Conditions: B-cell Chronic Lymphocytic Leukemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 317
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if lenalidomide (Revlimid®) is safe and effective as a maintenance therapy at improving further the quality of the response you achieved with your last therapy and at prolonging the duration of your response. This study will compare the effects (good and bad) of lenalidomide with the dummy drug.

Detailed description:
This is a phase 3, randomized (computer assigned by chance to treatment arm), study being completed an multiple sites to compare the safety and efficacy (how well a drug works) of lenalidomide maintenance therapy to placebo (dummy capsule that contains no lenalidomide or active substances) maintenance therapy.

Patients are assigned by a computer with a 50/50 chance to receive placebo or lenalidomide study treatment. Study drug will be taken once each day until the patient discontinues the study. Patients will remain on study drug until progression of disease.

Patients will visit their study doctor every 28 days until disease progression to complete safety and efficacy assessments. Quality of life assessments will be completed every other month. If a patient who discontinue study drug prior to disease progression (i.e. due to an adverse reaction to the study drug), they will continue to visit the study doctor each month to complete the efficacy assessments up to progression of disease. Safety assessments may include laboratory blood tests, ECG tests and questions about any medical conditions or side effects experienced during the study. Efficacy assessments may include laboratory blood tests and focused physical exams.

Computed tomography (CT) scans along with blood tests and bone marrow samples will be collected to confirm if a patient has improvement of response while on study.

After disease progression, patients will be contacted every 12 weeks for survival information, next CLL treatments and quality of life questions.

Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment immediately and complete the Treatment Discontinuation assessment. The subjects will then transition to the survival follow-up period.

Arms:
arm 1: Lenalidomide po qd on days 1-28 of a 28 day cycle arm 2: Placebo capsules given orally on days 1-28 of a 28 day cycle

Interventions: intervention 1: Lenalidomide intervention 2: Placebo
Intervention descriptions: intervention 1: Lenalidomide capsules given orally on days 1-28 of a 28 day cycle intervention 2: Placebo capsules given orally on days 1 - 28 of a 28 day cycle

Protocol document:
Prot_000.pdf: 
Lenalidomide (CC-5013) 
Protocol CC-5013-CLL-002 
 
Celgene Corporation 
Confidential and Proprietary 
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TITLE PAGE 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP 
STUDY OF THE EFFICACY AND SAFETY OF 
LENALIDOMIDE (REVLIMID®) AS MAINTENANCE 
THERAPY FOR PATIENTS WITH B-CELL CHRONIC 
LYMPHOCYTIC LEUKEMIA FOLLOWING SECOND-
LINE THERAPY  
(THE CONTINUUM TRIAL) 
STUDY DRUG: 
 Lenalidomide 
PROTOCOL NUMBER: 
 CC-5013-CLL-002 
EUDRACT NUMBER: 
 2007-001626-27 
DATE FINAL: 
 15 January 2008 
AMENDMENT #11: 
 16 March 2018 
 
 
 
              
 
 
 
 
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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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Original Protocol:  15 January 2008 
Amendment #1:  12 August 2008 
Amendment #2:  23 September 2008 
Amendment #3:  17 October 2008 
Amendment #4:  6 May 2009 
Amendment #5:  28 June 2010  
Amendment #6:  4 May 2011 
Amendment #7:  7 October 2011 
Amendment #8:  4 October 2012 
Amendment #9:  24 April 2015 
Amendment #10:  13 May 2016 
Amendment #11:  16 March 2018 
 
 
 


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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Original Protocol:  15 January 2008 
Amendment #1:  12 August 2008 
Amendment #2:  23 September 2008 
Amendment #3:  17 October 2008 
Amendment #4:  6 May 2009 
Amendment #5:  28 June 2010 
Amendment #6:  4 May 2011 
Amendment #7:  7 October 2011 
Amendment #8:  4 October 2012 
Amendment #9:  24 April 2015 
Amendment #10:  13 May 2016 
Amendment #11:  16 March 2018 
 
 
 
 
 
 


Lenalidomide (CC-5013) 
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Lenalidomide (CC-5013) 
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Lenalidomide (CC-5013) 
Protocol CC-5013-CLL-002 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company:  Celgene Corporation 
Name of Investigational Product:  lenalidomide 
Protocol Number:  CC-5013-CLL-002 
Protocol Title:  A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP STUDY OF THE EFFICACY AND 
SAFETY OF LENALIDOMIDE (REVLIMID®) AS MAINTENANCE THERAPY FOR 
PATIENTS WITH B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA FOLLOWING 
SECOND-LINE THERAPY 
Indication: Maintenance therapy in subjects with relapsed or refractory B-cell chronic 
lymphocytic leukemia (CLL) who have achieved at least partial response (PR) to second-line 
therapy. 
Study Duration:  Subjects randomized to the lenalidomide 
treatment arm and on treatment at the time of Amendment #10 
may, at the discretion of the investigator, continue on 
lenalidomide study treatment until disease progression (PD) 
develops.  Subjects randomized to the placebo treatment arm 
and on treatment at the time of Amendment #10 will enter the 
survival follow-up period.  Subjects who discontinue study 
treatment prematurely for reasons other than PD and subjects 
who develop PD (including disease transformation) will enter 
the survival follow-up period.   
Subjects will be followed until all subjects in the study have 
been followed for at least 5 years from the last randomization, 
October 2020, (or have died/become lost to follow-up before 
the 5 years).  
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue 
lenalidomide treatment immediately and complete the 
Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
Phase of development:  
Phase 3 
Objectives:  
Primary:  
x 
To compare the efficacy of lenalidomide versus placebo maintenance therapy. 
Secondary: 
x 
To evaluate the safety of lenalidomide versus placebo maintenance therapy. 
Study Endpoints: 
Primary 
x 
Overall Survival (OS) 


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Secondary 
x 
Safety [type, frequency, and severity of adverse events (AEs) and relationship of AEs 
to lenalidomide] 
x 
Progression-free survival 2 (PFS2) 
 
 
 
 
 
Study Design: 
CC-5013-CLL-002 is a phase 3, multicenter, randomized, placebo-controlled, parallel-group 
study that will compare the efficacy and safety of oral lenalidomide maintenance therapy to 
that of placebo in patients with B-cell CLL who achieved at least partial response (PR) with 
second-line therapy.  The primary efficacy objective of this study is to demonstrate superiority 
of lenalidomide over placebo in prolonging overall survival (OS) due to continued therapy, for 
all subjects, including subjects with or without poor prognostic factors, subjects of various ages 
and subjects with PR, nodular partial response (nPR), complete response with incomplete bone 
marrow recovery (CRi), complete response (CR) and minimal residual disease (MRD)-
negative CR.  All subjects randomized to the lenalidomide treatment arm, including those 
subjects who do not improve their response (PR, nPR, CRi or CR) and subjects who do not 
have the opportunity to improve their response further (MRD-negative CR) will be treated up 
to disease progression, with the objective to demonstrate prolongation of OS. 
Eligible subjects must have been treated with a purine analog-, a bendamustine-, an anti-CD20-
antibody-, or a chlorambucil-based regimen in first and/or second line and must have achieved 
at least PR to second-line induction therapy of sufficient duration.  Alemtuzumab- containing 
regimens will also be allowed for those subjects with 17p deletion.  Subjects who achieve 
stable disease (SD) only or who develop progressive disease (PD) at any time during induction 
therapy will not be eligible for participation in this study. 
Approximately, three hundred twenty (320) subjects with PR, nPR, CRi, CR or MRD-negative 
CR will be enrolled and randomized (1:1) into two arms:  placebo daily or lenalidomide 2.5 mg 
daily on days 1-28 of the first 28-day cycle.  If the 2.5 mg dose level is well tolerated, 
escalation to 5 mg daily on days 1-28 of each 28-day cycle is permitted starting with the 
second cycle; for those subjects who tolerate well the 5 mg dose, escalation to 10 mg daily on 
days 1-28 of each 28-day cycle after 5 continuous cycles at 5 mg will be permitted. 
Each treatment arm will be stratified according to 1) the response to second-line induction 
therapy (PR, nPR, CRi or CR versus MRD-negative CR); 2DJHYHUVXV!\HDUVDQG
3) presence of at least one of the following poor prognostic factors:  11q deletion, 17p deletion, 
unmutated IgVH or ȕ0!PJ/ (Yes versus No versus Unknown). 
The subjects randomized to the lenalidomide treatment arm will continue to receive 
lenalidomide study drug up to PD.  Subjects who discontinue therapy, will enter the survival 
follow-up phase of the study.  Subjects will be assessed for subsequent CLL therapies, second 
primary malignancies, recovery from serious adverse events (SAEs), and any new SAEs or 
AEs related to study procedures or prior maintenance therapy.   
Subjects randomized to the placebo arm and currently on treatment at the time of Amendment 
#10 and patients who previously discontinued from the study drug and will be followed every 
24 weeks for survival, subsequent CLL therapies, response to next therapy and progression 


