVALOX                                                               xx  (xx)                  xx  (xx)               xx  (xx)
NORFLOXACIN                                                          xx  (xx)                  xx  (xx)               xx  (xx)
AMINOALKYL ETHERS                                                       xx  (xx)                  xx  (xx)               xx  (xx)
DIPHENHYDRAMINE                                                      xx  (xx)                  xx  (xx)               xx  (xx)
DIPHENHYDRAMINE HYDROCHLORIDE                                        xx  (xx)                  xx  (xx)               xx  (xx)
TAVEGIL                                                              xx  (xx)                  xx  (xx)               xx  (xx)
DIMENHYDRINATE                                                       xx  (xx)                  xx  (xx)               xx  (xx)
VERTIGO-VOMEX                                                        xx  (xx)                  xx  (xx)               xx  (xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
            [a] ATC3 classification and preferred name are based on WHODD (coding dictionary) (indicate version of the dictionary used).
Program path: 
Data source:  CONMEDS
&(/*(1(35235,(7$5<,1)250$7,21
e xx of xx
e xx of xx
B (Interim
Interim
ation)
tion)
—————————
—————
ment B    
ment B    
XX)       
X)       
n   (%)  
n   (%)
——————————
———————
      xx  
     xx  
         
         
        
       
          
        
          
       
          
    
)         
)        
xx)        
xx)       
(xx)      
x)      
x  (xx)    
(xx)   
xx  (xx)  
xx  (xx)  
 xx  (xx
 xx  (x )
   xx  (x
   xx  (x
xx  
       xx 
      xx
        x
        x
         
         
          
        
          
    
         
       
       
     
          
         
          
         
         
        
         
   
          
     
         
         
      
      
          
        
          
       
*(
——————————
————————
d preferre
d preferre


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
71
Table 14.2.1
Duration of Exposure by Cycle - Safety Population
_______________________________________________________________________________________________________________________________________            
                                                                       
Number (%) of Patients                                                     
                                      ___________________________________________________________________________________________                  
                                        Treatment A             Treatment B            Treatment C                           
Exposure by Cycle Category                 N=  XX                  N=XX                    N=XX
                                            n(%)                    n(%)                    n(%)                                             
_________________________________________________________________________________________________________________________________                  
Cycles  1 or more                       XX (XX)                XX (XX)                XX (XX)                                
Cycles  2 or more                       XX (XX)                XX (XX)                XX (XX)                                     
Cycles  3 or more                       XX (XX)                XX (XX)                XX (XX)                                
Cycles  4 or more                       XX (XX)                XX (XX)                XX (XX)                                     
Cycles  5 or more                       XX (XX)                XX (XX)                XX (XX)                                
Cycles  6 or more                       XX (XX)                XX (XX)                XX (XX)                                     
Cycles 12 or more                       XX (XX)                XX (XX)                XX (XX)                                
Cycles 24 or more                       XX (XX)                XX (XX)                XX (XX)                                  
Cycles 30 or more                       XX (XX)                XX (XX)                XX (XX)                                
                                            
       
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Duration of Exposure by Cycle: Duration of the start of the cycle.   
Program path: 
Data source: SDR D_SDSUMM                                                                          
&(/*(1(35235,(7$5<,1)250$7,21
__
_________
___
         
        
__________
_________
         
      
          
        
__________
_________
         
         
         
      
          
     
          
         
          
     
          
         
          
       
          
      
X)        
X)        
—————————
——————
         
        


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
72
Celgene Corporation                                                                                                    Page X of X
Protocol:                                                                                                              DB (Interim) Lock Date:
Table 14.2.2
Exposure to Study Medication by Treatment Group - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A       Treatment B       Treatment C          
                                                                       (N=XX)            (N=XX)            (N=XX)            
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Total Duration (days) [a]
n                                                               xx                xx                xx               
Mean                                                            xx                xx                xx                
SD                                                              xx                xx                xx               
Median                                                         xx                xx                xx               
Min, Max                                                      xx, xx            xx, xx            xx, xx            
Daily dose (Units)
n                                                               xx                xx                xx
Mean                                                            xx                xx                xx
       SD                                                              xx                xx                xx
Median                                                          xx                xx                xx
Min, Max 
xx, xx            xx, xx            xx, xx
Total completed cycles [a]
n                                                               xx                xx                xx               
Mean                                                            xx                xx                xx               
SD                                                              xx                xx
xx               
Median                                                          xx                xx                xx                
Min, Max                                                      xx, xx 
xx, xx            xx, xx            
Average durations of cycles (days)
n                                                               xx                xx                xx               
Mean
xx                xx                xx               
SD                                                              xx                xx                xx               
Median                                                          xx                xx                xx                
Min, Max                                                      xx, xx            xx, xx            xx, xx           
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
[a] Give definition of how duration was calculated (e.g., Duration (days) = [date of last dose - date of first dose + 1 ]).
             Define the end of the cycle as the day before the onset date of next cycle.
Bolded sections are optional.
Program path: 
Data source: SDR D_SDSUMM                                                                          
&(/*(1(35235,(7$5<,1)250$7,21
Pag
Pa
        DB
      DB
)
—————————
—————————
Treatment 
reatment 
    (N=XX
    (N=X
—————————
———————
xx         
     
xx
xx
xx, xx   
x, xx   
x
         
      
         
       
         
         
xx        
xx        
xx
xx
    xx   
    xx   
      xx  
     xx 
        xx
       xx
        xx
       x
         
       
         
      
         
        
—————————
—————————
on was cal
on was cal
the day bef
he day be
   


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
73
Celgene Corporation                                                                                                  Page xx of xx
Protocol:        
DB (Interim) Lock Date:
Table 14.2.3 
Study Drug Dose Reduction Due to Adverse Events by Treatment Group - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A       Treatment B         Treatment C
(N=XX)            (N=XX)         
(N=XX)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Had at least one dose reduction due to AE
Yes                                                                             xx (xx)           xx (xx)            xx (xx)
No                                                                               xx (xx)           xx (xx)            xx (xx)
          Time to first dose reduction (days) due to AE[a]
n                                                                                  xx                xx               xx
Mean                                                                               xx                xx               xx
SD                                                                                 xx                xx               xx
Median                                                                             xx                xx               xx
Min, Max                                                                        xx, xx            xx, xx           xx, xx
 Had second dose reduction due to AE
Yes                                                                              xx (xx)           xx (xx)            xx (xx)
No                                                                               xx (xx)           xx (xx)            xx (xx)
Interval between first and second reduction (days)[b] due to AE
n                                                                                  xx                xx               xx
Mean                                                                               xx                xx               xx
SD                                                                                 xx                xx               xx
Median                                                                             xx                xx               xx
Min, Max                                                                       xx, xx            xx, xx           xx, xx
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
[a] Time to dose reduction is the time from first dose of study medication to the start of first reduction.
[b] Time from the start of the first dose reduction to the start of the second dose reduction.
Program path: 
       Data source: D_SDSUMM                                    
&(/*(1(35235,(7$5<,1)250$7,21
    Page 
    Page
DB 
DB 
)
—————————
—————————
 Treatmen
Treatmen
     (N=X
     (N=
—————————
———————
x)        
     
(xx)      
xx)      
xx
xx
xx
       xx 
       xx
        xx
      
          
         
E
          
     
         
        
         
      
—————————
—————
he time fro
e time fr
first dos
first dos
         
      


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
74
Celgene Corporation                                                                                                  Page xx of xx
Protocol:                                                                                                            DB (Interim) Lock Date:
Table 14.2.4
Study Drug Dose Interruption Due to Adverse Events by Treatment Group - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
                                                                     Treatment A       Treatment B         Treatment C
(N=XX)            (N=XX)             (N=XX)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Had at least one dose interruption due to AE
Yes                                                                              xx (xx)           xx (xx)            xx (xx)
No                                                                               xx (xx)           xx (xx)            xx (xx)
       Time to first dose interruption (days) due to AE[a]
n                                                                                  xx                xx               xx
Mean                                                                               xx                xx               xx
SD                                                                                 xx                xx               xx
Median                                                                             xx                xx               xx
Min, Max                                                                        xx, xx            xx, xx           xx, xx
Duration of first dose interruption (days) due to AE[b]
n                                                                                  xx                xx               xx
Mean                                                                              xx                xx               xx
SD                                                                                 xx                xx               xx
Median                                                                             xx                xx               xx
Min, Max                                                                        xx, xx            xx, xx           xx, xx
Had second dose interruption due to AE
Yes                                                                              xx (xx)           xx (xx)            xx (xx)
No                                                                              xx (xx)           xx (xx)            xx (xx)
Interval between first and second interruption (days)[c] due to AE
n                                                                                  xx                xx               xx
Mean                                                                               xx                xx               xx
SD                                                                                 xx                xx               xx
Median                                                                             xx                xx               xx
Min, Max                                                                        xx, xx            xx, xx           xx, xx
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
[a] Time to dose interruption is the time from first dose of study medication to the start of first interruption.
[b] Duration of dose interruption is the time from last dose of one dosing regimen to first dose of the next dosing regimen. A dosing
change is considered an interruption if the start of the new dosing record is greater than 1 day after the end of the previous
dosing record.
[c] Time from the start of the first dose interruption to the start of the second dose interruption.
Program path: 
Data source: D_SDSUMM                                    
&(/*(1(35235,(7$5<,1)250$7,21
  Page xx
  Page xx
DB (
B (I
on)
n)
—————————
—————————
Treatment 
Treatment
   (N=XX)
   (N=XX)
——————————
————————
          
     
x)        
     
xx
xx
xx
     xx  
    x
xx
xx
      xx, 
     xx
         
         
          
        
          
      
        
     
[c] due to
c] due t
         
         
          
       
         
       
         
        
——————————
———————
e time fro
e time fro
is the ti
is the ti
erruption 
rruption 
he first d
e first d
         
         


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
75
Celgene Corporation                                                                                              Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
Table 14.3.2.1
Summary of Adverse Events – Number (%) of Subjects by Treatment Group - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B    Treatment C
                                            (N=XX)        (N=XX)       (N=XX)
TEAE Category[a]                                                                                     n   (%)        n   (%)     n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE                                                                     xx  (xx)       xx  (xx)     xx  (xx)
Subjects with at least one TEAE related to study drug                                               xx  (xx)       xx  (xx)    xx  (xx)
Subjects with at least one CTC AE grade 3-4 (or severe) TEAE                                        xx  (xx)       xx  (xx)     xx  (xx)
Subjects with at least one CTC AE grade 3-4 (or severe) TEAE related to study drug                 xx  (xx)       xx  (xx)     xx  (xx)
Subjects with at least one serious TEAE [b]                                                         xx  (xx)       xx  (xx)     xx  (xx)
Subjects with at least one serious TEAE related to study drug                                       xx  (xx)       xx  (xx)    xx  (xx)
Subjects who discontinued due to TEAE                                                               xx  (xx)       xx  (xx)    xx  (xx)
Subjects who discontinued due to TEAE adverse event related to study drug                           xx  (xx)       xx  (xx)     xx  (xx)
Subjects with TEAE leading to a dose reduction                                                      xx  (xx)       xx  (xx)    xx  (xx)
Subjects with TEAE leading to a dose interruption                                                   xx  (xx)       xx  (xx)     xx  (xx)
Subjects who died[c] due to TEAE                                                                    xx  (xx)       xx  (xx)    xx  (xx)
Additional categories can be specified under “Subjects who died” (e.g., Disease progression).
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
[a] A subject with multiple occurrences of an AE is counted only once in the AE category.
[b] Specify how long serious adverse events were collected following the last dose of study medication.  This should be specified in the protocol.
[c] Specify how long deaths were collected following the last dose of study medication.  This should be specified in the protocol.
Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
Page xx of
Page xx o
 DB (
 DB (Inte
In
Population)
Populatio
—————————
———————
reatment A
reatmen
(N=XX)  
=XX) 
     n   (
    n   
——————————
—————————
          
        
         
        
drug     
drug     
         
         
          
          
         
        
study drug 
study drug 
         
       
          
       
          
         
Subjects w
Subjects w
—————————
—————————
ccurrences 
urrences 
s adverse e
verse 
s were col
s were col


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
76
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.3.2.2
Number (%) of Subjects With Treatment-Emergent Adverse Events by System Organ Class- (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B     Treatment C
(N=xx)       (N=xx)        (N=xx)
System organ class/ Preferred term [a]                                  
n    (%)      n    (%)      n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Blood and lymphatic system disorders                                                         xx  ( xx)     xx  ( xx)     xx  ( xx)
        Thrombocytopenia                                                                          xx  ( xx)     xx  ( xx)     xx  ( xx)
Neutropenia                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
Anaemia NOS                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
Leukopenia NOS                                                                            xx  ( xx)     xx  ( xx)     xx  ( xx)
Febrile neutropenia                                                                       xx  ( xx)     xx  ( xx)     xx  ( xx)
Pancytopenia                      
xx  ( xx)     xx  ( xx)     xx  ( xx)
Granulocytopenia                                                                          xx  ( xx)     xx  ( xx)     xx  ( xx)
Lymphadenopathy                                                                           xx  ( xx)     xx  ( xx)     xx  ( xx)
Polycythaemia NOS                                                                         xx  ( xx)     xx  ( xx)     xx  ( xx)
Splenomegaly                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Coagulopathy                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Haemolytic anaemia NOS                                                                    xx  ( xx)     xx  ( xx)     xx  ( xx)
Leukocytosis                                                                             xx  ( xx)     xx  ( xx)     xx  ( xx)
Lymphocytosis                                                                             xx  ( xx)     xx  ( xx)     xx  ( xx)
Skin and subcutaneous tissue disorders                                                       xx  ( xx)     xx  ( xx)     xx  ( xx)
Pruritus                                                                                  xx  ( xx)     xx  ( xx)    xx  ( xx)
Rash NOS                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Dry skin                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Contusion                                                                                 xx  ( xx)     xx  ( xx)     xx  ( xx)
Night sweats                                     
xx  ( xx)     xx  ( xx)     xx  ( xx)
Sweating increased                                                                        xx  ( xx)     xx  ( xx)     xx  ( xx)
Ecchymosis                                                                                xx  ( xx)     xx  ( xx)     xx  ( xx)
Erythema                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Rash pruritic                                                                             xx  ( xx)     xx  ( xx)     xx  ( xx)
Skin lesion NOS                                                                           xx  ( xx)     xx  ( xx)     xx  ( xx)
Alopecia                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Face oedema                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, 
                     ).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
             Program path: 
             Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
ge xx of x
ge xx of 
DB (Interim
nterim
Populatio
opulat
—————————
—————————
ent A   T
nt A   Tr
N=xx)     
N=xx)    
n    (%)   
n    (%) 
—————————
—————————
xx  ( 
xx  
       xx 
     
         x
        
          
       
         
     
          
        
          
         
         
         
         
         
          
         
          
       
          
        
          
        
          
        
         
      
         
        
          
        
          
          
   
         
       
          
       
          
         
         
        
         
        
         
        
—————————
—————————
preferred t
preferred t
rms are li
ms are li
UUHQFHVRIWK
UUHQFHVRIW


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
77
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
                             Table 14.3.2.3 
Number (%) of Subjects With Common (>= XX%) Treatment-Emergent Adverse Events by SOC - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B     Treatment C
(N=xx)       (N=xx)        (N=xx)
System organ class/ Preferred term [a]                                                        n    (%)      n    (%)      n    (%)
    ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Blood and lymphatic system disorders                                                         xx  ( xx)     xx  ( xx)     xx  ( xx)
Thrombocytopenia                                           
xx  ( xx)     xx  ( xx)     xx  ( xx)
Neutropenia                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
Anaemia NOS                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
Leukopenia NOS                                                                            xx  ( xx)     xx  ( xx)     xx  ( xx)
        Febrile neutropenia                                                                       xx  ( xx)     xx  ( xx)     xx  ( xx)
Pancytopenia                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Granulocytopenia                                                                          xx  ( xx)     xx  ( xx)     xx  ( xx)
Lymphadenopathy                                                                           xx  ( xx)     xx  ( xx)     xx  ( xx)
Polycythaemia NOS                                                                         xx  ( xx)     xx  ( xx)     xx  ( xx)
Splenomegaly                      
xx  ( xx)     xx  ( xx)     xx  ( xx)
Coagulopathy                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Haemolytic anaemia NOS                                                                    xx  ( xx)     xx  ( xx)     xx  ( xx)
Leukocytosis                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Lymphocytosis                                                                             xx  ( xx)     xx  ( xx)     xx  ( xx)
Skin and subcutaneous tissue disorders                                       
xx  ( xx)     xx  ( xx)     xx  ( xx)
Pruritus                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Rash NOS                                                                                 xx  ( xx)     xx  ( xx)     xx  ( xx)
Dry skin                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Contusion                                                                                 xx  ( xx)     xx  ( xx)     xx  ( xx)
Night sweats                                                                              xx  ( xx)     xx  ( xx)    xx  ( xx)
Sweating increased                                                                        xx  ( xx)     xx  ( xx)     xx  ( xx)
Ecchymosis                                                                                xx  ( xx)     xx  ( xx)     xx  ( xx)
Erythema                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Rash pruritic                                    
xx  ( xx)     xx  ( xx)     xx  ( xx)
Skin lesion NOS                                                                           xx  ( xx)     xx  ( xx)     xx  ( xx)
Alopecia                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Face oedema                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, 
                     ).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
             Program path: 
             Data source:  AE
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
&(/*(1(35235,(7$5<,1)250$7,21
xx of xx
x of 
Interim
Interim) L
) L
——————————
—————————
A   Treat
A   Treat
x)       (N
)       (
 (%)      
 (%)      
——————————
—————————
xx  ( 
xx  ( xx)
xx)
    xx  ( 
    xx  
xx  
xx 
       xx
     
          
          
          
      
         
         
         
        
          
          
         
         
         
         
          
        
          
        
         
        
         
       
          
       
         
        
         
        
         
         
          
         
          
        
        
     
         
       
          
         
——————————
———————
erred term
erred t
are liste
are liste
FHVRIWKHV
FHVRIWKHV
——————————
———


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
78
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.3.2.4
Number (%) of Subjects With Treatment-Emergent Adverse Events Related to Study Drug by System Organ Class 
- (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
                                                                                      Treatment A   Treatment B      Treatment C
(N=xx)        (N=xx)        (N=xx)
System organ class/ Preferred term [a]                                                  n    (%)      n    (%)      n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE related to study drug                                   xx ( xx)      xx ( xx)      xx ( xx)
Blood and lymphatic system disorders                                                    xx ( xx)      xx ( xx)      xx ( xx)
Thrombocytopenia                                                                     xx ( xx)      xx ( xx)      xx ( xx)
Neutropenia                  
xx ( xx)      xx ( xx)      xx ( xx)
Leukopenia NOS                                                                       xx ( xx)      xx ( xx)      xx ( xx)
Anaemia NOS                                                                          xx ( xx)      xx ( xx)      xx ( xx)
Febrile neutropenia                                                                  xx ( xx)      xx ( xx)      xx ( xx)
              Granulocytopenia                                                                     xx ( xx)      xx ( xx)      xx ( xx)
Pancytopenia                                                                         xx ( xx)      xx ( xx)      xx ( xx)
Polycythaemia NOS                                                                    xx ( xx)      xx ( xx)      xx ( xx)
Myelosuppression                                                                     xx ( xx)      xx ( xx)      xx ( xx)
Skin and subcutaneous tissue disorders                                                  xx ( xx)      xx ( xx)      xx ( xx)
Pruritus                                                                             xx ( xx)      xx ( xx)      xx ( xx)
Rash NOS                                                                             xx ( xx)      xx ( xx)      xx ( xx)
Dry skin                                                                            xx ( xx)      xx ( xx)      xx ( xx)
Rash pruritic                                                                        xx ( xx)      xx ( xx)      xx ( xx)
Ecchymosis                                                                          xx ( xx)      xx ( xx)      xx ( xx)
Erythema                                                                             xx ( xx)      xx ( xx)      xx ( xx)
Night sweats                                                                         xx ( xx)      xx ( xx)      xx ( xx)
Rash erythematous                                                                    xx ( xx)      xx ( xx)      xx ( xx)
Rash macular                                                                         xx ( xx)      xx ( xx)      xx ( xx)
Rosacea                                                                             xx ( xx)      xx ( xx)      xx ( xx)
Skin lesion NOS                                                                      xx ( xx)      xx ( xx)      xx ( xx)
Sweating increased                                                                  xx ( xx)      xx ( xx)      xx ( xx)
Urticaria NOS                                                                        xx ( xx)      xx ( xx)      xx ( xx)
Acute febrile neutrophilic dermatosis                                               xx ( xx)      xx ( xx)      xx ( xx)
Alopecia                                                                             xx ( xx)      xx ( xx)      xx ( xx)
Contusion                                                                           xx ( xx)      xx ( xx)      xx ( xx)
Exanthem                                                                             xx ( xx)      xx ( xx)      xx ( xx)
    Face oedema                                                                          xx ( xx)      xx ( xx)      xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
[a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, descending order of frequency for the Total 
column).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
e xx of xx
e xx of xx
(Interim
Interim)
Cla
Class 
s 
——————————
—————————
Treatment
Treatment
     (N=xx
     (
      n   
     n  
—————————
—————————
( xx)     
( xx) 
xx ( xx) 
xx ( xx)
   xx ( xx
xx ( 
xx ( 
x ( 
      xx 
    
        xx
       
          
          
         
        
         
       
          
         
          
       
         
         
          
         
          
        
         
        
          
       
          
        
         
        
         
         
         
         
          
        
          
        
         
         
          
       
          
         
——————————
—————
preferred 
preferred 
erms are li
ms are l
FXUUHQFHVR
FXUUHQFHVR


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
79
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                    DB (Interim) Lock Date:
Table 14.3.2.5
Number (%) of Subjects With Treatment-Emergent Adverse Events by System Organ Class and  Maximum CTC AE Grade (Maximum Severity)
- (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A     Treatment B      Treatment C      Treatment D
(N=xx)          (N=xx)           (N=xx)           (N=xx)
System organ class/ Preferred term / Intensity [a]                    n   (%)          n   (%)         n   (%)         n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one adverse event by maximum grade (severity)  xx ( xx)        xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Blood and lymphatic system disorders                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                               xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Cardiac disorders                                                     xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Ear and labyrinth disorders                                           xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
  Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)      
xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Note:  NCI CTC=National Cancer Institute Common Toxicity Criteria Version 2.  
[a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of the dictionary used).  
System organ classes are presented alphabetically and preferred terms are presented alphabetically within each system organ 
                 class. 0XOWLSOHRFFXUUHQFHVRIWKHVDPH SUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS and A subject with multiple 
NCI CTC grades (severity ratings) for an AE is only counted under the maximum grade (severity).
Program path:
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
age xx of 
ge xx of 
DB (
DB Inter
ter
CTC AE Gr
CTC AE G
———————
—————————
     Trea
    Trea
         
         
(%)        
(%)       
—————————
—————
xx ( xx)  
x ( xx)  
  xx ( xx
  xx ( x
    xx ( x
  xx ( 
      xx 
    
        xx
        x
)         
        
( xx)      
xx)     
x ( xx)    
 ( xx)    
xx ( xx)  
xx ( xx)
 xx ( xx)
 xx ( xx)
   xx ( x
   xx ( x
     xx ( 
    xx (
        x
        
         
         
          
        
     
   
          
        
          
       
          
          
          
        
         
   
         
        
          
      
—————————
—————
titute Com
titute Com
ferred ter
ferred te
resented a
resented a
HVRIWKHVD
VRIWKHVD
an AE is o
AE is 


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
80
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
Table 14.3.2.6
Number (%) Subjects With TEAE Related to Study Drug by System Organ Class, Preferred Term, Treatment Group, and 
Maximum NCI CTC Grade (Maximum Severity) - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A     Treatment B      Treatment C      Treatment D
(N=xx)          (N=xx)           (N=xx)           (N=xx)
System organ class/ Preferred term / Intensity [a]                    n   (%)          n   (%)         n   (%)         n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             Subjects with at least one related TEAE 
by maximum grade (severity)                                           xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate               
xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Blood and lymphatic system disorders                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                           
xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Cardiac disorders                                                     xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Ear and labyrinth disorders                                           xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                               xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Note:  NCI CTC=National Cancer Institute Common Toxicity Criteria Version 2.  
[a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of the dictionary used).  
System organ classes are presented alphabetically.  Preferred terms are presented alphabetically within each system organ class.  
0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS  A subject with multiple NCI CTC 
grades 
(severity ratings) for an AE is only counted under the maximum grade (severity).
Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
e xx of 
xx of xx
xx
B (Interim
Interim
p, and 
p, and 
—————————
—————
eatment C 
atment C 
 (N=xx)  
 (N=xx)  
   n   (%
  n   (%
—————————
——————
xx)       
xx)       
( xx)      
xx)  
x ( xx)    
x ( xx)   
xx ( xx)  
xx ( xx) 
  xx ( xx)
xx ( x
   xx ( x
  xx ( x
         x
         x
x)        
        
xx)      
xx)    
( xx)    
( xx)    
xx ( xx)   
xx ( xx)
xx ( xx) 
xx ( xx) 
    xx ( 
    xx (
      xx 
      xx 
        xx
        xx
          
        
         
       
         
        
        
     
          
        
         
         
          
        
          
    
—————————
—————————
tute Common
tute Commo
rred terms 
rred terms 
ented alph
ented al
VDPHSUHIHU
VDPHSUHIH
an AE 
 AE is o
is o


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
81
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
Table 14.3.2.7
                    Number (%) of Subjects With Adverse Events With CTC AE Grade 5 by System Organ Class - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B    Treatment C
(N=xx)       (N=xx)       (N=xx)
System organ class/ Preferred term [a]                                             n    (%)     n    (%)     n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one NCI CTC Grade 5 adverse event                           xx ( xx)     xx ( xx)     xx ( xx)
Infections and infestations               
xx ( xx)     xx ( xx)     xx ( xx)
Pneumonia NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Sepsis NOS                                                                      xx ( xx)     xx ( xx)     xx ( xx)
Bacteraemia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Cellulitis                                                                      xx ( xx)     xx ( xx)     xx ( xx)
Infection NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Central line infection                                                          xx ( xx)     xx ( xx)     xx ( xx)
Clostridial infection NOS                                                       xx ( xx)     xx ( xx)     xx ( xx)
Enterobacter sepsis                                                             xx ( xx)     xx ( xx)     xx ( xx)
Fungal infection NOS                                                            xx ( xx)     xx ( xx)     xx ( xx)
Influenza                                                                       xx ( xx)     xx ( xx)     xx ( xx)
Klebsiella sepsis                                                               xx ( xx)     xx ( xx)     xx ( xx)
        Lobar pneumonia NOS                                                             xx ( xx)     xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                                               xx ( xx)     xx ( xx)     xx ( xx)
Neutropenia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Thrombocytopenia                                                                xx ( xx)     xx ( xx)   
xx ( xx)
Anaemia NOS                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Febrile neutropenia                                                             xx ( xx)     xx ( xx)     xx ( xx)
Leukopenia NOS                                                                  xx ( xx)     xx ( xx)     xx ( xx)
Pancytopenia                                                                    xx ( xx)     xx ( xx)     xx ( xx)
Coagulopathy                                                                    xx ( xx)     xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             Note:  NCI CTC=National Cancer Institute Common Toxicity Criteria Version 2.  
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical,)
0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path: 
Data source:  AE (death page?)
&(/*(1(35235,(7$5<,1)250$7,21
  Page
 Page xx
xx
    DB (
   DB (I
Population
Populatio
—————————
———————
eatment B 
eatment 
  (N=xx)  
 (N=xx)  
  n    (%
  n    (%
—————————
—————
xx)     xx
xx)     x
x ( xx)   
x ( xx)  
xx ( xx) 
x ( xx) 
xx ( xx
xx 
    xx ( x
   xx ( 
xx (
xx 
       xx
       xx
         
       
          
          
          
        
          
        
         
         
          
        
          
          
         
         
         
        
          
      
          
        
          
     
         
         
         
       
          
      
—————————
————————
itute Commo
tute Comm
erred terms
erred terms
are listed
are liste
WHUPIURPD
WHUPIURPD
th page?)
th page?)


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
82
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
Table 14.3.2.8
Number (%) of Subjects With Treatment-Emergent SAE by System Organ Class - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B   Treatment C
                  (N=xx)       (N=xx)       (N=xx)
System organ class/ Preferred term [a]                                             n    (%)     n    (%)     n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TESAE                                                   xx ( xx)     xx ( xx)     xx ( xx)
Infections and infestations                                                        xx ( xx)     xx ( xx)     xx ( xx)
Pneumonia NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Sepsis NOS                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Bacteraemia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Cellulitis                                                                      xx ( xx)     xx ( xx)     xx ( xx)
Infection NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Central line infection                                                          xx ( xx)     xx ( xx)     xx ( xx)
Clostridial infection NOS                                                       xx ( xx)     xx ( xx)     xx ( xx)
       Enterobacter sepsis                                                             xx ( xx)     xx ( xx)     xx ( xx)
Fungal infection NOS                                                            xx ( xx)     xx ( xx)     xx ( xx)
Influenza                                                                       xx ( xx)     xx ( xx)     xx ( xx)
Klebsiella sepsis                                                               xx ( xx)     xx ( xx)     xx ( xx)
Lobar pneumonia NOS                                                             xx ( xx)     xx ( xx)     xx ( xx)
Sinusitis NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Sinusitis acute NOS                                                             xx ( xx)     xx ( xx)     xx ( xx)
Urinary tract infection NOS                                                     xx ( xx)     xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                                               xx ( xx)     xx ( xx)     xx ( xx)
Neutropenia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Thrombocytopenia                                                                xx ( xx)     xx ( xx)     xx ( xx)
Anaemia NOS                                                               
xx ( xx)     xx ( xx)     xx ( xx)
Febrile neutropenia                                                             xx ( xx)     xx ( xx)     xx ( xx)
Leukopenia NOS                                                                 xx ( xx)     xx ( xx)     xx ( xx)
Pancytopenia                                                                    xx ( xx)     xx ( xx)     xx ( xx)
Coagulopathy                                                                    xx ( xx)     xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, 
                 ).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
Page xx o
Page xx o
  DB (
 DB Inte
nt
Population
opulation
—————————
———————
tment B   
ment B   
(N=xx)    
(N=xx)  
n    (%)  
n    (%) 
—————————
—————————
)     xx (
    
( xx)     x
xx)     
x ( xx)    
xx)  
xx ( xx)  
x ( xx) 
 xx ( xx)
 xx 
   xx ( x
   xx ( 
     xx ( 
     xx ( 
       xx 
     xx 
        x
       
         
         
          
       
          
          
          
          
         
        
         
         
          
         
          
        
         
        
         
       
          
       
         
        
          
         
         
         
         
        
          
    
—————————
————————
ferred term
ferred te
s are liste
are liste
RIWKHVDPH
RIWKHVDPH


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
83
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
84
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
                                  Table 14.3.2.9
Number (%) of Subjects With Treatment-Emergent SAE Related to Study Drug by System Organ Class -
(Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
     Treatment A   Treatment B     Treatment C
(N=xx)       (N=xx)       (N=xx)
System organ class/ Preferred term [a]                                             n    (%)     n    (%)     n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TESAE related to study drug                             xx ( xx)     xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                                               xx ( xx)     xx ( xx)     xx ( xx)
Neutropenia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Febrile neutropenia                                                             xx ( xx)     xx ( xx)     xx ( xx)
Thrombocytopenia                                                                xx ( xx)     xx ( xx)     xx ( xx)
Leukopenia NOS                                                                  xx ( xx)     xx ( xx)     xx ( xx)
Anaemia NOS                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Pancytopenia                                                                    xx ( xx)     xx ( xx)     xx ( xx)
 Infections and infestations                                                        xx ( xx)     xx ( xx)     xx ( xx)
Pneumonia NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
             Cellulitis                                                                      xx ( xx)     xx ( xx)     xx ( xx)
Clostridial infection NOS                                                       xx ( xx)     xx ( xx)     xx ( xx)
Infection NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Klebsiella sepsis                                                               xx ( xx)     xx ( xx)     xx ( xx)
Lobar pneumonia NOS                                                             xx ( xx)     xx ( xx)     xx ( xx)
General disorders and administration site conditions                               xx ( xx)    xx ( xx)     xx ( xx)
Pyrexia                                                                         xx ( xx)     xx ( xx)     xx ( xx)
Asthenia                                                                        xx ( xx)     xx ( xx)     xx ( xx)
Fatigue                                                                         xx ( xx)     xx ( xx)     xx ( xx)
Respiratory, thoracic and mediastinal disorders                                    xx ( xx)     xx ( xx)     xx ( xx)
Pulmonary embolism                                                              xx ( xx)     xx ( xx)     xx ( xx)
Pulmonary hypertension NOS                                                      xx ( xx)     xx ( xx)     xx ( xx)
Pleural effusion                                                                xx ( xx)     xx ( xx)     xx ( xx)
Respiratory distress                                                            xx ( xx)     xx ( xx)     xx ( xx)
Skin and subcutaneous tissue disorders                                             xx ( xx)     xx ( xx)     xx ( xx)
Rash NOS                                                                       xx ( xx)     xx ( xx)     xx ( xx)
Acute febrile neutrophilic dermatosis                                           xx ( xx)     xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, 
                ).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
Page xx 
Page xx
   DB (
   DB (In
an Class 
an Class -
—————————
———————
eatment B 
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 (N=xx)   
(N=xx)  
  n    (%)
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——————————
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————————
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QFHVRIWKH
QFHVRIWKH


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
85
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
86
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
Table 14.3.2.10
Number (%) of Subjects With TEAE Leading to Discontinuation of Study Drug by System Organ Class -
(Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B    Treatment C
                        (N=xx)       (N=xx)       (N=xx)
System organ class/ Preferred term [a]                                             n    (%)     n    (%)     n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE leading to discontinuation of study drug           xx ( xx)     xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                                               xx ( xx)     xx ( xx)     xx ( xx)
Neutropenia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Febrile neutropenia                                                             xx ( xx)     xx ( xx)     xx ( xx)
Thrombocytopenia                                                                xx ( xx)     xx ( xx)     xx ( xx)
Leukopenia NOS                                                                  xx ( xx)     xx ( xx)     xx ( xx)
Anaemia NOS                                                                     xx ( xx)     xx ( xx)     xx ( xx)
    Pancytopenia                                                                    xx ( xx)     xx ( xx)     xx ( xx)
Infections and infestations                                                        xx ( xx)     xx ( xx)     xx ( xx)
Pneumonia NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Cellulitis                                                                      xx ( xx)     xx ( xx)     xx ( xx)
Clostridial infection NOS                                                       xx ( xx)     xx ( xx)     xx ( xx)
Infection NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Klebsiella sepsis                                                               xx ( xx)     xx ( xx)     xx ( xx)
Lobar pneumonia NOS                                                             xx ( xx)    xx ( xx)     xx ( xx)
General disorders and administration site conditions                               xx ( xx)     xx ( xx)     xx ( xx)
Pyrexia                                                                         xx ( xx)     xx ( xx)     xx ( xx)
Asthenia                                                                        xx ( xx)     xx ( xx)     xx ( xx)
Fatigue                                                                  
xx ( xx)     xx ( xx)     xx ( xx)
Respiratory, thoracic and mediastinal disorders                                    xx ( xx)     xx ( xx)     xx ( xx)
Pulmonary embolism                                                             xx ( xx)     xx ( xx)     xx ( xx)
Pulmonary hypertension NOS                                                      xx ( xx)     xx ( xx)     xx ( xx)
Pleural effusion                                      
xx ( xx)     xx ( xx)     xx ( xx)
Respiratory distress                                                            xx ( xx)     xx ( xx)     xx ( xx)
Skin and subcutaneous tissue disorders                                            xx ( xx)     xx ( xx)     xx ( xx)
Rash NOS                                                                        xx ( xx)     xx ( xx)     xx ( xx)
Acute febrile neutrophilic dermatosis                                           xx ( xx)     xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical,
).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path: 
Data source:  AE
Page xx o
Page xx o
DB (
DB Inte
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———————
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
87
Celgene Corporation                                                                                          Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
                                      Table 14.3.2.2.1
Number (%) of Subjects With Treatment-Emergent Adverse Events by System Organ Class and Age Group -
(Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
         Treatment A             Treatment B                Treatment C
(N=xx)                  (N=xx)                   (N=xx)
                                   ——————————————————————— ——————————————————————— ———————————————————————
<65         >=65        <65         >=65        <65         >=65
          System organ class/ Preferred term [a]                           (N=xx)      (N=xx)      (N=xx)      (N=xx)      (N=xx)      (N=xx)
n(%)        n(%)        n(%)         n(%)        n(%)         n(%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE                               xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                           xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Thrombocytopenia                                            xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Neutropenia                                                 xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Anaemia NOS                                                 xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Leukopenia NOS                                              xx ( xx)    xx ( xx)   xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Febrile neutropenia                                         xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Pancytopenia                                                xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Granulocytopenia                                            xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Lymphadenopathy                                             xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Polycythaemia NOS                                           xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Splenomegaly                                                xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Coagulopathy                                                xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Haemolytic anaemia NOS                                      xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Leukocytosis                                               xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Lymphocytosis                                               xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Monocytosis                                                 xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Myelosuppression                                            xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Thrombocythaemia                                            xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary(indicate the version of the dictionary used).  
                 System organ classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, 
                 ).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path: 
     Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
Page xx
Page xx
    DB (
  DB I
n Class an
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—————————
———————
Treatment 
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
88
Qol tables
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
89
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
90
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
91
Efficacy Tables
Summary of TTE
Population
Statistics
Arm A
(N = xxx)
Arm B
(N = xxx)
Total
(N = xxx)
Subjects included
N
xxx
xxx
xxx
Died
n(%)
xx (%)
xx (%)
xx (%)
Censored
n(%)
xx (%)
xx (%)
xx (%)
TTE since 
randomization (weeks)
Median
xx
xx
xx
95% CI
(xx , xx)
(xx , xx)
(xx , xx)
Hazard Ratio (A:B)
HR (95 CI)
x.xxx (x.xxx , x.xxx)
Log rank
Two sided P - value
0.xxx
xyz Test
Two sided P - value
0.xxx
uvw Test
Two sided P - value
0.xxx
TTE follow up
n(%)
xx (%)
xx (%)
xx (%)
Median (min , max)
xx (xx , xx)
xx (xx , xx)xx
xx (xx , xx)xx
Footnote: 
Source: sas code location 
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xx (%)
xx (%)
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xxx (x.xxx 
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xx (%
xx (
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xx
23


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
92
Summary of TTE Survival Rates
Population
Arm A
(N = xxx)
Arm B
(N = xxx)
Arm A - B
(N = xxx)
Endpoint / Time Points
Estimate (95% CI)
Estimate (95% CI)
Estimate (95% CI)
P - value
Endpoint #1
Interval 1
xx (%)
xx (%)
xx (%)
0.xxx
Interval 2
xx (%)
xx (%)
xx (%)
0.xxx
Interval 3
xx (%)
xx (%)
xx (%)
0.xxx
Endpoint #2
Interval 1
xx (%)
xx (%)
xx (%)
0.xxx
Interval 2
xx (%)
xx (%)
xx (%)
0.xxx
Interval 3
xx (%)
xx (%)
xx (%)
0.xxx
Endpoint #3
Interval 1
xx (%)
xx (%)
xx (%)
0.xxx
Interval 2
xx (%)
xx (%)
xx (%)
0.xxx
Interval 3
xx (%)
xx (%)
xx (%)
0.xxx
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(%)
xx (%)
x (%)
xx (%)
xx (%
xx (%)
xx (%)
xx (%)
xx (%)
xx (%
xx (
3


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
93
                           Summary of Response Rates
Population
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
len/D                     len/d                    Overall
n   (%)        
n   (%)                   n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Number of Patients: (N  (%))                                 
Response [a]
Complete Response (CR)                                    
Near Complete Response (N-CR)                             
Partial Response (PR)                                     
Minimal Response (MR)                                     
Stable Disease (SD)                                       
Progressive Disease (PD)                                  
Response Not Evaluable (NE)[b]                            
Dichotomized response (Response not incl. MR)
CR or N-CR or PR                                          
MR or SD or PD or NE                                      
  p-value [c]                                               
Odds ratio (len/D:len/d) (95% CI)[d]                      
Dichotomized response (Response incl. MR)
CR or N-CR or PR or MR      
SD or PD or NE                                            
p-value [c]                                              
Odds ratio (len/D:len/d) (95% CI)[d]                      
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Note: Response in this table is based on the review of all lymphoma assessment data using modified EBMT criteria.
IRAC=Independent Response Assessment Committee
[a] Response is the best assessment of response during the treatment phase of the study.
[b] Including patients who did not have adequate data for response assessment at baseline and/or post-baseline prior to the use of any
non-protocol anti-lymphoma therapy.
[c] Probability from Fisher's Exact test.
[d] CI=Confidence Interval
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 2, MULTICENTER, RANDOMIZED OPEN-LABEL STUDY TO DETERMINE 
THE EFFICACY OF LENALIDOMIDE (REVLIMID®) VERSUS INVESTIGATOR’S 
CHOICE IN PATIENTS WITH RELAPSED OR REFRACTORY MANTLE CELL 
LYMPHOMA
STUDY DRUG:
Lenalidomide/CC-5013
PROTOCOL NUMBER:
CC-5013-MCL-002
DATE FINAL:
26JUL2010
Prepared by:
Celgene International
Route de Perreux, 1
2017 Boudry, Switzerland
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION....................................................................................................9
3.
OBJECTIVES ........................................................................................................10
4.
INVESTIGATIONAL PLAN .................................................................................11
4.1.
Overall Study Design and Plan ...............................................................................11
4.1.1.
Discussion of Study Design ....................................................................................11
4.2.
Study Endpoints .....................................................................................................12
4.3.
Stratification , Randomization and Blinding............................................................12
4.4.
Sample Size............................................................................................................13
4.5.
Changes to the Planned Protocol Analysis ..............................................................14
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................15
5.1.
Reporting Conventions ...........................................................................................15
5.1.1.
Dates and partial dates imputation ..........................................................................15
5.1.2.
Calculations Using Dates........................................................................................16
5.1.3.
Calculation of Cycles..............................................................................................16
5.2.
Analysis Populations ..............................................................................................17
5.2.1.
Intent-to-Treat Population.......................................................................................17
5.2.2.
Full Analysis Set Population...................................................................................17
5.2.3.
Per Protocol Population ..........................................................................................17
5.2.4.
Safety Population....................................................................................................17
6.
PATIENT DISPOSITION ......................................................................................18
7.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................19
7.1.
Demographics.........................................................................................................19
7.2.
Baseline Clinical Characteristics.............................................................................19
7.3.
Medical History......................................................................................................19
7.4.
Prior Therapy..........................................................................................................19
7.5.
Prior Medications ...................................................................................................20
8.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................21
8.1.
Treatment Duration.................................................................................................21
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7.4.
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5.5


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8.2.
Cumulative Dose ....................................................................................................21
8.3.
Dose Intensity.........................................................................................................21
8.4.
Relative Dose Intensity...........................................................................................21
8.5.
Dose Modification..................................................................................................22
9.
CONCOMITANT MEDICATIONS .......................................................................24
10.
EFFICACY ANALYSIS ........................................................................................25
10.1.
General Statistical Methods ....................................................................................25
10.1.1.
Time to event endpoints..........................................................................................25
10.1.2.
Categorical endpoints .............................................................................................26
10.1.3.
Quality of Life endpoints........................................................................................26
10.2.
Expert Review of Disease Response .......................................................................26
10.3.
Analysis of Primary Efficacy Endpoint...................................................................26
10.4.
Analyses of Secondary Efficacy Endpoints.............................................................29
10.4.1.
Overall response rate ..............................................................................................29
10.4.2.
Duration of Response .............................................................................................29
10.4.3.
Tumor control rate..................................................................................................30
10.4.4.
Duration of Stable Disease......................................................................................30
10.4.5.
Time to progression (TTP)......................................................................................30
10.4.6.
Time to treatment failure (TTF)..............................................................................30
10.4.7.
Time to tumor response (TTR)................................................................................30
10.4.8.
Overall Survival (OS).............................................................................................30
10.5.
Subgroup Analysis..................................................................................................30
11.
SAFETY ANALYSIS ............................................................................................32
11.1.
Adverse Events.......................................................................................................32
11.2.
Clinical Laboratory Evaluations..............................................................................32
11.3.
Vital Sign Measurements........................................................................................32
11.4.
Physical Examination .............................................................................................33
11.5.
Electrocardiogram ..................................................................................................33
12.
QUALITY OF LIFE ANALYSIS...........................................................................34
12.1.
EORTC QLQ-C30..................................................................................................34
12.2.
Analysis of Quality of Life Scales...........................................................................36
13.
INTERIM ANALYSIS...........................................................................................37
13.1.
General Information................................................................................................37
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13.2.
Statistical Approaches for Control of Alpha............................................................38
14.
REFERENCES.......................................................................................................39
15.
APPENDICES........................................................................................................40
15.1.
Date Imputation Guideline......................................................................................40
15.1.1.
Impute Missing AE/ Prior or Concomitant Medications Start Dates........................40
15.2.
Cycle derivation Guideline .....................................................................................41
15.3.
Endpoints derivation...............................................................................................44
15.4.
Laboratory Values ..................................................................................................45
15.5.
Tables and listings shells ........................................................................................58
1
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Confidence Intervals...............................................................................................13
Table 3:
InvC drug recommended dose.................................................................................22
Table 4:
Censoring Rules for Time to event (Progression and/or Death) Endpoints...............27
Table 5:
Method b: Censoring Rules for Time to event (Progression and/or Death) 
Endpoints sensitivity analysis .................................................................................28
Table 6:
Method c: Censoring Rules for Time to event (Progression and/or Death) 
Endpoints sensitivity analysis .................................................................................29
Table 7:
EORTC QLQ-C30 scores .......................................................................................34
Table 8:
Response percentage and 95% exact confidence interval ........................................37
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
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7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
BSA
Body surface area
CR
Complete response
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data monitoring committee
DOB
Date of birth
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
GCP
Good Clinical Practice
HR
Hazard ratio
IC
Informed consent
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
InvC
Investigator’s choice
IRRC
Independent radiology review committee
ITT
Intent-to-treat
IVRS
Interactive voice response system
KM
Kaplan Meier
Len
Lenalidomide
MCL
Mantle Cell Lymphoma
MedDRA
Medical Dictionary for Drug Regulatory Activities
NCI-CTC
National Cancer Institute Common Toxicity Criteria
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
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8
Abbreviation or 
Specialist Term
Explanation
PFS
Progression-free survival
PI
Principal Investigator
The investigator who leads the study conduct at an individual study center.  
Every study center has a principal investigator.
PP
Per protocol
PR
Partial response
QoL
Quality of Life
SAE
Serious adverse event
SAP
Statistical analysis plan
SCT
Stem Cell Transplant
SD
Stable disease
SDev
Standard deviation
TEAE
Treatment emergent adverse event
TTF
Time to treatment failure
TTP
Time to tumor progression
TTR
Time to response
WHO
World Health Organization
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
9
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-5013-MCL-002 “A Phase 2, Multicenter, Randomized Open-Label Study To 
Determine The Efficacy Of Lenalidomide (REVLIMID®) Versus Investigator’s Choice In 
Patients With Relapsed Or Refractory Mantle Cell Lymphoma.” It contains definitions of 
analysis populations, derived variables and statistical methods for the analysis of efficacy and 
safety.
These analyses include one interim analysis for futility and one final analysis. Throughout this 
SAP, the treatment arms will be referred to as lenalidomide (Len) and Investigator’s choice 
(InvC).  The purpose of the SAP is to ensure the credibility of the study findings by specifying 
the statistical approaches to the analysis of study data prior to database lock for the final analysis. 
This SAP will be finalized and signed prior to the clinical database lock for the futility analysis. 
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.1.
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Lenalidomide/CC-5013
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3.
OBJECTIVES
The objective of the statistical analyses will be to investigate the efficacy and safety of 
lenalidomide monotherapy in patients with relapsed or refractory mantle cell lymphoma.
Primary objective
!
To compare the progression free survival (PFS) of lenalidomide monotherapy versus 
investigator’s choice single agent in patients with mantle cell lymphoma (MCL) who 
have relapsed after or are refractory to at least 1 and up to 3 prior chemotherapy
regimens.
Secondary objective
!
To determine the overall response rate (ORR) of lenalidomide monotherapy or 
investigator’s choice single agent in patients with relapsed or refractory MCL.
!
To evaluate the safety of lenalidomide monotherapy or investigator’s choice single 
agent in patients with relapsed or refractory MCL.
!
To determine the time to progression (TTP), and overall survival (OS) of patients 
with relapsed or refractory MCL who have received treatment with lenalidomide or 
investigator’s choice single agent.
!
To investigate the health-related quality of life (QoL) of patients treated with 
lenalidomide or investigator’s choice single agent treatment.
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Lenalidomide/CC-5013
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Celgene International
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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a multicenter, randomized, open-label, comparative, active controlled phase II study to 
determine the efficacy and safety of single agent lenalidomide over a concurrent control group 
treated with an investigator’s choice monotherapy in patients with MCL who have relapsed after 
or are refractory to at least 1 and up to 3 prior lines of therapy.
This multicenter study design aims to determine the PFS hazard ratio (HR) of lenalidomide over 
a single agent of investigator’s choice.
The investigator’s choice in the control arm comprises the monotherapy treatment with one of 
the following: chlorambucil, cytarabine, rituximab, fludarabine, or gemcitabine.  The 
investigator shall choose the single agent of choice in the control arm for each patient prior to 
randomization on to the study. Patients in the investigator’s choice arm will have the option to 
switch to lenalidomide at the time of progressive disease (cross over phase).
Patients will be stratified according to:
!
Time since diagnosis (< 3 years or ≥ 3 years)
!
Time since last treatment (< 6 months [refractory] or ≥ 6 months)
!
Prior stem cell transplant (yes or no).
This study will be conducted in four phases: 
1. A Screening Phase
2. An open label randomized Treatment Phase
3. A cross over phase (patients in the investigator’s choice Arm B only)
4. Follow-up phase.
4.1.1.
Discussion of Study Design
!
Duration of Treatment
Patients will be treated until progression in this study.  
!
Study Population
Patients with MCL who have relapsed after and up to 3 relapses are being assessed to evaluate 
the efficacy of lenalidomide. There is no standard of care for such patients.
!
Blinding
The open-label option was chosen because the five alternatives therapies on the InvC arm are 
given either IV or orally.
!
Cross-over
Due to ethical concerns and based on the fact there is no alternative for patients on the InvC arm 
who progress the possibility to cross-over to Len is offered. It is clearly a source of bias in the 
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Lenalidomide/CC-5013
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Celgene International
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analysis endpoints such as OS. Cross-over will not affect the primary endpoint (PFS) as it is 
allowed only after progression occurs.
4.2.
Study Endpoints
Following the implementation of Amendment #2 (dated 14 Dec 2009), PFS became the primary 
endpoint comparing PFS in patients who receive lenalidomide monotherapy versus 
investigator’s choice. Despite the change in the primary endpoint from ORR to PFS, there was 
no impact on the sample size calculation.
Primary
PFS is defined as the time from randomization to the first observation of disease progression or 
death due to any cause. If the patient has not progressed or died, PFS will be censored at the time 
of last completed assessment when the patient was known not to have progressed. Patients who 
receive a new treatment without documented progression will be censored at the last assessment 
date that the patient is known to be progression-free.
Secondary
!
ORR (complete response [CR], complete response unconfirmed [CRu], and partial 
response [PR]) will be assessed by a modification of the International Workshop 
Lymphoma Response Criteria (IWRC), which will hereafter be described as modified 
IWRC (Cheson,1999).
!
Duration of response
!
Duration of stable disease
!
Tumor control rate (Rates for CR, CRu, PR, and stable disease [SD])
!
Time to progression (TTP)
!
Time to treatment failure (TTF)
!
Time to tumor response (TTR)
!
Overall survival (OS)
!
Safety
!
Quality of Life (EORTC QLQ-C30 questionnaire)
4.3.
Stratification , Randomization and Blinding
An Interactive Voice Response System (IVRS) will be utilized to ensure a 2:1 central 
randomization based on a permuted-block randomization method. Patients will be randomized 
according to the following stratification factors: Time since diagnosis (< 3 years or ≥ 3 years), 
Time since last treatment (< 6 months [refractory] or ≥ 6 months), Prior stem cell transplant (yes 
or no).
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Lenalidomide/CC-5013
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Celgene International
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4.4.
Sample Size
The main objective of the study changed to demonstrate the efficacy of lenalidomide over a 
single agent of investigator’s choice based on PFS.
The primary analysis for the study is to compare PFS between lenalidomide and investigator’s 
choice monotherapy. For the primary efficacy variable PFS, a hazard ratio (HR) of 1.7 leading to 
an improvement in median PFS from 2.5 months for the control arm to at least 4.25 months for 
lenalidomide is considered to be clinically relevant.
These assumptions are supported by recent data published in relapsed refractory MCL (Witzig et 
al. 2007 and Hess et al., 2009 ). 
With a hazard ratio of 1.7, full information necessary for a one-sided log rank test with an overall 
alpha of 0.025, to have 80% power, will be achieved when approximately 128 patients have 
progressed or died (PFS).
Initially, the sample size was calculated to estimate the ORR; however, it remains adequate to 
estimate PFS.
The sample size calculation is based on the width of the 95% confidence interval around a 
certain point estimate for ORR that is considered significant clinical activity.
Based on preliminary data, a response rate in the range of 30% to 40% can reasonably be 
expected.
A sample size equal to 100 allows the construction of a two sided 95% confidence interval with a 
width of 9% (one direction) for an expected proportion of 30%. 
The lower observed confidence interval limit would be about 21%, which is still considered to be 
clinically meaningful.
This sample size allows a width (one direction) of 9.6% for an expected proportion of 40% and 
9.3% for an expected proportion of 35% (Table 2).
Table 2:
Confidence Intervals
95% Two-Sided Confidence Intervals (N = 100)
Response rate
30%
35%
40%
CIa
0.214 – 0.400
0.257 – 0.452
0.303 – 0.503
a Exact confidence intervals based on the Clopper-Pearson method
Using a one group chi-square ( ∀2) test with a 0.050 two-sided significance level a sample size of 
100 patients will have 81% power to detect the difference between the Null hypothesis 
proportion of 20% and the alternative proportion of 32%.
No formal sample size calculation will be done for the control arm. With a 2:1 ratio 50 patients 
are needed in the control arm.
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Lenalidomide/CC-5013
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Celgene International
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Assuming that 10% of patients will be lost to follow up, 167 patients will need to be randomized.
4.5.
Changes to the Planned Protocol Analysis
Not applicable.
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Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
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15
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
Summary tables, listings, and any supportive SAS output will include a “footer” of explanatory 
notes that will indicate, at a minimum, the following: 
!
Program source (e.g., SAS program name, including the path, that generates the output)
!
Data extraction date (e.g., the database lock date, run date).
!
Source listing(s) for the summary tables
The purpose of the data extraction date is to link the output to a final database, either active or 
archived, that is write-protected for replication and future reference.  An output date will also 
appear on each output page and will indicate the date the output was generated by the analysis 
program. Individual source listings will display all the relative values supporting the 
corresponding tables or figures.
5.1.1.
Dates and partial dates imputation
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9. datetime format in SAS) if complete dates are expected, 
for information (e.g: medical history, prior medications) dates can be reported in the YYYY-
MM-DD format.  Dates in the clinical database are classified into the categories of procedure 
dates, log dates, milestone dates, outcome dates, and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedures are 
performed.  They include the dates of laboratory testing, physical examinations, 
tumor scans, etc.  They should be present whenever data for a protocol-specified 
procedure is present and should only be missing when a procedure is marked as NOT 
DONE in the database.  Procedure dates will not be imputed.
!
Log Dates are dates recorded in case report form (CRF) data logs.  Specifically, they 
are the start and end dates for adverse events and concomitant 
medications/procedures.  They should not be missing unless an event or medication is 
marked as ongoing in the database.  Otherwise, incomplete log dates will be imputed 
according to the rules in Appendix 15.1 (eg, for duration or cycle assignment etc). 
However, in listings, log dates will be shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study termination, etc.  They should not be missing if the milestone occurs 
for a patient. They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc.  In most cases they are derived either from a milestone (eg, the 
survival date is derived from the death date), or a procedure date (eg, the progression 
date is derived from the date of the tumor scan that was used to determine progression
or from the date of clinical evaluation).  They may be subject to endpoint-specific 
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
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censoring rules if the outcome did not occur, but are not otherwise subject to 
imputation.
Dates recorded in comment fields will not be imputed or reported in any specific format.
5.1.2.
Calculations Using Dates
Calculations using dates (e.g., patient’s age or relative day after the first dose of study 
medication) will adhere to the following conventions: 
!
Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study medication (eg, 
lenalidomide) plus 1 day. The generalized calculation algorithm for relative day is as 
follows: STUDY DAY = [(TARGET DATE – DSTART) + 1] where DSTART = the 
start day of study drug.  Note that Study Day 1 is the first day of treatment of study 
drug.  Negative and zero study days are reflective of observations obtained during the 
baseline/screening period.  Note: in general, a partial date for the first date of study 
drug intake will not be imputed. All efforts should be made to avoid an incomplete 
study drug start date.
!
Age (expressed in days) is calculated: AGE = CONSENT – DATE of BIRTH + 1.  In 
practice, age will be transformed to years by dividing the difference by 365.25 days, 
then truncating.
o
The calculated age from the clinical database will be used preferentially. 
When not available, it will be permissible to use the calculated age from the 
CRF or IVRS
o
Partial birth date: impute missing day as 15th of the month; impute missing 
month as July; set missing age for missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS / 7.
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS / 30.4167.
5.1.3.
Calculation of Cycles
The start date of each treatment cycle will be calculated based on study drug exposure records 
for each patient. The start date of the first cycle will be the date when the patient receives any 
study drug.
The cycle will be derived following the algorithm given in Appendix 15.2. Rituximab drug has a 
cycle length of 56 days, whereas the other treatments have a 28 days schedule. Any 
programming should be adapted accordingly.
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Once the cycles are derived, they can be used to attribute adverse events to a specific cycle based 
upon the following rules: the start date of the adverse event should be included in a given cycle 
or if the start date does not fit in any defined cycle, the adverse event will be attributed to the 
previous cycle if the AE has started within 30 days after the end of the cycle.
5.2.
Analysis Populations
The primary efficacy analyses will be performed on the Intent-to-Treat (ITT) population for the 
primary and secondary endpoints. Sensitivity analyses will be conducted for the primary and 
secondary endpoints based on the Full Analysis Set (FAS) population.
The safety analyses will be conducted on the Safety population.
5.2.1.
Intent-to-Treat Population
The ITT population is defined as all patients who are randomized, independent of whether they 
received study treatment or not. The ITT population will be used for the primary efficacy 
analysis.
Patients will be analyzed according to the initial treatment to which they are assigned.
5.2.2.
Full Analysis Set Population
The FAS population includes all randomized patients that have received at least one single 
treatment dose with centrally confirmed histology of MCL as well as documented progression at 
entry.
5.2.3.
Per Protocol Population 
No per protocol population will be defined but major protocol violations will be reported.
Major protocol violations will be presented in data listing and summarized by categories in a 
table. Major protocol violations will be determined by careful medical review of the data prior to 
database lock and conduct of statistical analyses. Physician and clinical research scientist will be 
responsible to produce the final protocol violation file (formatted as a Microsoft Excel file) in 
collaboration with the clinical operation and the data management group. This file will include a 
description of the protocol violation and clearly identified whether or not this violation is 
considered as major or not.
5.2.4.
Safety Population
The Safety population or “All Treated Patients” analysis set is defined as all randomized patients 
who receive at least one dose of the study treatment (either lenalidomide or InvC).
Drug exposure and all safety analyses (including AEs, labs and deaths) will be based on the 
Safety population. Patients will be analyzed according to the initial treatment actually received.
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6.
PATIENT DISPOSITION
All patients enrolled/randomized will be included in the analyses listed below. Patient 
disposition will be summarized for the following analysis populations by initial dosing regimen:
!
ITT Population
!
FAS Population
!
Safety Population.
A separate listing will be provided for patients not randomized.
The number of patients who will cross-over will be also displayed.
The primary reasons for ending study treatment will be collected on the CRF and will be 
summarized for all randomized patients using the following categories:
!
Adverse events
!
Disease progression
!
Withdrew consent
!
Lost to follow-up
!
Death
!
Protocol violation
!
Other.
The primary reasons for study discontinuation in all randomized patients will also be collected 
on the CRF and summarized using the categories outlined above.
The number of patients who will enter the follow-up phase with or without progression will be 
displayed.
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7.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics and baseline characteristics will be summarized for the ITT 
population. Baseline clinical characteristics are defined as the latest data collected on or before 
day 1 (or randomization day in case day 1 is missing). When there are retested values, the retest 
values will be used for the analysis. Individual patient listings will be provided to support the 
tables.
Baseline characteristics will be summarized for the FAS population if the ITT and FAS 
populations differ by ≥ 10% in size.
7.1.
Demographics
Age, baseline weight, height, and body surface area (BSA) will be summarized descriptively by 
treatment group. Age is calculated based on the date of birth at the date of informed consent.
Body surface area (BSA) will be calculated, using the formula:
BSA (m²) = ( [Height(cm) x Weight(kg) ]/ 3600 )½      Mosteller formula
Baseline body mass index (BMI) will be calculated, using the formula:
BMI (kg/m²) = baseline weight / (height²) with weight expressed in kg and height in m.
The BMI will be summarized, and the frequency counts of the different categories (< 20, 20 to 
< 25, 25 to < 30, and ≥30) will be displayed.
Age categories (< 65, ≥65) and race will be summarized with frequency counts.
Baseline ECOG and baseline ECG (normal/abnormal) will be summarized with frequency 
counts.
7.2.
Baseline Clinical Characteristics
Time from initial diagnosis to the first study treatment, and time from the latest disease 
progression to the first study treatment, will be calculated in months and summarized 
descriptively.
Histological diagnosis (investigator’s assessment and confirmed histology) will be summarized.
7.3.
Medical History
A summary of medical history will be presented by MedDRA system organ class (SOC).  A 
similar summary will be generated for the concomitant disease (currently active medical history 
events).
7.4.
Prior Therapy 
Frequency tabulations of the number of patients with at least one prior therapy and the different 
types of previous therapies (chemotherapies, immunotherapies, Stem cell transplant (SCT)
separating autologus from allogenic if possible, radiation, and so on) will be given.
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.4.4


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7.5.
Prior Medications
Prior medications are defined as medications that were started before the start of the study 
treatment (whether or not ended before the start of the study treatment). Prior medications that 
continue into study treatment period will be also reported as concurrent therapy.  Frequency 
tabulations of the number of patients with at least one prior medication and the different types of 
prior medications will be provided.
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8.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
8.1.
Treatment Duration
Duration of treatment is the total number of days on treatment (date of last dose – date of first 
dose + 1).  For patients ongoing in the treatment phase of the study on the cut-off date for the 
final analysis, the cut-off date will be used as the date of last dose.
The treatment duration (weeks) is defined as: 
[(The study treatment end date) – (the first study drug start date) + 1] / 7
Summary statistics will be provided for treatment duration by treatment group. 
An additional table will be created for all treated patients, displaying number of patients by cycle 
and the treatment arm.
Days Dosed is the total number of days study drug was taken, adjusted for any treatment 
interruptions.  Days dosed will be calculated by cycle and overall.
Cycles Dosed is the total number of treatment cycles during which a patient took study drug.
Average Number of Days dosed per cycle is calculated as days dosed (overall) divided by 
cycles dosed.
8.2.
Cumulative Dose
Overall Cumulative dose is the total dose received during the treatment period.
Cumulative dose will be calculated separately for lenalidomide or InvC.  The cumulative dose 
during the treatment is defined as the sum of all doses taken across the treatment period (in 
milligrams).
Cumulative dose at each cycle is calculated as the total dose received up to and including the 
current cycle.  
8.3.
Dose Intensity
Dose intensity during the treatment is defined as the cumulative dose divided by treatment 
duration. Dose intensity will be calculated separately for lenalidomide and for InvC single agents
separately.  
The dose intensity per cycle is calculated as the overall cumulative dose divided by the number 
of cycles dosed. 
8.4.
Relative Dose Intensity
Relative dose intensity is the dose intensity divided by the planned dose intensity:
!
For lenalidomide the planned dose intensity is 25 mg/per 28 days.
!
For InvC single agents:
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Relative 


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Table 3:
InvC drug recommended dose
Investigator’s choice
mg/m2
days
q days
max # cycles
Chlorambucil PO
40 (total monthly 
dose)
Split over 3-10 
days
28
until PD or 
toxicity
Rituximab IV
375
1, 8, 15, 22
56#
until PD or 
toxicity
Cytarabine IV
1 -2 g/m2 once or 
twice per day
1, 2
28
6
Gemcitabine IV
1000
1, 8, 15
28
6
Fludarabine IV
25
1-5
28
6
Fludarabine PO
40
1-5
28
6
IV = intravenous; PD = progressive disease; PO = oral; q = days, repeated; y = years.
# Rituximab (single agent) is to be repeated every 56 days after Day 56 (given only on day 1 of every 56 days cycle).
For the prevention of cytokine release syndrome associated with the treatment of Rituximab ≤125 mg of 
methylprednisolone or equivalent are accepted on C1D1.
Descriptive statistics (n, mean, SD, median, max, min) of treatment duration, cumulative dose, 
dose intensity and relative dose intensity will be presented by treatment arm.
8.5.
Dose Modification
Dose reduction overall is the number and percent of patients with at least one dose reduction 
during the treatment period.  Dose reduction by cycle is the number and percent of patients with 
only one (patients with one dose reduction) or more than one (number of patients with two or 
more dose reductions) during a given cycle.
In order for a patient to have two or more dose reductions, study drug must have been reduced 
for one or more days, followed by another period of one or more days during which study drug 
dosing was reduced.
Dose interruption overall is the number and percent of patients who interrupted treatment with 
study drug for one or more days at least once during the treatment period.  Dose interruption by 
cycle is the number and percent of patients with only one (patients with one dose interruption) or 
more than one (number of patients with two or more dose interruptions) during a given cycle.  In 
order for a patient to have two or more dose interruptions, study drug must have been stopped for
one or more days, followed by dosing for one or more days, followed by another period of one or 
more days during which study drug dosing was stopped. 
Time to first dose reduction/interruption for patients with at least one dose 
reduction/interruption, is the time in days elapsed from the date of first dose of treatment to the 
date that first dose reduction/interruption occurred.
Interval between dose reduction/interruptions is the time from the start of the first dose 
reduction/interruption to the start of the second dose reduction/interruption.
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Dose reduction/interruption will be summarized by Intitial dosing regimen group. Summaries 
include patients who have at least one dose reduction/interruption, time to first dose 
reduction/interruption. Additional descriptive statistics will include first and second dose 
reduction/interruption due to AE, duration of first and second dose reduction/interruption due to 
AE and interval between first and second dose reduction/interruption due to AE.
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9.
CONCOMITANT MEDICATIONS
Concomitant mediations are defined as non-study medications that are started after the start (start 
included) but before the end of the study treatment, or started before the start of the study 
treatment and ended or remain ongoing during the study treatment.
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations.  The Anatomical Therapeutical Chemical (ATC) coding scheme of the World Health 
Organization (WHO) will be used to group medications into relevant categories for these 
tabulations.
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10.
EFFICACY ANALYSIS
All efficacy evaluations will be conducted using the ITT population. Supportive analysis of the 
primary and key secondary efficacy endpoints using the FAS population will be conducted for 
the final analysis.  Statistical comparisons will be made between lenalidomide and InvC.
10.1.
General Statistical Methods
10.1.1.
Time to event endpoints
Kaplan-Meier (KM) survival analysis will be performed (unadjusted for the stratification 
variables). The resulting survival estimates will be presented graphically for selected endpoints. 
The median, 25th and 75th percentile time-to-event data will be presented with 95% CIs (if they 
exist) unadjusted by strata and within strata for the primary endpoint only.  
The numerical difference (and CI of the difference) in the median, 25th and 75th percentiles 
between lenalidomide and InvC will be presented for the unstratified analysis.
In addition, the event rates at specific time-points will be computed, along with the standard 
errors (Greenwood’s formula; Klein, 1997), based on which the event rates at specific timepoints 
can be compared if necessary. 
The groups will be compared using the stratified log-rank test in order to assess superiority.
The stratified Cox proportional hazard regression models will be used to estimate the hazard 
ratios (HR) and associated 95% CIs for the HRs. 
More detailed methods (for example exploring additional covariates such as age) will be 
investigated as a robustness check and may also be presented. 
Underlying model assumptions will be investigated for the analysis of the PFS endpoint using 
diagnostic statistics and graphical methods and, if necessary, an alternative analysis technique 
may be used.
Any changes in methodology will be documented in the clinical study report (CSR), including 
the rationale for use.  The proportional hazards assumption will be assessed by graphical display 
of the log-log survival distribution function versus the log event time for each treatment group.  
The censoring distributions of the treatment groups will be assessed for possible differences 
using KM methods.  
KM curves will be displayed graphically by treatment group.  Additionally, reasons for 
censoring will be summarized (n, percent) for the TTP, PFS, and OS endpoints.
Individual survival time information and mortality data will be provided in patient data listings. 
In order to evaluate the effect of cross-over on overall survival a Mantel-Byar approach will be 
used. The estimation of the control arm without cross-over and the mixed arm (lenalidomide arm 
and cross-over patients) will be estimated. A weighted log rank test or Wilcoxon test will be used 
to take into account the effect of cross-over.
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Multivariate models will be used to identify those baseline and prognostic factors (eg absolute 
leukocyte count, time from diagnosis, number of prior therapies and any other variables 
suggested in the literature prior to the analysis) most predictive of response (Colett, 1991).
10.1.2.
Categorical endpoints
Categorical analyses will be based on the Fisher exact test.  Sensitivity analyses will be 
performed using the Cochran-Mantel-Haenszel test with the stratification factors as strata.  The 
p-values will be presented.  The null hypothesis is that incidence is equal for both treatment 
arms, the alternative hypothesis being that incidence is not equal.
The probability of response rates will be estimated using the proportion of patients with 
responses with exact two-sided 95% confidence intervals.
The response rate in the cross-over portion of patients in Arm B will be analyzed in a descriptive 
manner.
10.1.3.
Quality of Life endpoints
The EORTC QLQ-C30 will be analyzed using change from baseline and percentage of change 
from baseline according to the functional scores and the recommendations in the EORTC scoring 
manual. Statistical tests could be performed in an exploratory manner.
The EORTC Reference Data Manual will also be used to descriptively check comparability 
between patients in our trial and with other comparable populations.
Mann-Whitney tests for simple comparison and longitudinal data modeling techniques (ie Proc 
mixed in SAS) will be used to analyze QoL scores.
Patients who drop out of the study without being evaluated for QoL will be counted as 
non-responders. Responses from patients after they receive other anti-cancer treatments will be 
treated as non responders.
An update of the time to events endpoints and overall survival will be done at the end of the 
follow up. No adjustment for multiplicity will be applied.
10.2.
Expert Review of Disease Response
The independent review committee (IRC) is composed of two external independent radiologists 
(with an additional radiologist adjudicator in the event of a tie) and a hematologist/oncologist.  
The IRC will perform a blinded, independent assessment of radiological response (including 
assessment of Stable Disease [SD] and Progressive Disease [PD]), as well as reviewing the 
tumor response data and the dates of disease progression for each patient.
For further details please refer to Central Radiology Manual.
No central review will be performed for the patients who crossed over after progression.
10.3.
Analysis of Primary Efficacy Endpoint
PFS is defined as the time from randomization to the first observation of disease progression or
death due to any cause. If the patient has not progressed or died, PFS will be censored at the time 
of last completed assessment when the patient was known not to have progressed. Patients who 
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will receive a new treatment without documented progression will be censored at the last 
assessment date that the patient is known to be progression-free. These rules are based on FDA 
guidance for cancer trial endpoints (FDA guidance, 2007).
Table 4:
Censoring Rules for Time to event (Progression and/or Death) Endpoints
Situation
Date of Progression or Censoring
Situation 
Outcome
No baseline assessments
Randomization
Censored
Progression documented
First adequate assessment determined by 
central review
Progressed
No progression
Date of last adequate assessment with 
evidence of no progression
Censored
Study discontinuation for reasons other 
than disease progression or death
Date of last adequate assessment with 
evidence of no progression
Censored
New anti-lymphoma / non-protocol 
treatment started prior to progression
Date of last adequate assessment with 
evidence of no progression prior to the start of 
new anti-lymphoma treatment
Censored
Death before first PD assessment while on 
study
Date of death
Progressed
Death between adequate assessment visits
Date of death
Progressed
Progression after an extended lost-to-
follow-up time (two or more missed 
assessments)
Date of last adequate assessment with 
evidence of no progression
Censored
PD = progressive disease.
See details in Appendix 15.3.
As additional robustness checks of the primary endpoint and censoring definition, the time to 
event analysis will be repeated for the ITT population using the following modified definitions of 
PFS:
!
Using the investigator assessment instead the IRC central review 
!
Considering progression or death under a new anti-lymphoma treatment as an event 
(Table 4)
!
Considering Death or progression after an extended lost-to-follow-up time (two or 
more missed assessments) as an event (Table 5)
!
One using the earliest progression date either in investigator set or IRC set.
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Table 5:
Method b: Censoring Rules for Time to event (Progression and/or Death) 
Endpoints sensitivity analysis
Situation
Date of Progression or Censoring
Situation 
Outcome
No baseline assessments
Randomization
Censored
Progression documented
First adequate assessment determined by 
central review
Progressed
No progression
Date of last adequate assessment with 
evidence of no progression
Censored
Study discontinuation for reasons other 
than disease progression or death
Date of last adequate assessment with 
evidence of no progression
Censored
New anti-lymphoma / non-protocol 
treatment started prior to progression
First adequate assessment determined by 
central review
Progressed
Death before first PD assessment while on 
study
Date of death
Progressed
Death between adequate assessment visits 
Date of death
Progressed
Progression after an extended lost-to-
follow-up time (two or more missed 
assessments) 
Date of last adequate assessment with 
evidence of progression
Progressed
PD = progressive disease.
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Table 6:
Method c: Censoring Rules for Time to event (Progression and/or Death) 
Endpoints sensitivity analysis
Situation 
Date of Progression or Censoring 
Outcome 
No baseline assessment 
Randomization 
Censored 
Progression documented between scheduled visits 
As defined for the main analysis 
Progressed 
No progression 
Date of last visit with adequate 
assessment 
Censored 
Investigator claim of clinical progression 
Scheduled visit (or next scheduled 
visit if between visits) 
Progressed 
Treatment discontinuation for toxicity or other 
reason 
Date of last visit with adequate 
assessment 
Censored 
New anticancer treatment started with no claim of 
progression 
Date of last visit with adequate 
assessment 
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessment visits or after 
patient misses one assessment visit 
Date of death 
Progressed 
Progression after an extended lost-to-follow-up time 
(two or more missed assessments) 
Last visit with adequate assessment 
Censored 
PD = progressive disease.
10.4.
Analyses of Secondary Efficacy Endpoints
The secondary endpoints will be analyzed in an exploratory manner (see details in 
Appendix 15.3).
10.4.1.
Overall response rate
The Overall response rate will include best response of CR, CRu, or PR. The modified IWRC 
will be used and response assessed by CT scan/MRI every 56 days (± 7 days) for the first 
6 months and then every 90 days ± 15 days thereafter.
Patients who discontinue before any post-randomization efficacy assessments will be considered 
to be non-responders.
10.4.2.
Duration of Response
Duration of response will be measured from the time of initial response (at least PR) until 
documented tumor progression or death. Patients who do not progress at the time of analysis will 
be censored at the last assessment date that the patient is known to be progression-free. Patients 
who will receive a new treatment without documented progression will be censored at the last 
assessment date that the patient is known to be progression-free. 
This analysis will be restricted to the subgroup of responding patients.
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10.4.3.
Tumor control rate
Rates for CR, CRu, PR, and SD.
CR/CRu/PR/SD will be determined using the modified IWRC (Cheson, 1999).
10.4.4.
Duration of Stable Disease
SD is defined as less than PR but is not progressive disease or relapsed disease.
Duration of SD will be calculated as the time from the first evidence of SD to documented 
disease progression or documented response or death. Patients who do not progress or respond at 
the time of analysis will be censored at the last assessment date that the patient is known to be 
progression-free. Patients who will receive a new treatment without documented progression will 
be censored at the last assessment date that the patient is known to be progression-free. 
This analysis will be restricted to the subgroup of SD patients.
10.4.5.
Time to progression (TTP)
TTP will be defined as the time from randomization until objective tumor progression. TTP will 
not include deaths. Patients without progression at the time of analysis will be censored at the 
last assessment date that the patient is known to be progression-free. Patients who will receive a 
new treatment without documented progression will be censored at the last assessment date that 
the patient is known to be progression-free. Deaths due to progression of disease will be
considered as an event.
10.4.6.
Time to treatment failure (TTF)
TTF is defined as the time from the first dose of study drug to discontinuation of treatment for 
any reason, including disease progression, treatment toxicity or death. Patients who will be on 
drug or complete the treatment according to the protocol will be censored at the last date of drug 
intake.
10.4.7.
Time to tumor response (TTR)
This analysis will be restricted to the subgroup of responding patients.  Time to tumor response 
(TTR) will be defined as the time from randomization until initial response (CR, CRu, PR) if it 
has been confirmed.
10.4.8.
Overall Survival (OS)
OS will be defined as the time from randomization until death from any cause. Patients alive or 
lost to follow up at the time of analysis will be censored at the last date the patient was known to 
be alive.
10.5.
Subgroup Analysis
Subgroup analyses will be conducted in an exploratory manner in the following subgroups:
!
Time since diagnosis (< 3 years or ≥ 3 years)
!
Time since last treatment (<6 months [refractory] or ≥ 6 months)
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10.5.
10.5
ubgro
ubgro


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!
Prior stem cell transplant (yes or no)
!
Age and gender 
!
MCL International Prognostic Index (MIPI) score at initial time of diagnosis 
!
Number of prior treatment lines (with description of treatment regimens, including 
first line treatment and stem cell transplant)  (1,> 1)
!
Ki-67 index (as defined by Determann, 2008) labeling in the original pathology 
specimen at diagnosis, if available at time or at time of relapse
!
Absolute lymphocyte count at baseline (< 800/mm3 or ≥ 800/mm3)
!
Time since last rituximab to cycle 1 day 1 (< 230 days or ≥ 230 days)
!
Prior regimens received.
In addition any other possible prognostic factors may be used as exploratory analyses.
The methods described in previous sections will be used for each subgroup separately.
&(/*(1(35235,(7$5<,1)250$7,21
analyses.
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p sepa


Lenalidomide/CC-5013
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11.
SAFETY ANALYSIS
The purpose of this section is to define the safety parameters for the study. All summaries of 
safety data will be conducted using the Safety population. 
11.1.
Adverse Events
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version 12.0. The intensity of AEs will be graded according to the
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version 3.0 (same as protocol).
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on 
or after the first treatment of the study medication and within 30 days after the last dose. TEAEs,
TEAEs leading to study medication discontinuation, TEAEs leading to dose 
reduction/interruption, TEAEs related to study medication and treatment-emergent serious 
adverse events (SAEs) will be summarized by system organ class and preferred term for each 
treatment group. A summary of TEAEs with NCI CTCAE grade 3 or higher and most frequent 
preferred terms will also be provided.
If a patient experiences the same preferred term multiple times then the patient will be counted 
only once and by greatest severity.
Listings for the corresponding summary tables will be presented separately.
For the cross-over patients, any adverse events starting after the start of the drug will be assigned 
to lenalidomide even if the event has started within 30 days after the InvC end date. Additional 
summary tables will be provided for these TEAEs (cross-over lenalidomide).
Analysis of TEAEs of special interest, time to TEAEs of special interest will be presented. 
TEAEs of special interest will be defined using standardized MedDRA Queries (SMQs). The 
SMQ will be selected based on the Risk Management Plan (RMP) and the internal expertise on 
the drug and the disease.
11.2.
Clinical Laboratory Evaluations
Clinical laboratory values will be graded according to NCI CTCAE version 3.0 for applicable 
tests (see appendix 15.5 for details on standardization of the laboratory values). Frequency 
distributions for shift from baseline in severity grade to most extreme post-baseline value will be 
displayed in cross-tabulations for the whole study period for each treatment. Normal ranges will 
be used to determine the categories if High, Low, and Normal for lab tests that have no severity 
grade.  Listings of clinical laboratory data with abnormal flags will be provided by patients and 
tests. 
11.3.
Vital Sign Measurements
For vital signs, shift from baseline to worst during the treatment in below, within and above the 
normal ranges will be displayed in cross-tabulations for each treatment. Summary statistics (N, 
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11.3.
11.3.


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Mean, SDev, Median, Minimum, and Maximum) of observed and change from baseline values 
will be presented.
11.4.
Physical Examination
Shift tables regarding the evolution of the spleen, liver, lymphadenopathy will be displayed by 
treatment groups.
Presence or absence of lymphoma symptoms will be summarized by visit and treatment groups.
11.5.
Electrocardiogram
The overall ECG interpretation will be summarized by presenting the number and percentage of 
patients with ‘Normal’, ‘Abnormal, not clinically significant’, and ‘Abnormal, clinically 
significant’ by treatment. Shift from baseline to worst during the treatment in the overall ECG 
interpretation will be displayed in cross-tabulations for each treatment.
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e overall EC


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12.
QUALITY OF LIFE ANALYSIS
12.1.
EORTC QLQ-C30
QoL instrument: EORTC QLQ-C30 (see attachment 21.9)
The version 3.0 of the EORTC QLQ-C30 is a 30-item scale. The EORTC QLQ-C30 is composed 
of both multi-item scales and single-item measures. These include five functional scales, three 
symptom scales, a global health status / QoL scale, and six single items (Table 7).
Table 7:
EORTC QLQ-C30 scores
Functional Scales
(15 Questions)
Symptom Scales
(7 Questions)
Single Items
(6 Questions)
Global Quality Of 
Life
(2 Questions)
Physical
(items 1 to 5)
Fatigue 
(items 10, 12, 18)
Constipation
(item 16)
Global QoL
(items 29, 30)
Role
(items 6, 7)
Pain
(items 9, 19)
Diarrhea
(item 17)
Cognitive
(items 20,25)
Nausea / Vomiting
(items 14, 15)
Sleep
(item 11)
Emotional
(items 21 to 24)
Dyspnea
(item 8)
Social
(items 26, 27)
Appetite
(item 13)
Financial
(item 28)
All of the scales and single-item measures range in score from 0 to 100. A higher scale score 
represents a higher level of well being and better ability of daily functioning. A 10-point change 
in the scoring is considered to be meaningful change in QoL (Osoba, 1998).
Thus a high score for a functional scale represents a high/healthy level of functioning; a high 
score for the global health status/QoL represents a high QoL, but a high score for a symptom 
scale/item represents a high level of symptomatic problems.
Data collection and timing
Questionnaires must be filled out by the patient at 6 pre-specified time points (see below) when 
the patient comes for a scheduled visit. They will be handed out by a nurse or the treating 
physician/investigator, and ideally are collected again soon after the patient has filled it out.
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Patients will be asked to complete the questionnaire as completely and accurate as possible. The 
average time to complete the questionnaire is around 10to 15 minutes. The reasons for not 
completing the questionnaire will be recorded.
QoL will be assessed at 6 time points:
!
at screening/baseline (within 7 days prior to randomization)
!
after cycle 2 (C3D1)
!
after cycle 4 (C5D1)
!
after cycle 6 (C7D1)
!
after cycle 8 (C9D1)
!
and at time of discontinuation from treatment.
A ± 7 days time window will be allowed.
Compliance & Missing data
During the study compliance will be investigated at each time point. The compliance rate will be 
descriptively compared between the two arms. 
In the case that a patient still on study has not filled in the questionnaire, no more than ± 7 days 
delay is accepted.
The rate of compliance will be assessed after 40, 80, and 120 patients enrolled.
Missing data will be reported as recommended in the EORTC scoring manual (Fayers, 2002).
Scales scores: if at least 50% of the items have been answered, the scale scores will be 
calculated according to the standard equations given on the manual (any items with missing 
values will be ignored). In other cases, scores will be set to missing.
Single-item measures: the score will be set to missing.
Statistical considerations
No calculation in terms of sample size will be performed based on changes in QoL.
In the absence of more specific hypothesis, the global score will be used as the primary QoL 
outcome and physical functional score and fatigue item will be used as secondary outcomes.
Expectations are that the global score and the physical functional score are improved by 
lenalidomide. The fatigue item may be worse initially under lenalidomide, but improve in mid 
and long term in responding patients due to tumor control compared to control arm with shorter 
response duration
A difference of 10 points between the two arms is considered as clinically significant.
Derivation
For all scales, the Raw Score, RS, is the mean of the component items:
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and 120 pat
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the EORT
ve been ans
ve been an
ons given o
ns given 
scores will 
cores wil
ill be set to
l be set t
sample size
ample siz
specific hy
specific h
al funct
functioiona
n
e that the gl
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The fat
The fatigu
igu
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rm i
m n resp
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difference o
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Derivat
Derivatioio
r al


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For functional scales:
For symptom scales / items and Global health status / QoL:
Range is defined as the difference between the maximum possible value of RS and the minimum 
possible value, eg, most items are quoted from 1 to 4, the range is equal to 3.
12.2.
Analysis of Quality of Life Scales
The EORTC QLQ-C30 will be analyzed using change from baseline and percentage of change 
from baseline according to the functional scores and the recommendations in the EORTC scoring 
manual. Statistical tests could be performed in an exploratory manner.
The EORTC Reference Data Manual will also be used to descriptively check comparability 
between patients in our trial and with other comparable populations.
Mann-Whitney tests for simple comparison and longitudinal data modeling techniques (ie Proc 
mixed in SAS) will be conducted to analyze QOL scores.
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mum
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13.
INTERIM ANALYSIS
13.1.
General Information
An independent external Data Monitoring Committee (DMC) will review on an ongoing basis 
safety data throughout the study and efficacy for futility at a pre-defined time point. Specifics are 
outlined in the DMC charter. Summaries of safety information will be prepared for Data 
Monitoring Committee (DMC) review. The first safety analysis will occur after the first 
40 patients have received at least 2 cycles of treatment or have discontinued prior to completing 
2 cycles.  The second safety analysis, as well as an efficacy analysis for futility, will occur after 
80 patients complete 2 cycles or withdraw before completing 2 cycles. A third safety analysis 
will occur after 120 patients complete 2 cycles or withdraw before completing 2 cycles.
The futility analysis will be conducted when approximately 80 patients complete 2 cycles or 
withdraw before completing 2 cycles (around 54 patients in the lenalidomide arm) on 
investigator and central assessment.
The DMC will conduct an analysis for futility on PFS and ORR. No specific stopping rules will 
be given to the DMC for the PFS; the following rules might be used for ORR.
Based on a 95%CI approach, if the upper bound is below than 20% in the lenalidomide arm, the 
DMC should recommend stopping the trial. 
Table 8:
Response percentage and 95% exact confidence interval 
Frequency 
of Response
Binomial 
Proportion 
P
Exact Lower
Cl, Binomial
Proportiona
Exact Upper
Cl, Binomial
Proportiona
1
1.8519
0.04687
9.8915
2
3.7037
0.45173
12.7472
3
5.5556
1.16068
15.3885
4
7.4074
2.05510
17.8933
5
9.2593
3.07528
20.3002
6
11.1111
4.18838
22.6313
7
12.9630
5.37430
24.9012
8
14.8148
6.61976
27.1198
9
16.6667
7.91544
29.2941
10
18.5185
9.25455
31.4297
CI = confidence interval.
a Exact confidence intervals based on the Clopper-Pearson method.
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xact confid
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Cl, Bino
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Prop
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23
0
23
23
23
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56
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13.2.
Statistical Approaches for Control of Alpha
No formal adjustment is needed. Interim analysis is run only for futility.
&(/*(1(35235,(7$5<,1)250$7,21


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14.
REFERENCES
Cheson 1999 – please add complete reference
Collett, D. Modelling Binary Data. 1991; London: Chapman & Hall. 
Collett, D. Modelling Survival Data in Medical Research Second Edition. 2003; London: 
Chapman & Hall.
Determann O et al.; European Mantle Cell Lymphoma Network and the German Low Grade 
Lymphoma Study Group.Ki-67 predicts outcome in advanced-stage mantle cell lymphoma 
patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the 
European MCL Network and the German Low Grade Lymphoma Study Group. Blood. 2008 Feb 
15; 111(4):2385-7.
Fayers PM, Weeden S, Curran D on behalf of the EORTC Quality of Life Study Group.  EORTC 
QLQ-C30 Reference Values.  In:  EORTC, 1998.  ISBN:  2-930064-11-0.
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. 
FDA , May2007 
Hess G, et al., Phase III Study to Evaluate Temsirolimus Compared With Investigator’s Choice 
Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma. J Clin Oncol 
27:3822-3829.
Klein J.P, Moeschberger ML. Survival Analysis: Techniques for Censored and Truncated Data, 
1997; New York: Springer-Verlag.
Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 
22;317(17):1098 (letter) 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J.  Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16(1):139-44.
Stead ML, Brown JM, Velikova G, Kaasa S, Wisloff F, Child JA, et al.  Development of an 
EORTC questionnaire module to be used in health-related quality-of-life assessment for patients 
with multiple lymphoma.  European Organization for Research and Treatment of Cancer Study 
Group on Quality of Life.  Br J Haematol 1999 Mar;104(3):605-11.
Witzig TE, Reeder CB, Polikoff J, et al. Initial Results from an International Study in 
Relapsed/Refractory Aggressive Non-Hodgkin s Lymphoma to Confirm the Activity, Safety and 
Criteria for Predicting Response to Lenalidomide Monotherapy. Blood (ASH Annual Meeting 
Abstracts), Nov 2007; 110: 2572.
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a a 
of f the
od. 2008 F
od. 2008 
udy
udy Group.
Group
y
ancer Drugs
ancer Drug
pared Wi
pared W th
i h
e Cell Lym
 Cell Lym
chniques fo
hniques
y Surface A
Surface A
y
B, Pater J. 
, Pater J. 
J Clin Onc
J Clin On
a G, Kaasa 
a G, Kaasa 
le to be use
le to be use
 European 
 Europe
ife.  Br J H
fe.  Br J H
r CB, Polik
CB, Polik
ctory
ctory Aggr
Aggr
y
Predicting R
Predicting R
), Nov 2007
Nov 200


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15.
APPENDICES
15.1.
Date Imputation Guideline
15.1.1.
Impute Missing AE/ Prior or Concomitant Medications Start Dates
Missing day and month
!
If the year is same as the year of first day on study medication, then the day and month of the start date of study medication 
will be assigned to the missing fields
!
If the year is prior to the year of first day on study medication, then December 31 will be assigned to the missing fields.
!
If the year is after the year of first day on study medication, then January 1 will be assigned to the missing fields.
Missing day only 
!
If the month and year are same as the year and month of first day on study medication, then the start date of study medication 
will be assigned to the missing day.
!
If the month and year are before the year and month of first day on study medication, then the last day of the month will be 
assigned to the missing day.
!
If the month and year are after the year and month of first day on study medication, then the first day of the month will be 
assigned to the missing day.
!
If the stop date is non-missing and the imputed start date is after the stop date, the start date will be imputed by the stop date. 
Missing day, month, and year
Included as TEAE
Incomplete Stop Date: If the imputed stop date is before the start date then the imputed stop date will be equal to the start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dose date of study medication, then the day and month 
of the last dose date will be assigned to the missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dose date of double-blind study medication, then 
December 31 will be assigned to the missing fields. 
!
If the year of the incomplete stop date is after the year of the last dose date of study medication, then January 1 will be 
assigned to the missing fields.
Missing day only 
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date is the
signed to th
signed to th
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!
If the month and year of the incomplete stop date are the same as the month and year of the last dose date of study medication, 
then the day of the last dose date will be assigned to the missing day. 
!
If the month and year of the incomplete stop date are before the month and year of the last dose date of the study medication, 
then the last day of the month will be assigned to the missing day. 
!
If the month and year of the incomplete stop date are after the month and year of the last dose date of study medication, then 
the first day of the month will be assigned to the missing day.
15.2.
Cycle derivation Guideline
Subjects on Rituximab treatment have cycles of 56 days in duration past cycle 1. Cycle 2 day 1 will in fact correspond to day 56.
Programming need to be adapted accordingly.
eCRF 
pages 
completi
on
C1D1
C2D1
C3D1
C4D1
C5D1
C6D1
C7D1
days on 
study
1
28
56
84
112
140
168
Tumor 
assessme
nt
X
X
X
Rituxim
ab cycles
C1D1
C2D1
C3D1
C4D1
A cycle is defined as follows:
A new cycle is defined when the delay between the previous drug start date and the current start date is lower or equal to -26.
del <=-26 and del=lag1(SDRSTDT)-SDRSTDT;
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
42
If the data do not fulfill the previous condition, a cumulative duration (dur = Σ SDRENDT –SDRSTDT + 1) is calculated (including 
the previous record) to take into account the fact that several drug modifications could have appeared during one cycle.  If the 
cumulative duration does not exceed 28 days, there is no new cycle.
data drugcyl;
set drug_n;
by pt EXSTDT;
retain prevcum cumdur 0;
** Difference between the previous and current record;
del=lag1(EXSTDT)-EXSTDT;
** Duration for one record;
dur=EXENDT -EXSTDT+1;
** Interval between the previous end date and the start of the current cycle;
inter=lag1(EXENDT) -EXSTDT;
** Duration of the previous record ;
prevdur=lag1(dur);
**Initialization of the variable for the first drug record for any new patients;
if first.pt then do;del=.;prevdur=.;prevcum=0;inter=.;cumdur=dur;end;
** Condition for a new cycle;
if del <=-26 then  cycle=1;
if dur>=21 then  cycle=1;
if prevdur>=21 then cycle=1;
if cycle=1
then if .<del<=-21 then  do;cumdur=dur;prevcum=0;end;
else  do;cumdur=dur;prevcum=0;end;
** If condition not fulfilled, calculation of the cumulative duration including the previous duration;
skip:if cycle ne 1 then do;
cumdur=cumdur+dur;
prevcum=prevcum+del;
end;
if cumdur>=28 or prevcum<=-28  then do;cycle=1;
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
43
cumdur=0;prevcum=0;
goto skip;
end;
run;
&(/*(1(35235,(7$5<,1)250$7,21
pri
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
44
15.3.
Endpoints derivation
Efficacy evaluation window:
All efficacy assessments will be taken into account if they are occurred after the randomization date 
to the end the study, for patients who do not stop study medication and not start other non study anti-cancer therapy;
Best response
Best response is defined as best efficacy benefit response during the “window” for efficacy evaluation.
PFS:
PFS = PFS Ending Date – PFS Starting Date + 1
Starting date: the randomization date
Ending date: the earliest date among the following 4 events during the “window” for efficacy evaluation:
a. Death;
b. The earlier assessment date for the cycle with overall response is PD or Relapse; 
c. Study discontinue due to Disease progression specified; 
d. Treatment discontinue due to Disease progression specified;
For patients who have more than 1 consecutive missing regular assessments right before the earliest of the four events date and this 
non-assessed period last more than 118 days (this length is study-dependent),  then, the date of last adequate assessment indicating no 
progression before the date will be used, and the PFS will be censored.
If patients who do not have any of the 4 events listed above, then ending date is defined as the latest CT/MRI date for target or non-
target lesion that indicating no progression, if patients do not have such response, they will be censored at the day after the 
randomization date.
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
45
Duration of response (DoR)
DoR = Ending Date – Starting Date + 1
Starting date: The date of the first occurrence of CR, CRu or PR during the Window for efficacy evaluation
Ending date: the earliest date among the following 4 events during the “window” for efficacy evaluation:
a. Death;
b. The earlier assessment date for the cycle with overall response is PD or Relapse; 
c. Study discontinue due to Disease progression specified; 
d. Treatment discontinue due to Disease progression specified;
For patients who have more than 1 consecutive missing regular assessments right before the earliest of the four events date and this 
non-assessed period last more than 118 days,  then, the last adequate at least PR or better response assessment date before the date will 
be used, and the DoR will be censored.
If patients who do not have any of the 4 events listed above, then ending date is defined as the latest CT/MRI date for target or non-
target lesion with at least PR or better response after the DoR start date, if patients do not have such response, they will be censored at 
the day after the 1st response date
15.4.
Laboratory Values
The following calculations need to be performed for all patients in treatment arms A and B.  The lab values will be standardized using 
the normal range values collected in the eCRF.
Step 1:  Assign an upper (ULN) and lower (LLN) normal range value to each analyte at each visit collected by merging the ranges 
collected in the datasets labrng. Use the labseq variable to assign the appropriate normal ranges to a value.
If the ranges could not be assigned then use the default SI ranges after the conversion of the value..
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
46
Convert any raw lab values to the unit that corresponds to the normal range values as necessary.  These converted (if necessary) or 
raw (if conversion not needed) lab values and their associated ULN and LLN values will be referred to as the “base” values in the 
calculations given in Step 2. 
Step 2:  Convert all base values (lab, ULN, and LLN values) to the standardized units given in Table 1 below.  The standardized units 
are the units associated with the normal ranges to be used for mapping the lab value to a standardized value.  Calculations in Step 3 are 
based on these converted lab and normal range values (referred to as converted values). 
Hematology
Test
Normal 
Range Unit
Conversion 
Factor
SI Unit
Females
Male
Low
High
Low
High
Red Blood Cell 
Count (RBC)
10^6/uL
X 1 
1012/L
3.9
5.2
4.4
5.8
10^3/uL
÷ 1000
1012/L
3.9
5.2
4.4
5.8
10^9/L
X 1000
1012/L
3.9
5.2
4.4
5.8
10^12/L
X 1
1012/L
3.9
5.2
4.4
5.8
k/uL
÷ 1000
1012/L
3.9
5.2
4.4
5.8
10^6/mm^3
x 1
1012/L
3.9
5.2
4.4
5.8
10^6/cumm
X 1
1012/L
3.9
5.2
4.4
5.8
M/mL
÷ 1000
1012/L
3.9
5.2
4.4
5.8
Hemoglobin
g/dL
x 0.62058
mmol/liter
7.4
9.9
8.1
11.2
g/L
x 0.062058
mmol/liter
7.4
9.9
8.1
11.2
mmol/L
X 1
mmol/liter
7.4
9.9
8.1
11.2
Hematocrit
18-44 years
% 
X 0.01
fraction of red blood cells
0.35
0.45
0.39
0.49
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Fema
2
Low
Low
1)
,1
,1
,1
,1
,1
/L
/L
<
10
1012
12/L
/L
$5
10
1012/
7$
(7
5
35
1
23
÷ 1000
÷ 1000
52
x 0.6
x 0
35
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1(
/L
/L
1
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%
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
47
Proportion of 1.0
X 1
fraction of red blood cells
0.35
0.45
0.39
0.49
45-64 years
%
X 0.01
fraction of red blood cells
0.35
0.47
0.39
0.5
Proportion of 1.0
X 1
fraction of red blood cells
0.35
0.45
0.39
0.49
65-74 years
%
X 0.01
fraction of red blood cells
0.35
0.47
0.37
0.51
Proportion of 1.0
X 1
fraction of red blood cells
0.35
0.45
0.39
0.49
Platelets
10^3/uL
X 1
109/L
130
400
130
400
10^9/L
X 1
109/L
130
400
130
400
k/uL
X 1
109/L
130
400
130
400
cells/mcL
÷ 1000
109/L
130
400
130
400
10^3/mm^3
X 1
109/L
130
400
130
400
thous/mm^3
X 1
109/L
130
400
130
400
1000cumm
X 1
109/L
130
400
130
400
k/mL
÷ 1000
109/L
130
400
130
400
White Blood Cells
10^3/uL
X 1
109/L
4.5
11.0
4.5
11.0
10^9/L
X 1
109/L
4.5
11.0
4.5
11.0
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0.39
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7,2
0.47
47
$7
$7
$7
$7
$7
0.4
0.4
50
25
2
0.35
0.35
)2
,1
d cells
ce
,1
,1
,1
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/L
/L
5<
9/L
/L
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1
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^3/uL
^3/uL
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10^9/
10^9/
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
48
k/uL
X 1
109/L
4.5
11.0
4.5
11.0
cells/mcL
÷ 1000
109/L
4.5
11.0
4.5
11.0
10^3/mm^3
X 1
109/L
4.5
11.0
4.5
11.0
thous/mm^3
X 1
109/L
4.5
11.0
4.5
11.0
1000cumm
X 1
109/L
4.5
11.0
4.5
11.0
k/mL
÷ 1000
109/L
4.5
11.0
4.5
11.0
Absolute basophils
10^3/uL
X 1
109/L
0.0
0.03
0.0
0.03
10^9/L
X 1
109/L
0.0
0.03
0.0
0.03
k/uL
X 1
109/L
0.0
0.03
0.0
0.03
cells/mcL
÷ 1000
109/L
0.0
0.03
0.0
0.03
10^3/mm^3
X 1
109/L
0.0
0.03
0.0
0.03
thous/mm^3
X 1
109/L
0.0
0.03
0.0
0.03
1000cumm
X 1
109/L
0.0
0.03
0.0
0.03
k/mL
÷ 1000
109/L
0.0
0.03
0.0
0.03
Absolute 
eosinophils
10^3/uL
X 1
109/L
0.0
0.8
0.0
0.8
10^9/L
X 1
109/L
0.0
0.8
0.0
0.8
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4.5
4.5
21
4.5
4.
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11.0
11.0
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5
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5
1
50
25
4.5
4.5
)2
1 2
1
,1
/L
/L
<
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/L
$5
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1
23
X 1
X 1
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0^3/uL
^3/uL
*(
10^9/L
10^9/
/*
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
49
k/uL
X 1
109/L
0.0
0.8
0.0
0.8
cells/mcL
÷ 1000
109/L
0.0
0.8
0.0
0.8
10^3/mm^3
X 1
109/L
0.0
0.8
0.0
0.8
thous/mm^3
X 1
109/L
0.0
0.8
0.0
0.8
1000cumm
X 1
109/L
0.0
0.8
0.0
0.8
k/mL
÷ 1000
109/L
0.0
0.8
0.0
0.8
Absolute 
lymphocytes
10^3/uL
X 1
109/L
0.16
0.46
0.16
0.46
10^9/L
X 1
109/L
0.16
0.46
0.16
0.46
k/uL
X 1
109/L
0.16
0.46
0.16
0.46
cells/mcL
÷ 1000
109/L
0.16
0.46
0.16
0.46
10^3/mm^3
X 1
109/L
0.16
0.46
0.16
0.46
thous/mm^3
X 1
109/L
0.16
0.46
0.16
0.46
1000cumm
X 1
109/L
0.16
0.46
0.16
0.46
k/mL
÷ 1000
109/L
0.16
0.46
0.16
0.46
Absolute 
monocytes
10^3/uL
X 1
109/L
0.04
0.11
0.04
0.11
10^9/L
X 1
109/L
0.04
0.11
0.04
0.11
k/uL
X 1
109/L
0.04
0.11
0.04
0.11
cells/mcL
÷ 1000
109/L
0.04
0.11
0.04
0.11
10^3/mm^3
X 1
109/L
0.04
0.11
0.04
0.11
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0.0
0.0
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0.0
0.0
7,2
$7
0.8
$7
$7
$7
$7
0.8
0.8
50
25
0.0
0.0
25
25
25
25
0.0
0.0
)2
1
,1
,1
,1
,1
L
<
109/L
/L
$5
10
109/
7$
,(
35
35
35
35
35
X 1
X 1
23
÷ 1000
÷ 100
52
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1(
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uL
uL
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10^3/m
10^3/m
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
50
thous/mm^3
X 1
109/L
0.04
0.11
0.04
0.11
1000cumm
X 1
109/L
0.04
0.11
0.04
0.11
k/mL
÷ 1000
109/L
0.04
0.11
0.04
0.11
Absolute 
neutrophils
10^3/uL
X 1
109/L
0.45
0.75
0.45
0.75
10^9/L
X 1
109/L
0.45
0.75
0.45
0.75
k/uL
X 1
109/L
0.45
0.75
0.45
0.75
cells/mcL
÷ 1000
109/L
0.45
0.75
0.45
0.75
10^3/mm^3
X 1
109/L
0.45
0.75
0.45
0.75
thous/mm^3
X 1
109/L
0.45
0.75
0.45
0.75
1000cumm
X 1
109/L
0.45
0.75
0.45
0.75
k/mL
÷ 1000
109/L
0.45
0.75
0.45
0.75
MCV
μm^3
X 1.00
fl
78
102
78
100
fl
X 1.00
fl
78
102
78
100
Chemistry
Test
Normal 
Range Unit
Conversion 
Factor
SI Unit
Females
Male
Low
High
Low
High
Sodium
mmol/L
X 1.00
mmol/liter
135
145
135
145
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0.04
0.04
21
0.04
0.04
7,2
$7
11
0
11
0
$7
$7
$7
$7
0.75
0.75
0$
5
$
45
0
5
25
25
25
25
0.45
0.4
)2
1 2
0
1
,1
L
<
109/L
/L
$5
10
109
7$
5,(
35
35
35
35
35
X 1.00
X 1.00
2
35
al
al
ge Unit
ge Unit
(1
(1
(1
(1
mmol/
mmol/
(/
&


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
51
mEq/L
X 1.0
mmol/liter
135
145
135
145
Potassium
mmol/L
X 1.00
mmol/liter
3.5
5.1
3.5
5.1
mEq/L
X 1.0
mmol/liter
3.5
5.1
3.5
5.1
Chloride
mmol/L
X 1.00
mmol/L
95
108
95
108
mEq/L
X 1.0
mmol/L
95
108
95
108
Creatinine
mg/dL
X 88.4
umol/liter
53
97
62
105
umol/L
X 1
umol/liter
53
97
62
105
Glucose
mg/dL
x 0.05551
mmol/liter
3.9
6.1
3.9
6.1
mmol/L
X 1
mmol/liter
3.9
6.1
3.9
6.1
g/dL
X 55.51
mmol/liter
3.9
6.1
3.9
6.1
BUN
mg/dL
x 0.357
mmol/liter
2.9
8.9
2.9
8.9
mmol/L
1
mmol/liter
2.9
8.9
2.9
8.9
Albumin
g/dL
x 10
g/liter
31
43
31
43
g/L
1
g/liter
31
43
31
43
mg/dL
X 0.01
g/liter
31
43
31
43
Calcium (serum)
mg/dL
x 0.25
mmol/liter
2.1
2.6
2.1
2.6
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1
7,2
3.5
3.5
7,
7,
7,
7,
3.5
3.5
0$
5
8
50
25
108
108
)2
1
<
53
53
5<
<
3.3
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(7
mol/liter
mol/liter
(7
(7
(7
(7
mmol/
mm
35
52
357
357
52
52
52
52
1
3
1(
(1
(1
(1
(1
(1
mg/dL
mg/d
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mg/d
mg/d
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&


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
52
mmol/L
X 1
mmol/liter
2.1
2.6
2.1
2.6
Phosphorus
mg/dL
X 0.323
mmol/L
0.81
1.45
0.81
1.45
mmol/L
1
mmol/L
0.81
1.45
0.81
1.45
Alkaline 
Phosphatase
units/L 
X0.01667
ukat/L
0.50
2.00
0.50
2.00
U/L
X0.01667
ukat/L
0.50
2.00
0.50
2.00
IU/L
X0.01667
ukat/L
0.50
2.00
0.50
2.00
mU/ml or mU/mL
X0.01667
ukat/L
0.50
2.00
0.50
2.00
ukat/L
X 1
ukat/L
0.50
2.00
0.50
2.00
ALT (SGPT)
units/L
X0.01667
ukat/L
0.17
0.68
0.17
0.68
U/L
X0.01667
ukat/L
0.17
0.68
0.17
0.68
IU/L
X0.01667
ukat/L
0.17
0.68
0.17
0.68
mU/ml or mU/mL
X0.01667
ukat/L
0.17
0.68
0.17
0.68
ukat/L
X 1
ukat/L
0.17
0.68
0.17
0.68
AST (SGOT)
units/L
X0.01667
ukat/L
0.17
0.51
0.17
0.51
U/L
X0.01667
ukat/L
0.17
0.51
0.17
0.51
IU/L
X0.01667
ukat/L
0.17
0.51
0.17
0.51
mU/ml or mU/mL
X0.01667
ukat/L
0.17
0.51
0.17
0.51
ukat/L
X 1
ukat/L
0.17
0.51
0.17
0.51
Total Bilirubin
mg/dL
17.1
umol/liter
0
17
0
17
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
53
umol/L
X 1
umol/liter
0
17
0
17
g/dL
X17100
umol/liter
0
17
0
17
Lactate 
Dehydrogenase 
(LDH)
12-60 years
units/L
X0.01667
ukat/L
1.8
3.4
1.8
3.4
U/L
X0.01667
ukat/L
1.8
3.4
1.8
3.4
ukat/L
x1
ukat/L
1.8
3.4
1.8
3.4
mU/ml or mU/mL
X0.01667
ukat/L
1.8
3.4
1.8
3.4
IU/L
X0.01667
ukat/L
1.8
3.4
1.8
3.4
> 60 years
units/L
X0.01667
ukat/L
1.8
3.5
1.8
3.5
U/L
X0.01667
ukat/L
1.8
3.5
1.8
3.5
ukat/L
x1
ukat/L
1.8
3.5
1.8
3.5
mU/ml or mU/mL
X0.01667
ukat/L
1.8
3.5
1.8
3.5
IU/L
X0.01667
ukat/L
1.8
3.5
1.8
3.5
Total protein
g/dL
X 10
g/liter
64
83
64
83
g/L
X 1
g/liter
64
83
64
83
Uric acid
18-60 years
umol/L
÷ 1000
mmol/L
0.13
0.39
0.26
0.45
mg/dL
X 0.0595
mmol/L
0.13
0.39
0.26
0.45
> 60 years
umol/L
÷ 1000
mmol/L
0.2
0.43
0.25
0.47
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
54
mg/dL
X 0.0595
mmol/L
0.2
0.43
0.25
0.47
TSH
Test
Normal 
Range Unit
Conversion 
Factor
SI Unit
Females
Male
Low
High
Low
High
TSH
uU/mL
X 1
mU/L
0.32
5
0.32
5
uU/L
÷ 1000
mU/L
0.32
5
0.32
5
mU/L
X 1
mU/L
0.32
5
0.32
5
mIU/L
X 1
mU/L
0.32
5
0.32
5
MIU/mL
X 1
mU/L
0.32
5
0.32
5
uUI/ML or μUI/ML
X 1
mU/L
0.32
5
0.32
5
mME/L
UIU/mL
X 1
mU/L
0.32
5
0.32
5
Free T3
ng/dL
X 15.4
pmol/L
4.0
7.4
4.0
7.4
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
55
nmol/L
X 1000
pmol/L
4.0
7.4
4.0
7.4
pg/mL 
X1.54
pmol/L
4.0
7.4
4.0
7.4
pg/dL
X 0.0154
pmol/L
4.0
7.4
4.0
7.4
pmol/L
X 1
pmol/L
4.0
7.4
4.0
7.4
Free T4
ug/dL
X 12870
pmol/L
10.3
35.0
10.3
35.0
nmol/L
X 1000
pmol/L
10.3
35.0
10.3
35.0
pg/mL 
X 1.287
pmol/L
10.3
35.0
10.3
35.0
ng/dL
X 12.87
pmol/L
10.3
35.0
10.3
35.0
pmol/L
X 1
pmol/L
10.3
35.0
10.3
35.0
Step 3:  Determine, for each (converted) lab value, if it is within the (converted) normal range and assign a flag indicating where the 
value falls relative to the upper and lower limits of normal (eg, low (below lower limit normal), normal, or high (above upper limit 
normal).
Step 4:  Determine p, the value to be used for mapping the converted lab value to a standardized value as follows:
a)  If the converted lab value is within converted normal range then
        
            p = (lab value – LLN value) / (ULN value – LLN value)
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
56
b) If the converted lab value is less than converted LLN then
p = lab value / LLN value
c) If the converted lab value is greater than converted ULN then
            p = lab value / ULN value
Step 5:  Use the value of p calculated in Step 4 and the standardized ULN and LLN values
a)  If the converted lab value is within normal range then
        
            SLV = p(sULN value – sLLN value) + sLLN
b) If the converted lab value is less than LLN then
            SLV = p( sLLN value)
c) If the converted lab value is greater than ULN then
            SLV = p( sULN value)
Step 6: Use the SLV and the sLLN and sULN to assign the NCI-CTC grade and for summary statistics in all tables.  
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
57
Example calculations for standardizing lab values to the standard normal ranges
Patient X at CxD1 visit:
SGPT = 22 UI/L
Step 1:  normal range
LLN = 7 UI/L
ULN = 40 UI/L
Step 2:
Since the conversion factor for converting UI/L to U/L is 1.0, the converted values associated with unit=U/L remain the same as the
original values.
converted SGPT = 22 U/L
converted LLN = 7 U/L
converted ULN = 40 U/L
Step 3: 
Value of 22 U/L is within the normal range.
Normal range flag = N
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
58
Step 4:  Calculate p for 22 U/L based on formula a):
p = (lab value – LLN value) / (ULN value – LLN value)
   = (22 – 7) / (40 – 7)
   = 15 / 33
   = 0.45
Step 5:  Calculate SLV for p = 0.45 and sLLN = 6 U/L and sULN = 35 U/L.  
SLV = p(sULN value – sLLN value) + sLLN
        = 0.45(35 – 6) + 6
        = 19.2 U/L
Step 6:  NCI-CTC grade = 0, since the value is within normal limits.
15.5.
Tables and listings shells
The presented shells are not exhaustive.
Non efficacy Tables
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
59
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.1.1
Subject Disposition
Treatment A
Treatment B
Total
n
(%)[a]
n
(%)[a]
n
(%)[a]
Analysis Populations
Safety [b]
xx (xx)
xx (xx)
xx (xx)
Intent-to-treat
(ITT)[c]
xx (xx)
xx (xx)
xx (xx)
Subjects discontinued from study
xx (xx)
xx (xx)
xx (xx)
Primary reason for discontinuation from the study
Adverse event
xx (xx)
xx (xx)
xx (xx)
Lack of therapeutic effect/PD
xx (xx)
xx (xx)
xx (xx)
Subject withdrew consent
xx (xx)
xx (xx)
xx (xx)
Subject lost to follow-up
xx (xx)
xx (xx)
xx (xx)
Death
xx (xx)
xx (xx)
xx (xx)
Protocol violation
xx (xx)
xx (xx)
xx (xx)
Other
xx (xx)
xx (xx)
xx (xx)
Total number of subjects who completed study
xx (xx)
xx (xx)
xx (xx)
[a] Percents are based on the safety population.
[b] Define the safety population.
[c] Define the ITT population.
Order of appearance of treatment groups: Lowest dose of Celgene drug to Highest dose, active control and placebo.
Bolded sections are optional.
Program path: 
Data source: DISPO
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xx (xx)
xx (xx)
25
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xx (xx
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(xx)
(xx)
x (xx)
(xx)
xx (xx)
xx (xx)
xx (xx)
x (xx)
xx (x
x 
xx
xx
3
: Lowest d
Lowest d


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
60
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.1.2
Demographic and Baseline Characteristics - (Safety Population)
Treatment A
Treatment B
Overall
(N=XX)
(N=XX)
(N=XX)
Age (years)
   n                                                                  xx                       xx                     xx
   Mean                                                               xx                       xx                     xx
   SD                                                                 xx                       xx                     xx
   Median                                                             xx                       xx                     xx
   Min, Max                                                         xx, xx                   xx, xx                 xx, xx
Age category                                                       n  (%)                 n  (%)                   n  (%)
   <65                                                            xx  (xx)              xx  (xx)                 xx  (xx)
   >=65                                                             xx  (xx)               xx  (xx)                 xx  (xx)
   Missing                                                         xx  (xx)               xx  (xx)                 xx  (xx)
Sex                                                                 n  (%)                 n  (%)                   n  (%)
   Male                                                            xx  (xx)               xx  (xx)                 xx  (xx)
   Female                                                          xx  (xx)               xx  (xx)                 xx  (xx)
   Missing                                                         xx  (xx)               xx  (xx)                 xx  (xx)
Race [a]                                                            n  (%)                 n  (%)                   n  (%)
   White                                                           xx  (xx)               xx  (xx)                 xx  (xx)
   Black                                                           xx  (xx)               xx  (xx)                 xx  (xx)
   Asian/Pacific Islander                                          xx  (xx)               xx  (xx)                 xx  (xx)
   Other                                                           xx  (xx)               xx  (xx)                 xx  (xx)
   Missing                                                         xx  (xx)               xx  (xx)                 xx  (xx)
BMI (units)[b]
   N                                                                 xx                     xx                       xx
   Mean                                                              xx                     xx                       xx
   SD                                                                xx                     xx                       xx
   Median                                                            xx                     xx                       xx
   Min, Max                                                        xx, xx                 xx, xx                   xx, xx
[a]
Percents may add up to more than 100% since subjects were allowed to select more than one Race.  (Add this footnote ONLY if 
percents add up to >100%.)
[b]
Order of appearance of treatment groups: Lowest dose of Celgene drug to Highest dose, active control and placebo.
Bolded sections are optional.
Program path: 
Data source: DEMO 
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
61
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.1.3
                              Medical History - Number (%) of Subjects by Treatment Group - (Safety Population)
Treatment A
Treatment B
Total
   (N=XX)
  (N=XX)
(N=XX)
System organ class/Preferred term [a]
n  (%)
n  (%)
n  (%)[b]
Metabolism and nutrition disorders
xx (xx)
xx (xx)
xx
(xx)
Haemochromatosis
xx (xx)
xx (xx)
xx
(xx)
Diabetes mellitus NOS
xx (xx)
xx (xx)
xx
(xx)
Hyperlipidaemia NOS
xx (xx)
xx (xx)
xx
(xx)
Hypercholesterolaemia
xx (xx)
xx (xx)
xx
(xx)
Diabetes mellitus non-insulin-dependent
xx (xx)
xx (xx)
xx
(xx)
Hyperuricaemia
xx (xx)
xx (xx)
xx
(xx)
Gout
xx (xx)
xx (xx)
xx
(xx)
Haemosiderosis
xx (xx)
xx (xx)
xx
(xx)
Hypokalaemia
xx (xx)
xx (xx)
xx
(xx)
Glucose tolerance impaired
xx (xx)
xx (xx)
xx
(xx)
Hyperglycaemia NOS
xx (xx)
xx (xx)
xx
(xx)
Hypertriglyceridaemia
xx (xx)
xx (xx)
xx
(xx)
Hyponatraemia
xx (xx)
xx (xx)
xx
(xx)
Lactose intolerance
xx (xx)
xx (xx)
xx
(xx)
Obesity
xx (xx)
xx (xx)
xx
(xx)
Vitamin B12 deficiency
xx (xx)
xx (xx)
xx
(xx)
Anorexia
xx (xx)
xx (xx)
xx
(xx)
Appetite decreased NOS
xx (xx)
xx (xx)
xx
(xx)
Dehydration
xx (xx)
xx (xx)
xx
(xx)
Dyslipidaemia
xx (xx)
xx (xx)
xx
(xx)
Fluid retention
xx (xx)
xx (xx)
xx
(xx)
Hyperkalaemia
xx (xx)
xx (xx)
xx
(xx)
Hyperproteinaemia
xx (xx)
xx (xx)
xx
(xx)
Hypoalbuminaemia
xx (xx)
xx (xx)
xx
(xx)
Hypomagnesaemia
xx (xx)
xx (xx)
xx
(xx)
Impaired fasting glucose
xx (xx)
xx (xx)
xx
(xx)
Metabolic acidosis NOS
xx (xx)
xx (xx)
xx
(xx)
[a]  Medical History terms are coded using the MedDRA dictionary (indicate the version of the dictionary used).  System organ 
classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical).  Multiple occurrences of the same preferred 
term from a patient are counted only once within each treatment group.   Order of appearance of treatment groups: Lowest dose of 
Celgene drug to Highest dose, active control and placebo.
Program path: 
Data source: MEDHIST
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xx (xx)
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xx (xx)
xx (xx)
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
62
Celgene Corporation                                                                                          Page xx of xx
Protocol:                                                                                                    DB (Interim) Lock Date:
Table 14.1.4
Prior Medications – Number (%) of Subjects by Treatment Group (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A                Treatment B              Total
ATC3 Classification/                                                  (N=XX)                    (N=XX)                (N=XX)
Preferred Name[a]                                                    n   (%)                  n   (%)                n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one prior medication                            xx  (xx)                  xx  (xx)               xx  (xx)
PLATELET AGGREGATION INHIBITORS EXCL. HEPARIN                           xx  (xx)                  xx  (xx)               xx  (xx)
ACETYLSALICYLIC ACID                                                 xx  (xx)                  xx  (xx)               xx  (xx)
CLOPIDOGREL SULFATE                                                  xx  (xx)                  xx  (xx)               xx  (xx)
            ASPIRINE                                                             xx  (xx)                  xx  (xx)               xx  (xx)
ANAGRELIDE                                                           xx  (xx)                  xx  (xx)               xx  (xx)
CLOPIDOGREL                                                          xx  (xx)                  xx  (xx)               xx  (xx)
AGGRENOX                                                            xx  (xx)                  xx  (xx)               xx  (xx)
ASA                                                                  xx  (xx)                  xx  (xx)               xx  (xx)
ASPIRIN PROTECT                                                     xx  (xx)                  xx  (xx)               xx  (xx)
IRON CHELATING AGENTS                                                   xx  (xx)                  xx  (xx)               xx  (xx)
DEFEROXAMINE                                                         xx  (xx)                  xx  (xx)               xx  (xx)
DEFEROXAMINE MESILATE                                                xx  (xx)                  xx  (xx)              xx  (xx)
DEFERIPRONE                                                          xx  (xx)                  xx  (xx)               xx  (xx)
DESFERAL                                                             xx  (xx)    
xx  (xx)               xx  (xx)
OTHER PLAIN VITAMIN PREPARATIONS                                        xx  (xx)                  xx  (xx)               xx  (xx)
VITAMIN E                                                            xx  (xx)                  xx  (xx)               xx  (xx)
PYRIDOXINE                                                           xx  (xx)                  xx  (xx)               xx  (xx)
VITAMIN B     
xx  (xx)                  xx  (xx)               xx  (xx)
TOCOPHEROL                                                           xx  (xx)                  xx  (xx)               xx  (xx)
VITAMIN B6                                                           xx  (xx)                  xx  (xx)               xx  (xx)
OPTOVIT                                                              xx  (xx)                 xx  (xx)               xx  (xx)
PROTON PUMP INHIBITORS                                                  xx  (xx)                  xx  (xx)               xx  (xx)
OMEPRAZOLE                                                 
xx  (xx)                  xx  (xx)               xx  (xx)
PANTOPRAZOLE                                                         xx  (xx)                  xx  (xx)               xx  (xx)
ESOMEPRAZOLE                                                         xx  (xx)                  xx  (xx)               xx  (xx)
LANSOPRAZOLE                                                         xx  (xx)                  xx  (xx)               xx  (xx)
     ACIPHEX                                                              xx  (xx)                  xx  (xx)               xx  (xx)
PREVACID                                                             xx  (xx)                  xx  (xx)               xx  (xx)
NEXIUM                                                               xx  (xx)                  xx  (xx)               xx  (xx)
RABEPRAZOLE SODIUM                                                   xx  (xx)                  xx  (xx)               xx  (xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] ATC3 classification and preferred name are based on WHODD (coding dictionary) (indicate the version of the dictionary used).
Program path: 
Data source:  CONMEDS
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 of xx
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) L
 