Lenalidomide (CC-5013) 
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following next therapy, and second primary malignancies.  Subjects will be followed until all 
subjects in the study have been followed for at least 5 years from the last randomization, 
October 2020 (or have died/become lost to follow-up before 5 years).  
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
Screening 
Subjects will sign informed consent prior to undergoing any study-related procedures. 
Screening assessments for protocol eligibility will be performed within 28 days prior to 
randomization as outlined in Table 2: Schedule of Assessments.  Subjects who develop PD 
during screening will not be eligible to enroll into this study. 
All subjects will undergo both bone marrow aspirate and bone marrow biopsy procedures 
during screening.  MRD status will be assessed by peripheral blood and bone marrow flow 
cytometry at entry into the study for those subjects who achieved a complete response (CR) to 
second-line induction therapy.  Peripheral blood flow cytometry will be performed for all 
subjects at entry to confirm disease diagnosis by immunophenotyping and to perform immune 
cell (NK and T cell) analyses.  If subjects enter the study with MRD negativity, the disease 
diagnosis will be confirmed based on prior flow cytometry (documentation needed).  MRD 
status, immunophenotyping, and immune cell analyses will be performed at a central 
laboratory.   
A peripheral blood sample for direct antiglobulin test (DAT) will be collected during screening 
and analyzed at a central laboratory. 
Before randomization, subjects will be tested for cytogenetics by FISH, IgVH mutational status, 
DQGȕ07KHȕ0WHVWZLOOEHSHUIRUPHGGXULQJVFUHHQLQJXVLQJDSHULSKHUDOEORRGVDPSOH 
and analyzed at a central laboratory. 
FISH and IgVH testing will be performed prior to second line, during second line, in the 
interval between second-line therapy, and screening or during the screening period using a 
peripheral blood sample.  Because test results cannot be obtained during screening or between 
second line and screening in some subjects who achieve a good response due to the limited 
number of remaining CLL cells, we recommend conducting the FISH and IgVH tests preferably 
prior to second line or during second line.   
Samples for FISH and IgVH will be analyzed at a central laboratory. 
If tests do not yield results, subjects can be randomized and stratified based on historical data. 
Those subjects for whom results were not obtainable pre-randomization and for whom no 
historical data were available will be enrolled and grouped separately. 
During screening, CT scans of the chest, abdomen and pelvis will also be performed for all 
subjects; in particular, they will be used to document the status (PR or CR) of subjects entering 
the study.   
If, during the screening period, the subject has a correctable event that prevents randomization 
and the event cannot be corrected within the 28 day screening period, the subject may be re-
screened; however, the CT scans and bone marrow aspirate and biopsy will not need to be 
repeated if those tests were implemented within 56 days prior to randomization and the 
subject’s clinical status remains the same. 
Randomization 


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Randomization must occur no less than 8 weeks (56 days) and no greater than 20 weeks (140 
days) from the last day of the last cycle of second-line induction therapy received by the 
subject in order for the subject to be eligible for enrollment into this study.  Subjects meeting 
all eligibility criteria will be randomized (1:1) in a double-blind manner to receive maintenance 
therapy with either lenalidomide or placebo up to disease progression.  The randomization 
procedure will be accomplished by a validated interactive voice response system (IVRS).  
Subjects will be stratified at randomization by: 1) their response to second-line induction 
therapy (PR, nPR, CRi or CR versus MRD-negative CR); 2) age (YHUVXV!\HDUVDQG
3) presence of at least one of the following poor prognostic factors:  11q deletion, 17p deletion, 
unmutated IgVH or ȕ0!PJ/ (Yes versus No versus Unknown).   
Maintenance Therapy 
Study treatment for each subject begins on the same day the subject undergoes randomization.  
Study visits and serial measurements of safety and efficacy during maintenance therapy will be 
performed as outlined in Table 2.  Lenalidomide is administered orally.  Subjects will receive 
lenalidomide 2.5 mg once daily on Days 1 through 28 of the first 28-day cycle.  If the 2.5 mg 
dose is well tolerated (subject does not experience any Grade 3 or 4 study drug-related 
toxicities or any other toxicity [Grade 1 or 2] found to be unacceptable by the investigator or 
the subject), subjects should be escalated starting at the second cycle to 5 mg once daily on 
Days 1 through 28 of each 28-day cycle up to disease.  If a subject develops a Grade 1 or 2 
adverse event, the drug may be interrupted until resolution, however the subject must complete 
one full cycle at the 2.5 mg dose level prior to escalation to the 5 mg dose level. 
Subjects who complete 5 continuous cycles at the 5 mg dose level without experiencing any 
Grade 3 or 4 study drug-related toxicities and without experiencing any other toxicity (Grade 1 
or 2) found to be unacceptable by the investigator may be escalated to 10 mg once daily on 
Days 1 through 28 of each 28-day cycle up to disease progression. 
Dose interruptions/reductions are permitted for Grade 1 or 2 adverse events at the 
investigator’s discretion.  A guideline for the reduction of the dose of lenalidomide for dose-
limiting toxicity (DLT) is provided (see Section 10.2.1).  Dose re-escalation is permitted if the 
subject is able to complete 2 full cycles at the reduced dose level without experiencing a DLT 
or other toxicity deemed to be unacceptable by the investigator or subject.  In the event the 
dose reduction is implemented due to Grade 4 neutropenia, subjects may be re-escalated after 
one full cycle at the lower dose level if the neutropenia resolves to a Grade 2 or better by the 
end of the cycle and no other DLT is observed.  If that dose level is again not tolerated, the 
subject should be de-escalated to the dose below and remain at that tolerated dose level for the 
rest of the study. 
Subjects randomized to the lenalidomide treatment arm will continue to receive study 
lenalidomide maintenance therapy until PD develops.  Progressive disease is characterized by 
at least one of the following: 
x 
Lymphadenopathy.  Progression of lymphadenopathy discovered by physical 
examination.  Disease progression occurs if one of the following events is 
observed: 
- Appearance of any new lesion such as HQODUJHGO\PSKQRGHV!FP
splenomegaly, hepatomegaly or other organ infiltrates. 
- An increase by 50% or more in greatest determined diameter of any previous 
site.   


Lenalidomide (CC-5013) 
Protocol CC-5013-CLL-002 
 
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x 
An increase in the previously noted enlargement of the liver or spleen by 50% or 
more or the de novo appearance of hepatomegaly or splenomegaly. 
x 
An increase in the number of blood lymphocytes by 50% or more with at least 
%O\PSKRF\WHVSHUȝ/ 
x 
Transformation to a more aggressive histology (eg, Richter’s syndrome).  
Whenever possible, this diagnosis should be established by lymph node biopsy. 
x 
Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to 
CLL 
x 
During therapy:  cytopenias may occur as a side effect of many therapies and 
should be assessed according to Table 4.  During therapy, cytopenias cannot be 
used to define disease progression. 
x 
Post treatment:  The progression of any cytopenia (unrelated to autoimmune 
cytopenia), as documented by a decrease of hemoglobin levels by more than 2 
g/dL or to less than 10 g/dL, or by a decrease of platelet counts by more than 50% 
or to less than 100,000/ȝ/ZKLFKRFFXUVDWOHDVWPRQWKVDIWHUWUHDWPHQWGHILQHV
disease progression, if the marrow biopsy demonstrates an infiltrate of clonal CLL 
cells. 
Tumor response, including PD, will be assessed according to the International Workshop on 
Chronic Lymphocytic Leukemia (IWCLL) guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia (
  The severity of AEs will be graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 3.0 with modifications as noted in Section 10.2.1 of the protocol. 
Local hematology and chemistry tests will be performed for patient management/treatment 
decisions. 
Bone marrow aspirate and biopsy specimens obtained from each subject will be reviewed 
centrally prior to randomization. All repeat bone marrow aspirate and biopsy assessment will 
be completed at the discretion of the investigators and assessed locally.  The bone marrow 
aspirate and biopsy assessment is removed as part of protocol amendment #10.   
The CT scans of the chest, abdomen and pelvis will be performed for all subjects at baseline.  
All repeat CT scan assessment will be completed at the discretion of the investigator and 
assessed locally.  The CT scan assessment is removed as part of protocol amendment #10.  
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
 
Prophylaxis for Tumor Lysis Syndrome (TLS), thromboembolism and infection and treatment 
of tumor flare reaction (TFR) 
TLS prophylaxis, comprising of oral hydration and allopurinol 300 mg/day will be initiated 3 
days prior to starting maintenance therapy and for a minimum of the first treatment cycle at 
each dose level for those subjects entering the study with a PR to their second-line induction 
therapy.  Subjects with a known allergy to allopurinol and a PR will be excluded from 
the study.  Please refer to Section 10.2.1 for further guidance on allopurinol modification in 
the event of an adverse event.  If a subject is taking allopurinol for a condition other than for 
TLS prophylaxis, the subject should be continued on the allopurinol prescribed by their 


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physician and the dose titrated to 300 mg/day.  If, at any time, the allopurinol being taken for 
reasons other than TLS prophylaxis is discontinued and prophylaxis is still required per 
protocol, the subject should be administered commercial allopurinol.  To maintain fluid intake, 
subjects must be instructed to drink 8 to 10 eight ounce (240 mL) glasses of water each day for 
the first 14 days of Cycle 1 and the first cycle of each dose escalation.  Hydration levels should 
be adjusted according to age and clinical status, and lowered if the subject’s cardiovascular 
status indicates the possibility of volume overload.  At the investigator’s discretion, allopurinol 
prophylaxis may be omitted for subjects entering the study with a CR; however subjects must 
be advised of the need for adequate hydration as outlined above. 
Grade 1 TFR may be treated with non-steroidal anti-inflammatory drugs (NSAIDs) (ie, 
ibuprofen 400-600 mg orally every 4-KRXUVDVQHHGHGDQG7)5*UDGHVKRXOGEHWUHDWHG
with corticosteroids.  Narcotic analgesics may be added as needed for pain control in subjects 
H[SHULHQFLQJ*UDGHWXPRUIODUH 
Subjects will be monitored for TLS and TFR on Days 1, 8 and 15 for cycle 1.  Monitoring for 
TLS and TFR will continue on every 28 days thereafter and as clinically indicated. 
It is recommended that subjects receive low dose aspirin (75 mg to 100 mg) as prophylactic 
anti-thrombotic treatment while on study drug, however the use of aspirin should only be 
implemented after careful evaluation of the hemorrhagic risk and determination that the subject 
is at limited risk.  The investigator may use other anti-coagulation prophylactic therapies (ie, 
low-molecular weight (LMW) heparin, warfarin, etc.) at their discretion based on the subjects 
pre-disposing risk factors for thromboembolism (ie, subjects with a history of a 
thromboembolic event and/or taking a concomitant medication associated with an increased 
risk for a thromboembolic event and/or known hypercoagulable state regardless of 
thromboembolic history). 
$VSLULQVKRXOGEHLQWHUUXSWHGLIWKHSODWHOHWFRXQWGURSVEHORZȝ/ 
Prophylactic antibiotics should be considered in patients with neutropenia.  In addition, 
subjects who were on prophylactic treatment for infection while on alemtuzumab therapy 
should continue prophylactic treatment for at least 6 months following the discontinuation of 
alemtuzumab therapy and can be enrolled into the study while continuing prophylactic therapy.  
Subjects with an active infection requiring systemic antibiotics and subjects with a systemic 
LQIHFWLRQWKDWKDVQRWUHVROYHG!PRQWKVSULRUWRLQLWLDWLQJOHQDOLGRPLGHWUHDWPHQWLQVSLWHRI
adequate anti-infective therapy are excluded from entering the study. 
Treatment and Dose Modification for Tumor Lysis Syndrome (TLS) 
SubjectVPHHWLQJFULWHULDRIODERUDWRU\7/6RU*UDGH7/6DFFRUGLQJWRWKH&DLUR-Bishop 
definition and grading system should be treated as follows: 
x 
6XEMHFWVPXVWEHKRVSLWDOL]HGIRU*UDGH7/6)RUODERUDWRU\7/6KRVSLWDOL]DWLRQ
is left to the investigator’s discretion. 
x 
The following should be provided:  vigorous hydration and appropriate therapy (ie, 
rasburicase where available) as needed to reduce hyperuricemia, until correction of 
electrolyte abnormalities. 
x 
In cases of laboratory TLS and Grade 1 TLS, lenalidomide will be continued at the 
same dose without interruption or dose reduction.  Dose escalation to the next 
consecutive dose level will be permitted when laboratory TLS is resolved and Grade 1 
TLS is resolved to Grade 0. 
x 
SubjectVZLWK*UDGH7/6ZLOOKDYHWKHLUGRVHLQWHUUXSWHGDQGZLOOUHVXPH
lenalidomide at the next lower dose when electrolyte abnormalities are corrected (ie, 
Grade 0) as specified in the Dose Modification and Interruption section of the protocol.  


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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. 
x 
When those subjects that have been dose reduced complete two full cycles without 
PHHWLQJFULWHULDIRUODERUDWRU\7/6RU*UDGH7/6RUH[SHULHQFLQJWR[LFLWLHVUH-
escalation to their maximum dose level or to the next higher dose level is permitted. 
A total of 320 subjects will be enrolled (160 subjects/treatment arm) in order to detect a 61.3% 
improvement (hazard ratio of 0.62) in median OS and PFS in the lenalidomide treatment group 
compared to placebo-treated subjects with 80% statistical power (see Section 16).  Enrollment 
will close once 320 subjects are randomized or 160 adjudicated PFS events are reached, 
whichever comes first. 
Please refer to Figure 1 for an overall summary of the study design. 
Analysis and Reporting: 
The final analysis on OS will be performed and reported when 160 subjects have died (ie, 
when full information necessary to have 80% power for OS is achieved). 
Data Monitoring Committee 
An external independent Data Monitoring Committee will evaluate safety and efficacy data in 
an ongoing, periodic manner to assess benefit-to-risk considerations.  Since the study will be 
unblinded, the Data Monitoring Committee will not be utilized beginning with protocol 
amendment #10.  Safety reviews will be performed by Celgene annually for the remainder of 
the study. 
Response Adjudication Committee 
An independent Response Adjudication Committee will perform a blinded, independent 
assessment of response (including the development of PD) prior to the interim analysis 
database lock. Since the placebo arm is discontinued, the Response Adjudication Committee 
will not be utilized beginning with protocol amendment #10. 
Number of planned subjects: 320 (160 subjects per treatment arm) 
Enrollment will close once 320 subjects are randomized or 160 adjudicated PFS events are 
reached, whichever comes first. 
Study Population  
Key Inclusion Criteria 
1. Must understand and voluntarily sign an informed consent form. 
2. $JH\HDUVDWWKHWLPHof signing the informed consent form. 
3. Must be able to adhere to the study visit schedule and other protocol requirements. 
4. Must have a documented diagnosis of B-cell CLL (IWCLL guidelines for the diagnosis 
and treatment of chronic lymphocytic leukemia, 
 
5. Must have been treated with one of the following in first and/or second line: 
x 
a purine analog-containing regimen 
x 
a bendamustine-containing regimen  
x 
an anti-CD20 antibody-containing regimen 


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x 
a chlorambucil-containing regimen 
x an alemtuzumab-containing regimen (for those subjects with a 17p deletion) 
6. Must have achieved a minimum response of partial response (PR, nPR, CRi, CR, and 
MRD-negative CR) (IWCLL guidelines for the diagnosis and treatment of chronic 
lymphocytic 
 Appendix 22.4) following completion of 
second-line induction therapy prior to randomization (documentation of response 
status must be available).  Second-line induction therapy must be documented to have 
been of sufficient duration. 
7. Must have completed last cycle of second-line induction no less than 8 weeks (56 
days) and no greater than 20 weeks (140 days) prior to randomization. 
8. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score 
RI 
9. Females of childbearing potential (FCBP)† must: 
x 
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 22.6). This applies 
even if the subject practices complete and continued sexual abstinence. 
x 
Either commit to continued abstinence from heterosexual contact (which must be 
reviewed on a monthly basis) or agree to use, and be able to comply with, effective 
contraception without interruption, 28 days prior to starting study drug, during the 
study therapy (including dose interruptions), and for 28 days after discontinuation 
of study therapy, (see specifics in Appendix 22.6). 
10. Male subjects must: 
x 
Commit to continued abstinence from heterosexual contact or 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 22.6). 
x 
Agree to not donate semen during study drug therapy and for a period after end of 
study drug therapy (see specifics in Appendix 22.6). 
11. All subjects must: 
x 
Have an understanding that the study drug could have a potential teratogenic risk. 
x 
Agree to abstain from donating blood while taking study drug therapy and 
following discontinuation of study drug therapy (See specifics in Appendix 22.6). 
x 
Agree not to share study medication with another person. 
x 
All subjects must be counseled about pregnancy precautions and risks of fetal 
exposure (See Appendix 22.6). 
 