—————————
—————————
ent B      
B    
X)         
         
  (%)    
  (%)   
——————————
—————————
    xx  (x
   xx  
       xx
       xx
         
      
          
     
          
          
          
     
         
         
)         
      
xx)        
x)    
(xx)      
(xx)     
xx  (xx)  
xx  (xx
 xx  (xx)
 xx  (xx)
   xx  (x
   xx  
     xx  
     xx  
       xx 
      xx
         
        
          
         
         
        
         
      
          
        
         
         
         
        
         
       
          
       
         
         
         
        
         
       
          
         
——————————
—————————
preferred
preferred


Lenalidomide/CC-5013
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Celgene International
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63
Celgene Corporation                                                               
Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
          Table 14.1.5
Concomitant Medications – Number (%) of Subjects by Treatment Group (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A                Treatment B              Total
ATC3 Classification/                                                  (N=XX)                    (N=XX)                 (N=XX)
Preferred Name[a]                                                    n   (%)                   n   (%)                n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one concomitant medication                       xx  (xx)                  xx  (xx)               xx  (xx)
ANILIDES                                                                xx  (xx)                  xx  (xx)               xx  (xx)
ACETAMINOPHEN                                                        xx  (xx)                  xx  (xx)               xx  (xx)
TYLENOL                                                              xx  (xx)                  xx  (xx)               xx  (xx)
PARACETAMOL                                                          xx  (xx)                  xx  (xx)               xx  (xx)
ACETAMINOPHEN W/HYDROCODONE BITARTRATE                               xx  (xx)                  xx  (xx)               xx  (xx)
NYQUIL                       
xx  (xx)                  xx  (xx)               xx  (xx)
EXCEDRIN /USA/                                                       xx  (xx)                  xx  (xx)               xx  (xx)
   GALENIC /ACETYLSAL.ACID/CAFFEINE/PARACET                             xx  (xx)                  xx  (xx)               xx  (xx)
VICODIN                                                              xx  (xx)                  xx  (xx)      
xx  (xx)
ACETAMINOPHEN W/OXYCODONE                                            xx  (xx)                  xx  (xx)               xx  (xx)
GOODYS POWDERS                                                       xx  (xx)                  xx  (xx)               xx  (xx)
HYDROCODONE W/ACETAMINOPHEN                                          xx  (xx)                  xx  (xx)               xx  (xx)
THOMAPYRIN                                                           xx  (xx)                  xx  (xx)               xx  (xx)
TYLENOL ALLERGY SINUS                                                xx  (xx)                  xx  (xx)               xx  (xx)
VICKS DAYQUIL                                                        xx  (xx)                  xx  (xx)               xx  (xx)
FLUOROQUINOLONES                                                        xx  (xx)                  xx  (xx)               xx  (xx)
CIPROFLOXACIN                                                        xx  (xx)                  xx  (xx)               xx  (xx)
LEVOFLOXACIN                                                         xx  (xx)                  xx  (xx)               xx  (xx)
LEVAQUIN                                                             xx  (xx)                  xx  (xx)               xx  (xx)
GATIFLOXACIN                                                         xx  (xx)                  xx  (xx)               xx  (xx)
MOXIFLOXACIN                                                         xx  (xx)                  xx  (xx)               xx  (xx)
TAVANIC                   
xx  (xx)                  xx  (xx)               xx  (xx)
TEQUIN                                                               xx  (xx)                  xx  (xx)               xx  (xx)
AVALOX                                                               xx  (xx)                  xx  (xx)               xx  (xx)
NORFLOXACIN                                                          xx  (xx)                  xx  (xx)               xx  (xx)
AMINOALKYL ETHERS                                                       xx  (xx)                  xx  (xx)               xx  (xx)
DIPHENHYDRAMINE                                                      xx  (xx)                  xx  (xx)               xx  (xx)
DIPHENHYDRAMINE HYDROCHLORIDE                                        xx  (xx)                  xx  (xx)               xx  (xx)
TAVEGIL                                
xx  (xx)                  xx  (xx)               xx  (xx)
DIMENHYDRINATE                                                       xx  (xx)                  xx  (xx)               xx  (xx)
VERTIGO-VOMEX                                                        xx  (xx)                  xx  (xx)               xx  (xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
            [a] ATC3 classification and preferred name are based on WHODD (coding dictionary) (indicate version of the dictionary used).
Program path: 
Data source:  CONMEDS
&(/*(1(35235,(7$5<,1)250$7,21
e xx of xx
e xx of xx
B (Interim
Interim
ation)
tion)
—————————
—————
ment B    
ment B    
XX)       
X)       
n   (%)  
n   (%)
——————————
———————
      xx  
     xx  
         
         
         
        
          
        
          
       
          
    
)         
)        
xx)        
xx)       
(xx)      
x)      
x  (xx)    
(xx)   
xx  (xx)  
xx  (xx)  
 xx  (xx)
 xx  (x
   xx  (x
   xx  (x
xx  
       xx 
      xx
x
         
         
          
        
          
    
         
       
        
     
          
         
          
         
         
        
         
   
          
     
         
         
       
       
          
        
          
       
——————————
————————
d preferre
d preferre


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
64
Table 14.2.1
Duration of Exposure by Cycle - Safety Population
_______________________________________________________________________________________________________________________________________            
                                                                      
Number (%) of Patients                                                     
                                     ___________________________________________________________________________________________                  
                                        Treatment A             Treatment B            Treatment C                           
Exposure by Cycle Category                 N=  XX                  N=XX                    N=XX
                                            n(%)                    n(%)                    n(%)                                             
_________________________________________________________________________________________________________________________________                  
Cycles  1 or more                       XX (XX)                XX (XX)                XX (XX)                                
Cycles  2 or more                       XX (XX)                XX (XX)                XX (XX)                                     
Cycles  3 or more                       XX (XX)                XX (XX)                XX (XX)                                
Cycles  4 or more                       XX (XX)                XX (XX)                XX (XX)                                     
Cycles  5 or more                       XX (XX)                XX (XX)                XX (XX)                                
Cycles  6 or more                       XX (XX)                XX (XX)                XX (XX)                                     
Cycles 12 or more                       XX (XX)                XX (XX)                XX (XX)                                
Cycles 24 or more                       XX (XX)                XX (XX)                XX (XX)                                  
Cycles 30 or more                       XX (XX)                XX (XX)                XX (XX)                                
                                           
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Duration of Exposure by Cycle: Duration of the start of the cycle.   
Program path: 
Data source: SDR D_SDSUMM                                                                          
&(/*(1(35235,(7$5<,1)250$7,21
__
_________
___
         
        
__________
_________
         
      
          
        
__________
_________
         
         
         
      
          
     
          
         
          
     
          
         
          
       
          
      
X)        
X)        
—————————
——————
         
        


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
65
Celgene Corporation                                                                                                   Page X of X
Protocol:                                                                                                              DB (Interim) Lock Date:
Table 14.2.2
Exposure to Study Medication by Treatment Group - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A       Treatment B       Treatment C          
                                                                      (N=XX)            (N=XX)            (N=XX)            
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Total Duration (days) [a]
n                                                               xx                xx                xx               
Mean                                                           xx                xx                xx                
SD                                                              xx                xx                xx               
Median                                                          xx                xx                xx               
Min, Max                                                      xx, xx            xx, xx            xx, xx            
Daily dose (Units)
n                                                               xx                xx                xx
Mean                                                            xx                xx                xx
SD                                                              xx                xx                xx
Median                                                          xx                xx                xx
Min, Max                                                     xx, xx            xx, xx            xx, xx
Total completed cycles [a]
n                                                               xx                xx               xx               
Mean                                                            xx                xx                xx               
SD                                                              xx                xx                xx               
Median                                                          xx                xx                xx                
Min, Max                                                      xx, xx           xx, xx            xx, xx            
Average durations of cycles (days)
n                                                               xx                xx                xx               
Mean                                                            xx                xx                xx               
SD                                                              xx                xx                xx               
Median                                                          xx                xx                xx                
Min, Max                                                      xx, xx            xx, xx            xx, xx            
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
[a] Give definition of how duration was calculated (e.g., Duration (days) = [date of last dose - date of first dose + 1 ]).
             Define the end of the cycle as the day before the onset date of next cycle.
Bolded sections are optional.
Program path: 
Data source: SDR D_SDSUMM                                                                          
&(/*(1(35235,(7$5<,1)250$7,21
Pag
Pa
        DB
      DB
)
—————————
—————————
Treatment 
reatment 
    (N=XX
    (N=X
—————————
———————
xx         
     
xx
xx
xx, xx   
x, xx   
x
         
      
         
       
         
         
xx        
xx        
xx
xx
    xx   
    xx   
      xx  
     xx 
        xx
       xx
        xx
       x
         
       
         
      
         
        
—————————
—————————
on was cal
on was cal
the day bef
he day be
    


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
66
Celgene Corporation                                                                                                  Page xx of xx
Protocol:                                                                                                            DB (Interim) Lock Date:
Table 14.2.3 
Study Drug Dose Reduction Due to Adverse Events by Treatment Group - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
                                                                          Treatment A       Treatment B         Treatment C
(N=XX)            (N=XX)             (N=XX)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Had at least one dose reduction due to AE
Yes                                                                             xx (xx)           xx (xx)            xx (xx)
No                                                                               xx (xx)           xx (xx)            xx (xx)
        Time to first dose reduction (days) due to AE[a]
n                                                                                  xx                xx               xx
Mean                                                                              xx                xx               xx
SD                                                                                 xx                xx               xx
Median                                                                             xx                xx               xx
Min, Max                                                                        xx, xx            xx, xx           xx, xx
Had second dose reduction due to AE
Yes                                                                              xx (xx)           xx (xx)            xx (xx)
No                                                         
xx (xx)           xx (xx)            xx (xx)
Interval between first and second reduction (days)[b] due to AE
n                                                                                  xx                xx               xx
Mean                                                                               xx                xx               xx
SD                                                                                 xx                xx               xx
Median                                                                             xx                xx               xx
Min, Max                                                                        xx, xx            xx, xx           xx, xx
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
 [a] Time to dose reduction is the time from first dose of study medication to the start of first reduction.
[b] Time from the start of the first dose reduction to the start of the second dose reduction.
Program path: 
     Data source: D_SDSUMM                                    
&(/*(1(35235,(7$5<,1)250$7,21
    Page 
    Page
DB 
DB 
)
—————————
—————————
 Treatmen
Treatmen
     (N=X
     (N=
—————————
———————
x)        
     
(xx)      
xx)      
xx
xx
xx
       xx 
       xx
        xx
      
          
         
E
          
     
         
        
         
      
—————————
—————
he time fro
e time fr
first dos
first dos
         
      


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
67
Celgene Corporation                                                                                                  Page xx of xx
Protocol:                                                                                                            DB (Interim) Lock Date:
Table 14.2.4
Study Drug Dose Interruption Due to Adverse Events by Treatment Group - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
                                                                   Treatment A       Treatment B         Treatment C
(N=XX)            (N=XX)             (N=XX)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Had at least one dose interruption due to AE
Yes                     
xx (xx)           xx (xx)            xx (xx)
No                                                                               xx (xx)           xx (xx)            xx (xx)
     Time to first dose interruption (days) due to AE[a]
n                                                                                  xx                xx               xx
Mean                                                                              xx                xx               xx
SD                                                                                 xx                xx               xx
Median                                                                             xx                xx               xx
Min, Max                                                                        xx, xx            xx, xx           xx, xx
Duration of first dose interruption (days) due to AE[b]
n                                                                                  xx                xx               xx
Mean                                                                               xx                xx               xx
SD                                                                                 xx                xx               xx
Median                                                                            xx                xx               xx
Min, Max                                                                        xx, xx            xx, xx           xx, xx
Had second dose interruption due to AE
Yes                                                                              xx (xx)           xx (xx)            xx (xx)
No                                                                               xx (xx)           xx (xx)            xx (xx)
Interval between first and second interruption (days)[c] due to AE
n                                                                                  xx                xx               xx
Mean                                                                               xx                xx               xx
SD                                                                                xx                xx               xx
Median                                                                             xx                xx               xx
Min, Max                                                                        xx, xx            xx, xx           xx, xx
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
[a] Time to dose interruption is the time from first dose of study medication to the start of first interruption.
[b] Duration of dose interruption is the time from last dose of one dosing regimen to first dose of the next dosing regimen. A dosing
           change is considered an interruption if the start of the new dosing record is greater than 1 day after the end of the previous
dosing record.
[c] Time from the start of the first dose interruption to the start of the second dose interruption.
Program path: 
Data source: D_SDSUMM                                    
&(/*(1(35235,(7$5<,1)250$7,21
  Page xx
  Page xx
DB (
B (I
on)
n)
—————————
—————————
Treatment 
Treatment
   (N=XX)
   (N=XX)
——————————
————————
          
     
x)        
     
xx
xx
xx
     xx  
    x
xx
xx
      xx, 
     xx
         
         
          
        
          
      
         
        
[c] due to
c] due t
         
         
          
       
         
       
         
        
——————————
———————
e time fro
e time fro
is the ti
is the ti
erruption 
rruption 
he first d
e first d
         
         


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
68
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
Table 14.3.2.1
Summary of Adverse Events – Number (%) of Subjects by Treatment Group - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B    Treatment C
                                          (N=XX)        (N=XX)       (N=XX)
TEAE Category[a]                                                                                     n   (%)        n   (%)     n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE                                                                     xx  (xx)       xx  (xx)     xx  (xx)
Subjects with at least one TEAE related to study drug                                               xx  (xx)       xx  (xx)    xx  (xx)
Subjects with at least one CTC AE grade 3-4 (or severe) TEAE                                        xx  (xx)       xx  (xx)     xx  (xx)
Subjects with at least one CTC AE grade 3-4 (or severe) TEAE related to study drug                 xx  (xx)       xx  (xx)     xx  (xx)
Subjects with at least one serious TEAE [b]                                                         xx  (xx)       xx  (xx)     xx  (xx)
Subjects with at least one serious TEAE related to study drug                                       xx  (xx)       xx  (xx)    xx  (xx)
Subjects who discontinued due to TEAE                                                               xx  (xx)       xx  (xx)    xx  (xx)
Subjects who discontinued due to TEAE adverse event related to study drug                          xx  (xx)       xx  (xx)     xx  (xx)
Subjects with TEAE leading to a dose reduction                                                      xx  (xx)       xx  (xx)    xx  (xx)
Subjects with TEAE leading to a dose interruption                                                   xx  (xx)       xx  (xx)     xx  (xx)
Subjects who died[c] due to TEAE                                                                    xx  (xx)       xx  (xx)    xx  (xx)
Additional categories can be specified under “Subjects who died” (e.g., Disease progression).
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
[a] A subject with multiple occurrences of an AE is counted only once in the AE category.
[b] Specify how long serious adverse events were collected following the last dose of study medication.  This should be specified in the protocol.
[c] Specify how long deaths were collected following the last dose of study medication.  This should be specified in the protocol.
Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
Page xx of
Page xx o
 DB (
 DB (Inte
In
Population)
Populatio
—————————
———————
reatment A
reatmen
(N=XX)  
=XX) 
     n   (
    n   
——————————
—————————
          
        
         
        
drug     
drug     
         
         
          
          
         
        
study drug 
study drug 
         
       
          
       
          
         
Subjects w
Subjects w
—————————
—————————
ccurrences 
urrences 
s adverse e
verse 
s were col
s were col


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
69
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.3.2.2
Number (%) of Subjects With Treatment-Emergent Adverse Events by System Organ Class- (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B     Treatment C
(N=xx)       (N=xx)        (N=xx)
System organ class/ Preferred term [a]                                                        n    (%)      n    (%)      n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE 
xx  ( xx)     xx  ( xx)     xx  ( xx)
Blood and lymphatic system disorders                                                         xx  ( xx)     xx  ( xx)     xx  ( xx)
       Thrombocytopenia                                                                          xx  ( xx)     xx  ( xx)     xx  ( xx)
Neutropenia                                                                               xx  ( xx)    xx  ( xx)     xx  ( xx)
Anaemia NOS                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
Leukopenia NOS                                                       
xx  ( xx)     xx  ( xx)     xx  ( xx)
Febrile neutropenia                                                                       xx  ( xx)     xx  ( xx)     xx  ( xx)
Pancytopenia                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Granulocytopenia                                                                          xx  ( xx)     xx  ( xx)     xx  ( xx)
Lymphadenopathy                                                                           xx  ( xx)     xx  ( xx)     xx  ( xx)
Polycythaemia NOS                                                                         xx  ( xx)     xx  ( xx)     xx  ( xx)
Splenomegaly                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Coagulopathy                                                                             xx  ( xx)     xx  ( xx)     xx  ( xx)
Haemolytic anaemia NOS                                                                    xx  ( xx)     xx  ( xx)     xx  ( xx)
Leukocytosis                                
xx  ( xx)     xx  ( xx)     xx  ( xx)
Lymphocytosis                                                                             xx  ( xx)     xx  ( xx)     xx  ( xx)
Skin and subcutaneous tissue disorders                                                       xx  ( xx)     xx  ( xx)     xx  ( xx)
Pruritus                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Rash NOS                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Dry skin                                                                            
xx  ( xx)     xx  ( xx)     xx  ( xx)
Contusion                                                                                 xx  ( xx)     xx  ( xx)     xx  ( xx)
Night sweats                                                                             xx  ( xx)     xx  ( xx)     xx  ( xx)
Sweating increased                                                                        xx  ( xx)     xx  ( xx)     xx  ( xx)
Ecchymosis                                                                                xx  ( xx)     xx  ( xx)     xx  ( xx)
Erythema                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Rash pruritic                                                                             xx  ( xx)     xx  ( xx)     xx  ( xx)
Skin lesion NOS                                                                           xx ( xx)     xx  ( xx)     xx  ( xx)
Alopecia                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Face oedema                                                
xx  ( xx)     xx  ( xx)     xx  ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, 
                     ).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
             Program path: 
             Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
ge xx of x
ge xx of 
DB (Interim
nterim
Populatio
opulat
—————————
—————————
ent A   Tr
nt A   Tr
N=xx)     
N=xx)    
n    (%)   
n    (%) 
—————————
—————————
xx  ( 
xx  
       xx 
     
         x
        
          
       
         
     
          
        
          
         
         
         
         
         
          
         
          
       
          
        
          
        
          
        
         
      
         
        
          
        
          
          
     
   
         
       
          
       
          
         
         
        
         
        
         
        
—————————
—————————
preferred t
preferred t
rms are li
ms are li
UUHQFHVRIWK
UUHQFHVRIW


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
70
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
                             Table 14.3.2.3 
Number (%) of Subjects With Common (>= XX%) Treatment-Emergent Adverse Events by SOC - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B     Treatment C
                                                                   (N=xx)       (N=xx)        (N=xx)
System organ class/ Preferred term [a]                                                        n    (%)      n    (%)      n    (%)
    ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Blood and lymphatic system disorders                                                         xx  ( xx)     xx  ( xx)     xx  ( xx)
Thrombocytopenia                                                                          xx  ( xx)     xx  ( xx)     xx  ( xx)
Neutropenia                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
Anaemia NOS                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
Leukopenia NOS                                                                            xx  ( xx)     xx  ( xx)     xx  ( xx)
       Febrile neutropenia                                                                       xx  ( xx)     xx  ( xx)     xx  ( xx)
Pancytopenia                                                                              xx  ( xx)    xx  ( xx)     xx  ( xx)
Granulocytopenia                                                                          xx  ( xx)     xx  ( xx)     xx  ( xx)
Lymphadenopathy                                                      
xx  ( xx)     xx  ( xx)     xx  ( xx)
Polycythaemia NOS                                                                         xx  ( xx)     xx  ( xx)     xx  ( xx)
Splenomegaly                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Coagulopathy                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Haemolytic anaemia NOS                                                                    xx  ( xx)     xx  ( xx)     xx  ( xx)
Leukocytosis                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Lymphocytosis                                                                             xx  ( xx)     xx  ( xx)     xx  ( xx)
Skin and subcutaneous tissue disorders                                                       xx  ( xx)     xx  ( xx)     xx  ( xx)
Pruritus                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Rash NOS                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Dry skin                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Contusion                                                                                 xx  ( xx)     xx  ( xx)     xx  ( xx)
Night sweats                                                                              xx  ( xx)     xx  ( xx)     xx  ( xx)
Sweating increased                                                                        xx  ( xx)     xx  ( xx)     xx  ( xx)
Ecchymosis                                                                          
xx  ( xx)     xx  ( xx)     xx  ( xx)
Erythema                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Rash pruritic                                                                            xx  ( xx)     xx  ( xx)     xx  ( xx)
Skin lesion NOS                                                                           xx  ( xx)     xx  ( xx)     xx  ( xx)
Alopecia                                                                                  xx  ( xx)     xx  ( xx)     xx  ( xx)
Face oedema                                                                               xx  ( xx)     xx  ( xx)     xx  ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, 
                     ).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
             Program path: 
             Data source:  AE
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
&(/*(1(35235,(7$5<,1)250$7,21
xx of xx
x of 
Interim
Interim) L
) L
——————————
—————————
A   Treat
A   Treat
x)       (N
)       (
 (%)      
 (%)      
——————————
—————————
xx  ( x
xx  ( xx)
x)
    xx  ( 
    xx  
xx  
xx 
       xx
     
          
          
          
      
         
         
         
        
          
          
         
         
         
         
          
        
          
        
         
        
         
       
          
       
         
        
         
        
         
         
          
         
          
        
         
     
         
       
          
         
——————————
———————
erred term
erred t
are liste
are liste
FHVRIWKHV
FHVRIWKHV
——————————
———


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
71
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
Table 14.3.2.4
Number (%) of Subjects With Treatment-Emergent Adverse Events Related to Study Drug by System Organ Class 
- (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
                                                                                    Treatment A   Treatment B      Treatment C
(N=xx)        (N=xx)       (N=xx)
System organ class/ Preferred term [a]                                                  n    (%)      n    (%)      n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE related to study drug                                   xx ( xx)      xx ( xx)      xx ( xx)
Blood and lymphatic system disorders                                                    xx ( xx)      xx ( xx)      xx ( xx)
Thrombocytopenia                                                                     xx ( xx)      xx ( xx)      xx ( xx)
Neutropenia                                                                         xx ( xx)      xx ( xx)      xx ( xx)
Leukopenia NOS                                                                       xx ( xx)      xx ( xx)      xx ( xx)
Anaemia NOS                                                                          xx ( xx)      xx ( xx)      xx ( xx)
Febrile neutropenia                                                                  xx ( xx)      xx ( xx)      xx ( xx)
              Granulocytopenia                                                                     xx ( xx)      xx ( xx)      xx ( xx)
Pancytopenia                                                                         xx ( xx)      xx ( xx)      xx ( xx)
Polycythaemia NOS                                                                    xx ( xx)      xx ( xx)      xx ( xx)
Myelosuppression                                                                     xx ( xx)      xx ( xx)      xx ( xx)
Skin and subcutaneous tissue disorders                                                  xx ( xx)      xx ( xx)      xx ( xx)
Pruritus                                                                            xx ( xx)      xx ( xx)      xx ( xx)
Rash NOS                                                                             xx ( xx)      xx ( xx)      xx ( xx)
Dry skin                          
xx ( xx)      xx ( xx)      xx ( xx)
Rash pruritic                                                                        xx ( xx)      xx ( xx)      xx ( xx)
Ecchymosis                                                                           xx ( xx)      xx ( xx)      xx ( xx)
Erythema                                                                             xx ( xx)      xx ( xx)      xx ( xx)
          Night sweats                                                                         xx ( xx)      xx ( xx)      xx ( xx)
Rash erythematous                                                                    xx ( xx)      xx ( xx)      xx ( xx)
Rash macular                                                                         xx ( xx)      xx ( xx)      xx ( xx)
Rosacea                                                                              xx ( xx)      xx ( xx)      xx ( xx)
Skin lesion NOS                                                                      xx ( xx)      xx ( xx)      xx ( xx)
Sweating increased                                                                   xx ( xx)      xx ( xx)      xx ( xx)
Urticaria NOS                                                                        xx ( xx)      xx ( xx)      xx ( xx)
Acute febrile neutrophilic dermatosis                                                xx ( xx)      xx ( xx)      xx ( xx)
Alopecia                                                                             xx ( xx)      xx ( xx)      xx ( xx)
Contusion          
xx ( xx)      xx ( xx)      xx ( xx)
Exanthem                                                                             xx ( xx)      xx ( xx)      xx ( xx)
   Face oedema                                                                          xx ( xx)      xx ( xx)      xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
[a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, descending order of frequency for the Total 
column).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path:
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
e xx of xx
e xx of xx
(Interim
Interim)
Clas
Cla s 
s 
——————————
—————————
Treatment
Treatment
     (N=xx
     (
      n   
     n  
—————————
—————————
( xx)     
( xx) 
xx ( xx) 
xx ( xx)
   xx ( xx
xx ( 
xx ( 
x ( 
      xx 
    
        xx
       
          
          
         
        
         
       
          
         
          
       
         
         
          
         
          
        
         
        
          
       
          
        
         
        
         
         
         
         
          
        
          
        
  
         
         
          
       
          
         
——————————
—————
preferred 
preferred 
erms are li
ms are l
FXUUHQFHVR
FXUUHQFHVR


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
72
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                    DB (Interim) Lock Date:
Table 14.3.2.5
Number (%) of Subjects With Treatment-Emergent Adverse Events by System Organ Class and  Maximum CTC AE Grade (Maximum Severity)
- (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A     Treatment B      Treatment C      Treatment D
 (N=xx)          (N=xx)           (N=xx)           (N=xx)
System organ class/ Preferred term / Intensity [a]                    n   (%)          n   (%)         n   (%)         n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one adverse event by maximum grade (severity)  xx ( xx)        xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Blood and lymphatic system disorders                          
xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                               xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Cardiac disorders                                                     xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                          
xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Ear and labyrinth disorders                                           xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
  Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)       xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Note:  NCI CTC=National Cancer Institute Common Toxicity Criteria Version 2.  
[a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of the dictionary used).  
System organ classes are presented alphabetically and preferred terms are presented alphabetically within each system organ 
                 class. 0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS and A subject with multiple 
NCI CTC grades (severity ratings) for an AE is only counted under the maximum grade (severity).
Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
age xx of 
ge xx of 
DB (
DB Inter
ter
CTC AE Gr
CTC AE G
————————
——————— —
     Trea
    Trea
         
         
(%)        
(%)       
—————————
—————
xx ( xx)  
x ( xx)  
  xx ( xx
  xx ( x
    xx ( x
  xx ( 
      xx 
    
        xx
        x
)         
        
( xx)      
xx)     
x ( xx)    
 ( xx)    
xx ( xx)  
xx ( xx)
 xx ( xx)
 xx ( xx)
   xx ( x
   xx ( x
     xx ( 
    xx (
        x
        
         
         
          
        
      
    
          
        
          
       
          
          
          
        
         
   
         
        
          
      
—————————
—————
titute Com
titute Com
ferred ter
ferred te
resented a
resented a
HVRIWKHVD
VRIWKHVD
an AE is o
AE is 


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
73
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
Table 14.3.2.6
Number (%) Subjects With TEAE Related to Study Drug by System Organ Class, Preferred Term, Treatment Group, and 
Maximum NCI CTC Grade (Maximum Severity) - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A     Treatment B      Treatment C      Treatment D
                          (N=xx)          (N=xx)           (N=xx)           (N=xx)
System organ class/ Preferred term / Intensity [a]                    n   (%)          n   (%)         n   (%)         n   (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             Subjects with at least one related TEAE 
by maximum grade (severity)                                           xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Blood and lymphatic system disorders                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                            
xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Cardiac disorders                                                     xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                                xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Ear and labyrinth disorders                                   
xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 1/Mild                                                    xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 2/Moderate                                               xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 3/Severe                                                  xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Grade 4/Life-threatening                                        xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
Missing Grade                                                   xx ( xx)         xx ( xx)        xx ( xx)        xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Note:  NCI CTC=National Cancer Institute Common Toxicity Criteria Version 2.  
[a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of the dictionary used).  
System organ classes are presented alphabetically.  Preferred terms are presented alphabetically within each system organ class.  
0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS  A subject with multiple NCI CTC 
grades 
(severity ratings) for an AE is only counted under the maximum grade (severity).
Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
e xx of 
xx of xx
xx
B (Interim
Interim
p, and 
p, and 
—————————
—————
eatment C 
atment C 
 (N=xx)  
 (N=xx)  
   n   (%
  n   (%
—————————
——————
xx)       
xx)       
( xx)      
xx)  
x ( xx)    
x ( xx)   
xx ( xx)  
xx ( xx) 
  xx ( xx)
xx ( x
   xx ( x
  xx ( x
         x
         x
x)        
        
xx)      
xx)    
( xx)    
( xx)    
xx ( xx)   
xx ( xx)
xx ( xx) 
xx ( xx) 
    xx ( 
    xx (
      xx 
      xx 
        xx
        xx
          
        
         
       
         
        
         
       
          
        
         
         
          
        
          
    
—————————
—————————
tute Common
tute Commo
rred terms 
rred terms 
ented alph
ented al
VDPHSUHIHU
VDPHSUHIH
an AE i
 AE is o
s o


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
74
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
Table 14.3.2.7
                   Number (%) of Subjects With Adverse Events With CTC AE Grade 5 by System Organ Class - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B    Treatment C
(N=xx)       (N=xx)       (N=xx)
System organ class/ Preferred term [a]                                             n    (%)     n    (%)     n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one NCI CTC Grade 5 adverse event                           xx ( xx)     xx ( xx)     xx ( xx)
Infections and infestations                                                       xx ( xx)     xx ( xx)     xx ( xx)
Pneumonia NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Sepsis NOS                                                                      xx ( xx)     xx ( xx)     xx ( xx)
Bacteraemia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Cellulitis              
xx ( xx)     xx ( xx)     xx ( xx)
Infection NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Central line infection                                                          xx ( xx)     xx ( xx)     xx ( xx)
Clostridial infection NOS                                                       xx ( xx)     xx ( xx)     xx ( xx)
Enterobacter sepsis                                                             xx ( xx)     xx ( xx)     xx ( xx)
Fungal infection NOS                                                            xx ( xx)     xx ( xx)     xx ( xx)
Influenza                                                                       xx ( xx)     xx ( xx)     xx ( xx)
Klebsiella sepsis                                                               xx ( xx)     xx ( xx)     xx ( xx)
       Lobar pneumonia NOS                                                             xx ( xx)     xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                                               xx ( xx)     xx ( xx)     xx ( xx)
Neutropenia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Thrombocytopenia                                                                xx ( xx)     xx ( xx)    xx ( xx)
Anaemia NOS                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Febrile neutropenia                                                             xx ( xx)     xx ( xx)     xx ( xx)
Leukopenia NOS                                                                  xx ( xx)     xx ( xx)     xx ( xx)
Pancytopenia                                                                    xx ( xx) 
xx ( xx)     xx ( xx)
Coagulopathy                                                                    xx ( xx)     xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             Note:  NCI CTC=National Cancer Institute Common Toxicity Criteria Version 2.  
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical,)
0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path: 
Data source:  AE (death page?)
&(/*(1(35235,(7$5<,1)250$7,21
  Page 
 Page xx
xx
    DB (
   DB (I
Population
Populatio
—————————
———————
eatment B 
eatment 
  (N=xx)  
 (N=xx)  
  n    (%
  n    (%
—————————
—————
xx)     xx
xx)     x
x ( xx)   
x ( xx)  
xx ( xx) 
x ( xx) 
xx ( xx
xx 
    xx ( x
   xx ( 
xx (
xx 
       xx
       xx
         
       
          
          
          
        
          
        
         
         
          
        
          
          
         
         
         
        
          
      
          
        
          
     
         
         
         
       
          
      
—————————
————————
itute Commo
tute Comm
erred terms
erred terms
are listed
are liste
WHUPIURPD
WHUPIURPD
th page?)
th page?)


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
75
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
Table 14.3.2.8
Number (%) of Subjects With Treatment-Emergent SAE by System Organ Class - (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B   Treatment C
(N=xx)       (N=xx)       (N=xx)
System organ class/ Preferred term [a]                                             n    (%)     n    (%)     n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TESAE                                                   xx ( xx)     xx ( xx)     xx ( xx)
Infections and infestations                                                        xx ( xx)     xx ( xx)     xx ( xx)
Pneumonia NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Sepsis NOS                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Bacteraemia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Cellulitis                                                                      xx ( xx)     xx ( xx)     xx ( xx)
Infection NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Central line infection                                                          xx ( xx)     xx ( xx)     xx ( xx)
Clostridial infection NOS                                                       xx ( xx)     xx ( xx)     xx ( xx)
Enterobacter sepsis                                                             xx ( xx)     xx ( xx)     xx ( xx)
Fungal infection NOS                                                            xx ( xx)     xx ( xx)     xx ( xx)
Influenza                                                                       xx ( xx)     xx ( xx)     xx ( xx)
Klebsiella sepsis                                                               xx ( xx)     xx ( xx)     xx ( xx)
Lobar pneumonia NOS                                                             xx ( xx)     xx ( xx)     xx ( xx)
Sinusitis NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Sinusitis acute NOS                                                             xx ( xx)     xx ( xx)     xx ( xx)
Urinary tract infection NOS                                                     xx ( xx)     xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                                               xx ( xx)     xx ( xx)     xx ( xx)
Neutropenia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Thrombocytopenia                                                                xx ( xx)     xx ( xx)     xx ( xx)
Anaemia NOS                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Febrile neutropenia                                                             xx ( xx)     xx ( xx)     xx ( xx)
Leukopenia NOS                                                                  xx ( xx)     xx ( xx)     xx ( xx)
Pancytopenia                                                                    xx ( xx)     xx ( xx)     xx ( xx)
Coagulopathy                                               
xx ( xx)     xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, 
                 ).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
Page xx o
Page xx o
  DB (
 DB Inte
nt
Population
opulation
—————————
———————
tment B   
ment B   
(N=xx)    
(N=xx)  
n    (%)  
n    (%) 
—————————
—————————
)     xx (
    
( xx)     x
xx)     
x ( xx)    
xx)  
xx ( xx)  
x ( xx) 
 xx ( xx)
 xx 
xx ( x
xx ( 
     xx ( 
     xx ( 
       xx 
     xx 
        x
       
         
         
          
       
          
          
          
          
         
        
         
         
          
         
          
        
         
        
         
       
          
       
         
        
          
         
         
         
         
        
          
    
—————————
————————
ferred term
ferred te
s are liste
are liste
RIWKHVDPH
RIWKHVDPH


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
76
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
77
Celgene Corporation                                                
Page xx of xx
Protocol:                                                                                                         DB (Interim) Lock Date:
                                 Table 14.3.2.9
Number (%) of Subjects With Treatment-Emergent SAE Related to Study Drug by System Organ Class -
(Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B     Treatment C
(N=xx)       (N=xx)       (N=xx)
System organ class/ Preferred term [a]                                            n    (%)     n    (%)     n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TESAE related to study drug                             xx ( xx)     xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                                               xx ( xx)     xx ( xx)     xx ( xx)
Neutropenia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Febrile neutropenia                                                             xx ( xx)     xx ( xx)     xx ( xx)
Thrombocytopenia                                                                xx ( xx)     xx ( xx)     xx ( xx)
Leukopenia NOS                                                                  xx ( xx)     xx ( xx)     xx ( xx)
Anaemia NOS                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Pancytopenia                                                                    xx ( xx)     xx ( xx)     xx ( xx)
Infections and infestations                                                        xx ( xx)     xx ( xx)     xx ( xx)
Pneumonia NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
           Cellulitis                                                                      xx ( xx)     xx ( xx)     xx ( xx)
Clostridial infection NOS                                                       xx ( xx)     xx ( xx)     xx ( xx)
Infection NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Klebsiella sepsis                                                               xx ( xx)     xx ( xx)   
xx ( xx)
Lobar pneumonia NOS                                                             xx ( xx)     xx ( xx)     xx ( xx)
General disorders and administration site conditions                               xx ( xx)     xx ( xx)     xx ( xx)
Pyrexia                                                                         xx ( xx)     xx ( xx)     xx ( xx)
Asthenia                                                                        xx ( xx)     xx ( xx)     xx ( xx)
Fatigue                                                                         xx ( xx)     xx ( xx)     xx ( xx)
Respiratory, thoracic and mediastinal disorders                              
xx ( xx)     xx ( xx)     xx ( xx)
Pulmonary embolism                                                              xx ( xx)     xx ( xx)     xx ( xx)
Pulmonary hypertension NOS                                                     xx ( xx)     xx ( xx)     xx ( xx)
Pleural effusion                                                                xx ( xx)     xx ( xx)     xx ( xx)
Respiratory distress                                                            xx ( xx)     xx ( xx)     xx ( xx)
Skin and subcutaneous tissue disorders                                             xx ( xx)     xx ( xx)     xx ( xx)
Rash NOS                                                                        xx ( xx)     xx ( xx)     xx ( xx)
Acute febrile neutrophilic dermatosis                                           xx ( xx)     xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
                 classes and preferred terms are listed in (specify order of appearance, e.g., alphabetical, 
                ).  0XOWLSOHRFFXUUHQFHVRIWKHVDPHSUHIHUUHGWHUPIURPDSDWLHQWDUHFRXQWHGRQO\RQFHZLWKLQHDFKWUHDWPHQWJURXS
Program path: 
Data source:  AE
Page xx 
Page xx
   DB (
   DB (In
an Class 
an Class -
—————————
———————
eatment B 
eatment
 (N=xx)   
(N=xx)  
  n    (%)
 n    (%
——————————
—————————
xx)     xx 
xx)     x
 ( xx)    
xx)  
xx ( xx)  
x ( xx)  
 xx ( xx)
 xx 
   xx ( xx
   xx (
     xx ( 
     xx ( 
      xx 
     xx 
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
78
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
79
Celgene Corporation                                                                                               Page xx of xx
Protocol:                                                                                                        DB (Interim) Lock Date:
Table 14.3.2.10
Number (%) of Subjects With TEAE Leading to Discontinuation of Study Drug by System Organ Class -
(Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Treatment A   Treatment B    Treatment C
                       (N=xx)       (N=xx)       (N=xx)
System organ class/ Preferred term [a]                                             n    (%)     n    (%)     n    (%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE leading to discontinuation of study drug           xx ( xx)     xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                                               xx ( xx)     xx ( xx)     xx ( xx)
Neutropenia                                                                     xx ( xx)     xx ( xx)     xx ( xx)
Febrile neutropenia                                                             xx ( xx)     xx ( xx)     xx ( xx)
Thrombocytopenia                                                                xx ( xx)     xx ( xx)     xx ( xx)
Leukopenia NOS                                                                  xx ( xx)     xx ( xx)     xx ( xx)
Anaemia NOS                                                                     xx ( xx)     xx ( xx)     xx ( xx)
    Pancytopenia                                                                    xx ( xx)     xx ( xx)     xx ( xx)
Infections and infestations                                                        xx ( xx)     xx ( xx)     xx ( xx)
              Pneumonia NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Cellulitis                                                                      xx ( xx)     xx ( xx)     xx ( xx)
Clostridial infection NOS                                                       xx ( xx)     xx ( xx)     xx ( xx)
Infection NOS                                                                   xx ( xx)     xx ( xx)     xx ( xx)
Klebsiella sepsis                                                               xx ( xx)     xx ( xx)     xx ( xx)
Lobar pneumonia NOS                                                             xx ( xx)     xx ( xx)     xx ( xx)
General disorders and administration site conditions                               xx ( xx)     xx ( xx)     xx ( xx)
Pyrexia                                                                         xx ( xx)     xx ( xx)     xx ( xx)
Asthenia                                                                        xx ( xx)     xx ( xx)     xx ( xx)
Fatigue                                                                   
xx ( xx)     xx ( xx)     xx ( xx)
Respiratory, thoracic and mediastinal disorders                                    xx ( xx)     xx ( xx)     xx ( xx)
Pulmonary embolism                                                              xx ( xx)     xx ( xx)     xx ( xx)
Pulmonary hypertension NOS                                                      xx ( xx)     xx ( xx)     xx ( xx)
Pleural effusion                                                                xx ( xx)     xx ( xx)     xx ( xx)
Respiratory distress                                                            xx ( xx)     xx ( xx)     xx ( xx)
Skin and subcutaneous tissue disorders         
xx ( xx)     xx ( xx)     xx ( xx)
Rash NOS                                                                        xx ( xx)     xx ( xx)     xx ( xx)
Acute febrile neutrophilic dermatosis                                           xx ( xx)     xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary (indicate version of dictionary used).  System organ 
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Program path: 
Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
Page xx o
Page xx o
DB (
DB Inte
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—————————
———————
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(N=xx)    
(N=xx)  
n    (%)  
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene International
Confidential and Proprietary
80
Celgene Corporation                                                                                           Page xx of xx
Protocol:                                                                                                     DB (Interim) Lock Date:
                                     Table 14.3.2.2.1
Number (%) of Subjects With Treatment-Emergent Adverse Events by System Organ Class and Age Group -
          (Safety Population)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
         Treatment A             Treatment B                Treatment C
(N=xx)                  (N=xx)                   (N=xx)
                                  ——————————————————————— ——————————————————————— ———————————————————————
<65         >=65        <65         >=65        <65         >=65
        System organ class/ Preferred term [a]                           (N=xx)      (N=xx)      (N=xx)      (N=xx)      (N=xx)      (N=xx)
n(%)        n(%)        n(%)         n(%)        n(%)         n(%)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Subjects with at least one TEAE                          
xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Blood and lymphatic system disorders                           xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Thrombocytopenia                                            xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Neutropenia                                                 xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Anaemia NOS                                                 xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Leukopenia NOS                                              xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Febrile neutropenia                                         xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Pancytopenia                                               xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Granulocytopenia                                            xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Lymphadenopathy                                             xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Polycythaemia NOS                                           xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Splenomegaly                                                xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Coagulopathy                                                xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Haemolytic anaemia NOS                                      xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Leukocytosis                                                xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Lymphocytosis                                               xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Monocytosis                                                 xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Myelosuppression                                            xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
Thrombocythaemia                                            xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)    xx ( xx)     xx ( xx)
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
             [a] System organ classes and preferred terms are coded using the MedDRA dictionary(indicate the version of the dictionary used).  
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Program path: 
    Data source:  AE
&(/*(1(35235,(7$5<,1)250$7,21
Page xx
Page xx
    DB (
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—————————
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——————————
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Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
81
Qol tables
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
82
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
83
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
84
Efficacy Tables
Summary of TTE
Population
Statistics
Arm A
(N = xxx)
Arm B
(N = xxx)
Total
(N = xxx)
Subjects included
N
xxx
xxx
xxx
Died
n(%)
xx (%)
xx (%)
xx (%)
Censored
n(%)
xx (%)
xx (%)
xx (%)
TTE since 
randomization (weeks)
Median
xx
xx
xx
95% CI
(xx , xx)
(xx , xx)
(xx , xx)
Hazard Ratio (A:B)
HR (95 CI)
x.xxx (x.xxx , x.xxx)
Log rank
Two sided P - value
0.xxx
xyz Test
Two sided P - value
0.xxx
uvw Test
Two sided P - value
0.xxx
TTE follow up
n(%)
xx (%)
xx (%)
xx (%)
Median (min , max)
xx (xx , xx)
xx (xx , xx)xx
xx (xx , xx)xx
Footnote: 
Source: sas code location 
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23


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
85
Summary of TTE Survival Rates
Population
Arm A
(N = xxx)
Arm B
(N = xxx)
Arm A - B
(N = xxx)
Endpoint / Time Points
Estimate (95% CI)
Estimate (95% CI)
Estimate (95% CI)
P - value
Endpoint #1
Interval 1
xx (%)
xx (%)
xx (%)
0.xxx
Interval 2
xx (%)
xx (%)
xx (%)
0.xxx
Interval 3
xx (%)
xx (%)
xx (%)
0.xxx
Endpoint #2
Interval 1
xx (%)
xx (%)
xx (%)
0.xxx
Interval 2
xx (%)
xx (%)
xx (%)
0.xxx
Interval 3
xx (%)
xx (%)
xx (%)
0.xxx
Endpoint #3
Interval 1
xx (%)
xx (%)
xx (%)
0.xxx
Interval 2
xx (%)
xx (%)
xx (%)
0.xxx
Interval 3
xx (%)
xx (%)
xx (%)
0.xxx
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xx (%
xx (%)
xx (%)
xx (%)
xx (%)
xx (%
xx (
3


Lenalidomide/CC-5013
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
86
                           Summary of Response Rates
Population
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
len/D                     len/d                    Overall
n   (%)             
n   (%)                   n   (%)
—————————————————————————————————————————————————————————————
———
Number of Patients: (N  (%))                                
Response [a]
Complete Response (CR)                                   
Near Complete Response (N-CR)                            
Partial Response (PR)                                    
Minimal Response (MR)                                    
Stable Disease (SD)                                      
Progressive Disease (PD)                                 
Response Not Evaluable (NE)[b]                           
Dichotomized response (Response not incl. MR)
CR or N-CR or PR                                         
MR or SD or PD or NE                                     
p-value [c]                                              
Odds ratio (len/D:len/d) (95% CI)[d]                     
Dichotomized response (Response incl. MR)
CR or N-CR or PR or MR           
SD or PD or NE                                           
p-value [c]                                              
Odds ratio (len/D:len/d) (95% CI)[d]                     
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Note: Response in this table is based on the review of all lymphoma assessment data using modified EBMT criteria.
IRAC=Independent Response Assessment Committee
[a] Response is the best assessment of response during the treatment phase of the study.
[b] Including patients who did not have adequate data for response assessment at baseline and/or post-baseline prior to the use of any
non-protocol anti-lymphoma therapy.
[c] Probability from Fisher's Exact test.
[d] CI=Confidence Interval
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
1
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
TITLE PAGE
A PHASE 2, MULTICENTER, RANDOMIZED OPEN-LABEL 
STUDY TO DETERMINE THE EFFICACY OF LENALIDOMIDE 
(REVLIMID®) VERSUS INVESTIGATOR’S CHOICE IN 
PATIENTS WITH RELAPSED OR REFRACTORY MANTLE 
CELL LYMPHOMA
The “SPRINT” trial
STUDY DRUG:
Lenalidomide
PROTOCOL NUMBER:
CC-5013-MCL-002
DATE
21 October 2008
Amendment # 1
21 April 2009
Amendment # 2
14 December 2009
Amendment # 3
29 April 2011
Amendment # 4
27 September 2011
Amendment # 5
22 March 2013
Amendment # 6
31 May 2018
EudraCT NUMBER
2008-003389-25
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
Printed Name of Celgene Therapeutic Area Head
Date Signed __________________
dd/mmm/yy
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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May 2018
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2008-003
2008-003
tronic signa
ronic sig
5,(
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ene Thera
523


Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
2
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd/mmm/yy
Printed Name of Site Principal Investigator and Title
Site Number________
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, 
IRB/EC procedures, instructions from Celgene representatives, the Declaration of 
Helsinki, ICH Good Clinical Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations and local regulations governing the conduct of 
clinical studies.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
3
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
1.
STUDY CONTACT INFORMATION
Table 1:
Celgene Emergency Contact Information
Role in Study
Name
Address and Telephone Number
Responsible Clinical 
Research Physician / 
Medical Monitor
 
86 Morris Avenue 
Summit, NJ 07901
Phone :  
Mobile : 
Lead Study Manager
Celgene R&D SARL
Phone:  
Mobile : 
International Drug Safety 
Contact for EU countries
For Local Drug Safety 
Affiliate Office contact 
information, please refer 
to the Serious Adverse 
Event Report Form 
Completion Guidelines
Clinical Trial Safety
Celgene International Sàrl 
Route de Perreux 1
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Celgene Global Drug Safety
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Fax:    
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
4
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
2.
SYNOPSIS
Name of Sponsor/Company:  Celgene Corporation
Name of Investigational Product:  Lenalidomide/CC-5013
Protocol Number:  CC-5013-MCL-002
Protocol Title:  A Phase 2, multicenter, Randomized open-Label study to determine the 
efficacy of lenalidomide (revlimid®) versus investigator’s choice in patients with relapsed or 
refractory mantle cell lymphoma
Indication: Relapsed/refractory Mantle Cell Lymphoma (MCL)
Phase of development: Phase 2 Extended Access Phase
Study Duration:
Patients will continue study treatment until disease progression, unacceptable toxicity, or 
voluntary treatment withdrawal. Patients will be followed for survival until either 70% of the 
patients have died, or the median follow-up in responding patients is > 2 years, or the median 
duration of response (overall response and complete response [CR] / complete response 
unconfirmed [CRu]) has been reached, or 4 years from last patient randomized, whichever 
comes later, at which time the study will end for subjects still on lenalidomide treatment in 
countries where lenalidomide is available post-trial in the commercial setting. These subjects 
will have a “discontinuation from treatment” visit at the end of their 7 day rest period from 
their last on-study treatment cycle. At this “discontinuation from treatment” visit commercial 
lenalidomide will be dispensed to the subject. Between this visit and 28 days after, if a patient 
experiences a SAE, this SAE will be reported via the standard post marketing process. A 
pregnancy test should be performed 28 days post treatment discontinuation visit.
An Extended Access Phase will be made available for subjects on study treatment in 
countries where lenalidomide is only available under a clinical trial protocol as post-trial 
access. These subjects will have a “discontinuation from treatment” visit assessment prior to 
being transferred to the Extended Access Phase. 
The Extended Access Phase will end for ongoing subjects still on lenalidomide treatment as 
soon as lenalidomide can be accessed in the commercial setting. 
Guidance on the schedule of assessments for the Extended Access Phase is provided in 
Table 4.
The clinical database will be locked after the last eligible subject has been transferred to post-
trial access in the commercial setting or to the Extended Access Phase, whichever comes 
later. Clinical study data will no longer be collected on CRFs following the clinical database 
lock.
A 28-day safety follow-up assessment will not be required either for subjects transferred to 
post-trial access in the commercial setting or transferred to the Extended Access Phase (after 
the clinical database lock).
For subjects in the Extended Access Phase, SAE forms will be reported to Celgene Safety via 
the standard reporting process for SAEs (including second primary malignancies) in clinical 
trials and, drug accountability information will be reviewed periodically by the study monitor.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
5
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
The End of Trial is defined as either the date of the last visit of the last subject to complete 
the Extended Access Phase or the date of receipt of the last data point from the last subject in 
the Extended Access Phase, whichever comes later.
Objectives:
Primary: 
!
To compare the progression free survival (PFS) of lenalidomide monotherapy 
versus investigator’s choice single agent in patients with mantle cell lymphoma 
(MCL) who are refractory to their regimen or have relapsed once, twice or three 
times.
Secondary:
!
To determine the overall response rate (ORR) of lenalidomide monotherapy or 
investigator’s choice single agent in patients with relapsed or refractory MCL.
!
To evaluate the safety of lenalidomide monotherapy or investigator’s choice single 
agent in patients with relapsed or refractory MCL.
!
To determine the time to progression, and overall survival of patients with 
relapsed or refractory MCL who have received treatment with lenalidomide or 
investigator’s choice single agent.
!
To investigate the health-related quality of life (QoL) of patients treated with 
lenalidomide or investigator’s choice single agent treatment.
 
 
Protocol Amendment #4:
 
 
Study Endpoints:
Primary
!
Progression free survival defined as the time from randomization to the first 
observation of disease progression or death due to any cause. If the patient has not 
progressed or died, PFS will be censored at the time of last completed assessment 
when the patient was known not to have progressed. Patients who will receive a 
new treatment without documented progression will be censored at the last 
assessment date that the patient is known to be progression-free.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
6
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Secondary
!
Overall response rate (CR, CRu, and partial response [PR]) assessed by a 
modification of the International Workshop Response Criteria IWRC (Cheson, 
1999).
!
Duration of response
!
Tumor control rate (Rates for CR, CRu, PR, and stable disease [SD])  
!
Time to progression
!
Time to treatment failure
!
Time to tumor response
!
Overall survival (OS)
!
Safety
!
Quality of Life (EORTC QLQ-C30)
Background and Rationale:
Non-Hodgkin’s lymphoma (NHL) is a heterogeneous group of lymphoproliferative 
malignancies with differing patterns of behavior and responses to treatment (Armitage, 1993).  
Most (approximately 80-90%) of the NHLs are of B-cell origin and around 10-15% are of T-
cell origin. The prognosis depends on the histologic type, stage, and treatment. Mantle cell 
lymphoma (MCL) is a distinct subtype within B-cell non-Hodgkin’s lymphoma that is 
characterized by the t(11; 14)(q13; q32) chromosomal translocation subsequently leading to 
the overexpression of cyclin D1. This subtype accounts for approximately 5% of all newly 
diagnosed malignant lymphomas.  Although morphologically similar to indolent lymphomas, 
the natural history of MCL is more aggressive than that of indolent lymphomas.  CHOP 
chemotherapy, as well as more intensive chemotherapy regimens such as hyper-CVAD or 
autologous transplantation have been used, often in combination with anti-CD20 monoclonal 
antibody rituximab (Epner, 2007; Pan 2002).  Other agents, such as fludarabine based 
regimens, cytarabine, gemcitabine are also used to treat MCL (Tobinai, 2006).  However, 
MCL remains an incurable disease, and novel therapeutic strategies are needed. The 
increasing understanding of the MCL cell biology has led to the development of new 
therapeutic agents with antitumor activity that target crucial biological pathways, including 
cell cycle inhibitors (i.e. flavopiridol), mTOR inhibitors (i.e. temsirolimus, everolimus), 
proteasome inhibitors (bortezomib) and histone deacetylase inhibitors (Kouroukis, 2003;
Goy, 2005; O’Connor, 2005; Hess 2009). The combination of these new therapeutic 
strategies with existing standard chemotherapy regimens, and better risk stratification of the 
patients may change the management and outcome of MCL patients (Jares, 2008).
Lenalidomide is a member of immunomodulatory agents, IMiDs®, with potent immuno-
stimulatory, anti-angiogenic and pro-apoptotic activities in vitro. It has been shown to have 
efficacy in another B-cell malignancy, multiple myeloma.  Preliminary data is available on 
the activity of lenalidomide in relapsed or refractory MCL patients in two Celgene-sponsored 
clinical trials of lenalidomide in aggressive NHL, study CC-5013-NHL-002 and study CC-
5013-NHL-003.  In study CC-5013-NHL-002 of lenalidomide monotherapy in patients with 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
7
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
relapsed or refractory aggressive NHL (Wiernik, 2008), 15 of 49 patients had MCL. In these 
MCL patients lenalidomide therapy achieved an Overall Response Rate (ORR) of 53%. Three 
patients (20%) had a CR or unconfirmed CR, and 5 patients (33%) had a PR. The median 
duration of response was 13.7 months and median PFS was 5.6 months. The most common 
grade 4 adverse event was thrombocytopenia (13%) and the most common grade 3 adverse 
events were neutropenia (40%), leucopenia (27%), and thrombocytopenia (20%). 
(Habermann, 2009). In another ongoing study of lenalidomide monotherapy in patients with 
relapsed or refractory aggressive NHL (CC-5013-NHL-003), 57 of 217 patients had MCL 
(Witzig, 2011). In the 57 MCL patients who were evaluable for response assessment, 
lenalidomide therapy led to an objective response rate of 42% (25/57). Median progression-
free survival (PFS) was 5.7 months. Overall, the primary side effect of lenalidomide was 
reversible myelosuppression. Grades 3 or 4 neutropenia occurred in 41%, thrombocytopenia 
in 19%, anemia in 9.2%. Grade 3 and grade 4 febrile neutropenia occurred in only 2% of 
patients.
Based on these preliminary observations, the current study is being conducted to evaluate the 
activity and safety of lenalidomide in a larger population of patients with relapsed or 
refractory mantle cell lymphoma.
Study Design:
This is a multicenter, randomized, open-label, comparative controlled phase II study to 
determine the efficacy and safety of single agent lenalidomide over a concurrent control 
group treated with an investigator’s choice single agent in patients with mantle cell 
lymphoma who are refractory to their regimen or have relapsed once, twice or three times
(Figure 1). The study design aims to compare the PFS of lenalidomide therapy over a single 
agent of investigator’s choice. 
The investigator’s choice in the control arm comprises the monotherapy treatment with one of 
the following: chlorambucil, cytarabine, rituximab, fludarabine, or gemcitabine. The 
investigator shall choose the single agent of choice in the control arm for each patient prior to 
randomization on to the study. Patients in the investigator’s choice arm will have the option 
to switch to lenalidomide at time of progressive disease.
Patients will be stratified according to:
!
Time since diagnosis (<3 years or ≥ 3 years)
!
Time since last treatment (<6 months [refractory] or ≥ 6 months)
!
Prior stem cell transplant (yes or no)
Treatment and clinical characteristics will be assessed at screening/baseline, but not used for 
stratification:
!
Number of prior treatment lines (with description of treatment regimens, including 
first line treatment and stem cell transplant)
!
MCL International Prognostic Index (MIPI) score at time of initial diagnosis, if 
available
!
MIPI score at randomization
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
8
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
!
Ki-67 index in the original pathology specimen at diagnosis, if available or at time 
of relapse
!
Age and gender
!
Absolute lymphocyte counts at baseline
!
Time since last rituximab to cycle 1 day 1
The patients in the study will undergo three consecutive phases:  Screening phase, Treatment 
phase, and Follow-up phase.
Screening phase:
Patients will be screened for protocol eligibility within 28 days prior to randomization as 
outlined in Table 2: Schedule of Study Assessments.  Screening/baseline assessments will 
begin once the patient has accepted and signed the informed consent form. Complete blood 
count (CBC) and serum chemistry tests will be required within 7 days of first dose of study 
drug. Serology, for HBV (at least HBsAg, anti-HBs and anti-HBc) and for HCV will be 
required as screening assessment within 28 days of randomization in endemic areas.
Eligibility for the study is based on the local assessments (CBC, chemistry and serology as 
well as the local results of the archival tumor / lymph node biopsy) done during the 
screening/baseline phase of the study.
Confirmation of mantle cell lymphoma diagnosis by the central pathology is not required 
before randomization or treatment start, but will be performed centrally at a later stage. 
Eligibility for the study is based on assessment of the local pathology results by the 
investigator. Diagnosis based on needle aspirations are not considered acceptable pathologic 
data for entry in this study. 
The confirmation material submitted for Central Pathology Review must include a biopsy-
proven mantle cell lymphoma specimen, including overexpression of cyclin D1 by 
immunohistochemistry. In patients whose tumors are negative for Cyclin D1 overexpression, 
evidence of overexpression of cyclin D2 or D3 by immunohistochemistry will be acceptable. 
Tumor / lymph node biopsy specimen, which may be archival slides from specimen obtained 
at the time of initial diagnosis, with representative stained slides supporting the diagnosis of 
mantle cell lymphoma (H&E or Giemsa staining and Cyclin D1 staining), must be sent as 
soon as possible to central pathology before randomization but at the latest 8 weeks after 
randomization. It is highly recommended to submit also the original paraffin block (called 
tumor block) which will be returned to the original institution. If the tumor block cannot be 
sent, 4-5 additional unstained slides must be submitted. If such archival tissue is not available 
for submission, then a re-biopsy is required.
The translocation t(11;14)(q13:q32) by FISH is optional and is not sufficient as sole proof for 
diagnosis. Evidence of the translocation t(11;14)(q13:q32) by FISH can be submitted using 
the original slide or the corresponding confirming photographies. If available, it is also 
recommended to send, for central pathology review, slides containing immunostaining for
CD3, CD5, CD10, CD20, CD23, BCL2, Ki-67.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
9
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Furthermore, it is highly recommended to perform an unilateral bone marrow biopsy at 
screening, and to send it to Central Pathology for review at the latest 8 weeks after
randomization.
 
During the screening/baseline phase, the investigator must allocate one of the “investigator’s 
choice” options to the patient prior to the randomization.
Treatment phase:
Once all eligibility criteria are met and baseline assessments completed, patients will be 
randomized 2:1 to receive lenalidomide monotherapy or the investigator’s choice. The first 
treatment dose of the first cycle administered to the patient is called C1D1. Treatment should
start as soon as possible after randomization, but maximum time between randomization and 
C1D1 is 4 days, once the patient has fulfilled the requirements of the Lenalidomide
pregnancy prevention program (see Appendix 21.8). Patients will continue in the treatment 
phase until disease progression, unacceptable toxicity or voluntary treatment withdrawal. 
Toxicity will be assessed using the NCI CTCAE criteria version 3 and the dose of 
lenalidomide or the investigators choice single agent will be reduced accordingly (see Table 8
and Table 9 for dose reductions).
Serial assessments of safety and efficacy (CT scans with contrast /MRI with contrast every 56 
days ± 7 days for the first 6 months and then every 90 days ± 15 days thereafter) will be 
performed as outlined in the Schedule of Study Assessments or as directed in the dose 
modification section.  Patients may continue participation in the treatment phase of the study 
until disease progression or unacceptable toxicity or voluntary patient withdrawal from 
treatment, at which point, the patients will enter the follow-up phase.
Diagnostic imaging results (CT scan with contrast/MRI with contrast) will be reviewed 
locally and also sent for central review.
CT scans is the preferred procedure. If CT is contraindicated, MRI is acceptable. It is advised 
to stick to the same procedure for a given patient throughout the study.
 
 
 
 
 
  Patients who withdraw consent for treatment will continue to be followed for 
safety, efficacy (disease progression), second primary malignancies, and for survival.
Prophylaxis for TLS and thromboembolism and assessment and management of tumor 
flare in patients assigned to receive lenalidomide:
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leukemia treated with lenalidomide. Tumor flare and tumor lysis have also been noted in a 
smaller proportion of patients with non-Hodgkin’s lymphoma treated with lenalidomide, 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
10
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
based on limited data. Patients in this study should be monitored for tumor flare and tumor 
lysis.
Tumor lysis syndrome
Tumor lysis syndrome (TLS) is a well-known constellation of metabolic abnormalities 
resulting from spontaneous or treatment related tumor necrosis or fulminant apoptosis. The 
metabolic abnormalities include: hyperkalemia, hyperuricemia and hyperphosphatemia with 
secondary hypocalcaemia.
In patients with CLL, the onset of TLS is rapid, usually within 24 to 48 hours after the first 
dose but can also occur after the first week of treatment.  The presence of known risk factors 
like bulky disease, moderate renal insufficiency, high ALC and high uric acid levels (> 8 
mg/dL) prior to therapy increases the likelihood of TLS.  Early identification of patients 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, 2004).  
Patients in the lenalidomide arm in this study should receive tumor lysis prophylaxis 
(allopurinol or equivalent) and be well hydrated (orally) during the first 7 days of 
lenalidomide administration in the first cycle or as clinically indicated. Hydration levels 
should be adjusted according to age and clinical status. To monitor for tumor lysis syndrome 
and cytopenia(s), the patients will have a complete blood count (CBC) and chemistry drawn 
on Days 1, 2, 4, 8 and 15 of the first cycle and additionally as clinically indicated. TLS will 
be assessed by Cairo-Bishop Grading system. (See Appendix 21.6).
If a patient develops laboratory TLS (defined by the presence of two or more serum value 
abnormalities of uric acid, potassium, phosphorous or calcium) or ≥ Grade 1 TLS (defined by 
the presence of laboratory TLS and one or more of the following criteria: creatinine ≥ 1.5 x 
ULN, arrhythmia or seizures), appropriate medical management should be initiated according 
to the local standard of care in each institution with vigorous IV hydration (rasburicase 
treatment is considered appropriate if it is approved by the local Health Authority).
Tumor flare reaction 
Tumor flare reaction (TFR) is defined as a sudden and tender increase in the size of the 
disease bearing sites, including the lymph nodes, spleen and or the liver often accompanied 
by low-grade fever, non-pruritic diffuse rash and in some cases increase in the peripheral 
blood lymphocyte counts. In CLL patients, the onset of tumor flare may be as early as within 
a few hours after the first dose and has a median duration of 14 days. This usually occurs 
only during the first cycle of treatment. Tumor flare will be recorded as an AE (graded using 
the NCI CTCAE criteria version 3) and not as progressive disease (PD) and will be treated 
symptomatically first with non-steroidal anti-inflammatory agents (NSAIDs). Narcotics or 
prednisone may be used at the investigator’s discretion, to treat the tumor flare reaction.
Thromboembolism 
All patients treated with lenalidomide regardless of prior thromboembolic history will receive 
prophylactic aspirin [ASA] (70 – 100 mg) daily unless contraindicated.  If ASA is 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
11
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
contraindicated, use of low molecular weight heparin or warfarin (or equivalent Vitamin K 
antagonist) to keep the International normalized ratio (INR) in the range of 2-3 may be 
considered.
The choice of prophylactic agent(s), and also the interruption or discontinuation of such 
prophylaxis if needed, should be based on the local standard of care and the investigator’s 
best judgement after careful consideration of the benefit versus the potential risk for the 
individual patient.
Cross over (for patients in the investigators choice Arm B only): 
Patients in the investigator’s choice arm B, who have documented progressive disease will 
have the option to receive single agent lenalidomide treatment. Patients will undergo baseline 
assessments as outlined in the schedule of assessments of Table 3 for Cycle 1 Day 1. 
For patients in Arm B treatment with lenalidomide will start as soon as recovery from 
toxicities of prior treatments. The maximum duration between last day of last cycle of 
treatment in Arm B and first lenalidomide cycle is 10 weeks. Patients in cross-over treatment 
with lenalidomide will be assessed for safety, response evaluation, second primary 
malignancies, and overall survival follow-up. CT scans with contrast /MRI with contrast are 
recommended to be performed every 90 days (± 15 days) from the start of lenalidomide 
cross-over treatment until disease progression or treatment discontinuation for any other 
reason (i.e. toxicity) [Table 3]. Once a patient experiences disease progression or relapse or a 
patient has stopped treatment for other reasons the patient will enter the follow-up phase. In 
the follow-up phase for patients with progressive disease only assessments for safety 
(including second primary malignancies) and overall survival will be done. For patients who 
have entered the follow-up phase due to treatment discontinuation for other reasons 
additionally CT scans with contrast /MRI with contrast will be performed at pre-defined 
intervals and assessments for safety (including second primary malignancies) and overall 
survival will be done. Patients will be followed until either 70% of the patients have died or 
the median follow-up in responding patients is > 2 years or the median duration of response 
(overall response and CR/CRu) has been reached, or four years from last patient randomized, 
whichever comes later, at which time the study will end for ongoing subjects still on 
lenalidomide treatment in countries where lenalidomide is available post-trial in the 
commercial setting. Subjects on study treatment will be transferred to post-trial access in the 
commercial setting (wherever applicable). An Extended Access Phase will be made available 
for subjects on study treatment in countries where lenalidomide is only available under a 
clinical trial protocol as post-trial access. The Extended Access Phase will end for ongoing 
subjects as soon as lenalidomide can be accessed in the commercial setting.
Follow-up phase
Subjects withdrawn for any reason from the Extended Access Phase will not participate in a 
study follow-up phase. At their next visit 28 days later any SAEs experienced during this time 
window will be reported via the standard post-marketing process. Thereafter prescribers will 
be expected to follow the normal post-marketing SAE reporting requirements as applicable in 
their country
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
12
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Once a patient experiences disease progression or relapse or a patient has stopped treatment 
for other reasons, the patient will enter the follow up phase.  
!
All patients who discontinue treatment in either study arm or cross-over 
treatment will undergo a safety follow-up visit 28 days after last dosing day for 
assessment of adverse events (including a physical examination), lenalidomide 
counseling and for a medically supervised pregnancy test for FCBP in Arm A and 
in cross over as specified in Appendix 21.8. Vital signs, CBC with differential, 
and serum chemistry are to be performed as clinically indicated. A 28-day safety 
follow-up assessment will not be required either for subjects transferred to post-
trial access in the commercial setting or to the Extended Access Phase. These 
subjects will have a “discontinuation from treatment” visit at the end of their 7 day 
rest period from their last on-study treatment cycle. At this “discontinuation from 
treatment” visit commercial lenalidomide will be dispensed to the subject. 
Between this visit and 28 days after, if a patient experiences a SAE, this SAE will 
be reported via the standard post marketing process. A pregnancy test should be 
performed 28 days post treatment discontinuation visit.
!
Patients who discontinue treatment due to progressive disease or relapse:
∀
Should be followed by clinic visit or documented telephone contact every 90 
days (± 15 days) for survival, second primary malignancies and for the first 
subsequent antilymphoma therapy (including the time of and best response to 
the first antilymphoma treatment regimen utilized after discontinuation from 
treatment in this study)
!
Patients who discontinued treatment due to reasons other than progressive 
disease or relapse:
∀
Clinic visits should occur every 56 days to assess disease status (physical 
exam) until disease progression or relapse
∀
CT scan with contrast/MRI with contrast should occur every 56 days (± 7 
days) until disease progression or relapse up to 6 months from the start of 
study drug then every 90 days ± 15 days thereafter.
∀
After disease progression or relapse has occurred, patients should be followed 
by clinic visit or documented telephone contact every 90 days (± 15 days) for 
survival, second primary malignancies and for the first subsequent 
antilymphoma therapy (including the time of and best response to the first 
antilymphoma treatment regimen utilized after discontinuation from treatment 
in this study).
∀
Patients in the follow-up phase who withdraw consent for efficacy (disease 
progression) follow-up will continue to be followed for second primary 
malignancies and for survival. A full consent withdrawal must be documented 
to disallow survival follow up.
The follow-up phase will continue until either 70% of the patients have died or the median 
follow-up in responding patients is > 2 years or the median duration of response (overall 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
13
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
response and CR/CRu) has been reached, or four years from last patient randomized, 
whichever comes later, at which time the follow-up study phase will be closed.
Extended Access Phase:
Following the approval of Protocol Amendment #6 an Extended Access Phase will be made 
available for subjects on study treatment in countries where lenalidomide is only available 
under a clinical trial protocol as post-trial access.
These subjects will have a “discontinuation from treatment” visit assessment prior to being 
transferred to the Extended Access Phase.
Following the approval of Protocol Amendment #6, subjects on study treatment will be 
considered to have entered the study Extended Access Phase. Study visits and serial 
measurements of safety should continue to be performed as per guidance outlined in Table 4.
Subjects may remain on study until progressive disease or withdrawal for other reasons. Only 
serious adverse events (SAEs) including second primary malignancies (SPMs), and drug 
accountability record information will be collected and reported for these subjects. Follow-up 
survival data will no longer be collected by Celgene for these subjects.
The Extended Access Phase will end for ongoing subjects still on lenalidomide treatment as 
soon as lenalidomide can be accessed in the commercial setting.
Data Monitoring Committee 
An independent external Data Monitoring Committee (DMC) will review ongoing safety data 
throughout the study and efficacy for futility at a pre-defined time point. Specifics are 
outlined in the DMC charter. The first safety analysis will occur after the first 40 patients 
have received at least 2 cycles of treatment or have discontinued prior to completing 2 cycles.  
The second safety analysis as well as an efficacy analysis for futility will occur after 80
patients complete 2 cycles or withdraw before completing 2 cycles. A third safety analysis 
will occur after 120 patients complete 2 cycles or withdraw before completing 2 cycles. A 
fourth safety analysis will occur after 200 patients complete 2 cycles or withdraw before 
completing 2 cycles.
Independent External Pathological Review
An independent central pathologist will review the lymph node/tumor biopsy for 
retrospective confirmation of the diagnosis of mantle cell lymphoma. 
The confirmation material submitted for Central Pathology Review must include a biopsy-
proven mantle cell lymphoma specimen, including overexpression of cyclin D1 by 
immunohistochemistry. In patients whose tumors are negative for Cyclin D1 overexpression, 
evidence of overexpression of cyclin D2 or D3 by immunohistochemistry will be acceptable. 
Tumor / lymph node biopsy specimen, which may be archival slides from specimen obtained 
at the time of initial diagnosis, with representative stained slides supporting the diagnosis of 
mantle cell lymphoma (H&E or Giemsa staining and Cyclin D1 staining), must be sent as 
soon as possible to central pathology before randomization, but at the latest 8 weeks after 
randomization. It is highly recommended to submit also the original paraffin block (called 
tumor block) which will be returned to the original institution. If the tumor block cannot be 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
14
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
sent, 4-5 additional unstained slides must be submitted. If such archival tissue is not available 
for submission, then a re-biopsy is required.
The translocation t(11;14)(q13:q32) by FISH is optional and is not sufficient as sole proof for 
diagnosis. Evidence of the translocation t(11;14)(q13:q32) by FISH can be submitted using 
the original slide or the corresponding confirming photographies. If available, it is also 
recommended to send, for central pathology review, slides containing immunostaining for
CD3, CD5, CD10, CD23, CD20, BCL2, Ki-67.
Furthermore, it is highly recommended to perform an unilateral bone marrow biopsy at 
screening, and to send the tumor block to Central Pathology for review at the latest 8 weeks 
after randomization.
 
The central pathologist will also review any pathology specimens obtained as part of response 
assessment, including assessment of bone marrow biopsy required for response assessment of 
CR/CRu.  
For further details, please refer to central pathology manual.
Independent Review Committee (IRC):
The IRC is composed of two external independent radiologists (with an additional radiologist 
adjudicator in the event of a tie) and a hemato/-oncologist. The IRC will perform a blinded, 
independent assessment of radiological response (including assessment of Stable Disease 
[SD] and Progressive Disease [PD]); review the tumor response data and the dates of disease 
progression for each patient. The data reviewed by the IRC will be used in the primary 
analysis and these assessments will be included in the Clinical Study Report. 
∀
Number of patients: approximately 250 randomized patients 
Study Population 
Inclusion Criteria
!
Patients with histologically proven mantle cell non-Hodgkin’s lymphoma [MCL] 
{including overexpression of cyclin D1 by immunohistochemistry}. In patients 
whose tumors are negative for the cyclin D1 overexpression or translocation, 
evidence of overexpression of cyclin D2 or D3 by immunohistochemistry will be 
acceptable.
!
Patients who are refractory to their regimen or have relapsed once, twice or three 
times and who have documented progressive disease (Refractory to prior 
chemotherapy regimens is defined as not having reached a CR or PR to prior 
treatment)
!
Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 
2
!
Must be #18 years of age at the time of signing the informed consent form.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
15
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
!
Must have had at least one prior combination chemotherapy regimen with an 
alkylating agent, and comprising either an anthracycline and/or cytarabine and/or
fludarabine (with or without rituximab)
!
Prior stem cell transplant is allowed.
!
Must be ineligible for intensive chemotherapy and/or transplant at time of 
inclusion in the study
!
Must have measurable disease on cross sectional imaging by CT (or MRI, if CT is 
contraindicated) that is at least 2 cm in the longest diameter and measurable in two 
perpendicular dimensions
!
Must be able to adhere to the study visit schedule and other protocol requirements
!
Life expectancy of greater than 3 months
!
Females of childbearing potential (FCBP)† must:
∀
Have two negative medically supervised pregnancy tests prior to starting of 
study therapy. She must agree to ongoing pregnancy testing during the course 
of the study, and after end of study therapy (see specifics in Appendix 21.8).
This applies even if the patient practices complete and continued sexual 
abstinence
∀
Either commit to continued abstinence from heterosexual intercourse (which 
must be reviewed on a monthly basis) or agree to use, and be able to comply 
with, highly effective contraception without interruption, at least 28 days prior 
to starting study drug, during the study therapy (including dose interruptions), 
and for at least 28 days after discontinuation of study therapy (see specifics in 
Appendix 21.8) 
!
Male patients must:
∀
Agree to use a condom during sexual contact with a FCBP, even if they have 
had a vasectomy, throughout study drug therapy, during any dose interruption 
and after cessation of study therapy (see specifics in Appendix 21.8). Agree to 
not donate semen or sperm during study drug therapy and for at least 28 days 
after end of study drug therapy (see specifics in Appendix 21.8 )
!
All patients must:
∀
Have an understanding that the study drug could have a potential teratogenic 
risk.  
∀
Agree to abstain from donating blood while taking study drug therapy and for 
at least 28 days after end of study drug therapy (See specifics in 
Appendix 21.8)
∀
Agree not to share study medication with another person.
∀
Agree to be counseled about pregnancy precautions and risks of fetal 
† Definition found in appendices
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
16
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
exposure.  (See specifics in Appendix 21.8)
Exclusion Criteria
!
Diagnosis of lymphoma other than mantle cell lymphoma
!
Prior history of malignancies, other than mantle cell lymphoma, unless the patient 
has been free of the disease for ≥ 5 years. Exceptions include the following:
∀
Basal cell carcinoma of the skin
∀
Squamous cell carcinoma of the skin
∀
Carcinoma in situ of the cervix
∀
Carcinoma in situ of the breast
∀
Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
!
Transformed lymphoma
!
Prior use of lenalidomide
!
Patients who are candidates for autologous or allogeneic transplantation at the 
time of inclusion in the study
!
Prior allogeneic transplantation with persistent donor hematopoiesis
!
Prior radiotherapy within 4 weeks prior to randomization
!
Active CNS lymphoma with the exception of those patients whose CNS 
lymphoma has been treated with chemotherapy, radiotherapy or surgery, have 
remained asymptomatic for 90 days (3 months) and demonstrate no CNS 
lymphoma as shown by lumbar puncture, CT/brain MRI are eligible.  Patients 
with a history of CNS involvement or CNS symptoms will be required to have 
negative CSF cytology examination and a head CT during the screening period 
(known and active CNS or leptomeningeal involvement). 
!
Known seropositive for or active viral infection with human immunodeficiency 
virus (HIV)
!
Known seropositive for or active viral infection with hepatitis B virus:
∀
HBsAg positive.
∀
HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable
viral DNA.
∀
Patients who are HBsAg negative and viral DNA negative are eligible.
∀
Patients who had hepatitis B but have received an antiviral treatment and show 
no detectable viral DNA for 6 months are eligible.
∀
Patients who are seropositive because of hepatitis B virus vaccine are eligible. 
!
Known seropositive for or active viral infection with hepatitis C virus
∀
Patients who had hepatitis C but have received an antiviral treatment and show 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
17
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
no detectable viral RNA for 6 months are eligible.
!
Patients who are not willing to take DVT prophylaxis, if they are at risk (see 
definition in Section 10.1.6)
!
Patients should not be receiving corticosteroids 7 days prior to randomization,
except for prednisone ≤ 10 mg/day or equivalent for purposes other than treating 
MCL
!
Pregnant or lactating females
!
Any of the additional following laboratory abnormalities:
∀
Absolute neutrophil count (ANC) <1,500 cells/mm3 (1.5 x 109/L)
∀
Platelet count < 60,000/mm3(60 x 109/L)
∀
Serum aspartate transaminase (AST/SGOT) or alanine transaminase 
(ALT/SGPT) > 3.0 x upper limit of normal (ULN), except in patients with 
documented liver involvement by lymphoma
∀
Serum total bilirubin > 1.5 x ULN, except in case of Gilbert’s Syndrome and 
documented liver involvement by lymphoma.
∀
Calculated creatinine clearance (Cockcroft-Gault formula) of < 30 mL/min
!
Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the patient from signing the informed consent form.
!
Participation in another clinical trial during the screening/baseline phase and 
treatment phase of the study. 
!
Any use of experimental drug during 4 weeks prior to randomization.
Investigational product, dosage and mode of administration [Arm A]: 
!
Patients, who have a creatinine clearance ≥ 60 mL/min, will receive oral 
lenalidomide that is initiated on Day [D] 1 of Cycle 1 at a dose of 25 mg [p.o.] 
once daily for 21 days (D1 – D21) in each 28 day cycle. 
!
Patients 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 for 21 days (D1 – D21) in Cycle 1 and Cycle 2.  After Cycle 2, if the 
patient remains free of Grade 3 or Grade 4 toxicity, the dose will be increased to 
15 mg once daily for 21 days (D1 – D21) in each 28 day cycle.
Treatment is to be continued until disease progression or unacceptable toxicity.
Study Drug Supplies: 
Following the approval of Protocol Amendment #6, Celgene Corporation will supply 5 mg, 
10 -mg, 20 mg, and 25 mg strengths in countries where lenalidomide is only available under a 
clinical trial protocol. No more than a 21-day supply of study drug will be dispensed at a 
time.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
18
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Lenalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened.  Health care providers should consider wearing gloves when directly handling 
Revlimid (lenalidomide) capsules followed by standard hand washing.
Other recommended medications such as aspirin will be provided by the investigative site. 
Celgene will not provide these medications.
Patients in Arm B will receive investigator’s choice single agent reference therapy. This 
includes:
Chlorambucil tablets 2 mg;
Rituximab 500 mg vials;
Cytarabine Injection Solution 100 mg/ml;
Gemcitabine 1g vial;
Fludarabine 10 mg film-coated tablets;
Fludarabine 25mg/ml Concentrate for Solution for Injection or Infusion:
Please refer to the prescribing information provided by Celgene on all of the above
For dosing of the investigators choice single agents, please refer to Table 3 based on 
published data and expert opinions.
Investigators should refer to the approved Summary of Product Characteristics (SPC), 
provided by Celgene, for the investigator’s choice therapy for complete prescribing 
information including administration, warnings, precautions, contraindications, and adverse 
reactions and follow institutional procedures for the administration of the agents, where 
applicable. Paper prints will be provided in the Investigator's and Pharmacy binders.
The investigator’s choice treatment will be provided by Celgene.
Assessments:
Efficacy:
!
Date of documentation of disease progression
!
Overall response rate (PR or better) as defined by a modification of the
International Workshop Response Criteria (Cheson, 1999)
!
Tumor control rate (CR, CRu, PR or SD)
!
CT with contrast/MRI with contrast is performed at baseline then every 56 days
(±7 days) after Day 1, Cycle 1 for the first 6 months and then every 90 days ± 15 
days thereafter until documented progressive disease; or when clinically indicated
To ensure comparability, baseline and on-study methods for response 
assessment must be performed using identical techniques.
!
Bone marrow biopsy if the patient has met all other criteria for CR
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
19
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
!
Physical Exam 
Safety:
!
AEs / SAEs severity is graded using NCI CTCAE criteria version 3.0
!
Vital signs
!
Clinical laboratory evaluations
!
ECOG status 
!
Serum/urine beta-human chorionic gonadotropin (∃-hCG) (FCBP only)
!
Concomitant medications
!
Hospitalizations
!
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 21.1.9). This includes any second primary malignancy, regardless of 
causal relationship to study drug (lenalidomide or Investigator Choice arm drugs), 
occurring at any time for the duration of the study, from the time of signing the 
Informed Consent Document (ICD) through follow-up for overall survival. The 
Follow-Up Phase involves patient contact every 90 days (± 15 days) until patient 
death or until either 70% of the patients have died, or the median follow-up in 
responding patients is > 2 years, or the median duration of response (overall 
response and CR/CRu) has been reached, or four years from last patient 
randomized, whichever comes later, at which time the follow-up study phase will 
be closed. Events of second primary malignancy are to be reported using the SAE 
report form and must be considered an “Important Medical Event” even if no 
other serious criteria apply; these events must also be documented in the 
appropriate page(s) of the CRF and subject’s source documents.
!
Following the approval of Protocol Amendment #6, only SAE data (including 
SPMs) will continue to be collected and reported to Celgene on SAE CIOMs 
forms for subjects in the Extended Access Phase.
Statistical Analysis:  
Sample Size:
The main objective of the study is to demonstrate the efficacy of lenalidomide over an 
investigator’s choice single agent based on PFS. The primary analysis is to compare PFS 
between lenalidomide and investigator’s choice monotherapy. 
Protocol Amendment #4:
The third independent DMC meeting was held on July 22, 2011, in which the committee 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
20
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
members reviewed un-blinded both safety and efficacy data from 166 randomized patients. 
No safety concerns were noted.  The DMC observed that the interim PFS in the control arm is 
different from the intial assumptions which were used to calculate the sample size described 
in Protocol Amendment #2.  
The DMC therefore recommended increasing the sample size from 174 (number of patients 
randomized at the time of the DMC was held) to 250 patients and conducting the 
underpowered primary analysis one year after the last patient being randomized. This would 
allow a more reliable estimation of the treatment effect aiming at demonstrating a clinically 
meaningful improvement in PFS between the experimental arm and the control arm. In 
addition, the proposed timing for the analysis will allow a reasonable follow up for overall 
survival so full information on the clinical benefit of lenalidomide can be provided at the time 
of PFS analysis.
The type I error will be controlled with adequate methods and the details will be further 
described in the SAP.
Protocol Amendment #2
With a hazard ratio of 1.7, full information necessary for a one-sided log rank test with an 
overall alpha of 0.025, to have 80% power, will be achieved when approximately 128 patients 
have progressed or died (PFS).
Original Protocol
The sample size of this study was originally calculated to estimate the Overall Response Rate 
(ORR), which was the original objective of the study.  Sample size calculation was based on 
the width of the 95% confidence interval around a certain point estimate for ORR that is 
considered significant clinical activity. Based on preliminary data, a response rate in the 
range of 30% to 40% was reasonably expected.  A sample size equal to 100 allows us to 
construct a two sided 95% confidence interval with a width of 9% (one direction) for an 
expected proportion of 30%. The lower observed confidence interval limit would be about 
21%, which was still considered clinically meaningful. This sample size allowed a width (one 
direction) of 9.6% for an expected proportion of 40% and 9.3% for an expected proportion of 
35% (See Table 10).
Table 9
Confidence Intervals
95% Two-Sided Confidence Intervals (N=100)
Response rate
30%
35%
40%
CI1
0.214 – 0.400
0.257 – 0.452
0.303 – 0.503
1 Exact confidence intervals based on the Clopper-Pearson method
Using a one group χ2 test with a 0.050 two-sided significance level a sample size of 100 
patients will have 81% power to detect the difference between the Null hypothesis proportion 
of 20% and the alternative proportion of 32%. No formal sample size calculation will be done 
for the control arm. With a 2:1 ratio 50 patients are needed in the control arm. Assuming that 
10% of patients will be lost to follow up, 167 patients were to be randomized.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Efficacy Analysis:
The primary endpoint is progression free survival (PFS). PFS is defined as the time from 
randomization until objective tumor progression or death for any reason. Patients who do not 
progress at the time of analysis will be censored. Progression will be determined according to
the International Workshop Response Criteria (IWRC) (Cheson, 1999), as modified by Fisher 
et al 2006; Kane et al 2007 for target lesions will be used (see Section 21.5 and Table 8 for a 
detailed description of the modifications). The assessment will be reviewed by an 
independent review committee. The primary analysis will be done in the intent-to-treat (ITT) 
population for PFS, overall response rate, overall survival and secondary endpoints. All 
patients who have received at least one single treatment dose (C1D1) with centrally 
confirmed histology of mantle cell non-Hodgkin’s lymphoma will be included in the 
sensitivity analysis. Sensitivity analyses will be conducted for the primary and secondary 
endpoints based on the Full Analysis Set (FAS), and the Per Protocol set (if the PPS 
population differs ≥10% in size from the FAS).
Further secondary endpoints include:
!
Overall response rate (CR, CRu and PR)
!
Duration of response: will be measured from the time of initial response (at least 
PR) until documented tumor progression or death. Patients who do not progress at 
the time of analysis will be censored. This analysis will be restricted to responder
patients.
!
Tumor control rate (Rates for CR, CRu, PR and stable disease [SD])
!
Duration of stable disease: will be calculated as the time from the first evidence of 
stable disease to documented disease progression or documented response or 
death. Patients who do not progress or respond at the time of analysis will be 
censored. This analysis will be restricted to the subgroup of stable disease patients.
!
Time to progression, (TTP) is defined as the time from randomization until 
objective tumor progression; TTP does not include deaths. Patients without 
progression at the time of analysis will be censored. Deaths due to progression of 
disease will be considered as an event.
!
Time to tumor response (TTR) is defined as the time from randomization until 
confirmed response (CR, CRu, PR). Patients with SD or progression at the time of 
analysis will be censored. 
!
TTF is defined as the time from the first dose of study drug to discontinuation of 
treatment for any reason, including disease progression, treatment toxicity or 
death. Patients who are still on drug at the time of the analysis or complete the 
treatment according to the protocol will be censored.
!
Overall survival: defined as the time from randomization until death from any 
cause. Patients alive or lost to follow up at the time of analysis will be censored.
!
QoL (EORTC QLQ-C30)
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
22
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
!
Safety
Efficacy analysis will be conducted one year after the last patient is randomized. 
An update of the time to events endpoints and overall survival will be done at the end of the 
follow up. No adjustment for multiplicity will be applied.
All efficacy analysis will be conducted on intent to treat basis.
The Kaplan-Meier procedure will be used to characterize time to event endpoints and 
duration of response. Median times-to-event and their respective two-sided 95% confidence 
intervals will be provided for each of these variables. The stratified log-rank test will be used 
as the main analysis to compare treatment arms for time-to-event variables and an unstratified 
log-rank test will be used as supportive analysis. The Cox proportional hazards regression 
model will be used to assess the significance of stratification factors on treatment differences.
Any demographic or baseline characteristics variables considered as strong predictive or 
prognostic factors will also be included as part of the formal statistical analysis plan. The 
MIPI score at randomization will be analyzed as a stratification factor.
Data will be analyzed and displayed per treatment group in a descriptive manner.
The probability of response rate will be estimated using the proportion of patients with 
responses with exact two-sided 95% confidence intervals.
The EORTC QLQ-C30 will be analyzed using change from baseline and percentage of 
change from baseline according to functional scores and the recommendations in the EORTC 
manual.
The response rate in the cross-over portion of patients in Arm B will be analyzed in a 
descriptive manner.
Interim analysis and DMC:
An independent Data Monitoring Committee will review the safety data and efficacy data for 
futility to assess benefit to risk considerations throughout the study. 
Futility analysis will be conducted when approximately 80 patients complete 2 cycles or 
withdraw before completing 2 cycles (around 54 patients in the lenalidomide arm).
Additional efficacy and safety data might be provided to the DMC members on request as
outlined in the DMC charter.
DMC will conduct an analysis for futility on PFS and Overall response rate. No specific 
stopping rules will be given to the DMC for the PFS; the following rules might be used for 
overall response rate.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
23
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Based on a 95% CI approach, if the upper bound is below 20% in the lenalidomide arm, the 
DMC should recommend stopping the trial.
Frequency 
of response
Binomial 
Proportion 
P
Exact Lower
CL, Binomial
Proportion1
Exact Upper
CL, Binomial
Proportion1
1
1.8519
0.04687
9.8915
2
3.7037
0.45173
12.7472
3
5.5556
1.16068
15.3885
4
7.4074
2.05510
17.8933
5
9.2593
3.07528
20.3002
6
11.1111
4.18838
22.6313
7
12.9630
5.37430
24.9012
8
14.8148
6.61976
27.1198
9
16.6667
7.91544
29.2941
10
18.5185
9.25455
31.4297
1Exact confidence intervals based on the Clopper-Pearson method
Safety analysis:
Data from all patients who received at least one dose of study drug will be included in the 
safety analyses.
Adverse event severity will be classified using the NCI CTCAE criteria, version 3.0.
Adverse event frequency will be tabulated by body system, and MedDRA term. 
In the by-patient analysis, a patient having the same event more than once will be counted 
only once. Adverse events will be summarized by worst NCI CTCAE grade. Adverse events 
leading to death or to discontinuation from treatment, events classified as NCI CTCAE grade 
3 or higher, study-drug related events, and serious adverse events will be listed separately.
Second primary malignancies throughout the course of the study will be monitored as events 
of interest, and will be listed and be analyzed separately.
The probability of dose reduction will be estimated using the proportion of patients with dose 
reduction.
Laboratory data will be graded according to NCI CTCAE severity grade.
Extended Access Phase:
For the Extended Access Phase only SAE (including SPMs) data will be reported to Celgene 
drug safety. No statistical analysis is planned to be performed on this safety data. 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
24
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Table 2:
Schedule of Study Assessments for Arm A and Arm B patients 
(28 days = 1 cycle) 
Procedure
Screening/ Baseline
(-28 Days)
Every Cycle Day 1 ± 3 
days25
Cycle 1
Day 1, 2, 4, 8, 15
Cycles 2-4 Day 15 ± 1
day
Every 56 days After 
Cycle 1 Day 1
± 7 days for the first 6 
months and then every 
90 days ± 15 days 
thereafter
At Treatment 
Discontinuation
Follow-up for patients 
after PD21
Follow-up for non-PD 
patients22
Inclusion/exclusion criteria
X
Complete medical history
X
CNS Lymphoma Evaluation1
X
MCL International Prognostic Index 
(MIPI)2
X
Prior lymphoma therapy
X
Creatinine Clearance (Cockcroft-
Gault estimation)3
X
12-Lead ECG4
X
Lymph node or tumor biopsy 
specimen slides5
X
Eastern Cooperative Oncology Group 
(ECOG) performance status
X
X
X
Vital Signs6
X
X
X
CBC with Differential7
X
X
X9
X
X
Serum Chemistry8
X
X
X9
X
X
Serology HBV, HCV in endemic 
areas
X
Thyroid function test18
X
Pregnancy Testing (FBCP only)
X10
X11
X11
X11
X11
Lenalidomide Counseling and 
distribute lenalidomide Information 
Sheet12
X
X
X13
X13
Assessment of Lymphoma-related 
Symptoms
X
X
X
Adverse Events
X
X
X
X
X
X14
X14
Record Hospitalizations
X
X
Assessment of Second Primary 
Malignancies15
X
X
X
X
X
X
X
Tumor Flare / Tumor lysis 
Assessment16
X16
Concomitant medications/Procedures
X
X
X
X
Physical examination17
X
X
X
X
X
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
25
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Table 2:
Schedule of Study Assessments for Arm A and Arm B patients 
(28 days = 1 cycle) (Continued)
Procedure
Screening/ Baseline
(-28 Days)
Every Cycle Day 1 ± 3 
days25
Cycle 1
Day 1, 2, 4, 8, 15
Cycles 2-4 Day 15
Every 56 days After 
Cycle 1 Day 1
± 7 days for the first 6 
months and then every 
90 days ± 15 days 
thereafter 
At Treatment 
Discontinuation
Follow-up for patients 
after PD21
Follow-up for non-PD 
patients22
CT with contrast (or MRI 
with contrast, if CT 
contraindicated) of neck, 
chest, abdomen and pelvis19
X26
X19
X19
Target and non-target lesion 
measurements19
X
X19
Response assessment
X19
Progression-Free Survival20
X19
X
X
Overall survival
X21
X22
Quality of Life
X23
X23
X23
Bone Marrow Biopsy
X24a
X24b
Dispense study drug25
X25
Study drug return
X
X
1
Patients with a history of CNS involvement or CNS symptoms will be required to have negative CSF cytology 
examination, and a head CT/brain MRI during the screening/baseline period.  
2
MIPI: age, performance status, LDH, absolute leukocyte count, at time of diagnosis, if available.
3
Cockcroft-Gault estimation of creatinine clearance (CrCl): CrCl (mL/min) = (140 – age) (weight [kg]) / 72 
(serum creatinine [mg/dL]); for females, the formula is multiplied by 0.85. Creatinine clearance should be 
determined utilizing actual body weight or ideal body weight, which ever is less (Cockcroft, 1976; Luke, 1990).
4
12-Lead ECG is performed at baseline and as clinically indicated thereafter.
5
Representative slides documenting the diagnosis (H&E or Giemsa staining) and supporting the diagnosis of 
MCL (Cyclin D1 immunostaining), shall be sent together with the tumor block to central pathology as soon as 
possible, preferably before randomization for confirmation of mantle cell lymphoma, but at the latest 8 weeks 
after randomization. In patients whose tumor is negative for Cyclin D1, evidence of overexpression of Cyclin D2 
or D3 is acceptable. Additionally, slides supporting the translocation by FISH or corresponding confirming 
photographies shall be submitted at the same time, if available. It is also recommended to send for central 
pathology review, slides containing immunostaining for CD3, CD5, CD 10, CD23, CD20, BCL2, Ki-67. In case 
the tumor block can not be sent, 4-5 additional, unstained slides must also be submitted. If such archival tissue is 
not available for submission, then a re-biopsy is required.
6
Vital signs include weight, height (only at screening), blood pressure, temperature, and pulse.
7
Complete blood cell count (CBC) will include red blood cell count (RBC), hemoglobin, hematocrit, MCV, white 
blood cell (WBC) count with differential, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), 
and platelet count.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
26
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
8
Serum chemistry (total protein, albumin, calcium, phosphorous, glucose, uric acid, total bilirubin, alkaline 
phosphatase, AST, ALT, sodium, potassium, blood urea nitrogen, creatinine and LDH).
9
If screening/baseline assessment hematology, and chemistry labs are performed within 7 days before Cycle 1, 
Day 1, they do not need to be repeated on Cycle 1, Day 1. 
10 Only for patients in Arm A and patients in cross over: before starting study drug: Females of Childbearing 
Potential (FCBP) must confirm that they are using reliable methods of birth control, and must have two negative 
pregnancy tests prior to starting study drug: The first pregnancy test must be performed within 10-14 days prior 
to the start of study drug, and the second pregnancy test must be performed within 24 hours prior to the start of 
study drug. The patient may not receive study drug until the Investigator has verified that the results of these 
pregnancy tests are negative. All patients will be warned that sharing study drug is prohibited and will be 
counseled about pregnancy precautions and potential risks of fetal exposure. (See specifics as described in 
Appendix 21.8).
11 Only for patients in Arm A and patients in cross over: during the study participation and for 28 days following 
discontinuation from the study treatment: FCBP must agree to have two pregnancy tests (See specifics as 
described in Appendix 21.8). In addition to the required pregnancy testing, the investigator must confirm with 
FCBP that she is continuing to use reliable methods of birth control at each visit (See specifics as described in 
Appendix 21.8). 
12 Only for patients in Arm A and patients in cross over: all patients must be counseled about pregnancy 
precautions and risks of fetal exposure.
13 Only for patients in Arm A and patients in cross over: after 28 days post-last dose of lenalidomide.
14 Adverse events will be assessed 28 days post-last dose of treatment during follow-up.
15 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 21.1.9). This includes any second primary 
malignancy, regardless of causal relationship to study drug (lenalidomide or Investigator Choice arm drugs), 
occurring at any time for the duration of the study, from the time of signing the ICD through follow-up for 
overall survival. The Follow-Up Phase involves patient contact every 90 days (± 15 days) until patient death or 
until either 70% of the patients have died, or the median follow-up in responding patients is > 2 years, or the
median duration of response (overall response and CR/CRu) has been reached, or four years from last patient 
randomized, whichever comes later, at which time the follow-up study phase will be closed. Events of second 
primary malignancy are to be reported using the SAE report form and must be considered an “Important Medical 
Event” even if no other serious criteria apply; these events must also be documented in the appropriate page(s) of 
the CRF and subject’s source documents. Documentation on the diagnosis of the second primary malignancy 
must be provided at the time of reporting as a serious adverse event (e.g., any confirmatory pathology results, 
imaging results, etc.).
16 Tumor flare / tumor lysis syndrome assessment, only for patients in Arm A, at Cycle 1: Day 2, 4, 8, and 15, and 
when clinically indicated thereafter.
17 Physical examination including lymphadenopathy, hepatomegaly, and splenomegaly as clinically indicated.
Physical examination on study should be done at baseline, Cycle 1 D1 and D15 and then Day 1 of every Cycle. 
18 Thyroid function tests (TSH, fT3, fT4) are performed at baseline/screening only and as clinically indicated.
19 CT with contrast/MRI with contrast must be performed every 56 days (± 7 days) up to 6 months from the start of 
study drug then every 90 ±15 days thereafter, during the follow up phase for patients who have discontinued 
study treatment due to adverse events without evidence of progressive disease. CT scan with contrast /MRI with 
contrast does not need to be performed during follow-up for patients who discontinued due to disease 
progression or relapse. 
20 Progression free survival is assessed until progression of disease or until next lymphoma treatment is given, 
whichever comes first. Patients in the investigators choice Arm B have the option to receive lenalidomide at time 
of documented disease progression.
21 Patients will be followed (clinic visit or documented telephone contact) for overall survival every 90 days (± 15 
days) until death or either 70% of the patients have died or the median follow-up in responding patients is > 2 
years or the median duration of response (overall response and CR/CRu) has been reached, or four years from 
last patient randomized, whichever comes later. At this time the follow-up study phase will be closed. 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
27
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
22 Patients will be followed (clinic visit or documented telephone contact) for overall survival every 56 days (± 7 
days) until death or either 70% of the patients have died or the median follow-up in responding patients is > 2 
years or the median duration of response (overall response and CR/CRu) has been reached, or four years from 
last patient randomized, whichever comes later. At this time the study will end for ongoing subjects still on 
lenalidomide treatment in countries where lenalidomide can be accessed post-trial in the commercial setting. An 
Extended Access Phase will be made available for subjects on study treatment in countries where they can only 
access lenalidomide under a clinical trial protocol as post-trial access. These subjects will have a 
“discontinuation from treatment” visit assessment prior to being transferred to the Extended Access Phase. The 
Extended Access Phase will end for ongoing subjects as soon as lenalidomide can be accessed in the commercial 
setting. Follow-up survival data will no longer be collected by Celgene for these subjects.
23 QoL will be assessed at screening/baseline after Cycle 2 [C3D1] (±7 days), after Cycle 4 [C5D1] (±7 days), after 
Cycle 6 [C7D1] (±7 days), after Cycle 8 [C9D1] (±7 days), and at treatment discontinuation (±7 days).
24a Unilateral bone marrow biopsy is highly recommended at screening that will be submitted to Central Pathology 
for review at the latest within 8 weeks after randomization.
24b Unilateral bone marrow biopsy during treatment is required only if the patient has otherwise fulfilled the criteria 
for CR. The bone marrow procedure should be performed 28 days after the criteria for CR have otherwise been 
met. 
25 Dispense study drug on Day 1 only of each treatment cycle. Cycle 1 should start as soon as possible after 
randomization, but maximum time between randomization and C1D1 is 4 days, once the patient has fulfilled the 
requirements of the Lenalidomide pregnancy prevention program. For lenalidomide, a minimum 7 day rest 
period is mandatory before starting each new treatment cycle regardless of allowed ± visit windows.
 
 
 
 
 
 
 
 
 
 
 
 
27 If a CT scan or MRI was done within 28 days of the randomization, then the CT scan or MRI does not have to be 
repeated for the screening assessment.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
28
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Table 3:
Schedule of study assessments for patients with cross-over on lenalidomide 
after progression in investigator's choice Arm B (28 days = 1 cycle) – No 
more than 10 weeks after last day of last cycle of treatment in Arm B
Procedure
Every Cycle
Day 1 ± 3 days13
Cycle 1
Day 1, 2, 4, 8, 15
Cycles 2- 4
Day 15
Every 90 days After 
Cycle 1 Day 1
± 15 days
At Treatment 
Discontinuation
Follow-up for 
patients after PD11
Follow-up for non-
PD patients12
Eastern Cooperative Oncology Group (ECOG) 
performance status
X
X
Vital Signs1
X
X
CBC with differential2
X
X
X
X
Serum Chemistry3
X
X
X
X
Pregnancy Testing for FCBP4
X
X
Lenalidomide Counseling and distribute 
lenalidomide Information Sheet 5
X
Distribute Lenalidomide counseling sheet5
X
X
Dispense study drug13
X13
Study drug return
X
X
Adverse Events6
X
X
X
X
X6
Assessment of Second Primary Malignancies7
X
X
X
X
X
X
X
Tumor Flare /Tumor Lysis Assessment8
X
Record Hospitalizations
X
X
Concomitant medications/ Procedures
X
X
X
X
CT with contrast (or MRI with contrast, if CT
contraindicated) of neck, chest, abdomen and 
pelvis9
X
X9
Target and non-target lesion measurements
X
Response assessment
X
Progression-Free Survival10
X
X
X
Overall survival
X11
X12
1
Vital signs include weight, blood pressure, temperature, and pulse.
2
Complete blood cell count (CBC) will include red blood cell count (RBC), hemoglobin, hematocrit, MCV, white 
blood cell WBC) count with differential, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), 
and platelet count.
3
Serum chemistry (total protein, albumin, calcium, phosphorous, glucose, uric acid, total bilirubin, alkaline 
phosphatase, AST (SGOT), ALT (SGPT), sodium, potassium, blood urea nitrogen, creatinine and lactate 
dehydrogenase).
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
29
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
4
During the study participation and for 28 days following discontinuation from the study treatment: FCBP must 
agree to have pregnancy tests (See specifics as described in Appendix 21.8). In addition to the required 
pregnancy testing, the investigator must confirm with FCBP that she is continuing to use reliable methods of 
birth control at each visit (See specifics as described in Appendix 21.8).
5
All patients must be counseled about pregnancy precautions and risks of fetal exposure.
6
Adverse events will be assessed 30 days post-last dose during follow-up.
7
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 21.1.9).  This includes any second primary 
malignancy, regardless of causal relationship to study drug (lenalidomide or Investigator Choice arm drugs), 
occurring at any time for the duration of the study, from the time of signing the ICD through follow-up for 
overall survival. The Follow-Up Phase involves patient contact every 90 days (± 15 days) until patient death or 
until either 70% of the patients have died, or the median follow-up in responding patients is > 2 years, or the 
median duration of response (overall response and CR/CRu) has been reached, or four years from last patient 
randomized, whichever comes later, at which time the follow-up study phase will be closed. Events of second 
primary malignancy are to be reported using the SAE report form and must be considered an “Important Medical 
Event” even if no other serious criteria apply; these events must also be documented in the appropriate page(s) of 
the CRF and subject’s source documents. Documentation on the diagnosis of the second primary malignancy 
must be provided at the time of reporting as a serious adverse event (e.g., any confirmatory pathology results, 
imaging results, etc.).
8
Tumor flare/Tumor lysis assessment at Cycle 1: Day 2, 4, 8, and 15, and when clinically indicated.
9
CT with contrast/ or MRI with contrast must be performed every 90 days (± 15 days) from the start of 
lenalidomide cross-over treatment, and during the follow up phase for patients who have discontinued treatment 
due to adverse events without evidence of progressive disease. CT scan with contrast /MRI with contrast does 
not need to be performed during follow-up for patients who discontinued due to disease progression or relapse. 
10 Progression Free Survival is assessed until progression of disease or until next lymphoma treatment is given, 
whichever comes first.
11 Patients will be followed (clinic visit or documented telephone contact) for overall survival every 90 days (± 15 
days) until death or either 70% of the patients have died or the median follow-up in responding patients is > 2 
years or the median duration of response (overall response and CR/CRu) has been reached, or four years from 
last patient randomized, whichever comes later. At this time the follow-up study phase will be closed. 
12 Patients will be followed (clinic visit and CT scan/MRI) for overall survival every 90 days (± 15 days) from the 
start of lenalidomide cross-over treatment until death or either 70% of the patients have died or the median 
follow-up in responding patients is > 2 years or the median duration of response (overall response and CR/CRu) 
has been reached, or four years from last patient randomized, whichever comes later. At this time the study will 
end for ongoing subjects still on lenalidomide treatment in countries where lenalidomide can be accessed post-
trial in the commercial setting. An Extended Access Phase will be made available for subjects on study treatment 
in countries where they can only access lenalidomide under a clinical trial protocol as post-trial access. These 
subjects will have a “discontinuation from treatment” visit assessment prior to being transferred to the Extended 
Access Phase. The Extended Access Phase will end for ongoing subjects as soon as lenalidomide can be accessed 
in the commercial setting. Follow-up survival data will no longer be collected by Celgene for these subjects.
13 Starting cross-over lenalidomide treatment after disease progression is extensively documented in Arm B should 
be as soon as toxicities of prior Arm B treatments have resolved and all inclusion/exclusion criteria are met, but 
not later than 10 weeks after last day of last Arm B treatment cycle and as soon as the patient has fulfilled the 
requirements of the Lenalidomide pregnancy prevention program. Once lenalidomide treatment is started, a 
minimum 7-day rest period is mandatory before starting each new treatment cycle regardless of allowed ± visit 
windows.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
30
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Table 4:
Schedule of Study Assessments: Guidance for Extended Access Phase
Assessment
Day 1 of Each Cyclea
Extended Access Phase
(± 3 days)
Extended Access Phase 
Discontinuation
(at day of 
discontinuation)
Informed consentb
X
Prior to first cycle 
treatment
-
Lenalidomide counseling/distribute lenalidomide 
counseling sheet
X
X
Concomitant medication/therapies
X
recorded in the subjects’
records only
X
recorded in the subjects’
records only
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primary malignanciesc
SAEs only
SAEs only
Study drug dispensation/return/accountability
X
X
CBC with differentiald
X 
As per local practice
X
As per local practice
Serum Chemistrye
X
As per local practice
X
As per local practice
All other safety labs
X
As per local practice
X
As per local practice
Pregnancy Testing (FBCP only)f
X
X
and at 28 days post 
discontinuation treatment 
visit 
ALT = alanine transaminase; AST = aspartate transaminase; FCBP = female of childbearing potential; SGOT = 
serum glutamic-oxaloacetic transaminase; SGPT= serum glutamic-pyruvic transaminase. 
a. A cycle is equal to 28 days.  If the administration of study drug has not been interrupted, the next cycle of therapy 
and assessments are to be given/done as in the Treatment Phase of the protocol.
b. Informed consent for the Extended Access Phase must be signed and dated by subjects in countries where they can 
only continue receiving lenalidomide under a clinical trial protocol.
c. Second primary malignancies (SPMs) will be monitored as events of interest and must be reported as serious 
adverse events.  This includes any SPM, regardless of causal relationship to study drug, occurring at any time for 
the duration of the study, from the time of signing the informed consent up to and including the Extended Access 
Phase. Events of second primary malignancy are to be reported using the SAE report form and must be considered 
an “Important Medical Event” even if no other serious criteria apply.  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.).
d. According to local practice hematology tests should be performed for complete blood cell count (CBC) and will 
include red blood cell count (RBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), white blood cell 
(WBC) count with differential, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and platelet 
count. This information will no longer be collected by Celgene on an eCRF. however the information will continue 
to be recorded in the subjects’ medical records.
e. According to local practice serum chemistry tests should be performed (total protein, albumin, calcium, 
phosphorous, glucose, uric acid, total bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), sodium, 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
31
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
potassium, blood urea nitrogen, creatinine and lactate dehydrogenase. This information will no longer be collected 
by Celgene on an eCRF, however the information will continue to be recorded in the subjects’ medical records.
f. For FCBP with regular or no menses and on lenalidomide, pregnancy testing has to occur every 28 days after the 
first 4 weeks of therapy through 28 days following treatment discontinuation. For FBCP with irregular menses 
such testing must happen after the first four weeks of treatment though 28 days following treatment 
discontinuation.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
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32
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
3.
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
1.
STUDY CONTACT INFORMATION .....................................................................3
2.
SYNOPSIS...............................................................................................................4
3.
TABLE OF CONTENTS........................................................................................32
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................39
5.
INTRODUCTION..................................................................................................43
5.1.
Mantle Cell Lymphoma ..........................................................................................43
5.2.
Background and Rationale for Lenalidomide ..........................................................44
5.2.1.
Preclinical studies with Lenalidomide.....................................................................45
5.2.2.
Clinical Studies of lenalidomide in Non-Hodgkin’s Lymphoma..............................46
5.2.3.
Clinical Studies of Lenalidomide in Multiple Myeloma ..........................................47
5.2.4.
Clinical Studies of Lenalidomide in Myelodysplastic syndromes............................47
5.2.5.
Clinical Studies of Lenalidomide in Chronic Lymphocytic Leukemia.....................48
6.
STUDY OBJECTIVES...........................................................................................49
6.1.
Primary Objective...................................................................................................49
6.2.
Secondary Objectives .............................................................................................49
7.
STUDY ENDPOINTS............................................................................................50
7.1.
Primary...................................................................................................................50
7.2.
Secondary...............................................................................................................50
8.
OVERALL STUDY DESIGN ................................................................................51
8.1.
Design Rationale ....................................................................................................51
8.1.1.
Dose Rationale .......................................................................................................51
8.1.2.
Discussion of Study Design ....................................................................................52
8.1.2.1.
Stratification...........................................................................................................52
8.1.2.2.
Treatment Phase .....................................................................................................54
8.2.
Assessment of Second Primary Malignancies .........................................................57
8.3.
Data Monitoring Committee ...................................................................................58
8.4.
Independent External Pathological Review.............................................................58
8.5.
Independent Review Committee (IRC) ...................................................................59
9.
STUDY POPULATION.........................................................................................60
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
9.1.
Patient Inclusion Criteria ........................................................................................60
9.2.
Patient Exclusion Criteria .......................................................................................61
10.
DESCRIPTION OF TREATMENT........................................................................63
10.1.
Treatment Assignments ..........................................................................................63
10.1.1.
Arm A ....................................................................................................................63
10.1.2.
Arm B ....................................................................................................................63
10.1.3.
Dose Modification or Interruption for Lenalidomide - Arm A.................................64
10.1.4.
Dose Modification or Interruption for Investigator’s choice - Arm B ......................69
10.1.5.
Tumor Lysis and Tumor Flare - Lenalidomide........................................................69
10.1.6.
Thromboembolism - Lenalidomide.........................................................................70
10.1.7.
Prior/Concomitant medications and other permitted concomitant therapies.............70
10.1.8.
Prohibited concomitant therapy...............................................................................71
10.2.
Discontinuation from Treatment .............................................................................71
11.
STUDY DRUG MATERIALS AND MANAGEMENT .........................................72
11.1.
Supplier(s)..............................................................................................................72
11.2.
Dosage Form..........................................................................................................72
11.3.
Dosage Regimen.....................................................................................................72
11.3.1.
Lenalidomide..........................................................................................................72
11.3.2.
Investigators Choice ...............................................................................................72
11.4.
Drug Dispensing Requirements...............................................................................72
11.5.
Special Handling Instructions .................................................................................73
11.6.
Treatment Compliance............................................................................................73
11.7.
Packaging and Labeling..........................................................................................73
11.8.
Receipt and Storage................................................................................................73
11.9.
Record of Administration .......................................................................................73
11.10.
Accountability ........................................................................................................74
11.11.
Handling and Disposal............................................................................................74
12.
ASSESSMENT OF EFFICACY.............................................................................75
12.1.
Assessments ...........................................................................................................75
12.2.
Methods and Timing of Efficacy Assessments........................................................75
13.
ASSESSMENT OF SAFETY.................................................................................77
13.1.
Assessments ...........................................................................................................77
13.2.
Methods and Timing of Safety Assessments ...........................................................78
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
13.3.
Recording and Reporting of Adverse Events...........................................................78
15.
STATISTICAL ANALYSES..................................................................................82
15.1.
Study Population Definitions ..................................................................................82
15.1.1.
Intent-to-Treat Population (ITT) .............................................................................82
15.1.2.
Treated Set .............................................................................................................82
15.1.3.
Full Analysis Set (FAS)..........................................................................................82
15.1.4.
As Treated population.............................................................................................82
15.1.5.
Per-protocol Set (PPS)............................................................................................82
15.1.6.
Subgroup analysis...................................................................................................83
15.2.
Efficacy Evaluation ................................................................................................83
15.2.1.
Primary Efficacy Endpoints....................................................................................83
15.2.2.
Secondary Endpoints ..............................................................................................84
15.2.3.
Analysis Methods...................................................................................................88
15.3.
Background and Demographic Characteristics........................................................89
15.4.
Study Drug .............................................................................................................89
15.5.
Concomitant Therapy .............................................................................................89
15.6.
Safety Evaluation....................................................................................................89
15.7.
Interim Analyses.....................................................................................................90
15.8.
Sample Size and Power Considerations...................................................................91
15.9.
Other Topics...........................................................................................................92
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................93
16.1.
Monitoring .............................................................................................................93
16.2.
Audits and Inspections............................................................................................93
16.3.
Investigator(s) Responsibilities...............................................................................93
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
35
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
17.
REGULATORY CONSIDERATIONS...................................................................95
17.1.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................95
17.2.
Protocol Amendments.............................................................................................95
17.3.
Informed Consent ...................................................................................................95
17.4.
Patient Confidentiality............................................................................................96
18.
DATA HANDLING AND RECORDKEEPING.....................................................97
18.1.
Data/Documents.....................................................................................................97
18.2.
Data Management...................................................................................................97
18.3.
Retention of Records ..............................................................................................97
19.
PREMATURE DISCONTINUATION OF THE STUDY .......................................99
19.1.
Single Site ..............................................................................................................99
19.2.
Study as a Whole....................................................................................................99
20.
REFERENCES.....................................................................................................100
21.
APPENDICES......................................................................................................106
21.1.
Adverse Event ......................................................................................................106
21.1.1.
Abnormal laboratory values defined as adverse events..........................................106
21.1.2.
Serious adverse event ...........................................................................................107
21.1.3.
Classification of severity.......................................................................................108
21.1.4.
Classification of Relationship/Causality of adverse events (SAE/AE) to 
study drug.............................................................................................................108
21.1.5.
Duration ...............................................................................................................108
21.1.6.
Action Taken........................................................................................................108
21.1.7.
Outcome...............................................................................................................109
21.1.8.
Monitoring and reporting of adverse events ..........................................................109
21.1.9.
Immediate reporting of serious adverse events......................................................109
21.1.10.
Pregnancies ..........................................................................................................110
21.1.11.
Safety Queries ......................................................................................................110
21.1.12.
Expedited Reporting of Adverse Events................................................................110
21.2.
Declaration of Helsinki.........................................................................................112
21.2.1.
Introduction..........................................................................................................112
21.2.2.
Basic Principles for All Medical Research ............................................................113
21.2.3.
Additional Principles for Medical Research Combined with Medical Care............115
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Lenalidomide (CC-5013)
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Celgene Corporation
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36
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
21.3.
ECOG Performance Status Scale ..........................................................................117
21.4.
MCL International Prognostic Index (MIPI) score (Hoster, 2008).........................118
21.5.
Modified International Workshop Response Criteria (Cheson, 1999)....................119
21.6.
Cairo-Bishop Grading System for tumor lysis syndrome (TLS) ............................122
21.7.
Lenalidomide Pregnancy Prevention Plan for Subjects in Clinical Trials................123
21.8.
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and
Acceptable Birth Control Methods........................................................................123
21.8.1.
Risks Associated with Pregnancy..........................................................................123
21.8.1.1.
Definition of Females of Childbearing Potential ...................................................123
21.8.1.2.
Definition of Females Not of Childbearing Potential.............................................124
21.8.2.
Counseling ...........................................................................................................124
21.8.2.1.
Females of Childbearing Potential ........................................................................124
21.8.2.2.
Females Not of Childbearing Potential..................................................................124
21.8.2.3.
Males....................................................................................................................125
21.8.3.
Contraception .......................................................................................................125
21.8.3.1.
Female Subjects of Childbearing Potential............................................................125
21.8.3.2.
Male Subjects.......................................................................................................126
21.8.4.
Pregnancy Testing ................................................................................................126
21.8.5.
Pregnancy Precautions for Lenalidomide Use........................................................126
21.8.5.1.
Before Starting Lenalidomide ...............................................................................126
21.8.5.2.
During and After Study Participation....................................................................127
21.8.5.3.
Additional Precautions..........................................................................................128
21.9.
Lenalidomide Education and Counseling Guidance Document for Female
Subjects................................................................................................................129
21.9.1.
Female of Childbearing Potential: .........................................................................129
21.9.2.
Female Not of Childbearing Potential (Natural Menopause for at Least 24 
Consecutive Months, a Hysterectomy, or Bilateral Oophorectomy):......................131
21.10.
Lenalidomide Education and Counseling Guidance Document for Male
Subjects................................................................................................................132
21.11.
Lenalidomide Information Sheet............................................................................134
21.12.
EORTC QLQ-C30 Questionnaire .........................................................................136
123
23
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21.12.