 
† Definition found in appendices 
 


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Key Exclusion Criteria 
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study. 
2. Active infections requiring systemic antibiotics. 
3. 6\VWHPLFLQIHFWLRQWKDWKDVQRWUHVROYHG!PRQWKVSULRUWRLQLWLDWLQJOHQDOLGRPLGH
treatment in spite of adequate anti-infective therapy 
4. Autologous or allogeneic bone marrow transplant as second-line therapy. 
5. Pregnant or lactating females. 
6. Systemic treatment for B-cell CLL in the interval between completing the last cycle of 
second-line induction therapy and randomization. 
7. Participation in any clinical study or having taken any investigational therapy for a 
disease other than CLL within 28 days prior to initiating maintenance therapy. 
8. Known presence of alcohol and/or drug abuse. 
9. Central nervous system (CNS) involvement as documented by spinal fluid cytology or 
imaging.  Subjects who have signs or symptoms suggestive of leukemic meningitis or a 
history of leukemic meningitis must have a lumbar puncture procedure performed 
within two weeks prior to randomization. 
10. Prior history of malignancies, other than CLL, unless the subject has been free of the 
GLVHDVHIRU5 years.  Exceptions include the following: 
x 
Basal cell carcinoma of the skin 
x 
Squamous cell carcinoma of the skin 
x 
Carcinoma in situ of the cervix 
x 
Carcinoma in situ of the breast 
x 
Incidental histologic finding of prostate cancer (tumor-nodes-metastasis [TNM] 
stage of T1a or T1b) 
11. History of renal failure requiring dialysis. 
12. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) 
and/or active Hepatitis C Virus (HCV) infection. 
13. Prior therapy with lenalidomide. 
14. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (Appendix 22.5) 
(subjects may be enrolled upon correction of electrolyte abnormalities). 
15. Any of the following laboratory abnormalities: 
x 
Calculated (method of Cockroft-Gault) creatinine clearance of <60 mL/min 
x 
Absolute neutrophil count (ANC) < 1ȝ/1.0 X 109/L) 
x 
Platelet count < 50ȝ/50 X 109/L) 
x 
Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase 
(SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase 
6*37![XSSHUOLPLWRIQRUPDO8/1 
x 
6HUXPWRWDOELOLUXELQ!PJG/ (with the exception of Gilbert’s Syndrome) 
16. Grade 4 rash due to prior thalidomide treatment. 
17. Uncontrolled hyperthyroidism or hypothyroidism. 
18. Venous thromboembolism within one year. 


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19. *UDGH-2 neuropathy. 
20. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia. 
21. Disease transformation (active) (ie, Richter’s Syndrome, prolymphocytic leukemia). 
22. Known allergy to allopurinol for subjects assessed with PR following their second-line 
induction therapy. 
23. Prisoners. 
24. More than 2 prior lines of CLL therapy. 
Investigational product, dosage and mode of administration:  Celgene Corporation will 
supply lenalidomide 2.5 mg, 5 mg, and 10 mg capsules  for oral administration.  Subjects dose 
reduced to 7.5 mg dose level (as outlined in Section 10.2.1) will receive one 5.0 mg capsule 
and one 2.5 mg capsule daily. 
Study drug will be packaged in bottles containing study capsules for 28 days.  
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately.   Celgene will discontinue supply of lenalidomide as a part of Protocol 
Amendment #11.   


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Assessments: 
Efficacy: 
x 
Survival/Date of death 
Safety: 
x 
Clinical laboratory evaluations 
x 
Pregnancy testing 
 
 
x 
AEs by NCI CTCAE Version 3.0, with modifications recommended by the 
IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic 
 (Appendix 22.4) 
x 
Second primary malignancies will be monitored as events of interest and should be 
included as part of the assessment of adverse events throughout the course of the 
study.  Investigators are to report any second primary malignancies as serious 
adverse events regardless of causal relationship to 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 survival follow-up phase  
 
 
 
 
 
 
Statistical Analysis: 
Overview: 
The objective of the statistical analysis will be to compare the efficacy and safety of 
lenalidomide versus placebo as maintenance therapy in subjects with relapsed or refractory B-
cell chronic lymphocytic leukemia (CLL) having achieved PR or better after second-line 
therapy. 
Overall Survival (OS) will be the primary endpoint for the study following protocol 
amendment #10. 
Sample Size: 
For OS, a 61.3% improvement in median survival from randomization, from 3 years for 
placebo to 4.84 years on lenalidomide is considered clinically relevant.  The OS distribution is 
assumed to be exponential with a constant failure (hazard) rate.  At the conclusion of the study 
a two-sided log-rank test with an overall significance level of 0.025 would have 80% power to 
detect a hazard rate ratio of 0.62. To ensure timely completion of the study, 320 subjects will 
be enrolled, 160 in each treatment arm.  Enrollment will close once 320 subjects are 
randomized or 160 adjudicated PFS events are reached, whichever comes first. 
Demographic, Disposition, Study Medication:   
The baseline characteristics of subjects enrolled in each arm will be summarized.  An 
accounting will be made of the study course for all subjects who received study drug for each 
arm and, in particular, the number of subjects who expired or withdrew during treatment will 
be specified and reasons for withdrawal categorized.  
Efficacy Analysis: 
Efficacy analyses will be performed on the intent-to-treat (ITT) population that includes all 
subjects randomized.  


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Overall Survival (OS) will be the primary endpoint for the study following protocol 
amendment #10. 
 
 
  
Safety Analysis: 
All subjects who receive at least 1 dose of study medication will be included in the safety 
analyses. AEs, clinical laboratory information, 
 will be tabulated 
and summarized.  Subject incidence rates of all AEs (including serious, Grade 3, Grade 4, 
treatment-related [with and without discontinuation] and events requiring the discontinuation 
of investigational product), will be tabulated by system class, preferred term, and severity using 
Medical Dictionary for Regulatory Activities (MedDRA) terms and NCI CTCAE Version 3.0 
severity grades with modifications. (Section 10.2.1).  Time to first dose reduction will be 
summarized.  The adverse event of infection will also be analyzed according to the grading 
system as recommended by the IWCLL guidelines for the diagnosis and treatment of CLL 
(Appendix 22.4). 
Death and clinically important AEs (including tumor flare, tumor lysis, second primary 
malignancies, and thrombosis) will also be summarized. 
All other measurements will be summarized using means, standard deviations, medians, 
minimum, and maximum.  Graphical displays will be provided where useful in the 
interpretation of results. 
 


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Table 2: 
Schedule of Assessments 
 
Maintenance Therapy 
After Treatment Discontinuation 
Procedurea 
Screening < 28 days 
prior to Day 1 
Study Day 1 
Every 28 days  
(4 weeks) 
Tx discontinuation 
Survival Follow-up:b 
Every 24 weeks 
(+/- 7 days) 
ICF/Inclusion/Exclusion 
X 
-- 
-- 
-- 
-- 
Medical history 
X 
-- 
-- 
-- 
-- 
Pregnancy testc 
Xc 
-- 
Xc 
Xc 
-- 
Pregnancy and risks counselingd 
Xd 
Xd 
Xd 
Xd 
-- 
ECOG Performance Status 
X 
X 
-- 
X 
-- 
Evaluation of constitutional 
symptoms 
X 
X 
-- 
X 
-- 
Physical examination to assess 
lymphadenopathies, spleen, and 
livere 
X 
X 
-- 
X 
-- 
Vital signs including weightf 
X 
X 
-- 
X 
-- 
Hematologyg 
X 
X 
X 
X 
-- 
Chemistryh 
X 
X 
X 
X 
-- 
Calculated creatinine clearance 
(method of Cockroft-Gault) 
X 
-- 
-- 
-- 
-- 
 
 
 
 
 
 
Direct Antiglobulin Test (DAT)j 
X 
-- 
-- 
-- 
-- 
ECG (12 lead)k 
X 
X 
-- 
X 
-- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2 
Schedule of Assessments (Continued) 
 
Maintenance Therapy 
After Treatment Discontinuation 
Procedurea 
Screening <28 days 
prior to Day 1 
Study Day 1 
Every 28 days  
(4 weeks) 
Tx discontinuation 
Survival Follow-up:b 
Every 24 weeks 
(+/- 7 days) 
Tumor lysis monitoring and 
prophylaxis (allopurinol 
administration) and tumor flare 
reaction monitoringn 
X 
X 
X 
-- 
-- 
Study drug administrationo 
-- 
X 
X 
-- 
-- 
Adverse eventsb,p 
X 
X 
X 
X 
-- 
Assessment of Second Primary 
Malignanciesq 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Assessment of responser 
-- 
-- 
X 
X 
-- 
Survivalb 
-- 
-- 
-- 
-- 
X 
 