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LIST OF TABLES
Table 1:
Celgene Emergency Contact Information..................................................................3
Table 2:
Schedule of Study Assessments for Arm A and Arm B patients  (28 days = 1 
cycle)......................................................................................................................24
Table 3:
Schedule of study assessments for patients with cross-over on lenalidomide 
after progression in investigator's choice Arm B (28 days = 1 cycle) – No 
more than 10 weeks after last day of last cycle of treatment in Arm B.....................28
Table 4:
Schedule of Study Assessments: Guidance for Extended Access Phase...................30
Table 5:
Abbreviations and Specialist Terms........................................................................39
Table 6:
Overview of dosage of Investigator's choice drugs..................................................64
Table 7:
Dose Modification for Lenalidomide ......................................................................65
Table 8:
Dose reduction steps for Adverse Events related to Lenalidomide for patients 
initiating treatment at 25 mg daily on Days 1-21, every 28 days..............................68
Table 9:
Dose reduction steps for Adverse Events related to Lenalidomide for patients 
initiating treatment at 10 mg daily on Days 1-21, every 28 days..............................68
Table 10:
Confidence Intervals...............................................................................................92
Table 11:
Summary of Modified Response Criteria ..............................................................121
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Lenalidomide (CC-5013)
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................53
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide (CC-5013)
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table 5:
Abbreviations and Specialist Terms
Abbreviation or
specialist term
Explanation
AE
Adverse event
ALC
Absolute lymphocyte count 
ALT (SGPT)
Alanine transaminase (serum glutamic- pyruvic transaminase) 
ANC
Absolute neutrophil count
APC
Activated protein C
AST (SGOT)
Aspartate transaminase (serum glutamic-oxaloacetic 
transaminase)
ASA
Acetylsalicylic acid
ß- HCG
Beta human chorionic gonadotropin
BUN
Blood urea nitrogen
CBC
Complete blood count
CFR
Code of Federal Regulations
CLL
Chronic lymphocytic leukemia
CNS
Central nervous system
CR
Complete response
CrCl
Calculated creatinine clearance
CRu
Complete response unconfirmed
CRF
Case report form
CRP
C-reactive protein
CSF
Cerebrospinal fluid
CT
Computerized Tomography
CTCAE
Common terminology criteria for adverse events
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee
DVT
Deep vein thrombosis
ECG
Electrocardiogram
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Lenalidomide (CC-5013)
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Table 5:
Abbreviations and Specialist Terms (Continued)
Abbreviation or
specialist term
Explanation
ECOG
Eastern Cooperative Oncology Group
EMEA
European Agency for Evaluation of Medicinal Products
ESMO
European Society for Medical Oncology
FAS
Full Analysis Set
FCBP
Female of childbearing potential
FISH
Fluorescence in situ hybridization
FL
Follicular lymphoma
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF 
Granulocyte colony-stimulating factor
GM-CSF
Granulocyte-macrophage colony-stimulating factor
HBV
Hepatitis B virus 
HC
Health Canada
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
ICD
Informed Consent Document
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IL
Interleukin
IMiD®
Immunomodulatory drug
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
ITT
Intent to treat
IUD
Intrauterine device
&
IRC
IRC
&(/
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Table 5:
Abbreviations and Specialist Terms (Continued)
Abbreviation or
specialist term
Explanation
IUS
Intrauterine system
IWRC
International Workshop Response Criteria
LDH
Lactate dehydrogenase
MCL
Mantle cell lymphoma
MCV
Mean corpuscular volume
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Drug Regulatory Activities
MIPI
MCL International Prognostic Index
MITT
Modified intent to treat
MRI
Magnetic Resonance Imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NHL
Non-Hodgkin’s Lymphoma
NSAIDS
Non-steroidal anti-inflammatory drug
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PPS
Per-protocol (Set)
PR
Partial response
PTT
Partial thromboplastin time
PT
Prothrombin Time
QoL
Quality of Life
RDC
Response Determination Committee
RBC
Red blood cell
R-CHOP
Rituximab -Cyclophosphamide, Doxorubicin, Vincristine and 
Prednisolone
R-Hyper CVAD 
Rituximab -Cyclophosphamide Vincristine, Adriamycin and 
Dexamethasone
&
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Lenalidomide (CC-5013)
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Table 5:
Abbreviations and Specialist Terms (Continued)
Abbreviation or
specialist term
Explanation
RNA
Ribonucleic acid
SAE
Serious adverse event
SD
Stable disease
SOP
Standard Operating Procedure
SPC
Summary of product characteristics
SPD
Sum of the products of the greatest diameter
TCR
Tumor control rate
TFR
Tumor flare reaction
TFT
Thyroid function tests
TLS
Tumor lysis syndrome
TNF
Tumor necrosis factor
TSH
Thyroid stimulating hormone
TTF
Time-to-treatment failure 
TTP
Time to progression
TTR
Time to tumor response
ULN
Upper limit of normal
VEGF
Vascular endothelial growth factor
WBC
White blood cell
WHO
World Health Organization
WMA
World Medical Association
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Lenalidomide (CC-5013)
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
5.
INTRODUCTION
5.1.
Mantle Cell Lymphoma
Mantle-cell lymphoma (MCL) 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 the cyclin D1 are associated with the 
landmark t (11;14)(q13;q32) chromosomal translocation (Fernandez, 2005). In rare cases, 
overexpression of other cyclin D members is seen (Fu, 2005).  MCL accounts for approximately 
5% of all lymphomas and usually affects predominantly 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 led to an improved ability 
to diagnose MCL and recognition that most cases had a clinical behavior similar to aggressive 
lymphomas. There is a subgroup of MCL that show an indolent clinical course, and recent gene 
profiling studies in the tumor tissue demonstrated a signature of 13 genes that were 
underexpressed in the indolent tumors when compared to the conventional disease. Notably, 
SOX11 was absent in indolent cases. This was further validated in an independent series of 112 
MCL and lack of SOX11 was associated with increased overall survival (Fernandez, 2010).  In 
addition, several histopathological, cytologic distinct subtypes have been identified, mainly 
based on the growth pattern and type of proliferation: the typical nodular or diffuse proliferation 
of atypical lymphoid cells, and the blastoid variant. The blastoid variant mimics acute 
lymphocytic and follows an aggressive course with a particularly poor prognosis (Schlette, 
2001).
Recent efforts have been made to administer intensive chemotherapy including high-dose 
cytarabine based regimens with rituximab or autologous stem cell transplantation (ASCT) as the 
upfront therapy in younger patients with good performance status. Several randomized and non-
randomized studies have provided evidence that intensive chemotherapy followed by ASCT may 
benefit patients aged younger than 65 years (de Guibert, 2006; Dreyling, 2005; Geisler, 2008). 
The reported 3 year overall survival rates range from 70 to75% and thus are above the reported 
historical median survival data of 3 years. 
Unlike other lymphoma types, there is no clear agreement on the treatment to be used for front-
line therapy.  Most physicians have used rituximab-containing anthracycline-based 
chemotherapy regimens such as R-CHOP, or on high-dose cytarabine regimens such as R-Hyper 
CVAD or R-DHAP. Fludarabine-based regimens are also commonly used, however often in the 
relapsed setting, together with anthracyclines or alkylating agents. The European MCL network 
currently is conducting a randomized phase III trial comparing first line treatment of R-FC with 
R-CHOP.
In patients with mantle cell lymphoma who have relapsed after initial therapy including intensive 
chemotherapy or autologous transplantation, the prognosis is poor and there is no clear 
consensus on how such patients should be treated. One agent, the proteasome inhibitor 
Bortezomib has been approved in the US and other countries for the treatment of 
relapsed/refractory MCL (Fisher, 2006; Kane, 2007). In a single arm phase II study of 155 
patients a response rate of 31% was achieved with duration of 9 months. 
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Lenalidomide (CC-5013)
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The main concern with MCL is that relapses occur eventually in most patients and despite initial 
responses, the remission durations are short. Thus, patients need repeated treatment in order to 
control the disease as long as possible. Other agents that have been demonstrated to display 
activity in a variety of B-cell lymphomas are commonly used in relapsed MCL patients. 
Fludarabine single agent induces response rates of 30 – 40% when used in the first-line setting 
and 63% when combined with cyclophosphamide (Foran, 1999; Cohen, 2001). Single agent 
therapy with fludarabine is being used in the relapsed setting once patients have received 
anthracyclines and cytarabine. (Zinzani, 2000; Tobinai, 2006). Gemcitabine as another 
nucleoside analogue has distinct antitumor activity in relapsed MCL (Dumontet, 2001). A single 
center study of 30 patients treated with gemcitabine and dexamethasone showed a response rate 
of 36% (Morschhauser, 2007). Single agent rituximab led to objective antitumor responses in 
22% of the patients with MCL (Ghielmini, 2000). Chlorambucil as a backbone of the treatment 
of intermediate risk and indolent lymphomas is also used in MCL patients (Rai, 2000; Ardeshna, 
2003). Single agent intermediate and high dose cytarabine (2 – 8 g total dose according to the 
UK SPC, 2007 for Cytarabine) has shown activity in relapsed refractory non-Hodgkin’s 
lymphoma when administered at doses of 4 – 8 g/m2 in a 21 to 28 days cycle (Kantarjian, 1983).
However, options are limited for patients with relapsed mantle cell lymphoma and there is a clear 
need for novel innovative approaches. The increasing understanding of the MCL cell biology has 
led to the development of new therapeutic agents with antitumor activity that target crucial 
biological pathways, including cell cycle inhibitors [e.g. flavopiridol], mTOR inhibitors 
[temsirolimus (Hess, 2009), everolimus (Haritunians, 2007)] and histone deacetylase inhibitors. 
These new therapeutic approaches have been studied in patients previously treated with 
aggressive regimens (Kouroukis, 2003; Goy, 2005; O’Connor, 2005). The combination of these 
new therapeutic strategies and the correct stratification of the patients according to the risk may 
ultimately change the management and outcome of MCL patients (Jares, 2008).
5.2.
Background and Rationale for Lenalidomide
Lenalidomide (REVLIMID® Celgene Corp., NJ, USA) is a member of a class of pharmaceutical 
compounds known as immunomodulatory drugs. It offers potential benefit over the first 
commercially available IMiD® compound, thalidomide, in terms of both safety and efficacy in 
patients (Galustian, 2004). Thalidomide has been evaluated in 16 patients with 
relapsed/refractory mantle cell lymphoma patients for antitumor activity in combination with 
rituximab. Thirteen patients (81%) experienced objective response and the estimated 3 year 
survival ws 75% (Kaufmann, 2004).  The key to the therapeutic potential of lenalidomide lies in 
the fact that it has multiple mechanisms of action, which act to produce anti-inflammatory, anti-
angiogenic, and anti-tumor effects. These effects are thought to be contextual in that they depend 
on both the cell type and the triggering stimulus. To date, lenalidomide has been associated with 
TNF-α inhibitory, T-cell co-stimulatory, and anti-angiogenic effects (Galustian, 2004).
Lenalidomide is marketed in the United States, Canada and Argentina for the treatment of 
patients with transfusion-dependent anemia due to low- or intermediate-1-risk Myelodysplastic 
Syndrome (MDS) associated with a deletion 5q cytogenetic abnormality with or without 
additional cytogenetic abnormalities and in combination with dexamethasone for patients with 
previously treated multiple myeloma. Lenalidomide is also approved and marketed in multiple 
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countries including the US and EU, 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 treatment for various hematological and oncologic 
indications.  Studies have also been conducted in non-oncologic conditions including complex 
regional pain syndrome. 
5.2.1.
Preclinical studies with Lenalidomide
Lenalidomide displays antiproliferative effects against hematopoietic tumor cells, especially 
those of the B cell lineage, including mantle cell Lymphoma.  A dose-dependent upregulation of 
the p21WAF-1 expression was observed in Namalwa lymphoma- cell line, and in U266- and LP-
1 multiple myeloma cell lines (Verhelle, 2007).  The p21WAF-1 upregulation correlated with 
increased binding to the cyclin dependent kinases CDK2, CDK4 and CDK6 complexes leading 
to decreased retinoblastoma protein phosphorylation and G1/G0 cell cycle arrest (Verhelle, 
2007). These data suggest that the lenalidomide mechanism of action involves upregulation of 
p21WAF-1, which may be in part responsible for the antiproliferative activity observed against 
tumor cells. 
The effect of lenalidomide on proliferation of mantle cell lymphoma, and on the expression of 
several important genes involved in cancer cell cycle, was examined by quantitative real-time 
polymerase chain reaction. As mentioned before, mantle cell lymphoma usually has a t(11;14) 
translocation, resulting in cyclin D1 overexpression. Results indicate that high baseline cyclin D1 
and low p21 gene expression in MCL cell lines correlate with sensitivity to lenalidomide and 
may be predictive of a good clinical response to lenalidomide. In addition, monitoring of SPARC 
expression in MCL patients may enable early identification of patients who are responding to 
lenalidomide therapy. SPARC (osteonectin) is a gene coding for a matrix glycoprotein recently 
proposed to be a potential tumor suppressor and important for the inhibition of erythroid cell 
proliferation by lenalidomide. The level of constitutive cyclin D1 gene expression in MCL cell 
lines correlates with the order of sensitivity to lenalidomide. Conversely, the constitutive p21 
gene expression is inversely proportional to lenalidomide sensitivity. Therefore, the baseline 
cyclin D1 to p21 gene expression ratio could be predictive of patient response to lenalidomide 
therapy. It was also found that lenalidomide markedly increases SPARC gene expression in NHL 
cells in a manner that correlates with the anti-proliferative activity of lenalidomide. The order of 
sensitivity to lenalidomide by various NHL cell lines is Namalwa (Burkitt’s lymphoma)>Rec-
1>Jeko-1>Granta-519>JVM-2 (all MCL)> DB (diffuse large B cell lymphoma). Thus SPARC 
gene induction may be a biomarker of NHL or MCL tumor response to lenalidomide (Zhang, 
2007).
Lenalidomide also enhances T and NK cell stimulation, and augments NK cell-mediated 
hematopoietic tumor cell lysis, which may contribute to its clinical anti-tumor activity. In both 
freshly isolated T cells and in differentiated Th1 cells, lenalidomide enhanced T cell proliferation 
and augmented production of interleukin 2 (IL-2) and interferon % (IFN-%) following T cell 
receptor activation (Corral,1999; Schafer, 2003). Several pre-clinical studies show that the 
mechanism of lenalidomide comprises T cell activation and may involve induction of the Akt 
pathway and AP-1 transcriptional activity. 
The effects of lenalidomide on NK and T cell activity have also been examined. Using NKT 
cells from healthy donors and multiple myeloma (MM) patients, in vitro treatment with 
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lenalidomide significantly enhanced NKT cell expansion in response to stimulation with 
dendritic cells presenting the NKT ligand α-galactosyl-ceramide. Lenalidomide markedly 
enhanced in vitro NK-cell mediated lysis of both MM cell lines and autologous patient MM 
cells. When the tumor cells were co-cultured with PBMC, lenalidomide enhanced the apoptosis 
of both K562 cells and Raji cells (Zhu, 2008), supporting an NK cell mediated lysis mechanism.
Thus there is direct antiproliferative activity of lenalidomide against hematopoietic tumor cells, 
especially those of the B cell lineage and including MCL, via upregulation of the tumor 
suppressor genes p21 and SPARC. Furthermore, the immunomodulatory effects of lenalidomide 
on T and NK cells, alone and in combination with antibodies such as rituximab, may enhance its 
anti-tumor activity in MCL patients.
Furthermore, recent preclinical studies suggest that lenalidomide may promote restoration of 
anti-tumor immunological effects in patients with certain hematological malignancies.  It was 
reported that patients with CLL have a dysfunction of their T cells (Ramsay, 2008).  When the 
dysfunction was studied using an in vitro system, in which the restoration of the immunologic 
synapse was taken as the functional assay, treatment of both the patient’s T cells and the CLL 
cells was required for synapse formation. It was also reported that the impaired T cell 
immunological synapse formation was seen in both CD4 and CD8 T cells from follicular 
lymphoma (FL) patients compared to age-matched healthy donors (Ramsay, 2009). This defect 
was induced by tumor contact since T cell defects were induced in healthy T cells when they 
were co-cultured for 48 hr with allogeneic FL cells, but not with healthy allogeneic B cells.  In 
co-culture with FL cells, previously healthy T cells showed suppressed recruitment of integrin 
LFA-1, Lck, Itk, Rab27A and filamin-A to the synapse in subsequent T cell: APC interactions. It 
was further demonstrated that the immune synapse defects were repaired in part by treatment of 
the cells with the immunomodulatory drug lenalidomide. Treatment of both FL B cells and 
autologous T cells with lenalidomide (0.5 μM for 24h) was required to enhance formation of the 
F-actin synapse and recruitment of tyrosine-phosphorylated protein and filamin-A irrespective of 
the presence of exogenous antigen. 
Additionally, it was described that lenalidomide up-regulated the expression of genes involved in 
the immune response, such as co-stimulatory and antigen-presenting molecules (Gaidarova, 
2008). Furthermore, lenalidomide treatment induced actin cytoskeleton reorganization and 
polarization of MCL cells as early as 30 min, prior to a detectable increase of CD1c expression 
and could be responsible for re-localization of CD1c protein to polarized sites at the plasma 
membrane. Lenalidomide had similar effects on γδT cells, inducing actin cytoskeleton dynamics 
and polarization within minutes in these cells. Lenalidomide enhanced the number of γδT-MCL 
immune synapses and the lytic activity of γδT cells against the tumor cells. 
These laboratory observations of direct lenalidomide effects on tumor cells, in inducing the 
expression of potential tumor suppressor genes and proteins potentially involved in tumor cell 
recognition by T cells, as well as cellular lenalidomide effects on the host immune cells 
potentially to improve tumor cell recognition, serve as the scientific basis for the clinical 
approach described in the clinical trial protocol.
5.2.2.
Clinical Studies of lenalidomide in Non-Hodgkin’s Lymphoma
Three phase 2 studies of single-agent lenalidomide have been conducted in patients with 
relapsed/refractory NHL (CC-5013-NHL-001 in indolent NHL and CC-5013-NHL-002 and 
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NHL-003 in aggressive NHL).  The dose/regimen used in these studies was 25 mg p.o. once 
daily for 21 days (D1 – D21) in 28 day cycle, for maximum of either 52 weeks (NHL-001 or 
NHL-002) or until disease progression (NHL-003).  Patients with mantle cell lymphoma were 
included in NHL-002 and NHL-003.  
In the two phase 2 clinical studies that include aggressive histologies (including MCL, DLBCL, 
transformed and FL grade 3), the overall response rate (ORR) was 35% in NHL-002 and 36% in 
NHL-003, respectively (Wiernik, 2008). In NHL002, fifteen of 49 patients had MCL with a 
median duration of disease of 5.1 years and a median of 4 prior treatments before enrollment. In
these MCL patients an ORR of 53% was demonstrated. Three patients (20%) had a CR or 
unconfirmed CR, and 5 patients (33%) had a PR. The median duration of response was 13.7 
months and median PFS was 5.6 months. The most common grade 4 adverse event was 
thrombocytopenia (13%) and the most common grade 3 adverse events were neutropenia (40%), 
leucopenia (27%), and thrombocytopenia (20%). (Habermann, 2009). In the second study (NHL-
003) which was initiated in November 2006, 217 patients were enrolled. In the 57 MCL patients 
who were evaluable for response assessment, lenalidomide therapy led to an objective response 
rate of 42% (25/57). Median progression-free survival (PFS) was 5.7 months. Overall, the 
primary side effect of lenalidomide was reversible myelosuppression. Grades 3 or 4 neutropenia 
occurred in 41%, thrombocytopenia in 19%, anemia in 9.2%. Grade 3 and grade 4 febrile 
neutropenia occurred in only 2% of patients (Witzig, 2011).
5.2.3.
Clinical Studies of Lenalidomide in Multiple Myeloma
Two pivotal multicenter, randomized, placebo-controlled studies comparing lenalidomide plus 
dexamethasone to dexamethasone in relapsed or refractory patients determined that combination 
therapy with lenalidomide and high-dose pulse dexamethasone is significantly more effective 
than high-dose pulse dexamethasone therapy alone as judged by time to progression (TTP), 
progression free survival (PFS), time to –treatment failure (TTF), and the proportion of patients 
who responded to therapy (MM-009 and MM-010) (Dimopoulos, 2007; Weber, 2007).. In both 
trials, superior response rates (61% vs. 19.9 % in MM-009 [p < 0.001] and 60.2% vs. 24% in 
MM-010 [p <0.001]) and greater median times to progression (11.1 vs. 4.7 months in MM-009 
[p < 0.001] and11.4 vs. 4.7 months in MM-010 [p < 0.001]) were achieved by patients who were 
treated with the combination of lenalidomide and dexamethasone compared to patients who 
received placebo plus dexamethasone. Moreover, patients in the lenalidomide plus 
dexamethasone treatment group had a significant survival advantage compared to the placebo 
plus dexamethasone group (p < 0.001 and p = 0.03 in MM-009 and MM-010, respectively).
5.2.4.
Clinical Studies of Lenalidomide in Myelodysplastic syndromes
Lenalidomide has been investigated in patients with MDS in three phase 2 studies for the 
treatment of patients with transfusion-dependent anemia due to Low-or Intermediate-1-risk 
myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or 
without additional cytogenetic abnormalities.  In MDS, lenalidomide was studied at the 
dose/regimen of 10 mg daily (CC-5013-MDS-002/CC-5013-MDS-003) until disease 
progression. Results from the CC-5013-MDS-003 study, in MDS with an associated del 5 (q31-
33) cytogenetic abnormality, showed transfusion independence in 67 % of the patients.  Median 
duration from the date when red blood cell (RBC) transfusion independence was first declared 
(the last day of the 56-day RBC transfusion-free period) to the date when an additional 
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transfusion was received after the 56-day transfusion-free period among responders was 44 
weeks.  Cytogenetic response was achieved in approximately 75 % of patients. Grade 3/4 
neutropenia and thrombocytopenia are the most common AEs associated with the use of 
lenalidomide, but are manageable with dose reductions and/or interruptions (List, 2006).
5.2.5.
Clinical Studies of Lenalidomide in Chronic Lymphocytic Leukemia 
Lenalidomide monotherapy has been investigated in two investigator initiated trials (IIT) in 
patients with relapsed/refractory CLL (Chanan-Khan, 2006) (Chanan-Khan, 2007), (Ferrajoli, 
2008).  In one study patients with relapsed/refractory CLL were treated with lenalidomide at 
25mg x 21 d q 28 days (Chanan-Khan, 2006) (Chanan-Khan, 2007).  Results from this study 
showed an overall response rate of 53% with 18% of patients achieving a CR and 36% achieving 
a PR.  The median PFS time is 19.4 months (1.2 – 38+ months).  Fatigue (83%) and flare 
reaction (tender swelling of lymph nodes and/or rash) (58%) were the most common non-
hematologic AEs reported. Other important AEs reported were tumor lysis syndrome (5%); 
Grade 3 and 4 thrombocytopenia (45%), and Grade 3 and 4 neutropenia (70%).  Pulmonary 
embolism was reported in two patients (5%).  In the second IIT study (Ferrajoli, 2008), 
continuous dosing of lenalidomide was investigated in patients with relapsed/refractory CLL.  
Lenalidomide was administered daily for 28 days of 28-day cycles until disease progression.  An 
overall response rate of 32% was observed with 3 CR (7%), 1 nodular PR (2%), 10 PR (23%). 
Myelosuppression was the most common toxicity observed, 41% # Grade 3 neutropenia and 
16% Grade 3 thrombocytopenia.  
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6.
STUDY OBJECTIVES
6.1.
Primary Objective
!
To compare the Progression Free Survival (PFS) of lenalidomide monotherapy versus 
investigator’s choice single agent in patients with mantle cell lymphoma (MCL) who 
are refractory to their regimen or have relapsed once, twice or three times.
6.2.
Secondary Objectives
!
To determine the overall response rate (ORR) of lenalidomide monotherapy or 
investigator’s choice single agent in patients with relapsed or refractory MCL.
!
To evaluate the safety of lenalidomide monotherapy or investigator’s choice single 
agent in patients with relapsed or refractory MCL.
!
To determine the time to progression, and overall survival of patients with relapsed or 
refractory MCL who have received treatment with lenalidomide or of investigator’s 
choice single agent.  
!
To investigate the health-related quality of life (QoL) of patients treated with 
lenalidomide or investigator’s choice single agent treatment.
 
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7.
STUDY ENDPOINTS
7.1.
Primary
!
Progression free survival defined as the time from randomization to the first 
observation of disease progression or death due to any cause. If the patient has not 
progressed or died, PFS will be censored at the time of last completed assessment 
when the patient was known not to have progressed. Patients who will receive a new 
treatment without documented progression will be censored at the last assessment 
date that the patient is known to be progression-free.
7.2.
Secondary
!
Overall response rate (complete response [CR], complete response unconfirmed 
[CRu], and partial response [PR]) assessed by a modification of the International 
Workshop Response Criteria IWRC (Cheson, 1999)
!
Duration of response
!
Tumor control rate (Rates for CR, CRu, PR, and stable disease [SD])  
!
Time to progression
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Time to treatment failure
!
Time to tumor response
!
Overall survival (OS)
!
Safety
!
Quality of Life (EORTC QLQ-C30) 
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8.
OVERALL STUDY DESIGN
8.1.
Design Rationale
This study is designed to evaluate the efficacy and safety of lenalidomide therapy versus 
investigator’s choice in patients with relapsed and refractory mantle cell lymphoma. The primary 
efficacy objective is based on PFS. 
The multicenter nature of the study provides assurance that the results are likely to have general 
applicability. Patient eligibility criteria are consistent with those used in studies of this 
population. Patients are required to have measurable disease to facilitate the accurate assessment 
of response, the secondary efficacy endpoint. The International Workshop Response Criteria 
(IWRC) selected (Cheson, 1999) provides an international standard for the assessment of 
lymphoma. Minor modifications to the IWRC will be made to account for differences in the 
evaluation of response in mantle cell lymphoma, such as the evaluation of extranodal disease
(Kane, 2007; Fisher, 2006).  The use of this tool will ensure that data across centers are evaluated 
consistently. Safety will be assessed by evaluating AEs and laboratory data. Adverse event and 
abnormal laboratory value severity will be graded using version 3.0 of the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Monitoring for 
tumor flare and tumor lysis syndrome will be performed along with safety measures that are 
routinely assessed in investigational studies of hematologic malignancies. Tumor flare reaction 
and tumor lysis syndrome will be recorded as AEs.
Extended Access Phase:
Following the approval of Protocol Amendment #6 an Extended Access Phase will be made 
available for subjects on study treatment in countries where lenalidomide is only available under 
a clinical trial protocol as post-trial access.
These subjects will have a “discontinuation from treatment” visit assessment prior to being 
transferred to the Extended Access Phase
Following the approval of Protocol Amendment #6, subjects on study treatment will be 
considered to have entered the study Extended Access Phase. Study visits and serial 
measurements of safety should continue to be performed as per guidance outlined in Table 4.
Subjects may remain on study until progressive disease or withdrawal for other reasons. Only 
serious adverse events (SAEs) including second primary malignancies (SPMs), and drug 
accountability record information will be collected and reported to Celgene for these subjects.
Follow-up survival data will no longer be collected by Celgene for these subjects.
The Extended Access Phase will end for ongoing subjects still on lenalidomide treatment as soon 
as lenalidomide can be accessed in the commercial setting.
8.1.1.
Dose Rationale
The dose selected (25 mg [p.o.] once daily for 21 days (D1 – D21) in each 28 day cycle) has 
shown activity in three studies in NHL utilizing lenalidomide and is also the approved dose
schedule when used in combination with dexamethasone for patients with multiple myeloma 
who have been treated with at least one prior therapy.  
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8.1.2.
Discussion of Study Design
This is a multicenter, randomized, open-label, comparative controlled phase II study to 
determine the efficacy and safety of single agent lenalidomide over a concurrent control group 
treated with an investigator’s choice single agent in patients with mantle cell lymphoma who are 
refractory to their regimen or have relapsed once, twice or three times (Figure 1). The study aims 
to compare the PFS of lenalidomide therapy over a single agent of investigator’s choice. 
The investigator’s choice in the control arm comprises the monotherapy treatment with one of 
the following: chlorambucil, cytarabine, rituximab, fludarabine, or gemcitabine. The investigator 
shall choose the single agent of choice in the control arm for each patient prior to randomization 
on to the study. Patients in the investigator’s choice arm will have the option to switch to 
lenalidomide at time of progressive disease.
8.1.2.1.
Stratification
Patients will be stratified according to:
!
Time since diagnosis (<3 years or ≥ 3 years)
!
Time since last treatment (<6 months [refractory] or ≥ 6 months)
!
Prior stem cell transplant (yes or no)
Treatment and clinical characteristics will be assessed at screening/baseline, but not used for 
stratification, and will be used within an exploratory analysis:
!
Number of prior treatment lines (with description of treatment regimens, including 
first line treatment and stem cell transplant)
!
MCL International Prognostic Index (MIPI) score at time of diagnosis, if available
!
MIPI score at randomization
!
Ki-67 index (as defined by Determann et al, 2008) in the original pathology specimen 
at diagnosis, if available, or at time of relapse
!
Age and gender
!
Absolute lymphocyte counts at baseline
!
Time since last rituximab dose to cycle 1 day 1   
This study will be conducted in three phases as shown below in Figure 1: Screening phase, 
Treatment phase, and Follow-up phase. 
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Figure 1:
Overall Study Design
Following the approval of Protocol Amendment #6 an Extended Access Phase will be made available for subjects on 
study treatment in countries where lenalidomide is only available under a clinical trial protocol as post-trial access.
RELAPSED /
REFRACTORY MCL
RANDOMIZATION
(Treatment start [Cycle 1 Day 1] within 
4 days after randomization)
ARM A: Lenalidomide 25 mg daily on Days 1-
21 every 28 days (28-day cycle)
N=166
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(Chlorambucil, Rituximab, Cytarabine, 
Gemcitabine, or Fludarabine)
N=84
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treatment due to 
progressive disease or 
relapse
Discontinuation of treatment 
due to reasons other than 
progressive disease or 
relapse (i.e. toxicity)
Discontinuation of 
treatment due to 
progressive disease or 
relapse
Follow up (clinic visit and 
CT scanMRI)
every 56 days ± 7 days 
up to 6 months from the 
start of study drug then 
every 90 days ± 15 days 
thereafter.
Follow up (clinic visit or 
documented telephone 
contact) 
every 90 days ± 15 days
Option to enter into 
Lenalidomide Crossover 
Phase
Lenalidomide 25 mg daily on Days 
1-21 every 28 days (28-day cycle)
Follow up (clinic visit or 
documented telephone 
contact) 
every 90 days ± 15 days
Discontinuation of treatment due to 
progressive disease or relapse
Follow up (clinic visit or 
documented telephone contact) 
every 90 days ± 15 days
STUDY INCLUSION/ 
SCREENING
(Within 28 days of 
randomization)
Discontinuation of treatment 
due to reasons other than 
progressive disease or 
relapse (i.e. toxicity)
Discontinuation of treatment due to 
reasons other than progressive disease 
or relapse (i.e. toxicity)
Follow up (clinic visit and CT scan) 
every 90 days ± 15 days from the start of 
lenalidomide cross-over treatment
Follow up (clinic visit and CT 
scan/MRI) 
every 56 days ± 7 days up to 6 
months from the start of study 
drug then every 90 days ± 15 
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Screening Phase
Patients will be screened for protocol eligibility within 28 days prior to randomization as 
outlined in Table 2: Schedule of Study Assessments. Screening/baseline assessments will begin 
once the patient has accepted and signed the informed consent form. CBC and serum chemistry 
tests will be required within 7 days of first dose of study drug. Serology, for HBV (at least 
HBsAg, anti-HBs and anti-HBc) and for HCV will be required as screening assessment within 
28 days of randomization in endemic areas. Eligibility for the study is based on the local 
assessments (CBC, chemistry and serology as well as the local results of the archival tumor / 
lymph node biopsy) done during the screening/baseline phase of the study. 
Confirmation of mantle cell lymphoma diagnosis by the central pathology is not required before 
randomization or treatment start, but will be performed centrally at a later stage.  Eligibility for 
the study is based on assessment of the local pathology results by the investigator. Diagnosis 
based on needle aspirations are not considered acceptable pathologic data for entry in this study. 
The confirmation material submitted for Central Pathology Review must include a biopsy-
proven mantle cell lymphoma specimen, including overexpression of cyclin D1 by 
immunohistochemistry. In patients whose tumors are negative for Cyclin D1 overexpression, 
evidence of overexpression of cyclin D2 or D3 by immunohistochemistry will be acceptable. 
Tumor / lymph node biopsy specimen, which may be archival slides from specimen obtained at 
the time of initial diagnosis, with representative stained slides supporting the diagnosis of mantle 
cell lymphoma (H&E or Giemsa staining and Cyclin D1 staining), must be sent as soon as 
possible to central pathology before randomization but at the latest 8 weeks after randomization. 
It is highly recommended to submit also the original paraffin block (called tumor block) which 
will be returned to the original institution. If the tumor block cannot be sent, 4-5 additional 
unstained slides must be submitted. If such archival tissue is not available for submission, then a 
re-biopsy is required.
The translocation t(11;14)(q13:q32) by FISH is optional and is not sufficient as sole proof for 
diagnosis. Evidence of the translocation t(11;14)(q13:q32) by FISH can be submitted using the 
original slide or the corresponding confirming photographies. If available, it is also 
recommended to send, for central pathology review, slides containing immunostaining for CD3, 
CD5, CD 10, CD23, CD20, BCL2, Ki-67.
Furthermore, it is highly recommended to perform an unilateral bone marrow biopsy at 
screening, and to send the tumor block to Central Pathology for review at the latest 8 weeks after 
randomization.
 
During the screening/baseline phase, the investigator must allocate one of the “investigator’s 
choice” options to the patient prior to the randomization.
8.1.2.2.
Treatment Phase
Once all eligibility criteria are met and baseline assessments completed, patients will be 
randomized 2:1 to receive lenalidomide monotherapy or the investigator’s choice. The first 
treatment dose of the first cycle administered to the patient is called C1D1. Treatment should 
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start as soon as possible after randomization, but maximum time between randomization and 
C1D1 is 4 days, once the patient has fulfilled the requirements of the Lenalidomide pregnancy 
prevention program (see Section 21.7). Patients will continue in the treatment phase until disease 
progression, unacceptable toxicity or voluntary treatment withdrawal. Toxicity will be assessed 
using the NCI CTCAE criteria version 3 and the dose of lenalidomide or the investigators choice 
single agent will be reduced accordingly (see Table 8 and Table 9 for dose reductions).
Serial assessments of safety and efficacy (CT scans with contrast or MRI with contrast every 56 
days ± 7 days for the first 6 months and then every 90 days thereafter) will be performed as 
outlined in the Schedule of Study Assessments or as directed in the dose modification section.  
Patients may continue participation in the treatment phase of the study until disease progression 
or unacceptable toxicity or voluntary patient withdrawal from treatment, at which point, the 
patients will enter the follow-up phase.
Diagnostic imaging results (CT scan with contrast or MRI with contrast, if CT scan is 
contraindicated) will be reviewed locally and also submitted for central review.
CT scans is the preferred procedure. If CT is contraindicated, MRI is acceptable. It is advised to 
stick to the same procedure for a given patient throughout the study.
 
 
 
Patients who withdraw consent for treatment will continue to be followed for safety, efficacy 
(disease progression), second primary malignancies, and for survival.
Cross over (for patients in the investigators choice Arm B only): 
Patients in the investigator’s choice Arm B, who have documented progressive disease will have 
the option to receive single agent lenalidomide treatment. Patients will undergo baseline 
assessments as outlined in the schedule of assessments of Table 3 for Cycle 1 Day 1.
Treatment with lenalidomide will start as soon as recovery from toxicities of prior treatments of 
Arm B have resolved and all inclusion/exclusion criteria are met (i.e. laboratory parameters), but 
no longer than 10 weeks after last day of last treatment cycle in Arm B.
Assessments during treatment with lenalidomide will be for safety, response evaluation, second 
primary malignancies, and overall survival follow-up. CT scans with contrast/MRI with contrast 
are recommended to be performed every 90 days (± 15 days) until disease progression or 
treatment discontinuation for any other reason (i.e. toxicity). Once a patient experiences disease 
progression or relapse or a patient has stopped treatment for other reasons the patient will enter 
the follow-up phase. In the follow-up phase for patients with progressive disease only 
assessments for safety (including second primary malignancies) and overall survival will be 
done. For patients who have entered the follow-up phase due to treatment discontinuation for 
other reasons additional CT scans with contrast /MRI with contrast will be performed at pre-
defined intervals and assessments for safety (including second primary malignancies) and overall 
survival will be done. Patients will be followed until either 70% of the patients have died or the 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
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CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
median follow-up in responding patients is > 2 years or the median duration of response (overall 
response and CR/CRu) has been reached, or four years from last patient randomized, whichever 
comes later, at which time subjects on study treatment will be transferred to post-trial access in 
the commercial setting. 
Follow-up Phase
Subjects withdrawn for any reason from the Extended Access Phase will not participate in a 
study follow-up phase. At their next visit 28 days later any SAEs experienced during this time 
window will be reported via the standard post-marketing process.
Once a patient experiences disease progression or relapse or a patient has stopped treatment for 
other reasons, the patient will enter the follow-up phase.  
!
All patients who discontinue treatment in either study arm or cross-over treatment 
will undergo a safety follow-up visit 28 days after last dosing day for assessment of 
adverse events (including via a physical examination), lenalidomide counseling and 
for a medically supervised pregnancy test for FCBP in Arm A and in cross over as 
specified in Section 21.7 . Vital signs, CBC with differential, and serum chemistry are 
to be performed as clinically indicated. A 28-day safety follow-up assessment will not 
be required either for subjects transferred to post-trial access in the commercial 
setting or to the Extended Access Phase. These subjects will have a “discontinuation 
from treatment” visit at the end of their 7 day rest period from their last on-study 
treatment cycle. At this “discontinuation from treatment” visit commercial 
lenalidomide will be dispensed to the subject. Between this visit and 28 days after, if 
a patient experiences a SAE, this SAE will be reported via the standard post 
marketing process. A pregnancy test should be performed 28 days post treatment 
discontinuation visit.
!
Patients who discontinue treatment due to progressive disease or relapse:
∀
Should be followed by clinic visit or documented telephone contact every 90 days 
(± 15 days) for survival, second primary malignancies and for the first subsequent 
antilymphoma therapy (including the time of and best response to the first 
antilymphoma treatment regimen utilized after discontinuation from treatment in 
this study).
!
Patients who discontinued treatment due to reasons other than progressive disease 
or relapse:
∀
Clinic visits should occur every 56 days to assess disease status (physical exam) 
until disease progression or relapse
∀
CT scan with contrast/MRI with contrast should occur every 56 days (± 7 days)
up to 6 months from the start of study drug then every 90 days ± 15 days
thereafter until disease progression or relapse 
∀
After disease progression or relapse has occurred, patients should be followed by 
clinic visit or documented telephone contact every 90 days (± 15 days) for 
survival, second primary malignancies and for the first subsequent antilymphoma 
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Lenalidomide (CC-5013)
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therapy (including the time of and best response to the first antilymphoma 
treatment regimen utilized after discontinuation from treatment in this study).
∀
Patients in the follow-up phase who withdraw consent for efficacy (disease 
progression) follow-up will continue to be followed for second primary 
malignancies and for survival. A full consent withdrawal must be documented to 
disallow survival follow up.
The follow up phase will continue until either 70% of the patients have died or the median 
follow-up in responding patients is > 2 years or the median duration of response (overall 
response and CR/CRu) has been reached, or four years from last patient randomized, whichever 
comes later, at which time the follow-up study phase will be closed.
Extended Access Phase
Following the approval of Protocol Amendment #6 an Extended Access Phase will be made 
available for subjects on study treatment in countries where lenalidomide is only available under 
a clinical trial protocol as post-trial access.
These subjects will have a “discontinuation from treatment” visit assessment prior to being 
transferred to the Extended Access Phase
Following the approval of Protocol Amendment #6, subjects on study treatment will be 
considered to have entered the study Extended Access Phase. Study visits and serial 
measurements of safety should continue to be performed as per guidance outlined in Table 4. 
Subjects may remain on study until progressive disease or withdrawal for other reasons. Only 
serious adverse events (SAEs) including second primary malignancies (SPMs), and drug 
accountability record information will be collected and reported for these subjects. Follow-up 
survival data will no longer be collected by Celgene for these subjects.
The Extended Access Phase will end for ongoing subjects still on lenalidomide treatment as soon 
as lenalidomide can be accessed in the commercial setting.
8.2.
Assessment of Second Primary Malignancies
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 21.1.9).  This 
includes any second primary malignancy, regardless of causal relationship to study drug 
(lenalidomide or Investigator Choice arm drugs), occurring at any time for the duration of the 
study, from the time of signing the ICD through follow-up for overall survival. The Follow-Up 
Phase involves patient contact every 90 days (± 15 days) until patient death or until either 70% 
of the patients have died, or the median follow-up in responding patients is > 2 years, or the 
median duration of response (overall response and CR/CRu) has been reached, or four years 
from last patient randomized, whichever comes later. at which time the follow-up study phase 
will be closed.
Second primary malignancies (SPMs) will continue to be reported for subjects included in the 
Extended Access Phase.
hever 
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8.3.
Data Monitoring Committee
An independent external Data Monitoring Committee (DMC) will review ongoing safety data 
throughout the study and efficacy for futility at a pre-defined time point. Specifics are outlined in 
the DMC charter. The first safety analysis will occur after the first 40 patients have received at 
least 2 cycles of treatment or have discontinued prior to completing 2 cycles.  The second safety 
analysis as well as an efficacy analysis for futility will occur after 80 patients complete 2 cycles 
or withdraw before completing 2 cycles. A third safety analysis will occur after 120 patients 
complete 2 cycles or withdraw before completing 2 cycles. A fourth safety analysis will occur
after 200 patients complete 2 cycles or withdraw before completing 2 cycles.
8.4.
Independent External Pathological Review
An independent central pathologist will review the lymph node/tumor biopsy for retrospective 
confirmation of the diagnosis of mantle cell lymphoma. 
The confirmation material submitted for Central Pathology Review must include a biopsy-
proven mantle cell lymphoma specimen, including overexpression of cyclin D1 by 
immunohistochemistry. In patients whose tumors are negative for Cyclin D1 overexpression, 
evidence of overexpression of cyclin D2 or D3 by immunohistochemistry will be acceptable. 
Tumor / lymph node biopsy specimen, which may be archival slides from specimen obtained at 
the time of initial diagnosis, with representative stained slides supporting the diagnosis of mantle 
cell lymphoma (H&E or Giemsa staining and Cyclin D1 staining), must be sent as soon as 
possible to central pathology before randomization but at the latest 8 weeks after randomization. 
It is highly recommended to submit also the original paraffin block (called tumor block) which 
will be returned to the original institution. If the tumor block cannot be sent, 4-5 additional 
unstained slides must be submitted. If such archival tissue is not available for submission, then a 
re-biopsy is required.
The translocation t(11;14)(q13:q32) by FISH is optional and is not sufficient as sole proof for 
diagnosis. Evidence of the translocation t(11;14)(q13:q32) by FISH can be submitted using the 
original slide or the corresponding confirming photographies. If available, it is also 
recommended to send, for central pathology review, slides containing immunostaining for CD3, 
CD5, CD 10, CD20, CD23, BCL2, Ki-67.
Furthermore, it is highly recommended to perform an unilateral bone marrow biopsy at 
screening, and to send the tumor block to Central Pathology for review at the latest 8 weeks after 
randomization.
 
The central pathologist will also review any pathology specimens obtained as part of response 
assessment, including assessment of bone marrow biopsy required for response assessment of 
CR/CRu.  
For further details, please refer to central pathology manual.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
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59
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
8.5.
Independent Review Committee (IRC)
Diagnostic imaging results (CT with contrast /MRI with contrast) will be reviewed locally and 
also sent to IRC for central review. The IRC is composed of two external radiologists with an 
additional radiologist (adjudicator), in the event of a tie, and a hemato/-oncologist. The IRC will 
perform a blinded, independent assessment of radiological response (including assessment of SD 
and PD), review the tumor response data and the dates of disease progression for each patient. 
All these data reviewed by the IRC will be used in the primary analysis and these assessments 
will be included in the Clinical Study Report. 
For further details please refer to Central Radiology Manual.
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide (CC-5013)
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9.
STUDY POPULATION
9.1.
Patient Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Patients with histologically proven mantle cell non-Hodgkin’s lymphoma [MCL] 
{including overexpression of cyclin D1 by immunohistochemistry}. In patients whose 
tumors are negative for the cyclin D1 overexpression or translocation, evidence of 
overexpression of cyclin D2 or D3 by immunohistochemistry will be acceptable 
1. Patients who are refractory to their regimen or have relapsed once, twice or three times 
and who have documented progressive disease. (Refractory to prior chemotherapy 
regimens is defined as not having reached a CR or PR to prior treatment)
2. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
3. Must be #18 years of age at the time of signing the informed consent form
4. Must have had at least one prior combination chemotherapy regimen with an alkylating 
agent, and comprising either an anthracycline and/or cytarabine and/or fludarabine (with 
or without rituximab)
5. Prior stem cell transplant is allowed
6. Must be ineligible for intensive chemotherapy and/or transplant at time of inclusion in the 
study
7. Must have measurable disease on cross sectional imaging by CT or MRI, if CT is 
contraindicated that is at least 2 cm in the longest diameter and measurable in two 
perpendicular dimensions
8. Must be able to adhere to the study visit schedule and other protocol requirements
9. Life expectancy of greater than 3 months
10. Females of childbearing potential (FCBP)† must:
!
Have two negative medically supervised pregnancy tests prior to starting of study 
therapy. She must agree to ongoing pregnancy testing during the course of the study, 
and after end of study therapy (see specifics in Appendix 21.8). This applies even if 
the patient practices complete and continued sexual abstinence
!
Either commit to continued abstinence from heterosexual intercourse (which must be 
reviewed on a monthly basis) or agree to use, and be able to comply with, highly 
effective contraception without interruption, at least 28 days prior to starting study 
drug, during the study therapy (including dose interruptions), and for at least 28 days 
after discontinuation of study therapy (see specifics in Appendix 21.8).
†A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) 
has not been naturally postmenopausal (i.e., amenorrhea following cancer therapy does not rule out childbearing 
potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive 
months)
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11. Male patients must:
!
Agree to use a condom during sexual contact with a FCBP, even if they have had a 
vasectomy, throughout study drug therapy, during any dose interruption and after 
cessation of study therapy (see specifics in Appendix 21.8).
!
Agree to not donate semen or sperm during study drug therapy and for at least 28 
days after end of study drug therapy (see specifics in Appendix 21.8).
12. All patients must:
!
Have an understanding that the study drug could have a potential teratogenic risk
!
Agree to abstain from donating blood while taking study drug therapy and for at least 
28 days after end of study drug therapy (see specifics in Appendix 21.8).
!
Agree not to share study medication with another person
!
Agree to be counseled about pregnancy precautions and risks of fetal exposure.  See
Appendix 21.8)
9.2.
Patient Exclusion Criteria
1. Diagnosis of lymphoma other than mantle cell lymphoma
2. Prior history of malignancies, other than mantle cell lymphoma, unless the patient has 
been free of the disease for ≥ 5 years. Exceptions include the following:
!
Basal cell carcinoma of the skin
!
Squamous cell carcinoma of the skin
!
Carcinoma in situ of the cervix
!
Carcinoma in situ of the breast
!
Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
3. Transformed lymphoma
4. Prior use of lenalidomide
5. Prior radiotherapy within 4 weeks prior to randomization.
6. Patients who are candidates for autologous or allogeneic transplantation at the time of 
inclusion into the study.
7. Prior allogeneic transplantation with persistent donor hematopoiesis
8. Active CNS lymphoma with the exception of those patients whose CNS lymphoma has 
been treated with chemotherapy, radiotherapy or surgery, have remained asymptomatic 
for 90 days (3 months) and demonstrate no CNS lymphoma as shown by lumbar 
puncture, CT/brain MRI are eligible.  Patients with a history of CNS involvement or CNS 
symptoms will be required to have negative CSF cytology examination and a head CT 
during the screening period (known and active CNS or leptomeningeal involvement)
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9. Known seropositive for or active viral infection with human immunodeficiency virus 
(HIV)
10. Known seropositive for or active viral infection with hepatitis B virus: 
∀
HBsAg positive.
∀
HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral 
DNA.
∀
Patients who are HBsAg negative and viral DNA negative are eligible.
∀
Patients who had hepatitis B but have received an antiviral treatment and show no 
detectable viral DNA for 6 months are eligible.
∀
Patients who are seropositive because of hepatitis B virus vaccine are eligible.
11. Known seropositive for or active viral infection with hepatitis C virus (HCV)
∀
Patients who had hepatitis C but have received an antiviral treatment and show no 
detectable viral RNA for 6 months are eligible.
12. Patients who are not willing to take DVT prophylaxis, if they are at risk (see definition in
Section 10.1.6)
13. Patients should not be receiving corticosteroids 7 days prior to randomization, except for 
prednisone ≤ 10 mg/day or equivalent for purposes other than treating MCL
14. Pregnant or lactating females
15. Any of the additional laboratory abnormalities. 
!
Absolute neutrophil count (ANC) < 1,500 cells/mm3 (1.5 x 109/L)
!
Platelet count < 60,000/mm3(60 x 109/L)
!
Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT)
> 3.0 x upper limit of normal (ULN), except in patients with documented liver 
involvement by lymphoma
!
Serum total bilirubin > 1.5 x ULN, except in case of Gilbert’s Syndrome and 
documented liver involvement by lymphoma.
!
Calculated creatinine clearance (Cockcroft – Gault formula) of <30 mL/min
16. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the patient from signing the informed consent form
17. Participation in another clinical trial during the screening/baseline phase and treatment 
phase of the study
18. Any use of experimental drug during 4 weeks prior to randomization 
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Lenalidomide (CC-5013)
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10.
DESCRIPTION OF TREATMENT 
10.1.
Treatment Assignments
The duration of a treatment cycle will be 28 days. The first dose of lenalidomide in cycle 1 
defines day 1 of the treatment cycle, and each cycle thereafter will begin 29 days later.
The 28-day cycle length should be maintained throughout the entire treatment phase regardless 
of the dose interruptions and/or dose reductions.
10.1.1.
Arm A
All patients who qualify for enrollment into the study will be randomized 2:1 to receive 
lenalidomide monotherapy (Arm A) or the investigator’s choice (Arm B). 
Patients in Arm A, 
!
Patients, who have a creatinine clearance ≥ 60 mL/min, will receive oral lenalidomide 
that is initiated on Day [D] 1 of Cycle 1 at a dose of 25 mg p.o. once daily for 21 days
(D1 – D21) in each 28 day cycle. A minimum 7 day rest period is mandatory before 
starting each new treatment cycle regardless of allowed ± visit windows.
!
Patients 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
for 21 days (D1 – D21) in Cycle 1 and Cycle 2. A minimum 7 day rest period is 
mandatory before starting each new treatment cycle regardless of allowed ± visit 
windows. After Cycle 2, if the patient remains free of Grade 3 or Grade 4 toxicity, the 
dose will be increased to 15 mg once daily for 21 days (D1 – D21) in each 28 day 
cycle. 
Treatment is continued until disease progression or unacceptable toxicity. 
10.1.2.
Arm B
Patients in Arm B will receive investigator’s choice single agent reference therapy. This 
includes:
Chlorambucil tablets 2 mg;
Rituximab 500 mg vials;
Cytarabine Injection Solution 100 mg/ml;
Gemcitabine 1g vial;
Fludarabine 10 mg film-coated tablets;
Fludarabine 25mg/ml Concentrate for Solution for Injection or Infusion
Please refer to the prescribing information provided by Celgene on all of the above
For dosing of the investigators choice single agents, please refer to Table 6 based on published 
data and expert opinions.
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Lenalidomide (CC-5013)
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64
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Investigators should refer to the approved Summary of Product Characteristics (SPC), provided 
by Celgene, for the investigator’s choice therapy for complete prescribing information including 
administration, warnings, precautions, contraindications, and adverse reactions and follow 
institutional procedures for the administration of the agents, where applicable. Paper prints will 
be provided in the Investigator's and Pharmacy binders.
The investigator’s choice treatment will be provided by Celgene.
Table 6:
Overview of dosage of Investigator's choice drugs 
Investigator’s choice*
mg/m2
Days
q days
max # cycles
Chlorambucil p.o. 
(Rai, 2000; Ardeshna, 
2003)
40 (total monthly 
dose)
Split over 3-10
days
28
until PD or 
toxicity
Rituximab i.v. 
(Ghielmini, 2000)
375
1, 8, 15, 22
56#
until PD or 
toxicity
Cytarabine i.v. 
(Kantarjian, 1983;   
UK SPC)
1 -2 g/m2 once or 
twice per day
1, 2
28
6
Gemcitabine i.v. 
(Dumontet, 2001)
1000
1, 8, 15
28
6
Fludarabine i.v. 
(Decaudin, 1998;
Zinzani, 2000)
25
1-5
28
6
Fludarabine p.o.
(Tobinai, 2006)
40
1-5
28
6
q days, repeated; y, years; i.v., intravenous; p.o., oral; 
* Refer to the approved Summary of Product Characteristics (SPC), provided by Celgene for the investigator’s 
choice therapy for complete prescribing information including administration, warnings, precautions, 
contraindications, and adverse reactions and follow institutional procedures for the administration of the agents, 
where applicable.
# Rituximab (single agent) is to be repeated every 56 days after Day 56 (given only on day 1 of every 56 days 
cycle). For the prevention of cytokine release syndrome associated with the treatment of Rituximab ≤125mg of 
methylprednisolone or equivalent are accepted on C1D1.
Patients in Arm B need to follow the scheduled visits as displayed in Table 2. For some drugs, 
additional visits may be needed.
10.1.3.
Dose Modification or Interruption for Lenalidomide - Arm A
a) Dose modification 
Patients will be evaluated for adverse events at each visit with the NCI CTCAE v3.0 used as a 
guide for the grading of severity.  The dose of lenalidomide for each patient will be interrupted 
and modified following toxicity as described below.
Refer to Table 7 for instructions on dose modifications and Table 8 and Table 9 for dose 
reduction instructions for lenalidomide.
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Lenalidomide (CC-5013)
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Table 7:
Dose Modification for Lenalidomide
NCI CTCAE
Toxicity Grade
Action Required
Sustained(≥7 days) Grade 3 
neutropenia or ≥ Grade 3 associated 
with fever (temperature ≥ 38.5º C) or 
Grade 4 neutropenia
!
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 at 
the discretion of the investigator
Thrombocytopenia ≥Grade 3 (platelet 
count < 50,000 cells/mm³ [50x109/L])
!
Hold (interrupt dose)
!
Follow CBC weekly at least every seven days
!
If thrombocytopenia resolves to ≥ 60,000 cells/mm³ (60 x 
109/L) restart at next lower dose level.
Desquamating (blistering) Rash
≥ Grade 3 or
non-desquamating 
Rash Grade 4
!
Discontinue lenalidomide study drug
Allergic reaction or hypersensitivity
Grade 2
Grade 3-4
!
Hold (interrupt dose).  Follow at least every seven days
!
When the toxicity resolves to ≤ Grade 1 restart at next 
lower dose level
!
Discontinue lenalidomide study drug
Constipation
Grade 1-2
≥ Grade 3
!
Initiate bowel regimen and maintain dose level
!
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)
Newly developed ≥ Grade 3 peripheral 
neuropathy (this applies only to those 
toxicities which begin or worsen
while on study)
!
Hold (interrupt) dose
!
When the toxicity resolves to ≤ Grade 2 restart at next 
lower dose level
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Lenalidomide (CC-5013)
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Celgene Corporation
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Table 7:
Dose Modification for Lenalidomide (Continued)
NCI CTCAE
Toxicity Grade
Action Required
AST or ALT > 3 x ULN
Hold lenalidomide dosing; re-
test at least weekly until AST 
or ALT < 2.5 x ULN or return 
to baseline 
∀
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lenalidomide if the event is 
considered NOT related to 
study drug treatment
∀
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treatment at next lower 
dose level if the event is 
considered as related to 
drug treatment
Bilirubin > 3 x ULN*
Hold lenalidomide dosing; re-
test at least weekly until 
bilirubin < 1.5 x ULN 
∀
Resume the same dose of 
lenalidomide if the event 
is considered NOT related 
to study drug treatment
∀
Restart lenalidomide 
treatment at next lower 
dose level if the event is 
considered as related to 
drug treatment
Tumor Flare
Grade 3 or 4
!
Interrupt lenalidomide therapy and initiate therapy 
with corticosteroids, NSAIDs and/or narcotics
!
Resume lenalidomide (decrease one dose level) 
when symptoms resolve to & Grade 1
TLS
laboratory TLS and Grade 1 TLS
!
Same dose of lenalidomide may be continued 
without interruption or dose reduction at the 
investigator’s discretion.
!
Dose escalation to the next consecutive dose level 
is permitted when laboratory TLS is resolved and 
Grade 1 TLS is resolved to Grade 0.
TLS ≥ Grade 2
!
Interrupt lenalidomide therapy.
!
May resume lenalidomide when the TLS resolves 
to < Grade 1 (decrease one dose level)
!
If lenalidomide is resumed prior to the start of the 
subsequent cycle, a chemistry test should be
performed every other day for the first week 
following initiation of lenalidomide.
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Protocol: CC-5013-MCL-002
Celgene Corporation
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67
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Table 7:
Dose Modification for Lenalidomide (Continued)
NCI CTCAE
Toxicity Grade
Action Required
!
Re-escalation by one dose level at a time will be 
permitted after completion of one full cycle without 
laboratory TLS or ≥ Grade 1 TLS 
Any other lenalidomide-related non-
hematologic AE ≥ Grade 3 not 
requiring definitive treatment 
discontinuation
!
Hold (interrupt lenalidomide dose).  
!
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same or at next lower dose level according to 
investigator’s discretion
* For patients with Gilberts Syndrome or liver involvement by lymphoma, dose reductions should 
be made in consultation with the Celgene medical monitor
If a patient experiences an AE that requires a dose interruption, the patient can not be re-started 
on study medication until the AE has resolved or reached acceptable grade described in Table 7.  
Once the AE has resolved, the patient may continue back on lenalidomide (at the dose level 
required in Table 7, and refer to Table 8 and Table 9 for the actual dose) for the remainder of the 
cycle. Doses that were missed, because of toxicity or any other reason, will not be rescheduled. 
If a cycle is delayed due to an AE the patient can re-start lenalidomide within a next cycle once a
7-day rest period has occurred and the requirements mentioned below have been met. 
The study assessments should remain in line with dosing days (actual number of days that 
lenalidomide has been taken) but the tumor assessments will be determined from Cycle 1 Day 1 
following counting calendar days and do not follow the dosing cycles.
The next cycle of treatment may begin on the scheduled Day 1 if:
!
The minimum 7 day rest period has elapsed following the last dose of study drug in 
the prior cycle (the rest period is mandatory regardless of allowed ± visit windows)
!
The ANC is ≥1,000 cells/mm³ (1.0 X 109/L);
!
The platelet count is ≥ 60,000 cells/mm³ (60 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 definitive treatment discontinuation 
has resolved to ≤Grade 2 severity.
If these conditions are not met on Day 1 of a new cycle, the patient will be evaluated at least 
once every seven days and a new cycle of lenalidomide will not be initiated until the toxicity has 
resolved as described above.
If a new cycle is delayed for more than 28 days, the 
 Medical Monitor must be notified
and treatment can be resumed according to the treating physicians’ and 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
68
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Monitors’ clinical judgment. The Medical monitor may consult Celgene Clinical Research 
Physician for clinical judgment if appropriate.
If lenalidomide dosing was halted during the previous cycle and was restarted with a one-level 
dose reduction without requiring an interruption for the remainder of the cycle, then that reduced 
dose level will be initiated on Day 1 of the new cycle. 
There will be no more than one dose reduction from one cycle to the next.
Once a dose reduction occurred, no re-escalation is permitted.
b) Dose reduction
The daily dose of lenalidomide may be reduced successively by one level from the starting dose 
of 25 mg p.o. once daily for 21 days (D1 – D21) in each 28 day cycle for patients with a 
creatinine clearance ≥ 60 mL/min (refer to dose reduction steps in Table 8) in case of severe 
toxicity.  
Creatinine clearance (use Cockcroft – Gault formula) should be determined utilizing actual body 
weight or ideal body weight, which ever is less. For patients who have moderate renal 
insufficiency [creatinine clearance ≥ 30 mL/min but < 60 mL/min], refer to dose reduction steps 
in Table 9.
Table 8:
Dose reduction steps for Adverse Events related to Lenalidomide for patients 
initiating treatment at 25 mg daily on Days 1-21, every 28 days 
Starting Dose
25 mg daily on Days 1-21, every 28 days
Level –1 Dose
20 mg daily on Days 1-21, every 28 days
Level –2 Dose
15 mg daily on Days 1-21, every 28 days
Level –3 Dose
10 mg daily on Days 1-21, every 28 days
Level –4 Dose
5 mg daily on Days 1-21, every 28 days
Level –5 Dose*
5 mg every other day between Days 1-21, every 28 
days
*Once a patient’s dose has been reduced, no dose re-escalation is permitted.  Patients who cannot tolerate 
dose level 5 have to be discontinued from the Treatment Phase of the study.
Table 9:
Dose reduction steps for Adverse Events related to Lenalidomide for patients 
initiating treatment at 10 mg daily on Days 1-21, every 28 days
Starting Dose
10 mg daily on Days 1-21, every 28 days
Level –1 Dose*
5 mg daily on Days 1-21, every 28 days
Level –2 Dose*
5 mg every other day between Days 1-21, every 28 
days
*Once a patient’s dose has been reduced, no dose re-escalation is permitted.  Patients who cannot tolerate 
dose level -2 are to be discontinued from the Treatment Phase of the study.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
69
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
10.1.4.
Dose Modification or Interruption for Investigator’s choice - Arm B
Patients will be evaluated for adverse events at each visit with the NCI CTCAE v3.0 used as a 
guide for the grading of severity.  The dose of investigator’s choice for each patient will be 
interrupted and modified according to the clinical practice of the investigators institution, where 
applicable and in line with the approved prescribing information provided by Celgene. Doses 
that were missed because of toxicity or any other reason will not be made up.  Patients should 
continue with the next cycle when they are able.
10.1.5.
Tumor Lysis and Tumor Flare - Lenalidomide
In a preliminary report of a study conducted with lenalidomide in relapsed/refractory chronic 
lymphocytic leukemia (CLL), some patients experienced tumor lysis syndrome, tumor flare 
reaction and occasionally cytopenias (neutropenia and thrombocytopenia) during the first week 
of Cycle 1 (Chanan-Khan, 2006; Moutouh-de Parseval, 2007; Andritsos, 2008; Eve, 2010). In 
some CLL patients, tumor flare and tumor lysis have been life-threatening and fatal. Among the 
NHL patients treated with lenalidomide in Celgene sponsored clinical trials in NHL patients 
(total number of NHL patients in database of approximately 250), four patients with tumor flares 
and one patient with tumor lysis have been reported.  In addition, one patient with tumor flare 
and one patient with tumor lysis have been reported outside of clinical trials.  Thus, in this study, 
patients should be monitored for tumor flare and tumor lysis.  
Tumor lysis syndrome (TLS) can be defined as a 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. 
The onset of TLS is rapid, usually within 24 to 48 hours after the first dose but can also occur 
after the first week of treatment.  The presence of known risk factors like bulky disease, 
moderate renal insufficiency, high ALC and high uric acid levels (> 8 mg/dL) prior to therapy 
increases the likelihood of TLS.  Early identification of patients 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, 2004).  
Patients in the lenalidomide arm in this study should receive tumor lysis prophylaxis (allopurinol 
or equivalent) and be well hydrated (orally) during the first 7 days of lenalidomide 
administration in the first cycle or as clinically indicated. Hydration levels should be adjusted 
according to age and clinical status. To monitor for tumor lysis syndrome and cytopenia(s), the 
patients will have a (CBC) and chemistry drawn on Days 1, 2, 4, 8 and 15 of the first cycle and 
additionally as clinically indicated. TLS will be assessed by Cairo-Bishop Grading system (see 
Appendix 21.6).
If a patient develops laboratory TLS (defined by the presence of two or more serum value 
abnormalities of uric acid, potassium, phosphorous or calcium) or ≥ Grade 1 TLS (defined by the 
presence of laboratory TLS and one or more of the following criteria: creatinine ≥ 1.5 x ULN, 
arrhythmia or seizures), appropriate medical management should be initiated according to the 
local standard of care in each institution with vigorous IV hydration (rasburicase treatment is 
considered appropriate if it is approved by the local Health Authority).
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Lenalidomide (CC-5013)
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Tumor flare reaction (TFR) is defined as a sudden and tender increase in the size of the disease 
bearing sites, including the lymph nodes, spleen and or the liver often accompanied by low-grade 
fever, non-pruritic diffuse rash and in some cases increase in the peripheral blood lymphocyte 
counts. The onset of tumor flare may be as early as within a couple of hours after the first dose 
and has a median duration of 14 days. This usually occurs only during the first cycle of 
treatment. Tumor flare will be recorded as an AE (graded using the NCI CTCAE criteria version
3) and not as progressive disease (PD) and will be treated symptomatically first with non-
steroidal anti-inflammatory agents (NSAIDs). Narcotics or prednisone may be used at the 
investigator’s discretion, to treat the tumor flare reaction.
10.1.6.
Thromboembolism - Lenalidomide
All patients treated with lenalidomide regardless of prior thromboembolic history will receive 
prophylactic aspirin [ASA] (70 – 100 mg) daily unless contraindicated.  If ASA is 
contraindicated, use of low molecular weight heparin or warfarin (or equivalent Vitamin K 
antagonist) to keep the International normalized ratio (INR) in the range of 2-3 may be 
considered.
The choice of prophylactic agent(s), and also the interruption or discontinuation of such 
prophylaxis if needed, should be based on the local standard of care and the investigator’s best 
judgement after careful consideration of the benefit versus the potential risk for the individual 
patient.
10.1.7.
Prior/Concomitant medications and other permitted concomitant therapies
Prior/Concomitant Medications
All medications (prescription, non-prescription and herbal), treatments and therapies taken from 
30 days prior to the start of study drug through the last dose of study drug, must be recorded on 
the appropriate page of the electronic Case Report Form (eCRF). For subjects included in the 
Extension Access Phase information will no longer be collected on the eCRF. The investigator 
should ensure concomitant medications continue to be recorded in the subjects’ medical records.
Other permitted concomitant therapies
Other therapies considered necessary for the patient’s well being may be administered at the 
discretion of the Investigator. 
Other recommended medications such as ASA, allopurinol, low molecular weight heparin, 
warfarin, analgesics, antihistamines, or other medications such as growth factors, and 
transfusions of red blood cells, platelets, or fresh frozen plasma given to assist in the 
management of complications associated with cancer or its therapy, will be provided by the 
investigative site, Celgene will not provide these medications. 
Growth factors (e.g. G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) are not to be 
administered prophylactically, but may be prescribed by the investigator for rescue from severe 
hematologic events, if it is thought to be appropriate. They should be used in accordance with the 
American Society of Clinical Oncology’s (ASCO) and European Society for Medical Oncology
(ESMO) guidelines, and recorded on concomitant medications CRF page. 
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Confidential and Proprietary
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10.1.8.
Prohibited concomitant therapy
Concomitant use of other anti-cancer therapy while the patient is in the study is prohibited. 
Physiological doses of steroids (defined as ≤ 10 mg prednisone per day, or equivalent) are 
allowed during the study. Doses beyond 10 mg prednisone per day (or equivalent) are not 
allowed during the study or during the last 7 days of the screening period except for the 
treatment of tumor flare and for the prevention of cytokine release syndrome associated with the 
treatment of Rituximab on C1D1.
No investigational therapies or non-drug therapies shall be initiated while the patient is receiving 
lenalidomide.
Following the approval of Protocol Amendment #6, concomitant medications will no longer be 
collected and recorded in a specific CRF but should continue to be recorded in the subjects’
medical records.
10.2.
Discontinuation from Treatment
The following events are considered sufficient reasons for discontinuing a patient from study 
drug:
!
Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of study drug.
!
Disease Progression, disease relapse
!
Patient partially withdraws consent (withdraws from treatment only).
!
Patient is lost to follow-up
!
Death
!
Protocol violation
The reason for discontinuation should be recorded in the CRF and in the patient’s medical 
records. Celgene is to be notified of all discontinuations from study drug.
Following the approval of the Protocol Amendment #6 reasons for discontinuation will no longer 
be recorded on a CRF, but they will be recorded in the subjects' medical records.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
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11.
STUDY DRUG MATERIALS AND MANAGEMENT
11.1.
Supplier(s)
Celgene Corporation will supply oral lenalidomide capsules.
Celgene Corporation will provide commercial supplies of investigator choice therapies (see 
Table 6) and these therapies will be labeled appropriately as investigational material for the
study. Celgene will not provide other recommended medications such as aspirin.
11.2.
Dosage Form
Lenalidomide will be supplied as 5 mg, 10 mg, 20 mg and 25 mg capsules for oral 
administration.
The investigators choice therapies will be supplied as described in Table 6.
Following the approval of Protocol Amendment #6, Celgene Corporation will supply 5 mg, 10 -
mg, 20 mg, and 25 mg strengths in countries where lenalidomide is only available under a 
clinical trial protocol. No more than a 21-day supply of study drug will be dispensed at a time.
11.3.
Dosage Regimen
11.3.1.
Lenalidomide
Lenalidomide will be supplied in bottles containing a 21 day supply.  No more than a 28-day 
supply of study drug will be dispensed at a time. Treatment is to be continued as tolerated (see
Section 10.1.3 Dose Moderation or Interruption) until disease progression or an unacceptable 
toxicity occurs.
Lenalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened.  
Patients should be instructed to take the study drug at the same time each day.
11.3.2.
Investigators Choice 
The investigators choice therapies will be provided as commercial supply and in the dosages as 
described in Table 6. 
11.4.
Drug Dispensing Requirements
In investigational studies, lenalidomide will be dispensed through a qualified healthcare 
professional (including but not limited to, nurses, pharmacists and physicians).  These healthcare 
professionals will be trained by Celgene in requirements specific to counseling of study patients.  
Once trained these healthcare staff will counsel study patients prior to study drug being 
dispensed to ensure that the study patient (FCBP & males) has complied with all requirements 
including use of birth control and pregnancy testing (FCBP) and that the study patient
understands the risks associated with lenalidomide.  This step will be documented by completing 
the Education and Counseling Guidance Document (Appendix 21.9), and no study drug will be 
dispensed until this step occurs.  Counseling includes verification with the study patient that 
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
73
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
required pregnancy testing was performed and results were negative. A Lenalidomide 
Information Sheet will be supplied as described in (Appendix 21.11).
11.5.
Special Handling Instructions
Health care providers should consider wearing gloves when directly handling Revlimid 
(lenalidomide) capsules followed by standard hand washing. All patients should not extensively 
handle or open lenalidomide capsules and should maintain storage of capsules in the packaging 
until ingestion.
11.6.
Treatment Compliance
Study personnel will review the dosing instructions with the patient prior to dispensing the study 
drug. The study drug bottle will be packaged with enough capsules for each 21-day treatment 
period. The patient will be instructed to return the study drug bottles, including any unused study 
drug to the site at the next visit. Patient compliance will be noted on the appropriate CRFs and 
source records based on a capsule count. To monitor treatment compliance, reconciliation of 
lenalidomide capsules will be done at each scheduled study visit. For subjects included in the 
Extension Access Phase drug accountability information will no longer be collected on eCRF. 
For subjects included in the Extended Access Phase, accountability of the study drug, including 
any drug lost or damaged, will be documented in the subjects’ Drug Accountability and Dosing 
Record Sheets.The investigator should ensure concomitant medications continue reported in the 
subjects’ medical record
11.7.
Packaging and Labeling
The lenalidomide study drug will be packaged in bottles and each bottle will contain 21 capsules.
The label for study drug supplied by Celgene will bear Celgene’s name and address, the protocol 
number, EudraCT number (as applicable), product name, dosage form and strength, medication 
identification/kit number, lot number, expiry date, dosing instructions, storage conditions, the 
quantity of study drug contained, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as needed or as applicable.
11.8.
Receipt and Storage
The Investigator, or designee, is responsible for taking an inventory of each shipment of study 
drug received, and comparing it with the accompanying study drug shipping order/packing slip. 
The Investigator, or designee, will verify the accuracy of the information on the form, sign and 
date it, retain a copy in the study file, and return a copy to Celgene.
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access.
The study drug should be stored as directed on the respective package labels.
11.9.
Record of Administration
Following the approval of Protocol Amendment #6 for subjects included in the Extended Access 
Phase, accurate recording of study drug administration will be made in the subjects’ Drug 
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Lenalidomide (CC-5013)
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Accountability and Dosing Record Sheets. This information will reviewed by the study monitor 
at their site monitoring visits.
11.10.
Accountability
An accurate accounting of the dispensing/return of study drug for each study patient 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 patient misses a dose, this 
information should be documented in the study patient’s CRF and source documents.
Following the approval of Protocol Amendment #6 for subjects included in the Extended Access 
Phase, accountability of the study drug, including any drug lost or damaged, will be documented 
in the subjects’ Drug Accountability and Dosing Record Sheets.
11.11.
Handling and Disposal
Celgene will instruct the Investigator(s) on the return or destruction of unused study drug.
Following the approval of Protocol Amendment #6 for subjects included in the Extended Access 
Phase, accountability of the study drug, including any drug lost or damaged, will be documented 
in the subjects’ Drug Accountability and Dosing Record Sheets.
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12.
ASSESSMENT OF EFFICACY
12.1.
Assessments
The following efficacy assessments will be done at baseline and at scheduled intervals 
throughout the duration of the study as outlined in “Schedule of Study Assessments”.
12.2.
Methods and Timing of Efficacy Assessments
Response and progression will be evaluated using the international criteria proposed by the 
Modified International Workshop Response Criteria (IWRC) (Cheson, 1999; as modified in 
Kane, 2007; Fisher, 2006) for target and non-target lesions. 
Date of documentation of disease progression
The date of documentation of disease progression will be the date of confirmation of disease 
progression whether on clinical or radiographic grounds.
CT scan/MRI
CT with contrast or alternatively MRI with contrast, if CT is contraindicated, is performed at 
baseline then every 56 days (±7 days) after Day 1, Cycle 1 for the first 6 months and then every 
90 days ± 15 days thereafter until documented progressive disease; or when clinically indicated. 
To ensure comparability, baseline and on-study methods for response assessment must be
performed using identical techniques. 
Any suspicion of progressive disease and eventually leading to additional investigations (e.g. 
colonoscopy) must be complemented by a re-staging procedure using CT scan (or MRI).
Bone Marrow Biopsy
Unilateral bone marrow biopsy during treatment is required only if patients has otherwise 
fulfilled the criteria for CR. The bone marrow procedure should be performed 28 days after the 
criteria for CR have otherwise been met. 
Physical Examination and ECOG
All patients will be examined for ECOG status (Appendix 21.3), and receive a physical exam 
including lymphadenopathy, hepatomegaly and splenomegaly as described in Table 2 and as 
clinically indicated.
Progression-free survival/Overall Survival
All patients will be followed for progression-free survival and for overall survival after 
progression every 90 days. Cause of death, disease progression and lymphoma therapies are to be 
recorded in the CRF and the patient’s medical record. Once patients have been discontinued 
from study drug, they will be followed for progression of disease (if applicable), lymphoma 
treatments, second primary malignancies and death. Patients will be followed until death or until 
either 70% of the patients have died or the median follow-up in responding patients is > 2 years 
or the median duration of response (overall response and CR/CRu) has been reached, or four
years from last patient randomized, whichever comes later, at which time the study will end for 
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subjects still on lenalidomide treatment in countries where lenalidomide is available post-trial in 
the commercial setting.
Following the approval of Protocol Amendment #6 an Extended Access Phase will be made 
available for subjects on study treatment in countries where lenalidomide is only available under 
a clinical trial protocol as post-trial access.
Subjects in the Extended Access Phase may remain on study until progressive disease or 
withdrawal for other reasons. Only serious adverse events (SAEs) including second primary 
malignancies (SPMs), and drug accountability record information will be collected and reported 
for these subjects. Follow-up survival data will no longer be collected by Celgene for these 
subjects.
Patients who withdraw consent for treatment will continue to be followed for safety, efficacy 
(disease progression), second primary malignancies and for survival. Patients in the follow-up 
phase who withdraw consent for efficacy (disease progression) follow-up will continue to be 
followed for second primary malignancies and for survival. A full consent withdrawal must be 
documented to disallow follow up for second primary malignancies and for survival.
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13.
ASSESSMENT OF SAFETY
13.1.
Assessments
!
AEs/SAEs severity is graded using NCI CTCAE Version 3.0 (see Appendix 21.1)
!
ECOG Performance Status
!
Vital signs: Blood pressure, pulse, weight and height (screening only).
!
Clinical laboratory evaluations: 
i.
Hematology Labs: Red blood cell (RBC) count, hemoglobin, hematocrit, 
MCV, white blood cell (WBC) count with differential, absolute neutrophil 
count (ANC), absolute lymphocyte count (ALC), and platelet count.
ii.
Chemistry Labs: Sodium, potassium, calcium, phosphorus, blood urea 
nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline 
phosphatase, total bilirubin, aspartate transaminase (AST/SGOT), alanine 
transaminase (ALT/SGPT), lactate dehydrogenase (LDH) and uric acid.
!
Serum/urine beta-human chorionic gonadotropin (β-hCG) (FCBP only)
!
Concomitant medications 
!
Hospitalizations   
!
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 21.1.9).  This includes any second primary malignancy, regardless of 
causal relationship to study drug (lenalidomide or Investigator Choice arm drugs), 
occurring at any time for the duration of the study, from the time of signing the ICD 
through follow-up for overall survival. The Follow-Up Phase involves patient contact 
every 90 days (± 15 days) until patient death or until either 70% of the patients have 
died, or the median follow-up in responding patients is > 2 years, or the median 
duration of response (overall response and CR/CRu) has been reached, or four years 
from last patient randomized, whichever comes later, at which time the follow-up 
study phase will be closed.
!
12- lead ECG
!
Assessment of Lymphoma-related Symptoms 
!
Calculated creatinine clearance (Cockcroft-Gault formula)
!
Tumor Flare/Lysis Assessments (only for patients in Arm A and patients in cross 
over)
!
FCBP should be monitored during the course of the study and after the end of study 
therapy to (only for patients in Arm A and patients in cross over):
∀
Ensure that pregnancy tests are performed during the course of the study and after 
end of study therapy and are negative (See specifics as described in 
Appendix 21.8).
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∀
Ensure the study patient continues to practice abstinence or remains on adequate 
contraception (See specifics as described in Appendix 21.8).
∀
If a FCBP becomes pregnant, treatment should be stopped and the study patient
referred to the appropriate physician.
!
Male study patients should be monitored during the course of the study and after the 
end of study therapy to:
∀
Ensure they continue to use a condom during sexual contact with a FCBP
∀
If a female partner of a male study patient becomes pregnant she should be 
referred to the appropriate physician.
13.2.
Methods and Timing of Safety Assessments
Serial measurements of safety will be performed at baseline and at scheduled intervals 
throughout the duration of the study as outlined in “Schedule of Study Assessments (see
Table 2)” as well as for patients in the investigators choice Arm B who are crossing over to 
lenalidomide therapy (see Table 3).  All scheduled visits will have a ± 3 day window unless 
otherwise stated. The site’s local laboratory will perform laboratory testing.  
13.3.
Recording and Reporting of Adverse Events
The recording and reporting of adverse events is described in Appendix 21.1.
For Local Drug Safety Affiliate Office contact information, please refer to the Serious Adverse 
Event Report Form Completion Guidelines.
Extended Access Phase
Following the approval of Protocol Amendment #6, only serious adverse event reports will 
continue to be sent by the investigator to Celgene Safety. The SAE must be reported immediately 
(i.e., within 24 hours of the Investigators’ knowledge of the event) to Celgene Drug Safety by 
facsimile or e-mail.  An initial written report (prepared by the Investigator(s) using the SAE 
Report Form provided by Celgene) is to be faxed or e-mailed to Celgene Drug Safety. The 
immediate reporting process and timelines apply also to reporting second primary malignancies 
(see Appendix 21.1.2).
Non-serious adverse events will no longer be collected on a CRF by Celgene, but should be 
recorded by the investigator in the subjects’ medical records.
Post-trial Access in the commercial setting
Prescribers will be expected to follow the normal post-marketing reporting requirements as 
applicable in their country.
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15.
STATISTICAL ANALYSES
The objective of the statistical analyses will be to investigate the efficacy and safety of 
lenalidomide monotherapy in patients with relapse or refractory mantle cell lymphoma.
Following the approval of Protocol Amendment #6 and closure of the clinical database, no 
efficacy or safety analyses will be performed for the subjects in the Extended Access Phase.
15.1.
Study Population Definitions
The primary efficacy analyses will be performed on the Intent-to-Treat Population (ITT) for the 
primary and secondary endpoints. Sensitivity analyses will be conducted for the primary and 
secondary endpoints based on the Full Analysis Set (FAS), and the Per Protocol set (if the PPS 
population differs ≥10% in size from the FAS). 
The safety analyses will be conducted on the treated set.
15.1.1.
Intent-to-Treat Population (ITT)
All randomized patients. 
15.1.2.
Treated Set 
All enrolled patients who receive at least one dose of study drug.
15.1.3.
Full Analysis Set (FAS)
The population will include all randomized patients that have received at least one single 
treatment dose (C1D1) with centrally confirmed histology of mantle cell lymphoma as well as 
documented progression at entry.
15.1.4.
As Treated population
The As Treated population analysis set is defined as all randomized patients who receive at least 
two cycles of treatment regardless of the treatment arm.
This population will be used for exploratory analysis only, for the following endpoints: PFS, 
ORR and OS.
15.1.5.
Per-protocol Set (PPS)
Per-protocol population is defined as all MCL randomized subjects who have met eligibility 
criteria, who received at least one dose of study treatment and who had at least one valid post 
baseline response assessment without any major protocol violation.
If the FAS population and the PPS population differ <10% in size no analysis will be conducted 
on the PPS population but if the PPS population differs ≥10% in size from the FAS, the 
sensitivity analysis on the primary endpoint will be conducted on the PPS population.
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15.1.6.
Subgroup analysis
Subgroup analyses will be conducted in an exploratory manner for the following endpoints PFS, 
ORR and OS in the following subgroups:
!
Time since diagnosis (<3 years or ≥ 3 years)
!
Time since last treatment (<6 months [refractory] or ≥ 6 months)
!
Prior stem cell transplant (yes or no)
!
Age (< 65, ≥ 65) and gender
!
MCL International Prognostic Index (MIPI) score at initial time of diagnosis 
!
MIPI score at randomization
!
Ki-67 index (as defined by Determann, 2008) labeling in the original pathology 
specimen at diagnosis, if available at time or at time of relapse
!
Absolute lymphocyte count at baseline (< 800/mm3 or ≥ 800/mm3)
!
Time since last rituximab to cycle 1 day 1 (< 230 days or ≥ 230 days)
!
Number of prior treatment lines (with description of treatment regimens, including 
first line treatment and stem cell transplant) (1 vs >1), (<2 vs ≥2), (<3 vs ≥3)
!
Number of relapses (1 vs > 1 relapses), (<2 vs ≥2 relapses), (<3 vs ≥3 relapses)
In addition other potential subgroups or prognostic factors may be used as exploratory analyses, 
to be further detailed in the statistical analysis plan.
15.2.
Efficacy Evaluation
15.2.1.
Primary Efficacy Endpoints
Progression-free survival (PFS)
PFS is defined as the time from randomization to the first observation of disease progression or 
death due to any cause. If the patient has not progressed or died, PFS will be censored at the time 
of last completed assessment when the patient was known not to have progressed. Patients who 
will receive a new treatment without documented progression will be censored at the last 
assessment date that the patient is known to be progression-free (see table below).
Censoring Rules for Time to event (Progression and/or Death) Endpoints
Situation
Date of Progression or Censoring
Situation 
Outcome
No baseline assessments
Randomization
Censored
Progression documented 
First adequate assessment determined by 
central review
Progressed
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No progression
Date of last adequate assessment with 
evidence of no progression
Censored
Study discontinuation for reasons other 
than disease progression or death
Date of last adequate assessment with 
evidence of no progression
Censored
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Date of last adequate assessment with 
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on study
Date of death
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visits 
Date of death
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lost-to-follow-up time (two or more 
missed assessments) 
Date of last adequate assessment with 
evidence of no progression
Censored
As additional robustness checks of the primary endpoint and censoring definition, the time to 
event analysis will be repeated for the ITT population using the following modified methods of 
PFS:
a) Using the investigator assessment instead the IRC central review 
b) Considering progression or death under a new anti-lymphoma treatment as an event
c) Considering death or progression after an extended lost-to-follow-up time (two or more 
missed assessments) as an event 
d) One using the earliest progression date either in investigator set or IRC set.
Efficacy analysis will be conducted one year after the last patient is randomized.
15.2.2.
Secondary Endpoints
Overall Response
The primary response rate will include best response of Complete Response (CR), Complete 
Response unconfirmed (CRu), or Partial Response (PR). The Modified International Workshop 
Response Criteria (IWRC) (Cheson, 1999) will be used and response assessed by CT scan with 
contrast /MRI with contrast every 56 days (± 7 days) for the first 6 months and then every 90 
days ± 15 days thereafter.
Patients who discontinue before any post-randomization efficacy assessments will be considered 
non-responders.
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Duration of Response
Duration of response will be measured from the time of initial response (at least PR) until 
documented tumor progression or death. Patients who do not progress at the time of analysis will 
be censored at the last assessment date that the patient is known to be progression-free. Patients 
who will receive a new treatment without documented progression will be censored at the last 
assessment date that the patient is known to be progression-free.
This analysis will be restricted to the subgroup of responding patients.
Tumor control rate
Rates for Complete Response (CR) / Complete Response unconfirmed (CRu), Partial response 
(PR) / and Stable Disease (SD)
Complete response/ Complete response unconfirmed /Partial response/Stable disease will be 
determined using the Modified International Workshop Response Criteria (IWRC) (Cheson,
1999; Kane, 2007; Fisher, 2006).
Duration of Stable Disease
Stable disease is defined as less than a PR but is not progressive disease or relapsed disease.
Duration of stable disease will be calculated as the time from the first evidence of stable disease 
to documented disease progression or documented response or death. Patients who do not 
progress or respond at the time of analysis will be censored at the last assessment date that the 
patient is known to be progression-free. Patients who will receive a new treatment without 
documented progression will be censored at the last assessment date that the patient is known to 
be progression-free.
This analysis will be restricted to the subgroup of stable disease patients.
Time to progression (TTP)
TTP will be defined as the time from randomization until objective tumor progression; TTP will 
not include deaths. Patients without progression at the time of analysis will be censored at the 
last assessment date that the patient is known to be progression-free. Patients who will receive a 
new treatment without documented progression will be censored at the last assessment date that 
the patient is known to be progression-free. Deaths due to progression of disease will be 
considered as an event.
Time to treatment failure (TTF)
TTF is defined as the time from the first dose of study drug to discontinuation of treatment for 
any reason, including disease progression, treatment toxicity or death. Patients who will be on 
drug or complete the treatment according to the protocol will be censored at the last date of drug 
intake.
Time to tumor response (TTR)
Time to tumor response (TTR) will be defined as the time from randomization until initial 
response (CR, CRu, PR) if it has been confirmed. Patients with progression at the time of 
analysis will be censored at the first assessment date that the patient is known to have 
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progressed. Patients with SD at the time of analysis will be censored at the last assessment date 
that the patient is known to be progression-free.
Overall Survival (OS)
Overall survival will be defined as the time from randomization until death from any cause. 
Patients alive or lost to follow up at the time of analysis will be censored at the last date the 
patient was known to be alive.
Quality of Life
Background:
Health-related quality of life (QoL) is recognized to be an important element in the treatment of 
cancer patients. Over the last two decades, there has been an major progress in the development 
of robust validated tools to measure the QoL of cancer patients being used both before and 
during cancer treatments. QoL studies are becoming routinely used in the overall setting of 
clinical studies in oncology. 
Several QoL tools have been developed and validated; Two of the most widely used ones are the 
EORTC QLQ-C30 measure (Aaronson, 1993) as well as the functional assessment of cancer 
therapy (FACT-G). Of these two measures, the most frequently used and cited is the EORTC 
QLQ-C30 which has been most widely used in Europe (Bottomley, 2006; Fallowfield, 2002; 
Garret, 2002; Taphoorn, 2005). Meanwhile, they are recognized tools both by European and 
American regulatory authorities and the EORTC tool has been translated into over 70 languages, 
making it a valuable tool for international studies (Cull, 2002)
Rationale and objective:
QoL is important in relapsed and refractory MCL patients because cure is virtually not 
achievable and survival is poor. Therefore, the tolerability of a palliative intended treatment 
becomes even more important to maintain patients QoL as long as possible.
Commonly, patients with relapsed or refractory MCL often present with constitutional 
symptoms, such as asthenia, fatigue, weight loss and B-symptoms (including fever and night 
sweats). 
The EORTC QLQ-C30 measure will be used in this study, given it is robust and will address the 
key issues in these patients. The expectations are that lenalidomide may improve the global 
health status score as well as the physical functional score. The fatigue item could be worse 
initially under lenalidomide, but may improve mid and long term in responding patients due to 
tumor control in relation to the control arm with expected shorter response duration.
The primary QoL objective is therefore to determine the impact of lenalidomide on overall 
health/QoL. The H0 hypothesis will be tested that there is no difference in both arms during and 
after the treatment. 
A secondary QoL objective is to evaluate the effect of the treatment of various symptoms and 
functioning scales, with the two key ones being physical functional and fatigue. 
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QoL instrument: EORTC QLQ-C30 (see attachment Appendix 21.12)
The version 3.0 of the EORTC QLQ-C30 is a 30-item scale. The EORTC QLQ-C30 is composed 
of both multi-item scales and single-item measures. These include five functional scales, three 
symptom scales, a global health status / QoL scale, and six single items. 
FUNCTIONAL 
SCALES
(16 questions)
SYMPTOM SCALES
(6 questions)
SINGLE ITEMS
(6 questions)
GLOBAL QUALITY 
OF LIFE
(2 questions)
Physical
Fatigue
Constipation
Global QoL
Role
Pain
Diarrhoea
Cognitive
Nausea/vomiting
Sleep
Emotional
Dyspnoea
Social
Appetite
Financial
All of the scales and single-item measures range in score from 0 to 100. A higher scale score 
represents a higher level of well being and better ability of daily functioning. A 10 point change 
in the scoring is considered to be meaningful change in quality of life (Osoba, 1998).
Thus a high score for a functional scale represents a high/healthy level of functioning; a high 
score for the global health status/QoL represents a high QoL, but a high score for a symptom 
scale/item represents a high level of symptomatic problems.
Data collection and timing
Questionnaires must be filled out by the patient at 6 pre-specified time points (see below and
Table 2) when the patient comes for a scheduled visit. They will be handed out by a nurse or the 
treating physician/investigator, and ideally are collected again soon after the patient has filled it 
out.
Patients will be asked to complete the questionnaire as completely and accurate as possible. The 
average time to complete the questionnaire is around 10-15 minutes. The reasons for not 
completing the questionnaire will be recorded
Quality of life will be assessed at 6 time points (refer to Table 2)
!
at screening/baseline (within 7 days prior to randomization), 
!
after cycle 2 (C3D1)
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after cycle 4 (C5D1),
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and at time of discontinuation from treatment
A ± 7 days time window will be allowed.
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Compliance & Missing data
During the study compliance will be investigated at each time point. Compliance rate will be 
descriptively compared between the 2 arms. 
In the case that a patient still on study has not filled in the questionnaire, no more than ± 7 days
delay is accepted.
The rate of compliance will be assessed after 40, 80, 120 and 200 patients enrolled.
Missing data will be reported as recommended in the EORTC scoring manual (Fayers, 2001). 
!
Scales scores: If at least 50% of the items have been answered, the scale scores will 
be calculated according to the standard equations given on the manual (any items 
with missing values will be ignored). In other cases, scores will be set to missing
!
Single-item measures: the score will be set to missing 
Statistical considerations
No calculation in terms of sample size will be performed based on changes in QoL.
In the absence of more specific hypothesis, the global score will be used as the primary QoL
outcome and physical functional score and fatigue item will be used as secondary outcomes.
Expectations are that the global score and the physical functional score are improved by 
lenalidomide. The fatigue item may be worse initially under lenalidomide, but improve in mid 
and long term in responding patients due to tumor control compared to control arm with shorter 
response duration.
A difference of 10 points between the two arms is considered as clinically significant (Osoba, 
1998).
15.2.3.
Analysis Methods
All efficacy analyses will be conducted on intent to treat basis.
All efficacy analyses will be repeated on the Full Analysis Set (FAS) as sensitivity analysis for 
the primary endpoint.
The primary analysis for PFS to be performed on the ITT and FAS populations will be conducted 
one year after the last patient is randomized.
The Kaplan-Meier procedure will be used to characterize time to event endpoints (e.g., PFS, 
TTP, TTR, OS) and duration of response. Median times-to-event and their respective two-sided 
95% confidence intervals will be provided for each of these variables. 
The stratified log-rank test will be used as the main analysis to compare treatment arms for time-
to-event variables and an unstratified log-rank test will be used as supportive analysis. The Cox 
proportional hazards regression model will be used to assess the significance of stratification 
factors on treatment differences. Any demographic or baseline characteristics variables 
considered as strong predictive or prognostic factors will also be included as part of the formal 
statistical analysis plan.
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Patients who drop out of the study without being evaluated for will be counted as non-
responders. Responses from patients after they receive other anti-cancer treatments will be 
counted as non responder.
Secondary endpoints will be analyzed at the time of the primary analysis of response. An update
of the time to events endpoints and overall survival will be done at the end of the follow up. No 
adjustment for multiplicity will be applied.
The probability of response rates will be estimated using the proportion of patients with 
responses with exact two-sided 95% confidence intervals.
The EORTC QLQ-C30 will be analyzed using change from baseline and percentage of change 
from baseline according to the functional scores and the recommendations in the EORTC scoring 
manual.
The EORTC Reference Data Manual (Scott, 2008) will also be used to descriptively check 
comparability between patients in our trial and with other comparable populations. The response 
rate in the cross-over portion of patients in Arm B will be analyzed in a descriptive manner.
15.3.
Background and Demographic Characteristics
Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
provided for those variables measured on a continuous scale.  The frequency distribution (n %) 
will be provided for those variables measured on a nominal scale.
15.4.
Study Drug
Dosage statistics (mean, median, standard deviation and range) will be provided. Timing and 
reasons for dose adjustments will be summarized.
15.5.
Concomitant Therapy
By-patient listings will be provided for all concomitant medications and therapies taken during 
the trial.  They will be coded and categorized by the WHO drug coding system and frequency 
summaries provided.
15.6.
Safety Evaluation
Data from the treated population will be included in the safety analyses.
Adverse event severity will be classified using the NCI CTCAE criteria, version 3.0.
Adverse event frequency will be tabulated by body system, and MedDRA term. 
In the by-patient analysis, a patient having the same event more than once will be counted only 
once. Adverse events will be summarized by worst NCI CTCAE grade. Adverse events leading 
to death or to discontinuation from treatment, events classified as NCI CTCAE grade 3 or higher, 
study-drug related events, and serious adverse events will be listed separately.
Second primary malignancies throughout the course of the study will be monitored as events of 
interest, and will be listed and be analyzed separately.
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Protocol: CC-5013-MCL-002
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The probability of dose reduction will be estimated using the proportion of patients with dose 
reduction.
Laboratory data will be graded according to NCI CTCAE severity grade.
The frequencies of the worst severity grade observed during treatment will be displayed in cross-
tabulations by baseline status.
Vital signs, ECGs and ECOG Performance Status will be summarized as appropriate.
Graphical displays will be provided where useful to aid in the interpretation of results.
15.7.
Interim Analyses
An independent external Data Monitoring Committee (DMC) will review ongoing safety data 
throughout the study and efficacy for futility at a pre-defined time point. Specifics are outlined in 
the DMC charter. Summaries of safety information will be prepared for Data Monitoring 
Committee (DMC) review. The first safety analysis will occur after the first 40 patients have 
received at least 2 cycles of treatment or have discontinued prior to completing 2 cycles.  The 
second safety analysis as well as an efficacy analysis for futility will occur after 80 patients 
complete 2 cycles or withdraw before completing 2 cycles (around 54 patients in the 
lenalidomide arm). A third safety analysis will occur after 120 patients complete 2 cycles or 
withdraw before completing 2 cycles. A fourth safety analysis will occur after 200 patients 
complete 2 cycles or withdraw before completing 2 cycles. Additional efficacy and safety data 
might be provided to the DMC members on request as outlined in the DMC charter.
DMC will conduct an analysis for futility on PFS and Overall response rate. No specific stopping 
rules will be given to the DMC for the PFS, the following rules might be used for overall 
response rate.
Based on a 95% CI approach, if the upper bound is below 20% in the lenalidomide arm, the 
DMC should recommend stopping the trial.
Frequency 
of response
Binomial 
Proportion 
P
Exact Lower
CL, Binomial
Proportion1
Exact Upper
CL, Binomial
Proportion1
1
1.8519
0.04687
9.8915
2
3.7037
0.45173
12.7472
3
5.5556
1.16068
15.3885
4
7.4074
2.05510
17.8933
5
9.2593
3.07528
20.3002
6
11.1111
4.18838
22.6313
7
12.9630
5.37430
24.9012
8
14.8148
6.61976
27.1198
9
16.6667
7.91544
29.2941
10
18.5185
9.25455
31.4297
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The third DMC recommended an increase of sample size. An adjustment of the alpha level for 
the final analysis is needed. The type I error will be controlled with adequate methods and details 
will be further described in the SAP.
15.8.
Sample Size and Power Considerations
The main objective of the study is to demonstrate the efficacy of lenalidomide over an 
investigator’s choice single agent based on PFS. The primary analysis is to compare PFS 
between lenalidomide and investigator’s choice monotherapy. 
Protocol Amendment #4:
The third independent DMC meeting was held on July 22, 2011, in which the committee 
members reviewed un-blinded both safety and efficacy data from 166 randomized patients. No 
safety concerns were noted.  The DMC observed that the interim PFS in the control arm is 
different from the intial assumptions which were used to calculate the sample size described in 
Protocol Amendment #2.  
The DMC therefore recommended increasing the sample size from 174 (number of patients 
randomized at the time of the DMC was held) to 250 patients and conducting the underpowered 
primary analysis one year after the last patient being randomized. This would allow a more 
reliable estimation of the treatment effect aiming at demonstrating a clinically meaningful 
improvement in PFS between the experimental arm and the control arm. In addition the proposed 
timing for the analysis will allow a reasonable follow up for overall survival so full information 
on the clinical benefit of lenalidomide can be provided at the time of PFS analysis.
The type I error will be controlled with adequate methods and the details will be further 
described in the SAP.
Protocol Amendment #2
With a hazard ratio of 1.7, full information necessary for a one-sided log rank test with an 
overall alpha of 0.025, to have 80% power, will be achieved when approximately 128 patients 
have progressed or died (PFS).
Original Protocol
The sample size of this study was originally calculated to estimate the Overall Response Rate 
(ORR), which was the original objective of the study.  Sample size calculation was based on the 
width of the 95% confidence interval around a certain point estimate for ORR that is considered 
significant clinical activity. Based on preliminary data, a response rate in the range of 30% to 
40% was reasonably expected.  A sample size equal to 100 allows us to construct a two sided 
95% confidence interval with a width of 9% (one direction) for an expected proportion of 30%. 
The lower observed confidence interval limit would be about 21%, which was still considered 
clinically meaningful. This sample size allowed a width (one direction) of 9.6% for an expected 
proportion of 40% and 9.3% for an expected proportion of 35% (See Table 10).
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Table 10:
Confidence Intervals
95% Two-Sided Confidence Intervals (N=100)
Response rate
30%
35%
40%
CI1
0.214 – 0.400
0.257 – 0.452
0.303 – 0.503
1 Exact confidence intervals based on the Clopper-Pearson method
Using a one group χ2 test with a 0.050 two-sided significance level a sample size of 100 patients 
will have 81% power to detect the difference between the Null hypothesis proportion of 20% and 
the alternative proportion of 32%. No formal sample size calculation will be done for the control 
arm. With a 2:1 ratio 50 patients are needed in the control arm. Assuming that 10% of patients 
will be lost to follow up, 167 patients were to be randomized.
15.9.
Other Topics
Exploratory Analyses:
Any subgroup analysis will be conducted on exploratory data.
Statistical tests will be performed to compare the two treatment arms only for exploratory 
purpose for the secondary endpoints.
Exploratory analysis will be conducted also on the As Treated population for the following 
endpoints: PFS, ORR and OS. 
In order to evaluate the effect of cross over on overall survival a Mantel-Byar approach will be 
used. The estimation of the control arm without cross over and the mixed arm (Lenalidomide
arm and cross over patients) will be estimated. A weighted logrank test or wilcoxon test will be 
used to take into account the cross over effect (Anderson, 1983; Klein, 1997; Colett, 2003)
Multivariate models will be used to identify those baseline and prognostic factors (e.g. absolute 
leukocyte count, time from diagnosis, number of prior therapies and any other variables 
suggested in the literature prior to the analysis) most predictive of response (Colett, 1991).
Mann-Whitney tests for simple comparison and longitudinal data modeling techniques (i.e. Proc 
mixed in SAS) for the QOL score. Details will be given in the statistical analysis plan.
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score. D