ALC = absolute lymphocyte count; ANC = absolute neutrophil count; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CLL = chronic 
lymphocytic leukemia; CR = complete response; CRi = complete response with incomplete bone marrow recovery; CRF = case report form; CT = computed 
tomography; DAT = direct antiglobulin test; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group;  FISH = fluorescence in-situ 
hybridization; HCT = hematocrit; HGB = hemoglobin; ICF = informed consent form; NK = natural killer; nPR = nodular partial response; PD = progressive 
disease; PR = partial response; SAE = serious adverse event; WBC = white blood cell; ZAP-70 = Zeta-chain Associated Protein kinase 70 
a All study procedures should be performed within ± 3 days of the scheduled visit unless otherwise stated. 
b Subjects who discontinued from the study drug will be followed for survival, subsequent CLL therapies, response to next therapy and progression following 
next therapy, and second primary malignancies at each of these visits.  Subjects will be followed until all subjects in the study have been followed for at least 5 
years from last subject randomized, October 2020, (or have died/become lost to follow-up before 5 years). 
c Females of childbearing potential (FCBP) must have a medically supervised pregnancy test (serum or urine with sensitivity of at least 25 mIU/mL).  FCBP 
must have 2 negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting study drug. The first pregnancy test must be performed within 10 to 
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 (see Appendix 22.6).  For additional information on 
the frequency and schedule of pregnancy testing, see the document entitles “Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods” in Appendix 22.6.  For requirements regarding: 1) counselling and education of patients, including the reading of 


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the “Lenalidomide Information Sheet” by the patient; 2) reliable contraception methods; and 3) retention of Risk Management Plan documents 
concerning the pregnancy prevention program, see Appendix 22.6. 
d All male and FCBP patients must be counselled about pregnancy precautions and risks of fetal exposure.  All patients must also be counselled against sharing 
study drug and donating blood during and within 28 days of discontinuing study drug (see Appendix 22.6. for frequency). 
e Physical examination of lymphadenopathies, the spleen and liver will be performed at screening, Study Day 1, and at the treatment discontinuation visit.  
Lymph node evaluation will record the diameter, in two dimensions, of the largest palpable nodes in each of the following sites: cervical, axillary, 
supraclavicular, inguinal, and femoral. 
f Vital signs include:  temperature, pulse, blood pressure, weight, and height (height to be measured at baseline only) 
g Hematology includes WBC, HGB, HCT, platelet count, ANC, and ALC. 
h Chemistry includes potassium, calcium, phosphorus, creatinine, alkaline phosphatase, total bilirubin, AST/SGOT, ALT/SGPT, and uric acid. 
 
.  
j DAT (direct antiglobulin test) will be performed at screening and analyzed at the central laboratory.  The DAT test must be repeated if the investigator suspects 
haemolytic anemia during the course of the study. 
k ECG will be performed at baseline and at treatment discontinuation and interpreted locally. 
 
  
  
n Tumor lysis prophylaxis, consisting of oral hydration and allopurinol 300 mg/day, will be administered for 3 days prior to starting treatment and for at least 
the first cycle of each dose level. At the investigator’s discretion, allopurinol prophylaxis may be omitted for subjects entering the study with a CR; however 
subjects must be advised of the need for adequate hydration. 
o Study drug to be dispensed in 28-day cycles.  Subjects should be instructed to return the bottle every 28 days. 
p Adverse events that lead to study discontinuation should be followed until resolution or stabilization.  Serious adverse events should be monitored for 30 days 
after treatment discontinuation.  All SAEs should be followed until resolution or stabilization.  Any SAE deemed by the investigator to be related to study drug 
should be reported and followed until resolution. 
q Second primary malignancies will be monitored as events of interest and must be reported as serious adverse events.  This includes any second primary 
malignancy, 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 survival follow-up period.  Subjects will be followed until all subjects in the study have been followed for at least 5 years from 
randomization (or died/become lost to follow-up before 5 years).  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 (eg, any confirmatory histology or cytology results, X-rays, CT scans, etc.). 
r Investigators to provide assessment of CR, CRi, nPR, PR, and PD based on laboratory, physical exam, and if appropriate bone marrow aspirate/biopsy and CT 
scan findings.  To confirm a complete response, subjects must have maintained no evidence of disease for ! 8 weeks and partial response must be maintained 
for 8 weeks as per the IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia 
 
 
 
 


Lenalidomide (CC-5013) 
Protocol CC-5013-CLL-002 
 
 
 
 
 
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Confidential and Proprietary 
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Figure 1: 
Schema of Events 
 
 
                                                                                                                                 
                                                                                    
 
 
 
 
                                                                                                                                                                                                   
                                           
 
  
 
 
 
                                                                                                                                                    
                                                                                                                                                                   
                    
                                                                                                             
 
 
 
CLL= chronic lymphocytic leukemia, CR = complete response, CRi = complete response with incomplete bone marrow recovery, MRD = Minimal residual 
disease; nPR = nodular partial response, PO = oral, PD = progressive disease, PR = partial response, QD = every day
Screen 
PR, nPR, 
CRi, CR, or 
MRD-
negative 
CR 
Randomize to: 
Cycle 1:  2.5 mg 
po qd on days 1-
28 
Starting at cycle 
2 (if 2.5 mg well 
tolerated):  5 mg 
po qd on days 1-
28 every 28 days 
up to disease 
progression  
After 5 cycles at 
the 5 mg dose, if 
MRD-negativity 
is not achieved 
and 5 mg dose is 
tolerated, 
escalate to 10 
mg po qd on 
days 1-28 every 
28 days up to 
disease 
progression 
or 
placebo PO QD 
on Days 1-28 
every 28 days up 
PD or disease 
transformation: 
Discontinue 
study drug 
PR, nPR, CRi, CR or 
MRD-negative CR: 
Continue study drug 
up to disease 
progression or 
unacceptable 
toxicity 
Placebo patients 
will discontinue 
study drug in 
Amendment #10 
 
Follow for survival, 
subsequent CLL 
treatment regimens, 
and second primary 
malignancies,    
Lenalidomide 
patients will 
discontinue 
study drug in 
Amendment #11 


Lenalidomide (CC-5013) 
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3. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
 
 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS ...........................................................................................22 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................28 
 
 
 
 
 
 
6. 
STUDY OBJECTIVES ..............................................................................................42 
6.1. 
Primary Objective .......................................................................................................42 
6.2. 
Secondary Objective ...................................................................................................42 
7. 
STUDY ENDPOINTS ................................................................................................43 
7.1. 
Primary .......................................................................................................................43 
7.2. 
Secondary ...................................................................................................................43 
 
 
8. 
INVESTIGATIONAL PLAN .....................................................................................44 
8.1. 
Overall Study Design ..................................................................................................44 
 
 
9. 
STUDY POPULATION .............................................................................................59 
9.1. 
Subject Inclusion Criteria ...........................................................................................59 
9.2. 
Subject Exclusion Criteria ..........................................................................................60 
10. 
DESCRIPTION OF TREATMENT ...........................................................................62 
10.1. 
Description of Study Drug ..........................................................................................62 
10.1.1. 
Randomization ............................................................................................................62 
10.2. 
Treatment Assignments ..............................................................................................62 
10.2.1. 
Dose Modification or Interruption ..............................................................................63 
10.3. 
Blinding ......................................................................................................................69 
10.4. 
Emergency Unblinding ...............................................................................................69 
 
 
 
 


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10.6. 
Discontinuation from Treatment .................................................................................70 
11. 
EMERGENCY PROCEDURES ................................................................................72 
11.1. 
Emergency Contact .....................................................................................................72 
12. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................73 
12.1. 
Supplier(s) ...................................................................................................................73 
12.2. 
Dosage Form ...............................................................................................................73 
12.3. 
Dosage Regimen .........................................................................................................73 
12.4. 
Study Drug Packaging and Labeling ..........................................................................73 
12.5. 
Study Drug Receipt and Storage .................................................................................74 
12.6. 
Record of Administration ...........................................................................................74 
12.7. 
Study Drug Accountability .........................................................................................74 
12.8. 
Study Drug Handling and Disposal ............................................................................74 
13. 
ASSESSMENT OF EFFICACY ................................................................................75 
13.1. 
Assessments ................................................................................................................75 
13.2. 
Methods and Timing of Efficacy Assessments ..........................................................75 
14. 
ASSESSMENT OF SAFETY .....................................................................................76 
14.1. 
Assessments ................................................................................................................76 
14.2. 
Methods and Timing of Safety Assessments ..............................................................77 
14.3. 
Recording and Reporting of Adverse Events .............................................................77 
 
 
 
 
 
 
16. 
STATISTICAL ANALYSES .....................................................................................79 
16.1. 
Statistical Overview ....................................................................................................79 
16.2. 
Study Population Definitions ......................................................................................79 
16.2.1. 
Intent-to-Treat Population ..........................................................................................79 
16.2.2. 
Safety Population ........................................................................................................79 
16.2.3. 
Subgroup Analyses .....................................................................................................79 
16.3. 
Efficacy Evaluation ....................................................................................................79 
16.3.1. 
Primary Endpoint ........................................................................................................79 
16.3.2. 
Secondary Endpoint ....................................................................................................80 
16.3.3. 
Efficacy Analyses .......................................................................................................80 


Lenalidomide (CC-5013) 
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16.4. 
Background and Demographic Characteristics ..........................................................80 
16.5. 
Study Drug ..................................................................................................................81 
 
 
16.7. 
Safety Evaluation ........................................................................................................81 
 