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16.
QUALITY CONTROL AND QUALITY ASSURANCE
16.1.
Monitoring 
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  Before the study is initiated at a site visit or at an investigator meeting, all aspects of 
the study are reviewed with the Investigator and the staff.  Prior to enrolling study patients into 
the study, a Celgene representative will review the protocol, data collectors, procedures for 
obtaining informed consent, record keeping, and reporting of AEs/SAEs with the Investigator.  
Monitoring will include on-site visits with the investigator and his/her staff as well as any 
appropriate communications by mail, email, fax, or telephone.  At each monitoring visit, the 
facilities, study drug storage area, Case report forms (CRFs), study patient’s source documents, 
and all other study documentation will be inspected and reviewed by the Celgene representative 
for accuracy, adherence to the protocol and Good Clinical Practice.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  From time to time, representatives of this unit will conduct audits of 
clinical research activities in accordance with Celgene Standard Operating Procedures (SOPs) to 
evaluate compliance with Good Clinical Practice (GCP) guidelines and regulations.
The Investigator(s) is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of patient participation for audits and 
inspections by IRB/IECs, regulatory authorities (e.g. FDA, EMEA, and HC) and company 
authorized representatives.  The Investigator(s) should make every effort to be available for the 
audits and/or inspections.  If the Investigator(s) is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene immediately.
16.3.
Investigator(s) Responsibilities
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice and in the 
US Code of Federal Regulations.  Celgene or a representative will contact and select all principal 
investigators or co-investigators who in turn will select their staff.  The investigator must give 
the monitor access to relevant records to confirm the above.  
The Investigator(s) is responsible for keeping a record of all patients who sign an Informed 
Consent Form and are screened for entry into the study.  For those patients who fail screening the 
reason(s) for exclusion must be recorded in the patient’s source documents and on the Screening 
Log provided by Celgene.
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No procedure/assessment/measurement/test other than those outlined here, or in the schedule of 
study assessments, is to be performed without the prior written approval of Celgene, or unless 
deemed by the investigator(s) as necessary for the patient’s medical care.  Investigator(s) and/or 
authorized designee(s) must enter study data onto CRFs supplied by Celgene.  The data on the 
CRF will be recorded in an anonymous manner to protect the patient’s identity by using a unique 
identifier that will prevent personal identifiable information.
The Investigator(s), or a designated member of the Investigators’ staff, must be available at some 
time during monitoring visits to review data and resolve any queries and to allow direct access to 
the patient’s records (e.g., medical records, office charts, hospital charts, and study related 
charts) for source data verification.  The CRFs must be completed as soon as possible after the 
patient’s visit but no later than prior to each monitoring visit and be made available to the 
Celgene representative(s) so that the accuracy and completeness may be checked.
Following the approval of Protocol Amendment #6 and closure of the clinical database, clinical 
study data will no longer be collected on CRFs by the investigator in the Expanded Access 
Phase. The investigator will be required to complete the subjects’ Drug Accountability and 
Dosing Record Sheet at each subject visit, as well as to verify and assure appropriate filing in 
study files, and in subjects’ medical records
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Lenalidomide (CC-5013)
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17.
REGULATORY CONSIDERATIONS
17.1.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki (see Appendix 21.2).  The review of this protocol by the 
IRB/IEC and the performance of all aspects of the study, including the methods used for 
obtaining informed consent, must also be in accordance with principles enunciated in the 
declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 
50 Protection of Human Patients and Part 56 Institutional Review Boards.  Before implementing 
this study, the protocol, the proposed informed consent form and other information to patients, 
must be reviewed by a properly constituted Institutional Review Board/Independent Ethics 
Committee (IRB/IEC).  A signed and dated statement that the protocol and informed consent 
have been approved by the IRB/IEC must be given to Celgene before the study initiation.  The 
names and occupations of the chairman and the members of the IRB/IEC must be supplied to 
Celgene.  
The Investigator(s) will be responsible for preparing documents for submission to the relevant 
IRB/IEC and obtaining written approval for this study.  The approval will be obtained prior to 
the initiation of the study.
A copy of the IRB/IEC approval for the protocol and the Informed Consent is to be provided to 
Celgene. The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number.
The Investigator(s) is responsible for notifying the IRB/IEC of any serious deviations from the 
protocol, or anything else that may involve added risk to patients.
Any advertisements used to recruit patients for the study must be reviewed and approved by 
Celgene and the IRB/IEC prior to use.
17.2.
Protocol Amendments
Any amendment to this protocol that seems appropriate, as the study progresses (e.g. affects 
safety or efficacy) will be agreed upon between the coordinating and/or principal investigator(s) 
and the Celgene study physician.  Amendments will be submitted to the IRB/IEC for written 
approval before the implementation of the amended version.  The written signed approval from 
the IRB/IEC should refer specifically to the investigator(s) and to the protocol number and title 
and mention any amendment numbers that are applicable. Amendments that are administrative in 
nature do not require IRB/IEC approval but will be submitted to the IRB/IEC for information 
purposes.
17.3.
Informed Consent
The Investigator(s) must obtain informed consent of a patient or his/her designee prior to any 
study related procedures as per Good Clinical Practices (GCP) as set forth in the 21 CFR Parts 
50 and 56 and ICH guidelines.
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Documentation that informed consent occurred prior to the patient’s entry into the study and of 
the informed consent process should be recorded in the patient’s source documents.  The original 
consent form, signed and dated by the patient and by the person consenting the patient prior to 
the patient’s entry into the study, must be maintained in the Investigator’s study files and a copy 
given to the patient.  In addition, if a protocol is amended and it impacts on the content of the 
informed consent, the informed consent must be revised.  Patients participating in the study when 
the amended protocol is implemented must be re-consented with the revised version of the 
informed consent.  The revised consent form signed and dated by the patient and by the person 
consenting the patient must be maintained in the Investigator’s study files and a copy given to 
the patient.  
17.4.
Patient Confidentiality
Celgene affirms the patient’s right to protection against invasion of privacy. In compliance with 
United States federal regulations, Celgene requires the Investigator(s) to permit Celgene’s 
representatives and, when necessary, representatives of the FDA or other 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 
patient’s statement of informed consent, it is the responsibility of the Investigator(s) to obtain 
such permission in writing from the appropriate individual.
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18.
DATA HANDLING AND RECORDKEEPING
18.1.
Data/Documents
The investigator(s) must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is copies of CRFs and source documents, 
original documents, data, and records (e.g., hospital records; clinical and office charts; laboratory 
notes; memoranda; patient’s diaries or evaluation checklists; pharmacy dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives, microfilm, or magnetic media; x-
rays; patient files) and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical study are complete, accurate, and filed and retained.
18.2.
Data Management
Data will be entered into the clinical database per 
SOPs unless internal processes will be 
done by Data Management of Celgene, in this case Celgene SOPs will be used. 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.
Extended Access Phase
Following the approval of Protocol Amendment #6, CRF pages will no longer be completed. At 
each visit, the study monitor will be required to verify and assure appropriate filing in study files 
of the subjects’ Drug accountability and Dosing Record Sheets and verify the information therein 
with the source records of the subject. The study monitor will record changes in the subjects’
Drug Accountability and Dosing Record Sheet in their visit report.
18.3.
Retention of Records
The Investigator must maintain records of all study documents and supporting information 
relating to the conduct of the study in accordance with ICH GCP and applicable local regulatory 
requirements.  This documentation includes, but is not limited to, protocols, case report forms, 
advertising for study patient participation, adverse event reports, study patient source data, 
correspondence with health authorities and IRBs/IECs, informed consent documents, 
Investigator curricula vitae, monitor visit logs, laboratory reference ranges, laboratory 
certification or quality control procedures and laboratory director curriculum vitae.  Study patient
files and other source data must be kept for the maximum period of time permitted by the 
hospital, institution or private practice specified below.  The study monitor or designee must be 
consulted if the Investigator wishes to assign the study files to someone else, remove them to 
another location or is unable to retain them for a specified period.  The monitor will inform the 
Investigator of the dates for retention.  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.
For studies conducted in the United States under a US IND, the Investigator must retain the 
study records for a minimum of 2 years after a marketing application for the indication is 
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approved or for 2 years after the IND is withdrawn.  If no application is filed, or if the 
application is not approved for the indication, the records are to be retained for two years after 
the investigation (i.e., the IND) is discontinued, and FDA is notified of that fact.  For IND 
studies conducted outside the US, the Investigator must retain study records for the time period 
described above or according to local laws or requirements, whichever is longer.  For studies not 
conducted under the US IND, the Investigator records must be retained until at least 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 investigational product.  These documents 
should be retained for a longer period if required by other applicable regulatory requirements.
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19.
PREMATURE DISCONTINUATION OF THE STUDY
19.1.
Single Site
The responsible clinical Investigator as well as Celgene has the right to discontinue a single site 
at any time during the study for reasonable medical or administrative reasons.  Possible reasons
for termination of the study could be, but are not limited to:
!
Unsatisfactory enrollment with respect to quantity or quality
!
GCP noncompliance
∀
Inaccurate or incomplete data collection
∀
Falsification of records
∀
Failure to adhere to the study protocol
19.2.
Study as a Whole
Celgene reserves the right to terminate this clinical study at any time for reasonable medical or 
administrative reasons.
Any possible premature discontinuation would have to be documented adequately with reasons 
being stated, and information would be issued according to local requirements (e.g., IRB/IEC, 
regulatory authorities, etc.).
for reason
for reason
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20.
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cell lymphoma. J Clin Oncol. 2005; 23: 676-684.
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health-related quality-of-life scores. J Clin Oncol. 1998; 16(1):139-44
Pan D, Moskowitz CH,  Zelenetz AD, Straus D, Kewalaramani T, Noy A, et al. Rituximab for 
Aggressive Non-Hodgkin’s Lymphomas Relapsing After or Refractory to Autologous Stem Cell 
Transplantation. The Cancer Journal. 2002; 8(5): 371-376.
Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary 
therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343:1750–1757.
Ramsay AG, Johnson AJ, Lee AM, Gorgun G, Le Dieu R, Blum W, Byrd JC, Gribben JG. 
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22427-2437.
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synapse dysfunction that can be repaired with lenalidomide: implications for the tumor 
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phosphate in relapsed indolent B-Cell non-Hodgkins lymphoma. J Clin Oncol. 2006; 24(1):174-
180.
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21.
APPENDICES
21.1.
Adverse Event
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence occurring at 
any dose that may appear or worsen in a patient 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 patient’s health, including laboratory test values (as specified by the criteria below), 
regardless of etiology. Any medical condition that is presented prior to study treatment and that 
remains unchanged or improved should not be recorded as an AE. If there is a worsening of that 
medical condition this should be considered as an AE. A diagnosis or syndrome should be 
recorded on the AE page of the Case Report Form 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.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or other 
appropriate tests and procedures.
All AEs will be recorded by the Investigator(s) from time of signed informed consent through 
the end (see Table 3 and Appendix 21.1.9) of the designated follow-up period. AEs will be 
recorded on the AE page of the CRF and in the patient’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.
Following the approval of Protocol Amendment #6, only serious adverse event data (including 
second primary malignancies) on SAE forms will continue to be sent by the investigator to
Celgene.
Non-serious adverse events will no longer be collected on a CRF by Celgene, but should be 
recorded in the subjects’ medical records and reviewed by the study monitor.
21.1.1.
Abnormal laboratory values defined as adverse events
An abnormal laboratory value is considered to be an AE if the laboratory abnormality is
characterized by any of the following:
!
Results in discontinuation from the study.
!
Requires treatment, modification/interruption of study drug dose, or any other 
therapeutic intervention.
!
Is judged by the Investigator(s) to be of significant clinical importance.
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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 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.
21.1.2.
Serious adverse event
A serious adverse event (SAE) is any AE which:
!
Results in death
!
Is life-threatening (i.e., in the opinion of the Investigator(s) the patient is at immediate 
risk of death from the AE)
!
Requires inpatient hospitalization or prolongation of existing hospitalization
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
patient’s ability to conduct normal life functions)
!
Is a congenital anomaly/birth defect
!
Constitutes an important medical event
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the patient 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.
Events not considered to be SAEs are hospitalizations which: were planned before entry into the 
clinical study; are for elective treatment of a condition unrelated to the studied indication or its 
treatment; occur on an emergency outpatient basis and do not result in admission (unless 
fulfilling other criteria above); are part of the normal treatment or monitoring of the studied 
indication and are not associated with any deterioration in condition.
If an AE is considered serious, both the AE pages of the CRF and the SAE Report Form must be 
completed.
For each SAE, the Investigator(s) will provide information on severity, start and stop dates, 
relationship to study drug, action taken regarding study drug, and outcome.
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 Appendix 21.1.9).  
This includes any second primary malignancy, regardless of causal relationship to study drug 
(lenalidomide or Investigator Choice arm drugs), occurring at any time for the duration of the 
study, from the time of signing the ICD through follow-up for overall survival. The Follow-Up 
Phase involves patient contact every 90 days (± 15 days) until patient death or until either 70% 
of the patients have died, or the median follow-up in responding patients is > 2 years, or the 
median duration of response (overall response and CR/CRu) has been reached, or four years 
from last patient randomized, whichever comes later. Events of second primary malignancy are 
to be reported using the SAE report form and must be considered an “Important Medical Event” 
even if no other serious criteria apply; these events must also be documented in the appropriate 
page(s) of the CRF and subject’s source documents.  Documentation on the diagnosis of the 
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second primary malignancy must be provided at the time of reporting as a serious adverse event 
(e.g., any confirmatory pathology results, imaging results, etc.).
21.1.3.
Classification of severity
For both AEs and SAEs, the investigator(s) must assess the severity of the event. The severity of 
AEs will be graded based upon the patient’s symptoms according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) 
(http://ctep.cancer.gov/reporting/ctc.html). The AEs will be evaluated for severity according to 
the following scale:
Grade 1 = Mild
Grade 2 = Moderate
Grade 3 = Severe
Grade 4 = Life Threatening
Grade 5 = Death
21.1.4.
Classification of Relationship/Causality of adverse events (SAE/AE) to study 
drug
The Investigator(s) must determine the relationship between the administration of study drug and 
the occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
The temporal relationship of the adverse event to study drug 
administration makes a causal relationship unlikely or 
remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the 
observed event
Suspected:
The temporal relationship of the adverse event to study drug 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions 
do not provide a sufficient explanation for the observed event.
21.1.5.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
21.1.6.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(e.g., discontinuation or reduction of IP, as appropriate) and report if concomitant and/or 
additional treatments were given for the event. 
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21.1.7.
Outcome
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered (death due to another 
cause) or death (due to the SAE). 
21.1.8.
Monitoring and reporting of adverse events
All patients will be monitored for AEs during the study.  Assessments may include monitoring of 
any or all of the following parameters: the patient’s clinical symptoms; laboratory, pathological, 
radiological, or surgical findings; physical examination findings; or other appropriate tests and 
procedures.
Following the approval of Protocol Amendment #6, only serious adverse event data (including 
second primary malignancies) on SAE forms will continue to be sent by the investigator to
Celgene.
Non-serious adverse events will no longer be collected on a CRF by Celgene, but will be 
recorded in the subjects’ medical records.
21.1.9.
Immediate reporting of serious adverse events
Any AE that meets the criterion for any SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE pages of the CRF.  The Investigator(s) is required to ensure 
that the data on these forms is accurate and consistent.  This applies to all SAEs, regardless of 
relationship to study drug, that occur during the study, those made known to the Investigator(s) 
within 30 days after a patient’s last dose of study drug, any second primary malignancies 
occurring at any time for the duration of the study through follow-up for overall survival, and 
those made known to the investigator(s) at anytime that are suspected of being related to study 
drug.
The SAE must be reported immediately (i.e., within 24 hours of the Investigators’ knowledge of 
the event) to Celgene Drug Safety by facsimile.  An initial written report (prepared by the 
Investigator(s) using the SAE Report Form provided by Celgene) is to be faxed to Celgene Drug 
Safety. The immediate reporting process and timelines apply also to reporting second primary 
malignancies (see Appendix 21.1.2).
The SAE report should provide a detailed description of the SAE and include copies of hospital 
records and other relevant documents.  If a patient has died and an autopsy has been performed, 
copies of the autopsy report and death certificate are to be sent to Celgene as soon as these 
become available.  Any follow-up data will be detailed in a subsequent SAE Report Form, and 
sent to Celgene.
The Investigator(s) is responsible for informing the Institutional Review Board/Ethics 
Committee (IRB/IEC) of the SAE and providing them with all relevant initial and follow-up 
information about the event. The Investigator(s) must keep copies of all SAE information, 
including correspondence with Celgene and the IRB/IEC, on file.  All SAEs that have not 
resolved upon discontinuation of the patient’s participation in the study must be followed until 
either the event resolves completely, stabilizes/resolves with sequelae, or returns to baseline (if a 
baseline value is available).
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21.1.10.
Pregnancies
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female patient or the female partner of a male patient occurring while the 
patient is on study drug, or within 30 days of the patient’s last dose of study drug, are considered 
immediately reportable events. Immediate is defined as within 24 hours of the study site’s 
knowledge of the event. Study drug is to be discontinued immediately and the patient instructed 
to return any unused portion of the study drug to the investigator(s).  The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety immediately by 
facsimile using the SAE Report Form.
The female should be referred to an obstetrician-gynecologist experienced in reproductive 
toxicity for further evaluation and counseling.
The Investigator(s) will follow the female patient until completion of the pregnancy, and must 
notify Celgene Drug Safety of the outcome of the pregnancy as a follow-up to the initial SAE 
report. Infant follow-up will occur for one year following birth in a FCBP who was treated with 
lenalidomide.
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly [including that in an aborted 
fetus]), the Investigator(s) should follow the procedures for reporting SAEs (i.e., report the event 
to Celgene Drug Safety by facsimile within 24 hours of the Investigator’s knowledge of the 
event).
In the case of a live “normal” birth, Celgene Drug Safety should be advised by facsimile within 
24 hours of the Investigator’s knowledge of the event.
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator(s) suspects is 
related to the in utero exposure to the study drug should also be reported to Celgene Drug Safety 
by facsimile within 24 hours of the Investigators’ knowledge of the event.
If the female is found not to be pregnant, any determination regarding the patient’s continued 
participation in the study will be determined by the Investigator(s) and the Celgene Medical 
Monitor.
21.1.11.
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.
21.1.12.
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 and for 
chlorambucil, cytarabine, rituximab, fludarabine, or gemcitabine based on the UK SPCs.
For countries within the European Union, Celgene will report in an expedited manner to 
Regulatory Agencies and Ethics Committees concerned, adverse events in accordance with the 
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Detailed Guidance on the collection, verification and presentation of adverse reaction reports 
arising from clinical trials on medicinal products for human use (ENTR/CT3) and also in 
accordance with country specific requirements.
Celgene shall notify the Investigator of the following information:
!
Any AE associated with the use of study drug in this study or in other studies that is 
both serious and unexpected, i.e., suspected unexpected serious adverse reaction 
(SUSAR). Note that such cases from blinded studies will be unblinded for reporting 
purposes.
!
Any finding from tests in laboratory animals suggests a significant risk for human 
patients including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local regulations, the Investigator shall notify his/her IRB/IEC promptly of 
these new serious and unexpected AE(s) or significant risks to study subjects.
The Investigator must keep copies of all pertinent safety information, including correspondence 
with Celgene and the IRB/IEC, on file (see Section 18.3 for records retention information).
For Local Drug Safety Affiliate Office contact information, please refer to the Serious Adverse 
Event Report Form Completion Guidelines 
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21.2.
Declaration of Helsinki
Initiated: 1964 17.C
Original: English
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly
Helsinki, Finland, June 1964 and amended by the
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000
Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002
Note of Clarification on Paragraph 30 added by the EMA General Assembly, Tokyo 2004
21.2.1.
Introduction
1. The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human patients. Medical research involving human patients includes 
research on identifiable human material or identifiable data.
2. It is the duty of the physician to promote and safeguard the health of the people. The 
physician’s knowledge and conscience are dedicated to the fulfillment of this duty.
3. The Declaration of Geneva of the World Medical Association binds the physician with
the words, "The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient."
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human patients.
5. In medical research on human patients, considerations related to the well being of the 
human patient should take precedence over the interests of science and society.
6. The primary purpose of medical research involving human patients is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology 
and pathogenesis of disease. Even the best-proven prophylactic, diagnostic, and 
therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality.
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens.
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8. Medical research is patient to ethical standards that promote respect for all human beings 
and protect their health and rights. Some research populations are vulnerable and need 
special protection. The particular needs of the economically and medically disadvantaged 
must be recognized. Special attention is also required for those who cannot give or refuse 
consent for themselves, for those who may be patient to giving consent under duress, for 
those who will not benefit personally from the research and for those for whom the 
research is combined with care.
9. Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human patients in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human patients set forth in this Declaration.
21.2.2.
Basic Principles for All Medical Research
10. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human patient.
11. Medical research involving human patients must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation.
12. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected.
13. The design and performance of each experimental procedure involving human patients 
should be clearly formulated in an experimental protocol. This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
investigator, the sponsor or any other kind of undue influence. This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events. The researcher should also submit to 
the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for patients.
14. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration.
15. Medical research involving human patients should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human patient must always rest with a medically qualified person 
and never rest on the patient of the research, even though the patient has given consent.
16. Every medical research project involving human patients should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the patient or to others. This does not preclude the participation of healthy volunteers in 
medical research. The design of all studies should be publicly available.
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17. Physicians should abstain from engaging in research projects involving human patients 
unless they are confident that the risks involved have been adequately assessed and can 
be satisfactorily managed. Physicians should cease any investigation if the risks are found 
to outweigh the potential benefits or if there is conclusive proof of positive and beneficial 
results.
18. Medical research involving human patients should only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the patient. This is especially 
important when the human patients are healthy volunteers.
19. Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research.
20. The patients must be volunteers and informed participants in the research project.
21. The right of research patients to safeguard their integrity must always be respected. Every 
precaution should be taken to respect the privacy of the patient, the confidentiality of the 
patient’s information and to minimize the impact of the study on the patient's physical 
and mental integrity and on the personality of the patient.
22. In any research on human beings, each potential patient must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail. The patient should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal. After ensuring that the patient has understood the information, the physician 
should then obtain the patient's freely given informed consent, preferably in writing. If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed.
23. When obtaining informed consent for the research project the physician should be 
particularly cautious if the patient is in a dependent relationship with the physician or 
may consent under duress. In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship.
24. For a research patient who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons.
25. When a patient deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the investigator must obtain that assent in 
addition to the consent of the legally authorized representative.
26. Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
specific reasons for involving research patients with a condition that renders them unable 
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to give informed consent should be stated in the experimental protocol for consideration 
and approval of the review committee. The protocol should state that consent to remain in 
the research should be obtained as soon as possible from the individual or a legally 
authorized surrogate.
27. Both authors and publishers have ethical obligations. In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results. Negative as 
well as positive results should be published or otherwise publicly available. Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared 
in the publication. Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication.
21.2.3.
Additional Principles for Medical Research Combined with Medical Care
28. The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value. 
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research patients.
29. The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods. This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists.1
30. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best-proven prophylactic, diagnostic and therapeutic methods identified by 
the study.2
31. The physician should fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship.
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician’s judgment it offers hope of saving life, reestablishing 
health or alleviating suffering. Where possible, these measures should be made the object 
of research, designed to evaluate their safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, published. The other relevant guidelines of 
this Declaration should be followed.
1 Note of clarification on paragraph 29 of the WMA Declaration of Helsinki
The WMA hereby reaffirms its position that extreme care must be taken in making use of a 
placebo-controlled trial and that in general this methodology should only be used in the absence 
of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even 
if proven therapy is available, under the following circumstances:
!
Where for compelling and scientifically sound methodological reasons its use is 
necessary to determine the efficacy or safety of a prophylactic, diagnostic or 
therapeutic method; or
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!
Where a prophylactic, diagnostic or therapeutic method is being investigated for a 
minor condition and the patients who receive placebo will not be subject to any 
additional risk of serious or irreversible harm. 
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for 
appropriate ethical and scientific review. 6.10.2002
2 Note of clarification on paragraph 30 of the WMA Declaration of Helsinki
The WMA hereby reaffirms its position that it is necessary during the study planning process to 
identify post-trail access by study participants to prophylactic, diagnostic and therapeutic 
procedures identified as beneficial in the study or access to other appropriate care.  Post-trial 
access arrangements rot other care must be described in the study protocol so the ethical review 
committee may consider such arrangements during its review. 9.10.2004
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21.3.
ECOG Performance Status Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, 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
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21.4.
MCL International Prognostic Index (MIPI) score (Hoster, 2008)
Points
Age, y
ECOG
LDH ULN
WBC, 109/L
0
<50
0-1
<0.67
< 6.700
1
50-59
-
0.67 – 0.99
6.700-9.999
2
60-69
2-4
1 – 1.49
10.000 – 14.999
3
≥70
-
≥1.5
≥15.000
Low risk
0 – 3 points
Intermediate risk
4 -5 points
High risk
6 – 11 points
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21.5.
Modified International Workshop Response Criteria (Cheson, 1999)
Modifications will be applied (Fisher, 2006; Kane, 2007) to the Cheson criteria in order to 
alleviate the increased potential for variability of results in small nodes and to account for the
common manifestation of MCL as extranodal disease, where sites of dominant extranodal 
disease (Target Lesions) can be included in the assessment of the sum of the perpendicular 
diameters of measurable lesions
Complete Response (CR):
!
Complete disappearance of all detectable clinical and radiographic evidence of disease and 
disappearance of all disease-related symptoms if present before therapy, and normalization of 
those biochemical abnormalities (e.g., lactate dehydrogenase [LDH]) definitely assignable to 
NHL.
!
All lymph nodes and nodal masses must have regressed to normal size (& 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).
!
The spleen, if considered to be enlarged before therapy on the basis of CT scan, must have 
regressed in size and must not be palpable on physical examination. However, no normal size 
can be specified because of the difficulties in accurately evaluating splenic and hepatic size. 
For instance, spleens thought to be of normal size may contain lymphoma, whereas an 
enlarged spleen may not necessarily reflect the presence of lymphoma but variations in 
anatomy, blood volume, the use of hematopoietic growth factors, or other causes. The 
determinations of splenic volume or splenic index by CT scan are cumbersome and not 
widely used. Any macroscopic nodules in any organs detectable on imaging technique should 
no longer be present. Similarly, other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have decreased in size.
!
If the bone marrow was involved by lymphoma before treatment, the infiltrate must be 
cleared on repeat bone marrow aspirate and biopsy of the same site. The sample on which 
this determination is made must be adequate (≥ 20mm biopsy length in aggregate). Flow 
cytometric, molecular, or cytogenetic studies are not considered part of routine assessment to 
document persistent disease at the present time. These studies should only be incorporated 
into trials examining important research questions.
Complete Response Unconfirmed (CRu): Those patients who fulfill the criteria for CR above
but with one or more of the following features:
!
A residual lymph node mass and extranodal target lesion greater than 1.5 cm in greatest 
transverse diameter that has regressed by more that 75% in the SPD. Individual nodes and 
extranodal target lesions that were previously confluent must have regressed by more than 
75% in their SPD compared with the size of the original mass.
!
Indeterminate bone marrow (increased number or size of aggregates without cytologic or 
architectural atypia).
and 
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as liver an
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ly
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Partial Response (PR)
!
≥50% decrease in SPD of the six largest dominant nodes or nodal masses and extranodal 
measurable target lesions (including hepatic lesions), which together with nodal lesions must 
decrease by ≥ 50% from baseline in their SPD).  These nodes or masses should be selected 
according to the following features:
!
Clearly measurable in at least two perpendicular dimensions
!
From as disparate regions of the body as possible
!
Include mediastinal and retroperitoneal areas of disease whenever these sites are involved
!
No increase in the size of other nodes, liver, or spleen
!
In addition to splenic and hepatic nodules, involvement of other organs is permitted to be 
considered measurable target lesions
!
Bone marrow assessment is irrelevant for determination of PR because it is assessable and 
not measurable disease; however, if positive, the cell type should be specified on the report, 
e.g. large-cell lymphoma or low-grade lymphoma (i.e., small, lymphocytic small cleaved or 
mixed small and large cells)
!
No new sites of disease
Stable disease (SD): Stable disease is defined as less than a PR (see above) but is not 
progressive disease or relapsed disease (see below)
Relapsed disease in CR or CRu patients
!
Appearance of any new lesions or increase by ≥ 50% in the size of previously involved sites
!
≥50% increase in greatest diameter of any previously identified node or measurable 
extranodal disease greater than 1 cm in its short axis or in the SPD of more than one mode
Progressive disease (PD) in PR patients or nonresponders
!
≥50 % increase from nadir in the SPD of any previously identified abnormal node or 
measurable nodal or extranodal disease for PRs or nonresponders
!
Unequivocal progression of extranodal lesions, non-target lesions and the spleen and/or liver
!
Appearance of any new lesion, with GD > 15mm if nodes, during or at the end of therapy
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Table 11:
Summary of Modified Response Criteria
Response 
Category
Physical 
Examination
Lymph Nodes
Lymph Node 
Masses
Bone Marrow
Extranodal (i.e. 
spleen, liver)
CR
Normal
Normal
Normal
Normal
Normal
Cru
Normal
Normal
Normal
Indeterminate
Indeterminate
Normal
Normal
>75% decrease
Normal or 
indeterminate
>75% decrease
PR
Normal
Normal
Normal
Positive
Normal
Normal
#50% decrease
#50% decrease
Irrelevant
#50% decrease
Decrease in 
liver/spleen
#50% decrease
#50% decrease
Irrelevant
#50% decrease
Relapse/PD
Enlarging 
liver/spleen; 
new sites
New or 
increased
New or increased
Reappearance
New or 
increased
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21.6.
Cairo-Bishop Grading System for tumor lysis syndrome (TLS)
Grade
LTLS
Creatinine
Cardiac arrhythmia
Seizure
0
-
≤1.5 x ULN
None
None
I
+
1.5 x ULN
Intervention not 
indicated
None
II
+
>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
III
+
>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
IV
+
>6.0 x ULN
Life-threatening
Seizures of any kind are 
prolonged, repetitive or 
difficult to control
V
+
Death*
Death*
Death*
LTLS, local tumor lysis syndrome; ULN, upper limit of normal; ADL, activities of daily living.
* Probably or definitely attributable to clinical TLS.
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21.7.
Lenalidomide Pregnancy Prevention Plan for Subjects in Clinical
Trials
The Pregnancy Prevention Plan (PPP) applies to all subjects receiving lenalidomide within a 
clinical trial. The following PPP documents are included:
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods document (Section 21.8) provides the following 
information:
!
Potential risks to the fetus associated with lenalidomide exposure
!
Definition of female of childbearing potential (FCBP)/female not of childbearing 
potential (FNCBP)
!
Requirements for counseling of all subjects receiving lenalidomide about pregnancy 
precautions and the potential risks of fetal exposure to lenalidomide
!
Acceptable birth control methods for both female subjects of childbearing potential 
and male subjects receiving lenalidomide in the study
!
Pregnancy testing requirements for subjects receiving lenalidomide who are FCBP
2. The Lenalidomide Education and Counseling Guidance Document for each gender 
(female and male; Section 21.9 and Section 21.10 respectively) must be completed and 
signed by a trained counselor at the participating clinical center prior to each dispensing 
of lenalidomide. A copy of this document must be maintained in the subject’s records for 
each dispense.
3. The Lenalidomide Information Sheet (Section 21.11) will be given to each subject
receiving lenalidomide. The subject must read this document prior to starting
lenalidomide and each time the subject receives a new supply of lenalidomide.
21.8.
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines
and Acceptable Birth Control Methods
21.8.1.
Risks Associated with Pregnancy
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic 
active substance that causes severe life-threatening birth defects. An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of female 
monkeys who received the drug during pregnancy. A teratogenic effect of lenalidomide in 
humans cannot be ruled out. Therefore, a pregnancy prevention program must be followed.
21.8.1.1.
Definition of Females of Childbearing Potential
A FCBP is 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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.1.1.
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21.8.1.2.
Definition of Females Not of Childbearing Potential
Females who do not meet the above definition of FCBP should be classified as FNCBP.
21.8.2.
Counseling
21.8.2.1.
Females of Childbearing Potential
For a FCBP, lenalidomide is contraindicated unless all of the following are met (ie, all FCBP 
must be counseled concerning the following risks and requirements prior to the start of 
lenalidomide):
!
She understands the potential teratogenic risk to the unborn child
!
She understands the need for effective contraception, without interruption, 28 days 
before starting lenalidomide, throughout the entire duration of lenalidomide, during 
dose interruptions and for at least 28 days after the last dose of lenalidomide
!
She understands and agrees to inform the Investigator if a change or stop of method 
of contraception is needed
!
She must be capable of complying with effective contraceptive measures
!
She is informed and understands the potential consequences of pregnancy and the 
need to notify her study doctor immediately if there is a risk of pregnancy
!
She understands the need to commence lenalidomide as soon as it is dispensed 
following a negative pregnancy test
!
She understands and accepts the need to undergo pregnancy testing based on the 
frequency outlined in this plan (Section 21.8.4) and in the Informed Consent
!
She acknowledges that she understands the hazards lenalidomide can cause to an 
unborn fetus and the necessary precautions associated with the use of lenalidomide.
The Investigator must ensure that a FCBP:
!
Complies with the conditions of the pregnancy prevention plan, including 
confirmation that she has an adequate level of understanding
!
Acknowledges the aforementioned requirements.
21.8.2.2.
Females Not of Childbearing Potential
For a FNCBP, lenalidomide is contraindicated unless all of the following are met (ie, all FNCBP 
must be counseled concerning the following risks and requirements prior to the start of 
lenalidomide):
!
She acknowledges she understands the hazards lenalidomide can cause to an unborn 
fetus and the necessary precautions associated with the use of lenalidomide.
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21.8.2.3.
Males
Traces of lenalidomide have been found in semen. Male subjects taking lenalidomide must meet 
the following conditions (ie, all males must be counseled concerning the following risks and 
requirements prior to the start of lenalidomide):
!
Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a FCBP
!
Understand the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or a FCBP
!
Understand the potential teratogenic risk if the subject donates semen or sperm.
21.8.3.
Contraception
21.8.3.1.
Female Subjects of Childbearing Potential
Females of childbearing potential enrolled in this protocol must agree to use two reliable forms 
of contraception simultaneously or to practice complete abstinence (True abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence [eg calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal 
are not acceptable methods of contraception.) from heterosexual contact during the following 
time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while
taking lenalidomide; 3) during dose interruptions; and 4) for at least 28 days after the last dose of 
lenalidomide.
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. If the below contraception methods are not appropriate for
the FCBP, she must be referred to a qualified provider of contraception methods to determine the 
medically effective contraception method appropriate to the subject. The following are examples 
of highly effective and additional effective methods of contraception:
!
Examples of highly effective methods:
∀
Intrauterine device (IUD)
∀
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, 
ovulation inhibitory progesterone-only pills [e.g. desogestrel])
∀
Tubal ligation
∀
Partner’s vasectomy
!
Examples of additional effective methods:
∀
Male condom
∀
Diaphragm
∀
Cervical Cap
Because of the increased risk of venous thromboembolism in subjects with multiple myeloma 
taking lenalidomide and dexamethasone, combined oral contraceptive pills are not 
m.
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recommended. If a subject is currently using combined oral contraception the subject should 
switch to another one of the highly effective methods listed above. The risk of venous 
thromboembolism continues for 4 to 6 weeks after discontinuing combined oral contraception. 
The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone.
[Please note, the above highlighted text is applicable for protocols with dexamethasone-
containing lenalidomide regimens.]
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk 
of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in subjects with neutropenia.
21.8.3.2.
Male Subjects
Male subjects must practice complete abstinence (True abstinence is acceptable when this is in 
line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable methods 
of contraception.) or agree to use a condom during sexual contact with a pregnant female or a 
FCBP while taking lenalidomide, during dose interruptions and for at least 28 days after the last 
dose of lenalidomide, even if he has undergone a successful vasectomy.
21.8.4.
Pregnancy Testing
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for FCBP.
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at least
25 mIU/mL) prior to starting lenalidomide. The first pregnancy test must be performed within 10
to 14 days prior to the start of lenalidomide and the second pregnancy test must be performed 
within 24 hours prior to the start of lenalidomide. The subject may not receive lenalidomide until 
the study doctor has verified that the results of these pregnancy tests are negative.
Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 28 days while 
taking lenalidomide, at study discontinuation, and at Day 28 following the last dose of 
lenalidomide.
Females of childbearing potential with irregular menstrual cycles must agree to have pregnancy 
tests weekly for the first 28 days of study participation and then every 14 days while taking 
lenalidomide, at study discontinuation, and at Days 14 and 28 following the last dose of 
lenalidomide.
21.8.5.
Pregnancy Precautions for Lenalidomide Use
21.8.5.1.
Before Starting Lenalidomide
21.8.5.1.1. Female Subjects of Childbearing Potential
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at least
25 mIU/mL) prior to starting lenalidomide. The first pregnancy test must be performed within 10
to 14 days prior to the start of lenalidomide and the second pregnancy test must be performed 
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B
1.8.5.
1.8.5.


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within 24 hours prior to the start of lenalidomide. The subject may not receive lenalidomide until 
the study doctor has verified that the results of these pregnancy tests are negative.
Females of childbearing potential must use two reliable forms of contraception simultaneously, 
or practice complete abstinence (True abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) from heterosexual contact for at least 28 days before starting lenalidomide.
21.8.5.1.2. Male Subjects
Male subjects must agree to practice complete abstinence (True abstinence is acceptable when 
this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg 
calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) or agree to use a condom during sexual contact with a 
pregnant female or a FCBP while taking lenalidomide, during dose interruptions and for at least
28 days after the last dose of lenalidomide, even if he has undergone a successful vasectomy.
21.8.5.2.
During and After Study Participation
21.8.5.2.1. Female Subjects
!
Females of childbearing potential with regular or no menstrual cycles must agree to 
have pregnancy tests weekly for the first 28 days of study participation and then every
!
28 days while taking lenalidomide, at study discontinuation, and at Day 28 following 
the last dose of lenalidomide.
!
Females of childbearing potential with irregular menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every
!
14 days while taking lenalidomide, at study discontinuation, and at Days 14 and 28 
following the last dose of lenalidomide.
!
At each visit, the Investigator must confirm with the FCBP that she is continuing to 
use two reliable methods of birth control if not committing to complete abstinence, or 
confirm commitment to complete abstinence.
!
If a FCBP considers the need to change or to stop a method of contraception, the
!
Investigator must be notified immediately.
!
Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted at a minimum of every 28 days.
!
If pregnancy or a positive pregnancy test does occur in a subject, lenalidomide must 
be immediately discontinued.
!
Pregnancy testing and counseling must be performed if a subject misses her period or 
if her pregnancy test or her menstrual bleeding is abnormal. Lenalidomide must be 
discontinued during this evaluation.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
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!
Females must agree to abstain from breastfeeding while taking lenalidomide and for 
at least 28 days after the last dose of lenalidomide.
21.8.5.2.2. Male Subjects
!
Must practice complete abstinence (True abstinence is acceptable when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) or use a condom during sexual contact with a 
pregnant female or a FCBP while taking lenalidomide, during dose interruptions and 
for at least 28 days after the last dose of lenalidomide, even if he has undergone a 
successful vasectomy.
!
Must not donate semen or sperm while receiving lenalidomide, during dose 
interruptions or for at least 28 days after the last dose of lenalidomide.
!
Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted at a minimum of every 28 days.
!
If pregnancy or a positive pregnancy test does occur in the partner of a male subject 
while taking lenalidomide, the Investigator must be notified immediately.
21.8.5.3.
Additional Precautions
!
Subjects should be instructed to never give lenalidomide to another person.
!
Subjects should be instructed to return any unused capsules to the study doctor.
!
Subjects should not donate blood while receiving lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide.
!
No more than a 28-day lenalidomide supply may be dispensed with each cycle of 
lenalidomide.
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21.9.
Lenalidomide Education and Counseling Guidance Document for
Female Subjects
To be completed prior to each dispensing of lenalidomide.
Protocol Number: 
Patient Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy)
Check one risk category:
 FCBP (Female of childbearing potential): a female who: 1) has achieved menarche 
(first menstrual cycle) at some point, 2) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of 
both ovaries) 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 during the preceding 24 consecutive months)
 NOT FCBP
21.9.1.
Female of Childbearing Potential:
1. I have verified and counseled the subject regarding the following:
 Potential risk of fetal exposure to lenalidomide: A teratogenic potential of 
lenalidomide in humans cannot be ruled out. If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby. Females are 
advised to avoid pregnancy while taking lenalidomide. Females of childbearing 
potential must agree not to become pregnant while taking lenalidomide.
 That the required pregnancy tests performed are negative.
 The subject confirmed that she is using TWO reliable methods of birth control at the 
same time, or complete abstinence (True abstinence is acceptable when this is in line 
with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) from heterosexual contact (at least 28 days 
prior to receiving lenalidomide, while receiving lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide).
 One highly effective method and one additional method of birth control 
must be used AT THE SAME TIME. The following are examples of 
highly effective and additional effective methods of contraception:
!
Examples of highly effective methods:
∀
Intrauterine device (IUD)
∀
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, 
ovulation inhibitory progesterone-only pills [e.g. desogestrel])
∀
Tubal ligation
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∀
Partner’s vasectomy
!
Examples of additional effective methods:
∀
Male condom
∀
Diaphragm
∀
Cervical Cap
 The subject confirmed that even if she has amenorrhea she must comply 
with advice on contraception.
 Pregnancy tests before, during administration of lenalidomide and at the 
last dose of lenalidomide, even if the subject agrees not to have 
reproductive heterosexual contact.
 Frequency of pregnancy tests to be done:
!
Two pregnancy tests will be performed prior to receiving lenalidomide, one 
within 10 to 14 days, and a second within 24 hours of the start of lenalidomide.
!
Every week during the first 28 days of this study and a pregnancy test every 28 
days while the subject is taking lenalidomide if menstrual cycles are regular.
!
Every week during the first 28 days of this study and a pregnancy test every 14 
days while the subject is taking lenalidomide if menstrual cycles are irregular.
!
If the subject missed a period or has unusual menstrual bleeding.
!
When the subject is discontinued from the study and at Day 28 after the last
dose of lenalidomide if menstrual cycles are regular. If menstrual cycles are 
irregular, pregnancy tests will be done at discontinuation from the study and at
Days 14 and 28 after the last dose of lenalidomide.
 The subject confirmed that she will stop taking lenalidomide 
immediately in the event of becoming pregnant and to call her study 
doctor as soon as possible.
 The subject confirmed that she has not and will not breastfeed a baby 
while taking lenalidomide and for at least 28 days after the last dose of 
lenalidomide.
 The subject has not and will never share lenalidomide with anyone else.
 The subject has not and will not donate blood while taking lenalidomide, 
during dose interruptions and for at least 28 days after the last dose of 
lenalidomide.
 The subject has not and will not break, chew, or open lenalidomide 
capsules at any point.
 The subject confirmed that she will return unused lenalidomide capsules 
to the study doctor.
2. I have provided the Lenalidomide Information Sheet to the subject.
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


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21.9.2.
Female Not of Childbearing Potential (Natural Menopause for at Least 24 
Consecutive Months, a Hysterectomy, or Bilateral Oophorectomy):
1. I have verified and counseled the subject regarding the following:
 Potential risk of fetal exposure to lenalidomide: A teratogenic potential of 
lenalidomide in humans cannot be ruled out. If lenalidomide is taken 
during pregnancy, it may cause birth defects or death to any unborn baby.
 The subject has not and will never share lenalidomide with anyone else.
 The subject has not and will not donate blood while taking lenalidomide, 
during dose interruptions and for at least 28 days after the last dose of 
lenalidomide.
 The subject has not and will not break, chew, or open lenalidomide 
capsules at any point.
 The subject confirmed that she will return unused lenalidomide capsules 
to the study doctor.
2. I have provided the Lenalidomide Information Sheet to the subject.
DoNotDispenseLenalidomideif:
!
The subject is pregnant.
!
No pregnancy tests were conducted for a FCBP.
!
The subject states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence from heterosexual contact) at least 28 days prior 
to receiving lenalidomide, while receiving lenalidomide and during dose 
interruptions.
!
The subject stated that she has or does not want to adhere to pregnancy 
precautions outlined within this PPP.
Counselor Name (Print):
Counselor Signature: 
Date: ___ / ___ / ___ (dd/mmm/yyyy)
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s 
records.**
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.**
*


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Protocol: CC-5013-MCL-002
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21.10.
Lenalidomide Education and Counseling Guidance Document for
Male Subjects
To be completed prior to each dispensing of lenalidomide.
Protocol Number: 
Subject Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy)
1. I have verified and counseled the subject regarding the following:
 Potential risk of fetal exposure to lenalidomide: A teratogenic potential of 
lenalidomide in humans cannot be ruled out. If lenalidomide is taken 
during pregnancy, it may cause birth defects or death to any unborn baby.
 The subject confirmed that he has practiced complete abstinence (True 
abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) or used a condom when engaging in 
sexual contact (including those who have had a vasectomy) with a 
pregnant female or FCBP, while taking lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide.
 The subject confirmed that he has not impregnated his female partner 
while in the study.
 The subject confirmed that he will notify his study doctor if his female 
partner becomes pregnant and the female partner of a male subject taking 
lenalidomide confirmed that she will call her healthcare provider 
immediately if she becomes pregnant.
 The subject has not and will never share lenalidomide with anyone else.
 The subject confirmed that he has not donated and will not donate semen 
or sperm while taking lenalidomide or during dose interruptions and that 
he will not donate semen or sperm for at least 28 days after the last dose 
of lenalidomide.
 The subject has not and will not donate blood while taking lenalidomide, 
during dose interruptions and for at least 28 days after the last dose of 
lenalidomide.
 The subject has not and will not break, chew, or open lenalidomide 
capsules at any point.
 The subject confirmed that he will return unused lenalidomide capsules to the study 
doctor.
2. I have provided the Lenalidomide Information Sheet to the subject.
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Protocol: CC-5013-MCL-002
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Confidential and Proprietary
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DoNotDispenseLenalidomideif:
!
The subject stated that he has or does not want to adhere to pregnancy 
precautions outlined within this PPP.
Counselor Name (Print):
Counselor Signature: 
Date: ___ / ___ / ___ (dd/mmm/yyyy)
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s 
records.**
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
134
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
21.11.
Lenalidomide Information Sheet
For subjects enrolled in clinical research studies
Please read this Lenalidomide Information Sheet before you start taking lenalidomide and each 
time you get a new supply. This Lenalidomide Information Sheet does not take the place of an 
informed consent to participate in clinical research or talking to your study doctor or healthcare 
provider about your medical condition or your treatment.
What is the most important information I should know about lenalidomide?
1. Lenalidomide may cause birth defects (deformed babies) or death of an unborn 
baby. Lenalidomide is similar to the medicine thalidomide. It is known that thalidomide 
causes life-threatening birth defects.
If you are a female who is able to become pregnant:
!
Do not take lenalidomide if you are pregnant or plan to become pregnant
!
You must practice complete abstinence from sexual contact with a male or use 
two reliable, separate forms of effective birth control at the same time:
∀
for 28 days before starting lenalidomide
∀
while taking lenalidomide
∀
during breaks (dose interruptions) of lenalidomide
∀
for at least 28 days after the last dose of lenalidomide
!
You must have pregnancy testing done at the following times:
∀
within 10 to 14 days prior to the first dose of lenalidomide
∀
24 hours prior to the first dose of lenalidomide
∀
weekly for the first 28 days
∀
if you have regular menstrual periods: every 28 days after the first month
∀
if you have irregular menstrual periods: every 14 days after the first month
∀
if you miss your period or have unusual menstrual bleeding
∀
28 days after the last dose of lenalidomide (14 and 28 days after the last dose if 
menstrual periods are irregular)
!
Stop taking lenalidomide if you become pregnant while taking lenalidomide
∀
If you suspect you are pregnant at any time during the study, you must stop 
lenalidomide immediately and immediately inform your study doctor. Your study 
doctor will report all cases of pregnancy to Celgene Corporation.
!
Do not breastfeed while taking lenalidomide and for at least 28 days after the 
last dose of lenalidomide
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
135
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
∀
The study doctor will be able to advise you where to get additional advice on 
contraception.
If you are a female not able to become pregnant:
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor 
will confirm that you are not able to become pregnant.
If you are a male:
A small amount of lenalidomide is found in human semen. The risk to an unborn baby in 
females whose male partner is receiving lenalidomide is unknown at this time.
!
Male subjects (including those who have had a vasectomy) must practice complete 
abstinence or must use a condom during sexual contact with a pregnant female or a 
female that can become pregnant:
∀
While you are taking lenalidomide
∀
During breaks (dose interruptions) of lenalidomide
∀
For at least 28 days after the last dose of lenalidomide
!
Male subjects should not donate sperm or semen while taking lenalidomide, 
during breaks (dose interruptions) and for at least 28 days after the last dose of 
lenalidomide.
!
If you suspect that your partner is pregnant any time during the study, you must 
immediately inform your study doctor. The study doctor will report all cases of 
pregnancy to Celgene Corporation. Your partner should call their healthcare 
provider immediately if they become pregnant.
2. All subjects:
!
Do not share lenalidomide with other people. It must be kept out of the reach of 
children and should never be given to any other person.
!
Do not donate blood while you take lenalidomide, during breaks (dose interruptions)
and for at least 28 days after the last dose of lenalidomide.
!
Do not break, chew, or open lenalidomide capsules at any point.
!
You will get no more than a 28-day supply of lenalidomide at one time.
!
Return unused lenalidomide capsules to your study doctor.
Additional information is provided in the informed consent form and you can ask your 
study doctor for more information.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
136
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
21.12.
EORTC QLQ-C30 Questionnaire
EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the 
questions yourself by circling the number that best applies to you. There are no "right" or 
"wrong" answers. The information that you provide will remain strictly confidential.
Please fill in your initials:
Your birthdate (Day, Month, Year):
Today's date (Day, Month, Year):
Not at
All
A
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Quite
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Very
Much
1.
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short walk outside of 
the house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4
5.
Do you need help with eating, dressing, washing 
yourself or using the toilet?
1
2
3
4
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
137
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
During the past week:
Not at
All
A
Little
Quite
a Bit
Very
Much
6.
Were you limited in doing either your work or 
other daily activities?
1
2
3
4
7.
Were you limited in pursuing your hobbies or 
other leisure time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4
9.
Have you had pain?
1
2
3
4
10.
Did you need to rest?
1
2
3
4
11.
Have you had trouble sleeping?
1
2
3
4
12.
Have you felt weak?
1
2
3
4
13.
Have you lacked appetite?
1
2
3
4
14.
Have you felt nauseated?
1
2
3
4
15.
Have you vomited?
1
2
3
4
16.
Have you been constipated?
1
2
3
4
17.
Have you had diarrhea?
1
2
3
4
18.
Were you tired?
1
2
3
4
19.
Did pain interfere with your daily activities?
1
2
3
4
20.
Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television?
1
2
3
4
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4
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2
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pain interfe
pain interfere
Have you
Have yo
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like re


Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
138
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
During the past week:
Not at
All
A
Little
Quite
a Bit
Very
Much
21.
Did you feel tense?
1
2
3
4
22.
Did you worry?
1
2
3
4
23.
Did you feel irritable?
1
2
3
4
24.
Did you feel depressed?
1
2
3
4
25.
Have you had difficulty remembering things?
1
2
3
4
26.
Has your physical condition or medical treatment 
interfered with your family life?
1
2
3
4
27.
Has your physical condition or medical treatment 
interfered with your social activities?
1
2
3
4
28.
Has your physical condition or medical treatment 
caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that 
best applies to you
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
©
Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0
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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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Lenalidomide CC-5013
Summary of Changes CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
3
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
1.
JUSTIFICATION FOR AMENDMENT
This protocol is being amended to address the study treatment needs of subjects in countries 
where subjects can only receive lenalidomide treatment under a clinical trial protocol as post-
trial access following the final lock of the clinical trial database.
Following approval of Amendment 6 and the closure of the clinical database, only serious 
adverse events and drug administration data will be collected by Celgene. 
Amendment 6 will apply to 2 ongoing study subjects in Russia.
Significant changes included in this amendment are summarized below:
!
Study Treatment Allocation Procedure (IMS Drug Ordering System (IDOS) will replace 
Interactive Voice Recognition System (IVRS)), and removal of all Central Laboratory 
Contacts.
Updated section: Section 1
!
Extended Access Phase added
Updated sections: Synopsis, Table 2 footnotes, Table 3 footnotes, new Table 4, Section 8.1, 
Section 8.1.2.2, Section 8.2, Figure 1 footnote, Section 11.9, Section 11.11, Section 12.2, 
Section 13.3, Section 15, Section 16.3, Section 18.2.
!
Case report form (CRF) pages no longer need to be completed following closure of the 
clinical database
Updated sections: Synopsis, new Table 4, Section 8.1, Section 10.1.7, Section 10.1.8, Section 
10.2, Section 11.9, Section 11.11, Section 11.6, Section 13.3, Section 16.3, Section 18.2, 
Appendix 21.1, Appendix 21.1.8.
!
Added Table 4 Schedule of Study Assessment: Guidance for Extended Access Phase
!
Clarified collection of overall survival data
Updated sections; Synopsis, Table 2 footnotes, Table 3 footnotes, Section 8.1, Section 
8.1.2.2, Section 12.2.
!
Reporting of serious adverse events (SAEs) (including [second primary 
malignancies]SPMs) information to Celgene
Updated sections: Synopsis, new Table 4, Section 8.1, Section 8.1.2.2, Section 8.2, Section 
12.2, Section 13.3, Appendix 21.1, Appendix 21.1.8.
!
Included the statement in the case of pregnancies “Infant follow-up will occur for one 
year following birth in a FCBP who was treated with lenalidomide.”
Section 21.1.10
!
Clarified collection of drug accountability information.
Updated sections: Synopsis, new Table 4, Section 8.1, Section 8.1.2.2, Section 10.1.8, 
Section 10.2, Section 11.9, Section 11.11, Section 12.2, Section 16.3, Section 18.2.
!
Closure of study Follow-up phase
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Lenalidomide CC-5013
Summary of Changes CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
4
CC-5013-MCL-002 Amendment #6 Final: 31 May 2018
Updated sections: Synopsis, Table 2 footnotes, Table 3 footnotes, Section 8.1.2.2, Section 
12.2.
!
Access to lenalidomide in the commercial setting and ending of the study.
Updated sections: Synopsis, Table 2 footnotes, Table 3 footnotes, Section 8.1, Section 
8.1.2.2, Section 13.3.
!
Update of the Lenalidomide Pregnancy Prevention Program in Clinical Trials
Updated Sections: new Appendix 21.7, new Appendix 21.8, new Appendix 21.9, Section 
21.10, Section 21.11.
The amendment also includes other clarifications and corrections:
!
Coordinating Principal Investigator role discontinued
!
Change to Safety Contact Information for non European Union (EU) countries
!
Change to the Medical Monitor and Study Manager
Updated Section: Section 1
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
3           CC-5013-MCL-002  Amend #5 final: 22 Mar 2013
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
The amendment updates the study team contact information due to changes in personnel. 
∀
This is noted in Protocol section 1 (Table 1; and Name of central laboratory(ies) and 
other medical and/or technical department(s) and/or institutions).
!
The amendment modifies the requirement for thromboembolic prophylaxis (Synopsis: 
Thromboembolism; and Protocol section 10.1.6). 
∀
This modification was implemented following a DMC recommendation for 
implementing mandatory prophylaxis for all study patients on lenalidomide after the 
DMC observed an increase in thromboembolic events in the lenalidomide arm 
compared to the control arm, and that a number of the patients with thromboembolic 
events were not receiving anti-thromboembolic prophylaxis.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
3
CC-5013-MCL-002 Amend #4 Final:  27 Sep 2011
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
The amendment updates the Global Drug Safety address due to relocation. 
∀
This is noted in Protocol section 1: Table 1.
!
 
 
 
!
The amendment adds MIPI score at randomization to the list of treatment and clinical 
characteristics at screening/baseline, also to be analyzed as a stratification factor, and
also to the list for subgroup analysis in the Synopsis (Study design and Efficacy Analysis) 
and in Protocol sections 8.1.2.1 and 15.1.6).
∀
This addition was implemented following recommendation from the third DMC for 
analysis according to MIPI at randomization, after the DMC observed an imbalance in 
terms of risk factors between the study arms which was not mitigated by the 
stratification factors.
!
The amendment adds a fourth safety analysis to occur after 200 patients complete 2 cycles 
or withdraw before completing 2 cycles (Synopsis: Data Monitoring Committee; and 
Protocol sections 8.3 and 15.7).
∀
This addition was implemented to ensure ongoing safety monitoring with sample size 
increase to 250 pts.
!
The amendment increases the sample size to 250 patients (Synopsis: Number of patients; 
Protocol: Figure 1).
∀
This sample size increase was implemented following recommendation from the third 
DMC to allow a more reliable estimation of potential PFS differences between the 
study arms after the DMC observed that the outcome in the control arm of the study 
was different from the initial assumptions used to calculate the sample size.
!
The amendment modifies the duration of prior malignancy-free history (Synopsis: 
Exclusion Criteria; and Protocol section 9.2).
∀
This modification was implemented as requested by health authorities to reduce the 
risk of second primary malignancy (SPM) in patients treated with lenalidomide.
!
The amendment updates the safety wording on second primary malignancies in the 
Synopsis (Safety, footnote 15 to Table 2, footnote 7 to Table 3) and Protocol sections 8.2, 
13.1 and 21.1.2.
∀
This is the current SPM language according to the updated protocol template safety 
wording.
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Lenalidomide (CC-5013)
Protocol: CC-5013-MCL-002
Celgene Corporation
Confidential and Proprietary
4
CC-5013-MCL-002 Amend #4 Final:  27 Sep 2011
!
The amendment increases the sample size to 250 patients and modifies the Efficacy 
analysis (Synopsis: Statistical Analysis; and Protocol sections 15.2.1, 15.2.3, 15.7, and 
15.8 ).
These changes were implemented following recommendations from the third study DMC: 
∀
To allow a more reliable estimation of potential PFS differences between the study 
arms after the DMC observed that the outcome in the control arm of the study was 
different from the initial assumptions used to calculate the sample size; 
∀
Sub-populations and sub-groups are added to the analyses to evaluate potential 
correlation between safety and efficacy outcomes based on baseline characteristics or 
response to treatment in different patient populations; and 
∀
For analysis according to MIPI at randomization after the DMC observed an 
imbalance in risk factors between the study arms which was not mitigated by the 
stratification factors.
!
The amendment adds sub-populations and sub-groups to the study analyses (Synopsis: 
Table 4; and Protocol sections 15.1and 15.9).
∀
Sub-populations and sub-groups are added to the analyses to evaluate potential 
correlation between safety and efficacy outcomes based on baseline characteristics or 
response to treatment in different patient populations.
!
The amendment further clarifies and aligns the follow-up requirements for second 
primary malignancies in the Synopsis (Cross over) and Protocol sections 8.1.2.3 and 
8.1.2.4.
∀
Further clarification and protocol wording alignment of the SPM follow-up 
requirements.
!
The amendment adds a fourth EORTC QoL compliance assessment to occur after 200 
patients complete 2 cycles or withdraw before completing 2 cycles (Protocol section 
15.2.2).
∀
This addition was implemented to ensure ongoing monitoring of EORTC QoL 
compliance with sample size increase to 250 pts.
!
The amendment updates the safety language according to the updated protocol template 
safety wording in Protocol section 21.1.
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 !  (5"5)  
 ! ! 6   !#

&+  2 ,     +     +  ++  
3   4      + 3    +  9   +  
   +1    9   ,:+        , 
  3   +          +     +   ++4 

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 ,:+ +2    + 1    +   ,     ; 
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'      ! +   ' !     3    2 224 $ 7  3
=  2 2  + + 2 #   >         
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+1             51 3+2 +   4 

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  !!       
 ( ' 7& ! 8  '  
  9 & :#/;#/#4,#/)

$  3  +  3   +        3   
+         2   +1 3+     4

  !!      !  
!  ( ' 7'  !
  9 & 1#4;#//4#4/0#4#44/#0)#

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'  C 9  &     'C& 

  !!  !!!  *
  ( ' 7*9  <9 /9
& ;#/#4#<)#

$ ++  +     +   2   +      
       +         +  2  6 

   ++  +   ,        + 
     $,     +  ! 4

  !!    ! % ! *  4;
 ( ' 7* 9& ;#/#4#=)#

$ ++    5      ;        
   3 2 -              +  2 
 4 

  !!        '!! &
      >   !    ?  
 (    )?     
( ' 7'' 9& /-#/#4)#

  !!  !     *? 
! ! 9    *?   9
  !          
       !
    ( ' *   9& /0#4#<)#

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  !!      !        
  !     @!! %  
 @ ( ' *   9& /0#1)#

  !!   % !  !   ! *
!(  4<9& /-#/#//-#/#<)#

$ ++  +      1      ?      
   ,   + 3   ++1        , 
       3 > 2 3 34

  !! !      ! (  
:  ;)#

 +  ;            D   ;   
+  4 

$   2      +     2     +  4 
$    ,  3   ,        2     3+    
     +     3   +     +4 

  !!  % ! "! !   !
       (& /-#/#1/-#/#;)#

$ ;     /+ +    +        + +   
+            +  + 4

$ ;         ,          
      + 4
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  !!       ! 
$        
(&' /0#/#=)#

  !!    ( ' 7
B? 9& 0#/0#4#4/-#/#04-)#

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  *!!  $.   $3$  0       !   !  9 
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#               #      0 '  
   ;' .  ;' 3      K
          ;  H,+ # 5  R .      5    
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          ;  H:3/)813,063 H,+ H:3/)813,063 # 5  R . 
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6#        N" BB  ' 4+?   ' '         
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 2, MULTICENTER, RANDOMIZED OPEN-LABEL STUDY TO DETERMINE 
THE EFFICACY OF LENALIDOMIDE (REVLIMID®) VERSUS INVESTIGATOR’S 
CHOICE IN SUBJECTS WITH RELAPSED OR REFRACTORY MANTLE CELL 
LYMPHOMA
STUDY DRUG:
Lenalidomide/CC-5013
PROTOCOL NUMBER:
CC-5013-MCL-002
DATE FINAL:
26JUL2010
Date Amendment 1
18JUL2011
Date Amendment 2
19DEC2012
Prepared by:
Celgene International
Route de Perreux, 1
2017 Boudry, Switzerland
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
SUMMARY OF CHANGES ....................................................................................9
2.1.
From version 1.2.......................................................................................................9
3.
INTRODUCTION..................................................................................................11
4.
OBJECTIVES ........................................................................................................12
5.
INVESTIGATIONAL PLAN .................................................................................13
5.1.
Overall Study Design and Plan ...............................................................................13
5.1.1.
Discussion of Study Design ....................................................................................13
5.2.
Study Endpoints .....................................................................................................14
5.3.
Stratification , Randomization and Blinding............................................................15
5.4.
Sample Size............................................................................................................15
5.5.
Changes to the Planned Protocol Analysis ..............................................................17
6.
GENERAL STATISTICAL CONSIDERATIONS .................................................18
6.1.
Reporting Conventions ...........................................................................................18
6.1.1.
Dates and Partial Dates Imputation .........................................................................18
6.1.2.
Calculations Using Dates........................................................................................19
6.1.3.
Calculation of Cycles..............................................................................................19
6.2.
Analysis Populations ..............................................................................................20
6.2.1.
Intent-to-Treat Population.......................................................................................20
6.2.2.
Full Analysis Set Population...................................................................................20
6.2.3.
Per Protocol Set Population ....................................................................................20
6.2.4.
As treated Population..............................................................................................21
6.2.5.
Safety Population....................................................................................................21
7.
SUBJECT DISPOSITION......................................................................................22
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................23
8.1.
Demographics.........................................................................................................23
8.2.
Baseline Clinical Characteristics.............................................................................23
8.3.
Medical History......................................................................................................24
8.4.
Prior Anti-Lymphoma Therapies ............................................................................24
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.1.
2.2


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
3
8.5.
Prior Medications ...................................................................................................24
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................25
9.1.
Treatment Duration.................................................................................................25
9.2.
Cumulative Dose ....................................................................................................25
9.3.
Dose Intensity.........................................................................................................25
9.4.
Relative Dose Intensity...........................................................................................26
9.5.
Dose Modification..................................................................................................26
10.
CONCOMITANT MEDICATIONS .......................................................................28
11.
EFFICACY ANALYSIS ........................................................................................29
11.1.
General Statistical Methods ....................................................................................29
11.1.1.
Time to Event Endpoints ........................................................................................29
11.1.2.
Categorical Endpoints.............................................................................................30
11.1.3.
Quality of Life Endpoints .......................................................................................30
11.2.
Expert Review of Disease Response .......................................................................31
11.3.
Analysis of Primary Efficacy Endpoint...................................................................31
11.4.
Analyses of Secondary Efficacy Endpoints.............................................................34
11.4.1.
Overall Response Rate............................................................................................34
11.4.2.
Duration of Response .............................................................................................34
11.4.3.
Tumor Control Rate................................................................................................35
11.4.4.
Duration of Stable Disease......................................................................................35
11.4.5.
Time to Progression (TTP) .....................................................................................35
11.4.6.
Time to Treatment Failure (TTF)............................................................................35
11.4.7.
Time to Tumor Response (TTR).............................................................................35
11.4.8.
Overall Survival (OS).............................................................................................36
11.5.
Subgroup Analysis..................................................................................................36
12.
SAFETY ANALYSIS ............................................................................................37
12.1.
Adverse Events.......................................................................................................37
12.2.
Clinical Laboratory Evaluations..............................................................................39
12.3.
Vital Sign Measurements........................................................................................39
12.4.
Physical Examination .............................................................................................39
12.5.
Electrocardiogram ..................................................................................................39
13.
QUALITY OF LIFE ANALYSIS...........................................................................40
13.1.
EORTC QLQ-C30..................................................................................................40
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
4
13.2.
Analysis of Quality of Life Scales...........................................................................42
14.
INTERIM ANALYSIS...........................................................................................43
14.1.
General Information................................................................................................43
14.2.
Statistical Approaches for Control of Alpha............................................................44
14.2.1.
Primary Analysis ....................................................................................................44
14.2.2.
Interim Analysis .....................................................................................................45
15.
REFERENCES.......................................................................................................46
16.
APPENDICES........................................................................................................47
16.1.
Date Imputation Guideline......................................................................................47
16.1.1.
Impute Missing AE/ Prior or Concomitant Medications Start Dates........................47
16.2.
Cycle Derivation Guideline ....................................................................................48
16.3.
Endpoints Derivation..............................................................................................49
16.4.
Laboratory Values ..................................................................................................50
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Summary of Changes................................................................................................9
Table 3:
Confidence Intervals...............................................................................................16
Table 4:
InvC Drug Recommended Dose..............................................................................26
Table 5:
Censoring Rules for Time to Event (Progression and/or Death) Endpoints..............32
Table 6:
Method b: Censoring Rules for Time to Event (Progression and/or Death) 
Endpoints Sensitivity Analysis................................................................................33
Table 7:
Method c: Censoring Rules for Time to Event (Progression and/or Death) 
Endpoints Sensitivity Analysis................................................................................34
Table 8:
EORTC QLQ-C30 Scores.......................................................................................40
Table 9:
Response Percentage and 95% Exact Confidence Interval.......................................44
Table 10:
P-Value for Rejecting Null Hypothesis (Superiority) ..............................................45
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
AML
Acute Myelogenous Leukemia
BSA
Body surface area
CI
Confidence Interval
CR
Complete response
CRu
Complete response unconfirmed
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data monitoring committee
DOB
Date of birth
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
FAS
Full Analysis Set
FCBP 
Female of childbearing potential
GCP
Good Clinical Practice
HR
Hazard ratio
IC
Informed consent
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
InvC
Investigator’s choice
IRRC
Independent radiology review committee
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive voice response system
KM
Kaplan Meier
Len
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
8
Abbreviation or 
Specialist Term
Explanation
MCL
Mantle Cell Lymphoma
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Drug Regulatory Activities
NCI-CTC
National Cancer Institute Common Toxicity Criteria
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PI
Principal Investigator
The investigator who leads the study conduct at an individual study center.  
Every study center has a principal investigator.
PPS
Per Protocol Set
PR
Partial response
QoL
Quality of Life
SAE
Serious adverse event
SAP
Statistical analysis plan
SCT
Stem Cell Transplant
SD
Stable disease
SDev
Standard deviation
SPM
Second Primary Malignancy 
TEAE
Treatment emergent adverse event
TTF
Time to treatment failure
TTP
Time to tumor progression
TTR
Time to response
WHO
World Health Organization
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
9
2.
SUMMARY OF CHANGES 
2.1.
From version 1.2
Table 2:
Summary of Changes
Section N°
Change
5.4 Sample Size
Increase of sample size was reported
Rationale:
Implemented following recommendation from the third study 
DMC to allow a more reliable estimation of potential PFS 
differences between the study arms after the DMC observed that 
the outcome in the control arm of the study was different from 
the initial assumptions used to calculate the sample size.
5.5 Changes to the Planned 
Protocol Analysis
Initially it was planned not to present all the populations if they 
differ by less than 10% in size. All the populations will be 
presented regardless of the difference in size.
7 Subject disposition
PPS population was added into the list of populations presented 
in the disposition table.
8.1 Demographics 
Initially it was planned not to present all the populations if they 
differ by less than 10% in size for the demographic and baseline 
characteristic. All the populations will be presented regardless of 
the difference in size for the demographic and sensitivity and 
secondary analyses.
8.2 Baseline Clinical 
Characteristics
Update of the section with more details on the variables 
described.
9.3 Dose intensity
Change the denominator to total of days dosed instead of 
treatment duration
9.4 Relative Dose Intensity
Add 10 mg as reference dose for the moderate renal impairment.
9.5 Dose Modification
Update of the section with more details on the variables 
described.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
10
Table 2:
Summary of changes (Continued)
10 Concomitant 
medications
Update of the section with more details on the listings presented.
11 Efficacy Analysis
Clarify which population will be used for the primary analysis 
and for the supportive analyses.
Update of the section by adding additional subgroups based on 
the protocol amendment #4.
12 Safety Analysis
Clarify which population will be used for the safety analyses.
Update of the section by using targeted events instead of events 
of interest and adding paragraph on analyses of second primary 
malignancies
14.1 General Information
Update of the section by adding the additional DMC after 200 
subjects have been treated for at least 2 cycles.
14.2 Statistical Approaches 
for Control of Alpha
Update of the section by adding method to control alpha level 
after DMC made an unplanned sample size reassessment.
16.5 Tables and listings 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
11
3.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-5013-MCL-002 “A Phase 2, Multicenter, Randomized Open-Label Study To 
Determine The Efficacy Of Lenalidomide (REVLIMID®) Versus Investigator’s Choice In 
Subjects With Relapsed Or Refractory Mantle Cell Lymphoma.” It contains definitions of 
analysis populations, derived variables and statistical methods for the analysis of efficacy and 
safety.
These analyses include one interim analysis for futility and one final analysis. Throughout this 
SAP, the treatment arms will be referred to as lenalidomide (Len) and Investigator’s choice 
(InvC).  The purpose of the SAP is to ensure the credibility of the study findings by specifying 
the statistical approaches to the analysis of study data prior to database lock for the final analysis. 
This SAP will be finalized and signed prior to the clinical database lock for the futility analysis. 
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.1.
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9.1


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
12
4.
OBJECTIVES
The objective of the statistical analyses will be to investigate the efficacy and safety of 
lenalidomide monotherapy in subjects with relapsed or refractory mantle cell lymphoma.
Primary objective
To compare the progression-free survival (PFS) of lenalidomide monotherapy versus 
investigator’s choice single agent in subjects with mantle cell lymphoma (MCL) who are 
refractory to their regimen or have relapsed once, twice or three times..
Secondary objective
To determine the overall response rate (ORR) of lenalidomide monotherapy or investigator’s 
choice single agent in subjects with relapsed or refractory MCL.
To evaluate the safety of lenalidomide monotherapy or investigator’s choice single agent in 
subjects with relapsed or refractory MCL.
To determine the time to tumor progression (TTP), and overall survival (OS) of subjects with 
relapsed or refractory MCL who have received treatment with lenalidomide or investigator’s 
choice single agent treatment.
To investigate the health-related quality of life (QoL) of subjects treated with lenalidomide or 
investigator’s choice single agent treatment.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
13
5.
INVESTIGATIONAL PLAN
5.1.
Overall Study Design and Plan
This is a multicenter, randomized, open-label, comparative, active controlled phase II study to 
determine the efficacy and safety of single agent lenalidomide over a concurrent control group 
treated with an investigator’s choice monotherapy in subjects with MCL who are refractory to 
their regimen or have relapsed once, twice or three times.
This multicenter study design aims to determine the PFS hazard ratio (HR) of lenalidomide over 
a single agent of investigator’s choice.
The investigator’s choice in the control arm comprises the monotherapy treatment with one of 
the following: chlorambucil, cytarabine, rituximab, fludarabine, or gemcitabine.  The 
investigator shall choose the single agent of choice in the control arm for each subject prior to 
randomization on to the study. Subjects in the investigator’s choice arm will have the option to 
switch to lenalidomide at the time of progressive disease (cross over phase).
Subjects are stratified according to:
!
Time since diagnosis (< 3 years or ≥ 3 years)
!
Time since the end of last treatment (< 6 months [refractory] or ≥ 6 months)
!
Prior stem cell transplant (yes or no).
This study will be conducted in four phases: 
!
A Screening Phase
!
An open label randomized Treatment Phase
!
A cross over phase (subjects in the investigator’s choice Arm B only)
!
Follow-up phase.
5.1.1.
Discussion of Study Design
!
Duration of Treatment
Subjects will be treated until progression in this study.  
!
Study Population
Subjects with MCL who have relapsed once, twice or three times are being assessed to evaluate 
the efficacy of lenalidomide. There is no standard of care for such subjects.
!
Blinding
The open-label option was chosen because the five alternatives therapies on the InvC arm are 
given either intravenous (IV) or orally.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
14
!
Cross-over
Due to ethical concerns and based on the fact there is no alternative for subjects on the InvC arm 
who progress the possibility to cross-over to Len is offered. It is clearly a source of bias in the 
analysis endpoints such as OS. Cross-over will not affect the primary endpoint (PFS) as it is 
allowed only after progression occurs.
5.2.
Study Endpoints
Following the implementation of Amendment #2 (dated 14 Dec 2009), PFS became the primary 
endpoint comparing PFS in subjects who receive lenalidomide monotherapy versus 
investigator’s choice. Despite the change in the primary endpoint from ORR to PFS, there was 
no impact on the sample size calculation.
Primary
PFS is defined as the time from randomization to the first observation of disease progression or 
death due to any cause. If the subject has not progressed or died, PFS will be censored at the time 
of last completed assessment when the subject was known not to have progressed. Subjects who 
receive a new treatment without documented progression will be censored at the last assessment 
date that the subject is known to be progression-free.
Secondary
!
ORR (complete response [CR], complete response unconfirmed [CRu], and partial 
response [PR]) will be assessed by a modification of the International Workshop 
Lymphoma Response Criteria (IWRC), which will hereafter be described as modified 
IWRC (Cheson,1999).
!
Duration of response
!
Duration of stable disease
!
Tumor control rate (Rates for CR, CRu, PR, and stable disease [SD])
!
Time to tumor progression (TTP)
!
Time to treatment failure (TTF)
!
Time to tumor response (TTR)
!
Overall survival (OS)
!
Safety
!
Quality of Life (EORTC QLQ-C30 questionnaire)
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
15
5.3.
Stratification , Randomization and Blinding
An Interactive Voice Response System (IVRS) will be utilized to ensure a 2:1 central 
randomization based on a permuted-block randomization method. Subjects will be randomized 
according to the following stratification factors: Time since diagnosis (< 3 years or ≥ 3 years), 
Time since last treatment (< 6 months [refractory] or ≥ 6 months), Prior stem cell transplant (yes 
or no).
5.4.
Sample Size
Following the approval of Amendment #4 (dated 27SEP2011), the sample size increase was 
implemented after recommendation from the third DMC(held on July 22, 2011) to allow a more 
reliable estimation of potential PFS differences between the study arms after the DMC observed 
that the outcome in the control arm of the study was different from the initial assumptions used
to calculate the sample size.
The DMC therefore recommended increasing the sample size from 174 (number of subjects
randomized at the time of the DMC was held) to 250 subjects and conducting the underpowered
primary analysis one year after the last subject being randomized. This would allow a more
reliable estimation of the treatment effect aiming at demonstrating a clinically meaningful
improvement in PFS between the experimental arm and the control arm. In addition the 
proposed timing for the analysis will allow a reasonable follow up for overall survival so full 
information on the clinical benefit of lenalidomide can be provided at the time of PFS analysis.
The main objective of the study changed to demonstrate the efficacy of lenalidomide over a 
single agent of investigator’s choice based on PFS after protocol amendment #2. This change 
was already reflected in the SAP amendment 1.
The primary analysis for the study is to compare PFS between lenalidomide and investigator’s 
choice monotherapy.
Protocol amendment # 4:
After protocol amendment #4 the PFS assumptions used to determine sample size and the timing 
of the primary analysis could not be used anymore. The primary analysis will be conducted one 
year after the last subject is randomized.
Protocol amendment # 2:
For the primary efficacy variable PFS, a hazard ratio (HR) of 1.7 leading to an improvement in 
median PFS from 2.5 months for the control arm to at least 4.25 months for lenalidomide is 
considered to be clinically relevant.
These assumptions are supported by recent data published in relapsed refractory MCL (Witzig et 
al. 2007 and Hess et al., 2009 ). 
e wa
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
16
With a hazard ratio of 1.7, full information necessary for a one-sided log rank test with an overall 
alpha of 0.025, to have 80% power, will be achieved when approximately 128 subjects have 
progressed or died (PFS).
Initially, the sample size was calculated to estimate the ORR; however, it remains adequate to 
estimate PFS.
Original protocol:
The sample size calculation is based on the width of the 95% confidence interval around a 
certain point estimate for ORR that is considered significant clinical activity.
Based on preliminary data, a response rate in the range of 30% to 40% can reasonably be 
expected.
A sample size equal to 100 allows the construction of a two sided 95% confidence interval with a 
width of 9% (one direction) for an expected proportion of 30%. 
The lower observed confidence interval limit would be about 21%, which is still considered to be 
clinically meaningful.
This sample size allows a width (one direction) of 9.6% for an expected proportion of 40% and 
9.3% for an expected proportion of 35% (Table 3).
Table 3:
Confidence Intervals
95% Two-Sided Confidence Intervals (N = 100)
Response rate
30%
35%
40%
CIa
0.214 – 0.400
0.257 – 0.452
0.303 – 0.503
a Exact confidence intervals based on the Clopper-Pearson method
Using a one group chi-square ( ∀2) test with a 0.050 two-sided significance level a sample size of 
100 subjects will have 81% power to detect the difference between the Null hypothesis 
proportion of 20% and the alternative proportion of 32%.
No formal sample size calculation will be done for the control arm. With a 2:1 ratio 50 subjects 
are needed in the control arm.
Assuming that 10% of subjects will be lost to follow up, 167 subjects will need to be 
randomized.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
17
5.5.
Changes to the Planned Protocol Analysis
Initially it was planned not to present all the populations if they differ by less than 10% in size 
for the demographic and baseline characteristic. All the populations will be presented regardless 
of the difference in size for the demographic and any efficacy analyses.
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
18
6.
GENERAL STATISTICAL CONSIDERATIONS
6.1.
Reporting Conventions
Summary tables, listings, and any supportive SAS output will include a “footer” of explanatory 
notes that will indicate, at a minimum, the following: 
!
Program source (e.g., SAS program name, including the path, that generates the 
output)
!
Data extraction date (e.g., the database lock date, run date).
!
Source listing(s) for the summary tables
The purpose of the data extraction date is to link the output to a final database, either active or 
archived, that is write-protected for replication and future reference.  An output date will also 
appear on each output page and will indicate the date the output was generated by the analysis 
program. Individual source listings will display all the relative values supporting the 
corresponding tables or figures.
6.1.1.
Dates and Partial Dates Imputation
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9. datetime format in SAS) if complete dates are expected, 
for information (e.g: medical history, prior medications) dates can be reported in the YYYY-
MM-DD format.  Dates in the clinical database are classified into the categories of procedure 
dates, log dates, milestone dates, outcome dates, and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedures are 
performed.  They include the dates of laboratory testing, physical examinations, 
tumor scans, etc.  They should be present whenever data for a protocol-specified 
procedure is present and should only be missing when a procedure is marked as NOT 
DONE in the database.  Procedure dates will not be imputed.
!
Log Dates are dates recorded in case report form (CRF) data logs.  Specifically, they 
are the start and end dates for adverse events and concomitant 
medications/procedures.  They should not be missing unless an event or medication is 
marked as ongoing in the database.  Otherwise, incomplete log dates will be imputed 
according to the rules in Appendix 16.1 Date Imputation Guideline (eg, for duration 
or cycle assignment etc). However, in listings, log dates will be shown as recorded 
without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study termination, etc.  They should not be missing if the milestone occurs 
for a subject. They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc.  In most cases they are derived either from a milestone (eg, the 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
19
survival date is derived from the death date), or a procedure date (eg, the progression 
date is derived from the date of the tumor scan that was used to determine progression
or from the date of clinical evaluation).  They may be subject to endpoint-specific 
censoring rules if the outcome did not occur, but are not otherwise subject to 
imputation.
Dates recorded in comment fields will not be imputed or reported in any specific format.
6.1.2.
Calculations Using Dates
Calculations using dates (e.g., subject’s age or relative day after the first dose of study 
medication) will adhere to the following conventions: 
Study days after the start day of study drug will be calculated as the difference between the date 
of interest and the first date of dosing of study medication (eg, lenalidomide) plus 1 day. The 
generalized calculation algorithm for relative day is as follows: STUDY DAY = [(TARGET 
DATE – DSTART) + 1] where DSTART = the start day of study drug.  Note that Study Day 1 is 
the first day of treatment of study drug.  Negative and zero study days are reflective of 
observations obtained during the baseline/screening period.  Note: in general, a partial date for 
the first date of study drug intake will not be imputed. All efforts should be made to avoid an 
incomplete study drug start date.
!
Age (expressed in days) is calculated: AGE = CONSENT – DATE of BIRTH + 1.  In 
practice, age will be transformed to years by dividing the difference by 365.25 days, 
then truncating.
The calculated age from the clinical database will be used preferentially. When not available, it 
will be permissible to use the calculated age from the CRF or IVRS
Partial birth date: impute missing day as 15th of the month; impute missing month as July; set 
missing age for missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS / 7.
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS / 30.4167.
6.1.3.
Calculation of Cycles
The start date of each treatment cycle will be calculated based on study drug exposure records 
for each subject. The start date of the first cycle will be the date when the subject receives any 
study drug.
between the
between the
plus 1 day
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
20
The cycle will be derived following the algorithm given in Appendix 16.2. Rituximab drug has a 
cycle length of 56 days, whereas the other treatments have a 28 days schedule. Any 
programming should be adapted accordingly.
Once the cycles are derived, they can be used to attribute adverse events to a specific cycle based 
upon the following rules: the start date of the adverse event should be included in a given cycle 
or if the start date does not fit in any defined cycle, the adverse event will be attributed to the 
previous cycle if the AE has started within 30 days after the end of the cycle.
6.2.
Analysis Populations
The primary efficacy analyses will be performed on the Intent-to-Treat (ITT) population for the 
primary and secondary endpoints. Sensitivity analyses will be conducted for the primary and 
secondary endpoints based on the Full Analysis Set (FAS) population and the additional 
populations defined in this section.
The safety analyses will be conducted only on the Safety population.
6.2.1.
Intent-to-Treat Population
The ITT population is defined as all subjects who are randomized, independent of whether they 
received study treatment or not. The ITT population will be used for the primary efficacy 
analysis.
Subjects will be analyzed according to the initial treatment to which they are assigned.
6.2.2.
Full Analysis Set Population
The FAS population includes all randomized subjects that have received at least one single 
treatment dose with centrally confirmed histology of MCL as well as documented progression at 
entry.
6.2.3.
Per Protocol Set Population 
The PPS population includes all randomized subjects that have received at least one single 
treatment dose with centrally confirmed histology of MCL as well as documented progression at 
entry without protocol violations.
Protocol violations will be presented in data listing and summarized by categories in a table. 
Protocol violations will be determined by careful medical review of the data prior to database 
lock and conduct of statistical analyses. Physician and clinical research scientist will be 
responsible to produce the final protocol violation file (formatted as a Microsoft Excel file) in 
collaboration with the clinical operation and the data management group. This file will include a 
description of the protocol violations and deviations.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
21
6.2.4.
As treated Population
The As treated population  analysis set is defined as all randomized subjects who receive at least 
two cycles of treatment regardless the treatment arm received. The subjects will be analyzed in 
the treatment group they actually received.
6.2.5.
Safety Population
The Safety population or “All Treated Subjects” analysis set is defined as all randomized 
subjects who receive at least one dose of the study treatment (either lenalidomide or InvC).
Drug exposure and all safety analyses (including AEs, labs and deaths) will be based on the 
Safety population. Subjects will be analyzed according to the initial treatment actually received.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
22
7.
SUBJECT DISPOSITION
All subjects enrolled/randomized will be included in the analyses listed below. Subject
disposition will be summarized for the following analysis populations by initial dosing regimen:
!
ITT Population
!
FAS Population
!
PPS Population
!
As Treated Population
!
Safety Population.
A separate listing will be provided for subjects not randomized.
The number of subjects who will cross-over will be also displayed.
The primary reasons for ending study treatment will be collected on the CRF and will be 
summarized for all treatment discontinued subjects using the following categories:
!
Adverse events
!
Disease progression
!
Withdrew consent
!
Lost to follow-up
!
Death
!
Protocol violation
!
Other.
The primary reasons for study discontinuation in all randomized subjects will also be collected 
on the CRF and summarized using the categories outlined above.
The number of subjects who will enter the follow-up phase with or without progression will be 
displayed.
A summary tabulation will be provided for subjects enrolled by study center and country. 
Duration of study participation, defined as from date of first dose to date of discontinuation (or
the date of last visit), will be summarized.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
23
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be summarized for the all the defined populations
in section 6.2 Analysis Populations .
Baseline clinical characteristics are defined as the latest data collected on or before day 1 (or 
randomization day in case day 1 is missing). When there are retested values, the retest values
will be used for the analysis. Individual subject listings will be provided to support the tables.
8.1.
Demographics
Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
provided for variables measured on a continuous scale, e.g. age, height, and weight. The 
frequency distribution (n, %) will be provided for those variables measured on a nominal scale.
Subject demographics (age, age group (<65, ≥65), sex, race/ethnicity, renal function status at 
baseline: severe (<30 ml/min) or moderate ( 30 to <60 ml/min) or normal (≥60 ml/min) will be 
tabulated with summary statistics: N, mean, SD, median, minimum and maximum for continuous
variables, and N, percent for categorical variables. 
Baseline ECOG and baseline ECG (normal/abnormal) will be summarized with frequency 
counts.
8.2.
Baseline Clinical Characteristics
Time from the latest disease progression to the first study treatment will be calculated in months 
and summarized descriptively.
Other baseline characteristics, including number of prior treatment regimens (< 3 or ≥3), prior 
high-intensity therapy (defined as transplant or hyper-CVAD or R-hyper-CVAD [yes or no]), 
prior transplant (yes or no), time from last prior therapy (< 6 months, ≥ 6 months), MCL staging 
at randomization (stage I+II or stage III+IV), MIPI score at randomization (high or intermediate 
or low), baseline ECOG score, baseline LDH, baseline WBC count, time from initial diagnosis to 
first dose (< 3 years vs > 3 years), prior bone marrow involvement, baseline tumor burden (high 
vs. low; high tumor burden defined as at least one lesion that is ≥5 cm in diameters or 3 lesions 
that are 3 cms or greater in diameter), bulky disease (Yes vs. No; bulky disease defined as at 
least one lesion that is ≥ 7cm in the longest diameter by central radiology review) will also be
tabulated.
Histological diagnosis (investigator’s assessment and confirmed histology) will be summarized.
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ab ated.
ated.


Lenalidomide (CC-5013)
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8.3.
Medical History
A summary of medical history will be presented by MedDRA system organ class (SOC).  A 
similar summary will be generated for the concomitant disease (currently active medical history 
events).
8.4.
Prior Anti-Lymphoma Therapies
Frequency tabulations of the number of subjects with at least one prior therapy and the different 
types of previous therapies (chemotherapies, immunotherapies, Stem cell transplant (SCT)
separating autologus from allogenic if possible, radiation, and so on) will be given.
8.5.
Prior Medications
Prior medications are defined as medications that were started before the start of the study 
treatment (whether or not ended before the start of the study treatment). Prior medications that 
continue into study treatment period will be also reported as concurrent therapy.  Frequency 
tabulations of the number of subjects with at least one prior medication and the different types of 
prior medications will be provided.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
Duration of treatment is the total number of days on treatment (date of last dose – date of first 
dose + 1).  For subjects ongoing in the treatment phase of the study on the cut-off date for the 
final analysis, the cut-off date will be used as the date of last dose.
The treatment duration (weeks) is defined as: 
[(The study treatment end date) – (the first study drug start date) + 1] / 7
Summary statistics will be provided for treatment duration by treatment group. 
An additional table will be created for all treated subjects, displaying number of subjects by 
cycle and the treatment arm.
Days Dosed is the total number of days study drug was taken, adjusted for any treatment 
interruptions.  Days dosed will be calculated by cycle and overall.
Cycles Dosed is the total number of treatment cycles during which a subject took study drug.  
Any cycle which has started will be counted as a complete one.
Average Number of Days dosed per cycle is calculated as days dosed (overall) divided by 
cycles dosed.
9.2.
Cumulative Dose
Overall Cumulative dose is the total dose received during the treatment period.
Cumulative dose will be calculated separately for lenalidomide or InvC.  The cumulative dose 
during the treatment is defined as the sum of all doses taken across the treatment period (in 
milligrams).
Cumulative dose at each cycle is calculated as the total dose received up to and including the 
current cycle.  
9.3.
Dose Intensity
Dose intensity during the treatment is defined as the cumulative dose divided by the total 
number of days dosed. Dose intensity will be calculated separately for lenalidomide and for InvC
single agents separately.  
The dose intensity per cycle is calculated as the overall cumulative dose divided by the number 
of cycles dosed. 
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Lenalidomide (CC-5013)
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9.4.
Relative Dose Intensity
Relative dose intensity is the dose intensity divided by the planned dose intensity:
!
For lenalidomide the planned dose intensity is 25 mg/per 28 days (10 mg/per 28 days
if moderate renal impairment).
!
For InvC single agents:
Table 4:
InvC Drug Recommended Dose
Investigator’s choice
mg/m2
days
q days
max # cycles
Chlorambucil PO
40 (total monthly 
dose)
Split over 3-10 
days
28
until PD or 
toxicity
Rituximab IV
375
1, 8, 15, 22
56#
until PD or 
toxicity
Cytarabine IV
1000 -2000 once 
or twice per day
1, 2
28
6
Gemcitabine IV
1000
1, 8, 15
28
6
Fludarabine IV
25
1-5
28
6
Fludarabine PO
40
1-5
28
6
IV = intravenous; PD = progressive disease; PO = oral; q = days, repeated; y = years.
# Rituximab (single agent) is to be repeated every 56 days after Day 56 (given only on day 1 of every 56 days cycle).
For the prevention of cytokine release syndrome associated with the treatment of Rituximab ≤125 mg of 
methylprednisolone or equivalent are accepted on C1D1.
Descriptive statistics (n, mean, SD, median, max, min) of treatment duration, cumulative dose, 
dose intensity and relative dose intensity will be presented by treatment arm.
9.5.
Dose Modification
Dose reduction overall is the number and percent of subjects with at least one dose reduction 
during the treatment period.  Dose reduction by cycle is the number and percent of subjects with 
only one (subjects with one dose reduction) or more than one (number of subjects with two or 
more dose reductions) during a given cycle.
In order for a subject to have two or more dose reductions, study drug must have been reduced 
for one or more days, followed by another period of one or more days during which study drug 
dosing was reduced.
Number of subjects who have one dose reduction, two dose reductions, three dose reductions, or 
four or more dose reductions due to AEs will be summarized.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
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Only dose interruption due to AE will be considered. It is defined as the number and percent of
subjects who interrupted treatment with study drug for one or more days at least once during the 
treatment period due to AE.  Dose interruption due to AE by cycle is the number and percent of 
subjects with only one (subjects with one dose interruption) or more than one (number of 
subjects with two or more dose interruptions) during a given cycle.  In order for a subject to have 
two or more dose interruptions, study drug must have been stopped for one or more days, 
followed by dosing for one or more days, followed by another period of one or more days during 
which study drug dosing was stopped due to AE.
Time to first dose reduction/interruption for subjects with at least one dose 
reduction/interruption, is the time in days elapsed from the date of first dose of treatment to the 
date that first dose reduction/interruption occurred.
Interval between dose reduction/interruptions is the time from the start of the first dose 
reduction/interruption to the start of the second dose reduction/interruption.
Dose reduction/interruption will be summarized by Initial dosing regimen group. Summaries 
include subjects who have at least one dose reduction/interruption, time to first dose 
reduction/interruption. Additional descriptive statistics will include first and second dose 
reduction/interruption due to AE, duration of first and second dose reduction/interruption due to 
AE and interval between first and second dose reduction/interruption due to AE.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
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10.
CONCOMITANT MEDICATIONS
Concomitant mediations are defined as non-study medications that are started after the start (start 
included) but before the end of the study treatment, or started before the start of the study 
treatment and ended or remain ongoing during the study treatment.
All concomitant treatments documented during the study period will be summarized in frequency 
tabulations.  The Anatomical Therapeutical Chemical (ATC) coding scheme of the World Health 
Organization (WHO) will be used to group medications into relevant categories for these 
tabulations.
By-subject listings will be provided for all prior and concomitant medications and therapies 
taken during the trial. 
Other tables such as therapies received after study discontinuation, baseline diagnostic tests and 
baseline physical exam are provided.
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Lenalidomide (CC-5013)
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11.
EFFICACY ANALYSIS
All efficacy analyses will be performed for the ITT, FAS, PPS and As treated populations. 
Efficacy analyses on the FAS, PPS and As treated populations are supportive to ensure 
robustness of efficacy findings.
The primary efficacy analyses will be based on data from the central review by the IRC with the 
ITT population. Data from investigator assessments will be used as supportive analysis for the 
primary and key secondary efficacy endpoints.
Statistical comparisons will be made between lenalidomide and InvC.
11.1.
General Statistical Methods
11.1.1.
Time to Event Endpoints
Kaplan-Meier (KM) survival analysis will be performed (unadjusted for the stratification 
variables). The resulting survival estimates will be presented graphically for selected endpoints. 
The median, 25th and 75th percentile time-to-event data will be presented with 95% CIs (if they 
exist) unadjusted by strata and within strata for the primary endpoint only.  
The numerical difference (and CI of the difference) in the median, 25th and 75th percentiles 
between lenalidomide and InvC will be presented for the unstratified analysis.
In addition, the event rates at specific time-points will be computed, along with the standard 
errors (Greenwood’s formula; Klein, 1997), based on which the event rates at specific timepoints 
can be compared if necessary. 
The groups will be compared using the stratified log-rank test in order to assess superiority and 
the unstratified log-rank test as supportive analysis. New statistic test will also be built to take 
into account the unplanned sample size reassessment recommended by the DMC and it will be 
used as primary analysis (see section 14.2 Statistical Approaches for Control of Alpha for more 
details).
The stratified Cox proportional hazard regression models will be used to estimate the hazard 
ratios (HR) and associated 95% CIs for the HRs. 
If any imbalances appear in the demographic or baseline characteristics variables considered as 
important  prognostic factors to clinical outcomes, the variables will be analyzed as the 
stratification factors. They will be included as covariates in the Cox model to provide estimate of 
lenalidomide treatment effect adjusted for these factors and in the stratified log-rank test.
The MIPI score at randomization will be analyzed as a stratification factor.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
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More detailed methods (for example exploring additional covariates such as age) will be 
investigated as a robustness check and may also be presented. 
Underlying model assumptions will be investigated for the analysis of the PFS endpoint using 
diagnostic statistics and graphical methods and, if necessary, an alternative analysis technique 
may be used.
Any changes in methodology will be documented in the clinical study report (CSR), including 
the rationale for use.  The proportional hazards assumption will be assessed by graphical display 
of the log-log survival distribution function versus the log event time for each treatment group.  
The censoring distributions of the treatment groups will be assessed for possible differences 
using KM methods.  
KM curves will be displayed graphically by treatment group.  Additionally, reasons for 
censoring will be summarized (n, percent) for the TTP, PFS, and OS endpoints.
Individual survival time information and mortality data will be provided in subject data listings. 
In order to evaluate the effect of cross-over on overall survival a Mantel-Byar approach will be 
used. The estimation of the control arm without cross-over and the mixed arm (lenalidomide arm 
and cross-over subjects) will be estimated. A weighted log rank test or Wilcoxon test will be 
used to take into account the effect of cross-over.
Multivariate models will be used to identify those baseline and prognostic factors (eg absolute 
leukocyte count, time from diagnosis, number of prior therapies and any other variables 
suggested in the literature prior to the analysis) most predictive of response (Colett, 1991).
11.1.2.
Categorical Endpoints
Categorical analyses will be based on the Fisher exact test.  Sensitivity analyses will be 
performed using the Cochran-Mantel-Haenszel test with the stratification factors as strata.  The 
p-values will be presented.  The null hypothesis is that incidence is equal for both treatment 
arms, the alternative hypothesis being that incidence is not equal.
The probability of response rates will be estimated using the proportion of subjects with 
responses with exact two-sided 95% confidence intervals.
The response rate in the cross-over portion of subjects in Arm B will be analyzed in a descriptive 
manner.
11.1.3.
Quality of Life Endpoints
The EORTC QLQ-C30 will be analyzed using change from baseline and percentage of change 
from baseline according to the functional scores and the recommendations in the EORTC scoring 
manual. Statistical tests could be performed in an exploratory manner.
The EORTC Reference Data Manual will also be used to descriptively check comparability 
between subjects in our trial and with other comparable populations.
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play
play
group. 
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ences
ences
sons for 
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nts.
nts
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subj
ntel
tel-Byar a
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e mixed a
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k test or 
k test o W
line and pro
line and pr
or therapie
or therap
most predict
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the Fishe
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Lenalidomide (CC-5013)
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Mann-Whitney tests for simple comparison and longitudinal data modeling techniques (ie Proc 
mixed in SAS) will be used to analyze QoL scores.
Subjects who drop out of the study without being evaluated for QoL will be counted as 
non-responders. Responses from subjects after they receive other anti-cancer treatments will be 
treated as non responders.
An update of the time to events endpoints and overall survival will be done at the end of the 
follow up. No adjustment for multiplicity will be applied.
11.2.
Expert Review of Disease Response
The independent review committee (IRC) is composed of two external independent radiologists 
(with an additional radiologist adjudicator in the event of a tie) and a hematologist/oncologist.  
The IRC will perform a blinded, independent assessment of radiological response (including 
assessment of Stable Disease [SD] and Progressive Disease [PD]), as well as reviewing the 
tumor response data and the dates of disease progression for each subject.
For further details please refer to Central Radiology Manual.
No central review will be performed for the subjects who crossed over after progression.
11.3.
Analysis of Primary Efficacy Endpoint
PFS is defined as the time from randomization to the first observation of disease progression or
death due to any cause. If the subject has not progressed or died, PFS will be censored at the time 
of last completed assessment when the subject was known not to have progressed. Subjects who 
will receive a new treatment without documented progression will be censored at the last 
assessment date that the subject is known to be progression-free. These rules are based on FDA 
guidance for cancer trial endpoints (FDA guidance, 2007).
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nt radio
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ponse (inclu
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own to b
ts (FDA gu
s (FDA g


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
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32
Table 5:
Censoring Rules for Time to Event (Progression and/or Death) Endpoints
Situation
Date of Progression or Censoring
Situation 
Outcome
No baseline assessments
Randomization
Censored
Progression documented
First adequate assessment determined by 
central review
Progressed
No progression
Date of last adequate assessment with 
evidence of no progression
Censored
Study discontinuation for reasons other 
than disease progression or death
Date of last adequate assessment with 
evidence of no progression
Censored
New anti-lymphoma / non-protocol 
treatment started prior to progression
Date of last adequate assessment with 
evidence of no progression prior to the start of 
new anti-lymphoma treatment
Censored
Death before first PD assessment while on 
study
Date of death
Progressed
Death between adequate assessment visits
Date of death
Progressed
Progression after an extended lost-to-
follow-up time (two or more missed 
assessments)
Date of last adequate assessment with 
evidence of no progression
Censored
PD = progressive disease.
See details in Appendix 16.3 .
As additional robustness checks of the primary endpoint and censoring definition, the time to 
event analysis will be repeated for the ITT population using the following modified definitions of 
PFS:
!
Using the investigator assessment instead the IRC central review 
!
Considering progression or death under a new anti-lymphoma treatment as an event 
(Table 5)
!
Considering death or progression after an extended lost-to-follow-up time (two or 
more missed assessments) as an event (Table 6)
!
One using the earliest progression date either in investigator set or IRC set.
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for the ITT
vest
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!
One 
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
33
Table 6:
Method b: Censoring Rules for Time to Event (Progression and/or Death) 
Endpoints Sensitivity Analysis
Situation
Date of Progression or Censoring
Situation 
Outcome
No baseline assessments
Randomization
Censored
Progression documented
First adequate assessment determined by 
central review
Progressed
No progression
Date of last adequate assessment with 
evidence of no progression
Censored
Study discontinuation for reasons other 
than disease progression or death
Date of last adequate assessment with 
evidence of no progression
Censored
New anti-lymphoma / non-protocol 
treatment started prior to progression
First adequate assessment determined by 
central review
Progressed
Death before first PD assessment while on 
study
Date of death
Progressed
Death between adequate assessment visits 
Date of death
Progressed
Progression after an extended lost-to-
follow-up time (two or more missed 
assessments) 
Date of last adequate assessment with 
evidence of progression
Progressed
PD = progressive disease.
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Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
34
Table 7:
Method c: Censoring Rules for Time to Event (Progression and/or Death) 
Endpoints Sensitivity Analysis
Situation 
Date of Progression or Censoring 
Outcome 
No baseline assessment 
Randomization 
Censored 
Progression documented between scheduled visits 
As defined for the main analysis 
Progressed 
No progression 
Date of last visit with adequate 
assessment 
Censored 
Investigator claim of clinical progression 
Scheduled visit (or next scheduled 
visit if between visits) 
Progressed 
Treatment discontinuation for toxicity or other 
reason 
Date of last visit with adequate 
assessment 
Censored 
New anticancer treatment started with no claim of 
progression 
Date of last visit with adequate 
assessment 
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessment visits or after 
subject misses one assessment visit 
Date of death 
Progressed 
Progression after an extended lost-to-follow-up time 
(two or more missed assessments) 
Last visit with adequate assessment 
Censored 
PD = progressive disease.
11.4.
Analyses of Secondary Efficacy Endpoints
The secondary endpoints will be analyzed in an exploratory manner (see details in 
Appendix 16.3 ).
11.4.1.
Overall Response Rate
The Overall response rate will include best response of CR, CRu, or PR. The modified IWRC 
will be used and response assessed by CT scan/MRI every 56 days (± 7 days) for the first 
6 months and then every 90 days ± 15 days thereafter.
Subjects who discontinue before any post-randomization efficacy assessments will be considered 
to be non-responders.
11.4.2.
Duration of Response
Duration of response will be measured from the time of initial response (at least PR) until 
documented tumor progression or death. Subjects who do not progress at the time of analysis 
will be censored at the last assessment date that the subject is known to be progression-free. 
Subjects who will receive a new treatment without documented progression will be censored at 
the last assessment date that the subject is known to be progression-free. 
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,2
ored 
ored
,2
,2
7,2
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Progresse
$7
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C
50
50
50
50
dequate
dequate
2
1)
th
< ,1
st visit with 
visit wit
$5
(7
Efficacy 
Efficac
nalyzed 
lyzed in a
n
nse 
se Rate
ate
ate w
ate will inc
inc
ponse asse
onse asse
en every
n every 90
90
y
discont
discontinu
inu
responders
sponders
11.4.2.
1.4.2.
Durati
Durati


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This analysis will be restricted to the subgroup of responding subjects.
11.4.3.
Tumor Control Rate
Rates for CR, CRu, PR, and SD.
CR/CRu/PR/SD will be determined using the modified IWRC (Cheson, 1999).
11.4.4.
Duration of Stable Disease
SD is defined as less than PR but is not progressive disease or relapsed disease.
Duration of SD will be calculated as the time from the first evidence of SD to documented 
disease progression or documented response or death. Subjects who do not progress or respond 
at the time of analysis will be censored at the last assessment date that the subject is known to be 
progression-free. Subjects who will receive a new treatment without documented progression 
will be censored at the last assessment date that the subject is known to be progression-free. 
This analysis will be restricted to the subgroup of SD subjects.
11.4.5.
Time to Progression (TTP)
TTP will be defined as the time from randomization until objective tumor progression. TTP will 
not include deaths. Subjects without progression at the time of analysis will be censored at the 
last assessment date that the subject is known to be progression-free. Subjects who will receive a 
new treatment without documented progression will be censored at the last assessment date that
the subject is known to be progression-free.
11.4.6.
Time to Treatment Failure (TTF)
TTF is defined as the time from the first dose of study drug to discontinuation of treatment for 
any reason, including disease progression, treatment toxicity or death. Subjects who will be on 
drug or complete the treatment according to the protocol will be censored at the last date of drug 
intake.
11.4.7.
Time to Tumor Response (TTR)
This analysis will be restricted to the subgroup of responding subjects.  Time to tumor response 
(TTR) will be defined as the time from randomization until initial response (CR, CRu, PR) if it 
has been confirmed.
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cumented 
umented 
ogress or re
ogress or r
subject
ubject is k
is k
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to be progr
o be progr
n unt
n until obje
il obj
n at the time
at the time
to be prog
to be prog
ssion will b
ssion will b
free.
ee
nt F
t Failure 
ailure
fro
rom th
t e f
disease prog
disease pro
e treatment
treatment
Time t
Time t
s analysis w
s analysis w
(TTR)
TTR) will
will
has been
has bee


Lenalidomide (CC-5013)
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Celgene 
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36
11.4.8.
Overall Survival (OS)
OS will be defined as the time from randomization until death from any cause. Subjects alive or 
lost to follow up at the time of analysis will be censored at the last date the subject was known to 
be alive.
11.5.
Subgroup Analysis
Subgroup analyses will be conducted in an exploratory manner for the following endpoints PFS, 
ORR and OS in the following subgroups:
!
Time since diagnosis (< 3 years or ≥ 3 years)
!
Time since the end of last treatment (<6 months [refractory] or ≥ 6 months)
!
Prior stem cell transplant (yes or no)
!
Age(<65;≥65)
!
Gender 
!
MCL International Prognostic Index (MIPI) score at initial time of diagnosis 
!
MIPI score at randomization
!
Number of prior treatment lines (with description of treatment regimens, including 
first line treatment and stem cell transplant)  (1,> 1), (<2;≥2), (<3; ;≥3) and by single 
category (1, 2, 3, 4, and >4)
!
Ki-67 index (as defined by Determann, 2008) labeling in the original pathology 
specimen at diagnosis, if available at time or at time of relapse
!
Absolute lymphocyte count at baseline (< 800/mm3 or ≥ 800/mm3)
!
Time since last rituximab to cycle 1 day 1 (< 230 days or ≥ 230 days)
!
Type of prior regimens received (rituximab containing regimens; Ara-C containing 
regimens; and fludarabine containing regimens).
!
Number of relapses ( 1 vs > 1), (<2 vs ;≥2 relapses), (<3; ;≥3 relapses)
!
Any demographic or baseline characteristic considered as important prognostic 
factors with imbalance in two treatment arms.
In addition any other possible prognostic factors may be used as exploratory analyses.
The methods described in previous sections will be used for each subgroup separately.
&(/*(1(35235,(7$5<,1)250$7,21
PFS, 
PFS
onths)
onths)
init
initial time
ial time
iption of tre
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nt)  (1,> 1)
mann, 2008
ann, 2008
5,
able at time
able at time
nt at baselin
nt at bas
mab to cy
mab to cyclc
mens recei
mens recei
fludarabine
udarabine
f relapses 
f relapses (
emographi
emographi
ors wi
ors w th
th
i
i
h m
n any
any other 
other 
y
ethods des
ethods des


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
37
12.
SAFETY ANALYSIS
The safety analyses will be performed using the safety population.
Adverse event and medical history coding will be performed using the Medical Dictionary for 
Drug Regulatory Activities (MedDRA) Version 15.1.
12.1.
Adverse Events
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) version 15.1. The intensity of AEs will be graded according to the
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version 3.0 (same as protocol).
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on 
or after the first treatment of the study medication and within 30 days after the last dose. TEAEs,
TEAEs leading to study medication discontinuation, TEAEs leading to dose 
reduction/interruption, TEAEs related to study medication and treatment-emergent serious 
adverse events (SAEs) will be summarized by system organ class and preferred term for each 
treatment group. A summary of TEAEs with NCI CTCAE grade 3 or higher and most frequent 
preferred terms will also be provided.
If a subject experiences the same preferred term multiple times then the subject will be counted 
only once and by greatest severity.
Listings for the corresponding summary tables will be presented separately.
For the cross-over subjects, any adverse events starting after the start of the drug will be assigned 
to lenalidomide even if the event has started within 30 days after the InvC end date. Additional 
summary tables will be provided for these TEAEs (cross-over lenalidomide).
Analysis of targeted TEAEs, time to targeted TEAEs will be presented. Targeted TEAEs will be 
defined using standardized MedDRA Queries (SMQs). The SMQ will be selected based on the 
internal expertise on the drug and the disease.
Second Primary Malignancies (SPMs) will be summarized by frequency for the following 
categories: 
!
Invasive SPMs will include hematologic malignancies and solid tumor malignancies.  
Hematological malignancies will be subcategorized into B-cell malignancies, acute 
myelogenous leukemia (AML), myelodysplastic syndrome (MDS), MDS to AML 
and other hematological malignancies.
!
Non-invasive SPMs (non-melanoma skin cancers)
Incidence per 100 person-years will be calculated. Confidence intervals will be provided using 
the Mid-P exact test. The following formulae will be applied:
&(/*(1(35235,(7$5<,1)250$7,21
CTCAE
TCAE)
or worsen
or worsen
the last dos
the last do
dose
se 
ent
ent-em
emerg
erg
and 
n pref
preferr
er
f
e 3 or 
e 3 or high
times then
times th
ll be presen
l be prese
ts starti
ts starting 
ng 
i
d within 3
within 3
se 
se TEAEs
TEAE
o targeted 
targeted
DRA
DRA Quer
Quer
and the dis
and the di
ignancies (
gnancies 
vasive SPM
asive SPM
Hem
Hematol
atolog
og
myelog
myelog
and o
and
!
N


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
38
The notation for the formulae is:
a = the observed numerator
PT = is the observed denominator in person-time units
rate = a/PT
Z1-α/2= the two-sided Z value (eg. Z=1.96 for a 95% confidence interval).
Exact Tests (Mid-P and Fisher)
The limits for ‘a’ with 100(1-α) percent confidence are the iterative solutions 
a
and
a
.
Computing iterative solutions  
a
and
a
is below………
Mid-P exact test (see Rothman and Boice):
Lower bound:  
2
1
!
!
2
1
1
0
#
∃
%
&
∋
(
)
∗
+
,
−
∃
%
∃
∃
a
k
k
a
a
a
k
a
e
a
a
e
Upper bound:  
2
!
!
2
1
1
0
#
%
&
∋
(
)
∗
+
,
−
∃
%
∃
∃
a
k
k
a
a
a
k
a
e
a
a
e
If appropriate, competing risk analysis considering death as competing event will be conducted.
If the number of events observed is sufficient, multivariate analysis to identify demographic and 
clinical factors predictive of SPMs will be conducted. Univariate Cox regression analysis will be 
used to select the subset of relevant factors for inclusion in a multivariate model, with variable 
selection set at the p < 0.20 level.  Backward selection procedures will be used for final model 
determination, with p < 0.10 selected as the p value for retention in the multivariate model.  
These analyses will be performed for all invasive SPMs as well as for hematologic malignancies 
and solid tumors separately.
  The table output will display the number of cycles received, the overall total dose, the treatment 
duration and the time to onset of the SPM.  A supportive listing will include, at minimum, the 
verbatim and the SPM category, the treatment duration, start and stop date, action taken on 
treatment, gender and age.
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5
a
d
.
risk analysi
sk analys
s observed 
s observed
dict
dictive of S
ive of S
 subset of 
subset of
t the p < 0
he p < 0
ion, wi
n, with
th
i
p
h
nalyses wil
nalyses wi
olid tumor
lid tumo
The ta
The ta


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
39
Hospitalizations will be summarized by the primary cause of hospitalization.
The FCBP status along with pregnancy test results will be summarized for female subjects.
12.2.
Clinical Laboratory Evaluations
Clinical laboratory values will be graded according to NCI CTCAE version 3.0 for applicable 
tests (see Appendix 16.4 Laboratory Values for details on standardization of the laboratory 
values). Frequency distributions for shift from baseline in severity grade to most extreme post-
baseline value will be displayed in cross-tabulations for the whole study period for each 
treatment. Normal ranges will be used to determine the categories if High, Low, and Normal for 
lab tests that have no severity grade.  Listings of clinical laboratory data with abnormal flags will 
be provided by subjects and tests. 
12.3.
Vital Sign Measurements
For vital signs, shift from baseline to worst during the treatment in below, within and above the 
normal ranges will be displayed in cross-tabulations for each treatment. Summary statistics (N, 
Mean, SDev, Median, Minimum, and Maximum) of observed and change from baseline values 
will be presented.
12.4.
Physical Examination
Shift tables regarding the evolution of the spleen, liver, lymphadenopathy will be displayed by 
treatment groups.
Presence or absence of lymphoma symptoms will be summarized by visit and treatment groups.
12.5.
Electrocardiogram
The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with ‘Normal’, ‘Abnormal, not clinically significant’, and ‘Abnormal, clinically 
significant’ by treatment. Shift from baseline to worst during the treatment in the overall ECG 
interpretation will be displayed in cross-tabulations for each treatment.
stst-
Normal for 
ormal for
mal flags w
mal flags w
below, wit
below, w
eatment. Su
atment. Su
d and chan
d and chan
pleen, liver
pleen, liver
ymptoms w
mptoms
iogram
gram
pretation w
pretation w
mal’l’, ‘Abno
‘Abno
reatment. S
reatment. S
will
will b
l e dis
e dis


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
40
13.
QUALITY OF LIFE ANALYSIS
13.1.
EORTC QLQ-C30
QoL instrument: EORTC QLQ-C30 (see attachment 21.9)
The version 3.0 of the EORTC QLQ-C30 is a 30-item scale. The EORTC QLQ-C30 is composed 
of both multi-item scales and single-item measures. These include five functional scales, three 
symptom scales, a global health status / QoL scale, and six single items (Table 8).
Table 8:
EORTC QLQ-C30 Scores
FUNCTIONAL 
SCALES
(15 QUESTIONS)
SYMPTOM SCALES
(7 QUESTIONS)
SINGLE ITEMS
(6 QUESTIONS)
GLOBAL QUALITY 
OF LIFE
(2 QUESTIONS)
PHYSICAL
(ITEMS 1 TO 5)
FATIGUE 
(ITEMS 10, 12, 18)
CONSTIPATION
(ITEM 16)
GLOBAL QOL
(ITEMS 29, 30)
ROLE
(ITEMS 6, 7)
PAIN
(ITEMS 9, 19)
DIARRHEA
(ITEM 17)
COGNITIVE
(ITEMS 20,25)
NAUSEA /
VOMITING
(ITEMS 14, 15)
SLEEP
(ITEM 11)
EMOTIONAL
(ITEMS 21 TO 24)
DYSPNEA
(ITEM 8)
SOCIAL
(ITEMS 26, 27)
APPETITE
(ITEM 13)
FINANCIAL
(ITEM 28)
All of the scales and single-item measures range in score from 0 to 100. A higher scale score 
represents a higher level of well being and better ability of daily functioning. A 10-point change 
in the scoring is considered to be meaningful change in QoL (Osoba, 1998).
Thus a high score for a functional scale represents a high/healthy level of functioning; a high 
score for the global health status/QoL represents a high QoL, but a high score for a symptom 
scale/item represents a high level of symptomatic problems.
Data collection and timing
Questionnaires must be filled out by the subject at 6 pre-specified time points (see below) when 
the subject comes for a scheduled visit. They will be handed out by a nurse or the treating 
physician/investigator, and ideally are collected again soon after the subject has filled it out.
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OBAL QUA
OBAL Q
OF L
F L
(2 QUE
(2 QU
5
1
N
)
G
1)
,1
RHEA
HEA
TEM 17)
M 17)
<
SLEEP
LEEP
(ITEM
(ITEM
$5
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5,
35
52
3
and single
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high score 
high score 
e for the glo
e for the gl
cale/item re
cale/item re
Data col
Data c


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
41
Subjects will be asked to complete the questionnaire as completely and accurate as possible. The 
average time to complete the questionnaire is around 10to 15 minutes. The reasons for not 
completing the questionnaire will be recorded.
QoL will be assessed at 6 time points:
!
at screening/baseline (within 7 days prior to randomization)
!
after cycle 2 (C3D1)
!
after cycle 4 (C5D1)
!
after cycle 6 (C7D1)
!
after cycle 8 (C9D1)
!
and at time of discontinuation from treatment.
A ± 7 days time window will be allowed.
Compliance & Missing data
During the study compliance will be investigated at each time point. The compliance rate will be 
descriptively compared between the two arms. 
In the case that a subject still on study has not filled in the questionnaire, no more than ± 7 days 
delay is accepted.
The rate of compliance will be assessed after 40, 80, and 120 and 200 subjects enrolled.
Missing data will be reported as recommended in the EORTC scoring manual (Fayers, 2002).
Scales scores: if at least 50% of the items have been answered, the scale scores will be 
calculated according to the standard equations given on the manual (any items with missing 
values will be ignored). In other cases, scores will be set to missing.
Single-item measures: the score will be set to missing.
Statistical considerations
No calculation in terms of sample size will be performed based on changes in QoL.
In the absence of more specific hypothesis, the global score will be used as the primary QoL 
outcome and physical functional score and fatigue item will be used as secondary outcomes.
Expectations are that the global score and the physical functional score are improved by 
lenalidomide. The fatigue item may be worse initially under lenalidomide, but improve in mid 
and long term in responding subjects due to tumor control compared to control arm with shorter 
response duration
A difference of 10 points between the two arms is considered as clinically significant.
Derivation
For all scales, the Raw Score, RS, is the mean of the component items:
&(/*(1(35235,(7$5<,1)250$7,21
The c
The com
o p
m
est
estioionnaire
nair
and 120
nd 120 and
and
the EORT
the EORTC
ve been ans
ve been an
ons given o
ns given 
scores will 
cores wil
ill be set to
l be set t
sample size
ample siz
specific hy
specific h
al funct
functioiona
n
e that the gl
e that the g
The fat
The fatigu
igu
erm
rm i
m n resp
n resp
se duration
e duration
difference o
ifference o
Derivat
Derivatioio
r al


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
42
For functional scales:
For symptom scales / items and Global health status / QoL:
Range is defined as the difference between the maximum possible value of RS and the minimum 
possible value, eg, most items are quoted from 1 to 4, and the range is equal to 3.
13.2.
Analysis of Quality of Life Scales
The EORTC QLQ-C30 will be analyzed using change from baseline and percentage of change 
from baseline according to the functional scores and the recommendations in the EORTC scoring 
manual. Statistical tests could be performed in an exploratory manner.
The EORTC Reference Data Manual will also be used to descriptively check comparability 
between subjects in our trial and with other comparable populations.
Mann-Whitney tests for simple comparison and longitudinal data modeling techniques (ie Proc 
mixed in SAS) will be conducted to analyze QOL scores.
&(/*(1(35235,(7$5<,1)250$7,21
mum
rcentage of
rcentage o
s in the
in the EO
ively check
vely check
tioions.
ns.
al data mod
data mo
s.


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
43
14.
INTERIM ANALYSIS
14.1.
General Information
An independent external Data Monitoring Committee (DMC) will review on an ongoing basis 
safety data throughout the study and efficacy for futility at a pre-defined time point. Specifics are 
outlined in the DMC charter. Summaries of safety information will be prepared for Data 
Monitoring Committee (DMC) review. The first safety analysis will occur after the first 
40 subjects have received at least 2 cycles of treatment or have discontinued prior to completing 
2 cycles.  The second safety analysis, as well as an efficacy analysis for futility, will occur after 
80 subjects complete 2 cycles or withdraw before completing 2 cycles. A third safety analysis 
will occur after 120 subjects complete 2 cycles or withdraw before completing 2 cycles.
After amendment #4, an additional DMC will be added when the first 200 subjects complete 2 
cycles or withdraw before completing 2 cycles.
The futility analysis will be conducted when approximately 80 subjects complete 2 cycles or 
withdraw before completing 2 cycles (around 54 subjects in the lenalidomide arm) on 
investigator and central assessment.
The DMC will conduct an analysis for futility on PFS and ORR. No specific stopping rules will 
be given to the DMC for the PFS; the following rules might be used for ORR.
Based on a 95%CI approach, if the upper bound is below than 20% in the lenalidomide arm, the 
DMC should recommend stopping the trial. 
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leting
leting
ur after 
after 
y analysis
analysis
cycles.
ycles.
bjects comp
bjects comp
bject
e s com
comp
m
lenalido
enal
m
d O
d ORR
RR. No
. N
might
might be u
be u
s below tha
s below th


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
44
Table 9:
Response Percentage and 95% Exact Confidence Interval 
FREQUENCY 
OF RESPONSE
BINOMIAL 
PROPORTION 
P
EXACT LOWER
CL, BINOMIAL
PROPORTIONA
EXACT UPPER
CL, BINOMIAL
PROPORTIONA
1
1.8519
0.04687
9.8915
2
3.7037
0.45173
12.7472
3
5.5556
1.16068
15.3885
4
7.4074
2.05510
17.8933
5
9.2593
3.07528
20.3002
6
11.1111
4.18838
22.6313
7
12.9630
5.37430
24.9012
8
14.8148
6.61976
27.1198
9
16.6667
7.91544
29.2941
10
18.5185
9.25455
31.4297
CI = confidence interval.
a Exact confidence intervals based on the Clopper-Pearson method.
14.2.
Statistical Approaches for Control of Alpha
14.2.1.
Primary Analysis
The sample size increase recommended by the DMC was not supported by any planned interim 
analyses; therefore adjustment for controlling the alpha level was not planned in the original 
protocol and has to be described in this section.
The final level will be  determined using an α-spending function of the O’Brien-Fleming type 
and a new group sequential test procedure will also be used to preserve the type I error following 
method developed by Cui et al. and adapted by Wassmer for time to event endpoints.
Final alpha level:
At the time of the DMC#3, 67 events have been reported on the 128 needed at this time for the 
final analysis. If one interim analysis had been planned at 52% of the information the upper 
boundary for superiority would have been based on an α-spending function of the O’Brien-
Fleming type with overall α = 0.025, one-tailed.  
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7
$7
$7
$7
$7
0$
50
9012
01
25
27.1198
27.1198
)2
1
29.294
29.29
1)
,1
31
3
,1
,1
,1
< ,1
trol of Alp
trol of Alp
ded by the
ded by th
r controllin
r controlli
d in this se
d in this se
 determine
determine
quent
quential 
ial tes
tes
ed by Cui e
ed by Cui 
level:
level:
*(
me of the D
me of the 
analysi
analys s. If
s. 
undary
undary f
y or 
or
f
Fleming ty
Fleming ty


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
45
Table 10:
P-Value for Rejecting Null Hypothesis (Superiority)
P-Value for Rejecting Null Hypothesis (Superiority)
Interim 1 (52%)
0.002
Final
0.024
Note:   « program East Version 4 » (Cytel Statistical Software Company).
New test procedure :
test
LogRank
the
is
LR
events
of
number
observed
the
is
d
where
d
d
LR
d
LR
d
Z
1
2
*
1
1
*
2
2
*
2
∃
∃
%
Estimating the Hazard ratio and the confidence interval :
events
of
number
ected
the
is
where
w
and
w
r
r
d
r
r
d
d
d
w
h
with
h
w
u
h
z
w
k
k
k
k
k
k
k
k
k
k
k
k
k
k
k
k
exp
)
1
1
(
)
)
(
(
exp
1
2
2
1
1
1
1
1
2
1
1
2
1
2
/
1
2
2
1
.
.
.
.
∃
%
%
&
∃
&
∃
%
/
∃
∃
∃
%
∃
%
%
−
−
−
Despite the change in the test statistic the usual KM median will be provided. 
14.2.2.
Interim Analysis 
Formal adjustment is needed as an unplanned sample size reassessment has been made in 
addition to the planned interim analysis for futility.
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nterval :
nterval :
7$
52
52
3
numbe
numb
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ted
r
d
r
k
kr
1
1
1
.
∃
&
∃
change in
change in
.2.2.
.2.
In
In
Formal
ormal a
l
didititi
i


Lenalidomide (CC-5013)
Statistical Analysis Plan. Protocol CC-5013-MCL-002
Celgene 
Confidential and Proprietary
46
15.
REFERENCES
Cheson B, Horning S, Coiffier B, Shipp M, Fisher R, Connors J, et al. Report of an international 
workshop to standardize response criteria for non-Hodgkin's lymphoma. J Clin Oncol.1999; 17: 
1244-53.
Collett, D. Modelling Binary Data. 1991; London: Chapman & Hall. 
Collett, D. Modelling Survival Data in Medical Research Second Edition. 2003; London: 
Chapman & Hall.
Cui L, Hung HMJ, Wang SJ ; Modification of sample size in group sequential clinical trials. 
Biometrics 1999; 55:853-857.
Determann O et al.; European Mantle Cell Lymphoma Network and the German Low Grade 
Lymphoma Study Group.Ki-67 predicts outcome in advanced-stage mantle cell lymphoma 
subjects treated with anti-CD20 immunochemotherapy: results from randomized trials of the 
European MCL Network and the German Low Grade Lymphoma Study Group. Blood. 2008 Feb 
15; 111(4):2385-7.
Fayers PM, Weeden S, Curran D on behalf of the EORTC Quality of Life Study Group.  EORTC 
QLQ-C30 Reference Values.  In:  EORTC, 1998.  ISBN:  2-930064-11-0.
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. 
FDA , May2007 
Hess G, et al., Phase III Study to Evaluate Temsirolimus Compared With Investigator’s Choice 
Therapy for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma. J Clin Oncol 
27:3822-3829.
Klein J.P, Moeschberger ML. Survival Analysis: Techniques for Censored and Truncated Data, 
1997; New York: Springer-Verlag.
Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 
22;317(17):1098 (letter) 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J.  Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16(1):139-44.
Stead ML, Brown JM, Velikova G, Kaasa S, Wisloff F, Child JA, et al.  Development of an 
EORTC questionnaire module to be used in health-related quality-of-life assessment for subjects 
with multiple lymphoma.  European Organization for Research and Treatment of Cancer Study 
Group on Quality of Life.  Br J Haematol 1999 Mar;104(3):605-11.
Wassmer G, Planning and Analyzing Adaptive Group Sequential Survival Trials.  Biometrical 
Journal 48 (2006) 4, 714–729.
Witzig TE, Reeder CB, Polikoff J, et al. Initial Results from an International Study in 
Relapsed/Refractory Aggressive Non-Hodgkin s Lymphoma to Confirm the Activity, Safety and 
Criteria for Predicting Response to Lenalidomide Monotherapy. Blood (ASH Annual Meeting 
Abstracts), Nov 2007; 110: 2572.
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ririals.s. 
n Low Grad
n Low Grad
ell lympho
ell lympho
mized tri
mized trialal
y Group. B
y Group. 
ity y of
of Life S
f
30064-11-
30064-1
pproval o
proval of
olimus Com
olimus Co
actory
ctory Man
Ma
y
Analysis: T
Analysis:
atatioion of Bo
n of B
Myles J, Zee
Myles J, 
f-f life score
life scor
JM, Veliko
JM, Veliko
onnaire mod
onnaire mo
e lympho
lymphom
Qualit
uality y of
of
mer G,
mer G Pl
Plan
urnal
rnal 48 (20
48 (2
l
Wit
W zig TE
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elaps


Lenalidomide (CC-5013)
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16.
APPENDICES
16.1.
Date Imputation Guideline
16.1.1.
Impute Missing AE/ Prior or Concomitant Medications Start Dates
Missing day and month
!
If the year is same as the year of first day on study medication, then the day and month of 
the start date of study medication will be assigned to the missing fields
!
If the year is prior to the year of first day on study medication, then December 31 will be 
assigned to the missing fields.
!
If the year is after the year of first day on study medication, then January 1 will be 
assigned to the missing fields.
Missing day only 
!
If the month and year are same as the year and month of first day on study medication, 
then the start date of study medication will be assigned to the missing day.
!
If the month and year are before the year and month of first day on study medication, 
then the last day of the month will be assigned to the missing day.
!
If the month and year are after the year and month of first day on study medication, then 
the first day of the month will be assigned to the missing day.
!
If the stop date is non-missing and the imputed start date is after the stop date, the start 
date will be imputed by the stop date. 
Missing day, month, and year
Included as TEAE
Incomplete Stop Date: If the imputed stop date is before the start date then the imputed stop date 
will be equal to the start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dose date of 
study medication, then the day and month of the last dose date will be assigned to the 
missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dose date of double-
blind study medication, then December 31 will be assigned to the missing fields. 
!
If the year of the incomplete stop date is after the year of the last dose date of study 
medication, then January 1 will be assigned to the missing fields.
Missing day only 
!
If the month and year of the incomplete stop date are the same as the month and year of 
the last dose date of study medication, then the day of the last dose date will be assigned 
to the missing day. 
!
If the month and year of the incomplete stop date are before the month and year of the 
last dose date of the study medication, then the last day of the month will be assigned to 
the missing day. 
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Lenalidomide (CC-5013)
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Celgene 
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!
If the month and year of the incomplete stop date are after the month and year of the last 
dose date of study medication, then the first day of the month will be assigned to the 
missing day.
16.2.
Cycle Derivation Guideline
Subjects on Rituximab treatment have cycles of 56 days in duration past cycle 1. Cycle 2 day 1 
will in fact correspond to day 56. Programming need to be adapted accordingly.
eCRF 
pages 
completion
C1D1
C2D1
C3D1
C4D1
C5D1
C6D1
C7D1
days on 
study
1
28
56
84
112
140
168
Tumor 
assessment
X
X
X
Rituximab 
cycles
C1D1
C2D1
C3D1
C4D1
A cycle is defined as follows:
A new cycle is defined when the delay between the previous drug start date and the current start 
date is lower or equal to -26.
del <=-26 and del=lag1(SDRSTDT)-SDRSTDT;
If the data do not fulfil the previous condition, a cumulative duration (dur = Σ SDRENDT –
SDRSTDT + 1) is calculated (including the previous record) to take into account the fact that 
several drug modifications could have appeared during one cycle.  If the cumulative duration 
does not exceed 28 days, there is no new cycle.
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Lenalidomide (CC-5013)
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16.3.
Endpoints Derivation
Efficacy evaluation window:
All efficacy assessments will be taken into account if they are occurred after the randomization 
date 
to the end the study, for subjects who do not stop study medication and not start other non 
study anti-cancer therapy;
Best response
Best response is defined as best efficacy benefit response during the “window” for efficacy 
evaluation.
PFS:
PFS = PFS Ending Date – PFS Starting Date + 1
Starting date: the randomization date
Ending date: the earliest date among the following 4 events during the “window” for efficacy 
evaluation:
a. Death;
b. The earlier assessment date for the cycle with overall response is PD or Relapse; 
c. Study discontinue due to Disease progression specified; 
d. Treatment discontinue due to Disease progression specified;
For subjects who have more than 1 consecutive missing regular assessments right before the 
earliest of the four events date and this non-assessed period last more than 118 days (this length is 
study-dependent),  then, the date of last adequate assessment indicating no progression before the 
date will be used, and the PFS will be censored.
If subjects who do not have any of the 4 events listed above, then ending date is defined as the 
latest CT/MRI date for target or non-target lesion that indicating no progression, if subjects do 
not have such response, they will be censored at the day after the randomization date.
Duration of response (DoR)
DoR = Ending Date – Starting Date + 1
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Lenalidomide (CC-5013)
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Starting date: The date of the first occurrence of CR, CRu or PR during the Window for efficacy 
evaluation
Ending date: the earliest date among the following 4 events during the “window” for efficacy 
evaluation:
a. Death;
b. The earlier assessment date for the cycle with overall response is PD or Relapse; 
c. Study discontinue due to Disease progression specified; 
d. Treatment discontinue due to Disease progression specified;
For subjects who have more than 1 consecutive missing regular assessments right before the 
earliest of the four events date and this non-assessed period last more than 118 days,  then, the 
last adequate at least PR or better response assessment date before the date will be used, and the 
DoR will be censored.
If subjects who do not have any of the 4 events listed above, then ending date is defined as the 
latest CT/MRI date for target or non-target lesion with at least PR or better response after the 
DoR start date, if subjects do not have such response, they will be censored at the day after the 
1st response date
16.4.
Laboratory Values
The following calculations need to be performed for all subjects in treatment arms A and B.  The 
lab values will be standardized using the normal range values collected in the eCRF.
Step 1:  Assign an upper (ULN) and lower (LLN) normal range value to each analyte at each visit 
collected by merging the ranges collected in the datasets labrng. Use the labseq variable to assign 
the appropriate normal ranges to a value.
  If the ranges could not be assigned then use the default SI ranges after the conversion of the 
value..
  Convert any raw lab values to the unit that corresponds to the normal range values as necessary.  
These converted (if necessary) or raw (if conversion not needed) lab values and their associated 
ULN and LLN values will be referred to as the “base” values in the calculations given in Step 2. 
Step 2:  Convert all base values (lab, ULN, and LLN values) to the standardized units given 
(please refer to the Data Transfer Guidelines in the data management plan).  The standardized
units are the units associated with the normal ranges to be used for mapping the lab value to a 
standardized value.  Calculations in Step 3 are based on these converted lab and normal range 
values (referred to as converted values). 
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Step 3:  Determine, for each (converted) lab value, if it is within the (converted) normal range 
and assign a flag indicating where the value falls relative to the upper and lower limits of normal 
(eg, low (below lower limit normal), normal, or high (above upper limit normal).
Step 4:  Determine p, the value to be used for mapping the converted lab value to a standardized 
value as follows:
a)  If the converted lab value is within converted normal range then
        
            p = (lab value – LLN value) / (ULN value – LLN value)
b) If the converted lab value is less than converted LLN then
            p = lab value / LLN value
c) If the converted lab value is greater than converted ULN then
            p = lab value / ULN value
Step 5:  Use the value of p calculated in Step 4 and the standardized ULN and LLN values
a)  If the converted lab value is within normal range then
            SLV = p(sULN value – sLLN value) + sLLN
b) If the converted lab value is less than LLN then
            SLV = p( sLLN value)
c) If the converted lab value is greater than ULN then
SLV = p( sULN value)
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Step 6: Use the SLV and the sLLN and sULN to assign the NCI-CTC grade and for summary
statistics in all tables.  
Example calculations for standardizing lab values to the standard normal ranges
Subject X at CxD1 visit:
SGPT = 22 UI/L
Step 1:  normal range
LLN = 7 UI/L
ULN = 40 UI/L
Step 2:
Since the conversion factor for converting UI/L to U/L is 1.0, the converted values associated 
with unit=U/L remain the same as the original values.
converted SGPT = 22 U/L
converted LLN = 7 U/L
converted ULN = 40 U/L
Step 3: 
Value of 22 U/L is within the normal range.
Normal range flag = N
Step 4:  Calculate p for 22 U/L based on formula a):
p = (lab value – LLN value) / (ULN value – LLN value)
   = (22 – 7) / (40 – 7)
   = 15 / 33
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   = 0.45
Step 5:  Calculate SLV for p = 0.45 and sLLN = 6 U/L and sULN = 35 U/L.  
SLV = p(sULN value – sLLN value) + sLLN
        = 0.45(35 – 6) + 6
        = 19.2 U/L
Step 6:  NCI-CTC grade = 0, since the value is within normal limits.