 
16.9. 
Sample Size and Power Considerations .....................................................................82 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................83 
17.1. 
Monitoring ..................................................................................................................83 
17.2. 
Audits and Inspections ................................................................................................83 
17.3. 
Investigator(s) Responsibilities ..................................................................................83 
18. 
REGULATORY CONSIDERATIONS ......................................................................85 
18.1. 
Institutional Review Board/Independent Ethics Committee Review and 
Approval .....................................................................................................................85 
18.2. 
Protocol Amendments ................................................................................................85 
18.3. 
Informed Consent .......................................................................................................85 
18.4. 
Patient Confidentiality ................................................................................................86 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................87 
19.1. 
Data/Documents .........................................................................................................87 
19.2. 
Data Management .......................................................................................................87 
19.3. 
Retention of Records ..................................................................................................87 
20. 
PREMATURE DISCONTINUATION OF THE STUDY .........................................89 
20.1. 
Single Site ...................................................................................................................89 
20.2. 
Study as a Whole ........................................................................................................89 
 
 
22. 
APPENDICES ............................................................................................................94 
22.1. 
Adverse Event .............................................................................................................94 
22.2. 
Declaration of Helsinki .............................................................................................100 
22.3. 
ECOG Performance Status Scale ..............................................................................101 
 
 
 
 
 


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22.6. 
Pregnancy Prevention Risk Management Plans .......................................................115 
22.6.1. 
Lenalidomide Pregnancy Prevention Risk Management Plan ..................................115 
22.6.1.1. 
Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials .......115 
22.6.2. 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods ...........................................................................116 
22.6.2.1. 
Lenalidomide Education and Counseling Guidance Document ...............................120 
22.6.2.2. 
Lenalidomide Information Sheet ..............................................................................123 
 
 
 


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LIST OF TABLES 
 
 
Table 2: 
Schedule of Assessments ............................................................................................18 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................28 
Table 4: 
Grading Scale for Hematological Toxicity in CLL Studies .......................................63 
Table 5: 
Dose Reduction Steps .................................................................................................64 
Table 6: 
Dose Reduction and Modification Guidelines ............................................................64 
 
 
 
 
 
 
 
 
 
 


Lenalidomide (CC-5013) 
Protocol CC-5013-CLL-002 
 
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LIST OF FIGURES 
Figure 1: 
Schema of Events .......................................................................................................21 
 
 


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Protocol CC-5013-CLL-002 
 
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Confidential and Proprietary 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 3: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALT (SGPT) 
Alanine transaminase (serum glutamate 
pyruvic transaminase) 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
Aspartate transaminase (serum glutamic 
oxaloacetic transaminase) 
ATC 
Anatomic Therapeutic Chemical  
ɴϮD 
Beta-2 Microglobulin 
ɴ –HCG 
Beta-human chorionic gonadotropin hormone 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLL 
Chronic lymphocytic leukemia 
Clb 
Chlorambucil 
CNS 
Central nervous system 
CR 
Complete response 
Cri 
Complete response with incomplete bone 
marrow recovery 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
DAT 
Direct antiglobulin test 
DCF 
Data Clarification Form 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency  


Lenalidomide (CC-5013) 
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Abbreviation or Specialist Term 
Explanation 
EU 
European Union 
Table 3: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Explanation 
F 
Fludarabine 
FC 
Fludarabine and Cyclophosphamide 
FCBP 
Female of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in Situ Hybridization 
GClb 
Obinutuzumab and Chlorambucil 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HGB 
Hemoglobin 
HCT 
Hematocrit 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgVh 
Immunoglobulin Heavy-chain Variable-region 
IL-6 
Interleukin 6 
IL-10 
Interleukin 10 
IMiD 
Immunomodulatory drug 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
IVRS 
Interactive Voice Response System 
IWCLL 
International Workshop on Chronic 
Lymphocytic Leukemia 
LMW 
Low-molecular weight 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation or Specialist Term 
Explanation 
MRD 
Minimal residual disease 
NCI CTCAE  
National Cancer Institute Common 
Terminology Criteria for Adverse Events  
 
Table 3: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Explanation 
NCI-WG 
National Cancer Institute Working Group 
criteria for chronic lymphocytic leukemia 
NK cells 
Natural killer cells 
nPR 
Nodular partial response 
NSAID 
Non-steroidal anti-inflammatory drug 
ORR 
Overall response rate 
OS 
Overall Survival 
PCR 
Pentostatin, cyclophosphamide, and rituximab 
PD 
Progressive disease 
PFS 
Progression free survival 
PFS2 
Progression free survival 2 
PR 
Partial Response 
RClb 
Rituxan and Chlorambucil 
RIC 
Reduced intensity conditioning 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Serum-Glutamic-Oxaloacetic Transaminase 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse 
reaction 
TFR 
Tumor flare reaction 
TLS 
Tumor lysis syndrome 
TNF D 
Tumor necrosis factor alpha 
TNM 
Tumor-nodes-metastasis 
ULN 
Upper limit of normal 
US 
United States 


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Abbreviation or Specialist Term 
Explanation 
VEGF 
Vascular endothelial growth factor 
VTE 
Venous thromboembolism 
WBC 
White blood cell count 
WG 
Working Group 
 
Table 3: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Explanation 
WHO 
World Health Organization 
ZAP 70 
Zeta-Chain-Associated Protein Kinase 70 






















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6. 
STUDY OBJECTIVES  
6.1. 
Primary Objective 
x To compare the efficacy of lenalidomide versus placebo maintenance therapy 
6.2. 
Secondary Objective 
x To evaluate the safety of lenalidomide versus placebo maintenance therapy 


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7. 
STUDY ENDPOINTS 
7.1. 
Primary 
x Overall Survival (OS) 
7.2. 
Secondary 
x Safety [type, frequency, and severity of AEs and relationship of AEs to lenalidomide] 
x Progression-Free Survival 2 (PFS2) 
 
 
 
 
 
 
 
 


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8. 
INVESTIGATIONAL PLAN 
8.1. 
Overall Study Design  
CC-5013-CLL-002 is a phase 3, multicenter, randomized, placebo-controlled, parallel-group 
study that will compare the efficacy and safety of oral lenalidomide maintenance therapy to that 
of placebo in subjects with B-cell CLL who achieved at least partial response (PR) with second-
line therapy.  The primary efficacy objective of this study is to demonstrate superiority of 
lenalidomide over placebo in prolonging OS due to continued therapy, for all subjects, including 
subjects with or without poor prognostic factors, subjects of various ages and subjects with PR, 
nodular partial response (nPR), complete response with incomplete bone marrow recovery (CRi), 
complete response (CR), and minimal residual disease (MRD)-negative CR.  All subjects 
randomized to the lenalidomide arm, including those subjects who do not improve their response 
(PR, nPR, CRi, or CR) and subjects who do not have the opportunity to improve their response 
further (MRD-negative CR) will be treated up to disease progression with the objective to 
demonstrate prolongation of OS. 
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
Eligible subjects must have been treated with a purine analog-, a bendamustine-, an anti-CD20 
antibody-, or a chlorambucil-based regimen in first and/or second line and must have achieved at 
least PR to second-line induction therapy of sufficient duration. Alemtuzumab- containing 
regimens will also be allowed for those patients with 17p deletion.  Subjects who achieve stable 
disease (SD) only or who develop progressive disease (PD) at any time during induction therapy 
will not be eligible for participation in this study. 
Approximately, three hundred twenty (320) subjects with PR, nPR, CRi, CR or MRD-negative 
CR will be enrolled and randomized (1:1) into two arms:  placebo daily or lenalidomide 2.5 mg 
daily on days 1-28 of the first cycle.  If the 2.5 mg dose level is well tolerated, escalation to 5 mg 
daily on days 1-28 of each 28-day cycle is permitted starting with the second cycle.  If a subject 
develops a Grade 1 or 2 adverse event, the drug may be interrupted until resolution, however the 
subject must complete one full cycle at the 2.5 mg dose level prior to escalation to the 5 mg dose 
level.  For those subjects who tolerate the 5 mg dose without unacceptable toxicity, escalation to 
10 mg daily on days 1-28 of each 28-day cycle after 5 continuous cycles at 5 mg will be 
permitted.  Each treatment arm will be stratified according to 1) the response to second-line 
induction therapy (PR, nPR, CRi or CR versus MRD-QHJDWLYH&5DJHYHUVXV!
years); and 3) presence of at least one of the following poor prognostic factors:  11q deletion, 
17p deletion, unmutated IgVH or ȕ0!PJ/ (Yes versus No versus Unknown). 
The subjects randomized to the lenalidomide treatment will continue to receive lenalidomide up 
to PD.  For those subjects who discontinue therapy for reasons other than PD (ie, unacceptable 
toxicity) they will transition to the survival follow-up period.  
Subjects who discontinued from the study drug will be followed every 24 weeks for survival, 
subsequent CLL therapies, response to next therapy and progression following next therapy, and 


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second primary malignancies.  Subjects will be followed until all subjects in the study have been 
followed for at least 5 years from the last randomization, October 2020, (or have died/become 
lost to follow up before 5 years).     
Screening: 
Potential study subjects will be screened for protocol eligibility within 28 days prior to 
randomization as outlined in Table 2.  Please refer to Figure 1. 
During the screening process for potentially protocol-eligible subjects, complete blood counts 
(CBCs), serum chemistries, thyroid function tests, quantitative immunoglobulin tests, a 12-lead 
electrocardiogram (ECG), physical exam to assess lymphadenopathies, the spleen and the liver, 
vital signs (with weight), Eastern Cooperative Oncology Group (ECOG) performance status, and 
evaluation of constitutional symptoms will be performed. 
Bone marrow biopsies and aspirates are to be performed on all subjects at screening.  A central 
review of the bone marrow aspirate and biopsy specimens will be performed to confirm disease 
status.  Subjects who develop PD during screening will not be eligible to enroll into this study.  
Peripheral blood will be sent to a central laboratory for flow cytometry for all subjects for 
disease diagnosis confirmation (by immunophenotyping), to perform immune cell (NK and T 
cell) analyses and for subjects entering the study with a CR for determination of MRD status. If 
peripheral blood is MRD negative, a bone marrow flow cytometry will be implemented. If 
subjects enter the study with MRD negativity, the disease diagnosis will be confirmed based on 
prior flow cytometry (documentation needed). 
A peripheral blood sample for a direct antiglobulin test (DAT) will be collected and analyzed at a 
central laboratory. 
Before randomization, subjects will be tested for cytogenetics by FISH, IgVH mutational status, 
DQGȕ07KHȕ0WHVWZLOOEHSHUIRUPHGGXULQJVFUHHQLQJXVLQJDSHULSKHUDOEORRGVDPSOHDQG
analyzed at a central laboratory. 
FISH and IgVH testing will be performed prior to second line, during second line, in the interval 
between second-line therapy and screening or during the screening period using a peripheral 
blood sample.  Because test results cannot be obtained during screening or between second line 
and screening in some subjects who achieve a good response due to the limited number of 
remaining CLL cells, we recommend conducting the FISH and IgVH tests preferably prior to 
second line or during second line.   
Samples for FISH and IgVH will be analyzed at a central laboratory. 
If tests do not yield results, subjects can be randomized and stratified based on historical data. 
Those subjects for whom results were not obtainable pre-randomization and for whom no 
historical data were available will be enrolled and grouped separately. 
An additional peripheral blood sample will be collected at baseline and stored at -70° at a central 
laboratory until the completion of the study; subjects will be re-consented if additional testing is 
to be performed. 
Computed tomography (CT) scans of the chest, abdomen, and pelvis will be performed at 
baseline for all subjects to document the subject’s status (PR or CR).   


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If, during the screening period, the subject has a correctable event that prevents randomization 
and the event cannot be corrected within the 28 day screening period, the subject may be 
re-screened; however, the CT scans and bone marrow aspirate and biopsy will not need to be 
repeated if those tests were implemented within 56 days prior to randomization and the subject’s 
clinical status remains the same. 
Females of childbearing potential (FCBP) must have two negative pregnancy tests performed at 
the study site prior to initiating lenalidomide therapy. The first pregnancy test will be performed 
within 10-14 days prior to randomization and the second test within 24 hours prior to starting 
study drug.  FCBP must agree to birth control requirements as outlined in Appendix 22.6 during 
the following time periods related to this study: 1) for at least 28 days before starting study drug; 
2) while participating in the study; and 3) at least 28 days after the treatment discontinuation 
visit.  FCBP must be referred to a qualified provider of contraceptive methods, if needed.  Males 
must commit to continued abstinence from heterosexual contact or agree to use appropriate 
contraceptive methods during any sexual contact with FCBP during study participation and for at 
least 28 days following the treatment discontinuation visit as outlined in Appendix 22.6.  Male 
subjects must agree to abstain from donating blood, semen or sperm during study participation 
and for at least 28 days after the treatment discontinuation visit.  Subjects must be counseled 
about pregnancy precautions and the potential risk of fetal exposure. 
Randomization: 
Randomization must occur no less than 8 weeks (56 days) and no greater than 20 weeks (140 
days) from the last day of the last cycle of second-line induction therapy received by the subject 
in order for the subject to be eligible for enrollment into this study.  Subjects meeting all 
eligibility criteria will be randomized (1:1) in a double-blind fashion to receive either 
lenalidomide or placebo.  The randomization procedure will be accomplished by a validated 
interactive voice response system (IVRS) (see Section 10.1.1). Subjects will be stratified at 
randomization by: 1) their response to second-line induction therapy (PR, nPR, CRi or CR versus 
MRD-QHJDWLYH&5DJHYHUVXV!\HDUVDQGpresence of at least one of the 
following poor prognostic factors:  11q deletion, 17p deletion, unmutated IgVH or ȕ0!
mg/L (Yes versus No versus Unknown).   
Maintenance Therapy: 
Study treatment for each subject begins on the same day the subject undergoes randomization.  
Lenalidomide is administered orally.  Subjects will receive lenalidomide 2.5 mg once daily on 
Days 1 through 28 of the first 28-day cycle.  If the 2.5 mg dose is well tolerated (subject does not 
experience any Grade 3 or 4 study drug-related toxicities or any other toxicity [Grade 1 or 2] 
found to be unacceptable by the investigator or the subject), subjects should be escalated starting 
at the second cycle to 5 mg once daily on Days 1 through 28 of each 28-day cycle up to disease 
progression.  If a subject develops a Grade 1 or 2 adverse event, the drug may be interrupted 
until resolution, however the subject must complete one full cycle at the 2.5 mg dose level prior 
to escalation to the 5 mg dose level. 
Subjects who complete 5 continuous cycles at the 5 mg dose level without experiencing any 
Grade 3 or 4 study drug-related toxicities and without experiencing any other toxicity (Grade 1 
or 2) found to be unacceptable by the investigator may be escalated to 10 mg once daily on Days 
1 through 28 of each 28-day cycle up to disease progression. 


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Dose de-escalation to 7.5 mg from 10 mg and to 5 mg from 7.5 mg and to 2.5 mg from 5 mg and 
to 2.5 mg every other day from 2.5 mg will be permitted for those subjects who experience a 
Grade 3 or 4 study drug-related toxicity or any other Grade 1 or 2 toxicity found to be 
unacceptable by the investigator or subject. 
Dose interruptions are also permitted for Grade 1 or 2 adverse events at the investigator’s 
discretion.  A guideline for the reduction of the dose of lenalidomide for dose-limiting toxicity 
(DLT) is provided (see Section 10.2.1). 
Dose re-escalation is permitted if the subject is able to complete 2 full cycles at the reduced dose 
level without experiencing a DLT or other toxicity deemed to be unacceptable by the investigator 
or subject.  In the event the dose reduction is implemented due to Grade 4 neutropenia, subjects 
may be re-escalated after one full cycle at the lower dose level if the neutropenia resolves to a 
Grade 2 or better by the end of the cycle and no other DLT is observed.  If that dose level is 
again not tolerated, the subject should be de-escalated to the dose below and remain at that 
tolerated dose level for the rest of the study. 
Study visits and serial measurements of safety and efficacy will be performed as outlined in 
Table 2. 
Females of childbearing potential must have a pregnancy test (conducted by the study site) 
within 24 hours prior to starting study drug; the subject may not receive study drug until the 
Investigator has verified that the pregnancy test is negative. Pregnancy testing for FCBP will 
continue throughout the study as outlined in Table 2 and Appendix 22.6.   
Counseling regarding blood, eggs and ovum donation, and contraceptive use and the potential 
risks of fetal exposure should be performed as outlined in Appendix 22.6. 
FCBP should be monitored during the course of the study and after the end of study therapy to: 
x Ensure that pregnancy tests are performed during the course of the study and after end 
of study therapy and are negative (see specifics in Appendix 22.6). 
x Ensure the subject continues to practice abstinence or remains on adequate 
contraception (see specifics in Appendix 22.6). 
If a FCBP becomes pregnant, treatment should be stopped and the subject referred to the 
appropriate physician. 
Male subjects should be monitored during the course of the study and after the end of study 
therapy to: 
x Ensure they commit to continued abstinence from heterosexual contact or continue to 
use a condom during sexual contact with a FCBP. 
x If a female partner of a male subject becomes pregnant she should be referred to the 
appropriate physician. 
CBCs will be monitored on Days 1, 8, and 15 of cycle 1, on Day 1 of each cycle thereafter, and 
at the treatment discontinuation visit.  In the event of Grade 4 hematologic toxicity, monitoring 
of CBCs will continue weekly until resolution to grade 3 or better.  It is recommended to utilize 
myeloid and erythroid growth factors as per the American Society of Clinical Oncology (ASCO) 


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guidelines.  The use of myeloid growth factors is encouraged when the absolute neutrophil count 
(ANC) LVOHVVWKDQȝ/ 
If a subject develops Grade 4 neutropenia or thrombocytopenia, the drug will be withheld until 
the toxicity has recovered to Grade 3 or better.  The drug may then be restarted at one dose level 
lower.  If the treatment has been withheld and the next cycle is delayed beyond 29 days after day 
1 of the prior treatment cycle, then day 1 of the next treatment cycle will be defined as the first 
day that the treatment is resumed. 
Serum chemistries will be performed on Days 1, 8, and 15 of cycle 1, on Day 1 of each cycle 
thereafter, and at the treatment discontinuation visit.   
Scheduled laboratory studies (CBCs, chemistries) will be sent to the site’s local laboratory for 
analysis purposes.  
The DAT test must be repeated if the investigator suspects haemolytic anemia and will be 
analysed centrally during the course of the study. 
ECOG Performance Status will be measured at the treatment discontinuation visit. 
Evaluation of constitutional symptoms will be performed at the treatment discontinuation visit. 
Vitals signs will be monitored at the treatment discontinuation visit.  A physical examination to 
assess in particular lymphadenopathies, spleen and liver will be performed at the treatment 
discontinuation visit. 
An ECG will be performed at the treatment discontinuation visit. 
Investigators will assess subjects for response every 28 days and at the treatment discontinuation 
visit.  Investigators will provide an assessment of CR (MRD-negative or MRD-positive), CRi, 
nPR, PR, and PD based on laboratory, physical exam, and if appropriate local assessments for 
CT scan findings, flow cytometry and bone marrow aspirate and biopsy.  To confirm a CR, 
subjects must have maintained no evidence of disease IRU8 weeks and PR must be maintained 
IRU 8 weeks as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
guidelines for the diagnosis and treatment of chronic lymphocytic leukemia (Hallek, 2008).   
FCBP must have a pregnancy test at the treatment discontinuation visit. 
Subjects will receive study maintenance therapy until PD develops; any disease transformation 
will need to be documented by lymph node biopsies for Richter’s syndrome and percent of 
peripheral blood or bone marrow prolymphocytes for prolymphocytic leukemia.  Progressive 
disease is characterized by at least one of the following: 
x Lymphadenopathy.   Progression of lymphadenopathy discovered by physical 
examination.  Disease progression occurs if one of the following events is observed: 
 $SSHDUDQFHRIDQ\QHZOHVLRQVXFKDVHQODUJHGO\PSKQRGHV!FP
splenomegaly, hepatomegaly or other organ infiltrates. 
 An increase by 50% or more in greatest determined diameter of any previous site.   
x An increase in the previously noted enlargement of the liver or spleen size by 50% or 
more or the de novo appearance of hepatomegaly or splenomegaly. 


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x An increase in the number of blood lymphocytes by 50% or more with at least 5,000 
%O\PSKRF\WHVSHUȝ/ 
x Transformation to a more aggressive histology (eg, Richter’s syndrome).  Whenever 
possible, this diagnosis should be established by lymph node biopsy. 
x Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to 
CLL. 
x During therapy:  cytopenias may occur as a side effect of many therapies and should 
be assessed according to Table 4.  During therapy, cytopenias cannot be used to 
define disease progression. 
x Post treatment:  The progression of any cytopenia (unrelated to autoimmune 
cytopenia), as documented by a decrease of hemoglobin levels by more than 2 g/dL 
or to less than 10 g/dL, or by a decrease of platelet counts by more than 50% or to 
OHVVWKDQȝ/ZKLFKRFFXUVDWOHDVWPRQWKVDIWHUWUHDWPHQWGHILQHVGLVHDVH
progression, if the marrow biopsy demonstrates an infiltrate of clonal CLL cells. 
Prophylaxis for TLS, thromboembolism and infection and treatment of tumor flare reaction 
(TFR): 
TLS prophylaxis, comprising of oral hydration and allopurinol 300 mg/day will be initiated 3 
days prior to starting maintenance therapy and for a minimum of the first treatment cycle at each 
dose level for those subjects entering the study with a PR to their second-line induction therapy.  
Subjects with a known allergy to allopurinol with a response of PR  will be excluded from the 
study.  Please refer to Section 10.2.1 for further guidance on allopurinol modification in the 
event of an adverse event.  If a subject is taking allopurinol for a condition other than for TLS 
prophylaxis, the subject should be continued on the allopurinol prescribed by their physician and 
the dose titrated to 300 mg/day.  If, at any time, the allopurinol being taken for reasons other than 
TLS prophylaxis is discontinued and prophylaxis is still required per protocol, the subject should 
be administered commercial allopurinol.  To maintain fluid intake, subjects must be instructed to 
drink 8 to 10 eight ounce (240 mL) glasses of water each day for the first 14 days of cycle 1 and 
the first cycle of each dose escalation.  Hydration levels should be adjusted according to age and 
clinical status, and lowered if the subject’s cardiovascular status indicates the possibility of 
volume overload.  At the investigator’s discretion, allopurinol prophylaxis may be omitted for 
subjects entering the study with a CR;  however subjects must be advised of the need for 
adequate hydration as outlined above. 
Grade 1 TFR may be treated with non-steroidal anti-inflammatory drug (NSAIDs) (ie, ibuprofen 
400-600 mg orally every 4-KRXUVDVQHHGHGDQG7)5Grade 2 should be treated with 
corticosteroids.  Narcotic analgesics may be added as needed for pain control in subjects 
H[SHULHQFLQJ*UDGHWXPor flare. 
Subjects will be monitored for TLS and TFR on Days 1, 8, and 15 for cycle 1 and the first cycle 
of each dose escalation.  Monitoring for TLS and TFR will continue on Days 1 and 15 for the 
second cycle of each dose level, at least every 28 days thereafter, and as clinically indicated. 
It is recommended that subjects receive low dose aspirin (75 mg to 100 mg) as prophylactic 
anti-thrombotic treatment while on study drug, however the use of aspirin should only be 


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implemented after careful evaluation of the hemorrhagic risk and determination that the subject 
is at limited risk.  The investigator may use other anti-coagulation prophylactic therapies (ie, 
low-molecular weight (LMW) heparin, warfarin, etc.) at their discretion based on the subjects 
pre-disposing risk factors for thromboembolism (ie, subjects with a history of a thromboembolic 
event and/or taking a concomitant medication associated with an increased risk for a 
thromboembolic event and/or known hypercoagulable state regardless of thromboembolic 
history). 
Aspirin should be interrupted if the platelet count dropVEHORZȝ/ 
Prophylactic antibiotics should be considered in patients with neutropenia.  In addition, subjects 
who were on prophylactic treatment for infection while on alemtuzumab therapy should continue 
prophylactic treatment for at least 6 months following the discontinuation of alemtuzumab 
therapy and can be enrolled into the study while continuing prophylactic therapy.  Subjects with 
an active infection requiring systemic antibiotics and subjects with a systemic infection that has 
QRWUHVROYHG! 2 months prior to initiating lenalidomide treatment in spite of adequate 
anti-infective therapy are excluded from entering the study. 
Treatment and Dose Modification for Tumor Lysis Syndrome (TLS): 
SubjectVPHHWLQJFULWHULDRIODERUDWRU\7/6RU*UDGHTLS according to the Cairo-Bishop 
definition and grading system should be treated as follows: 
x 6XEMHFWVPXVWEHKRVSLWDOL]HGIRU*UDGH7/6)RUODERUDWRU\7/6KRVSLWDOL]DWLRQ
is left to the investigator’s discretion. 
x The following should be provided:  vigorous hydration and appropriate therapy (ie, 
rasburicase where available) therapy as needed to reduce hyperuricemia, until 
correction of electrolyte abnormalities. 
x In cases of laboratory TLS and Grade 1 TLS, lenalidomide will be continued at the 
same dose without interruption or dose reduction.  Dose escalation to the next 
consecutive dose level will be permitted when laboratory TLS is resolved and Grade 
1 TLS is resolved to Grade 0. 
x SubjectVZLWK*UDGH7/6ZLOOKDYHWKHLUGRVHLQWHUUXSWHGDQGZLOOresume 
lenalidomide at the next lower dose when electrolyte abnormalities are corrected (ie, 
Grade 0) as specified in the Dose Modification and Interruption section of the 
protocol.  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. 
x When those subjects that have been dose reduced complete two full cycles without 
PHHWLQJFULWHULDIRUODERUDWRU\7/6RU*UDGH7/6RUH[SHULHQFLQJWR[LFLWLHVUH-
escalation to their maximum dose level or to the next higher dose level is permitted. 
The severity of AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 with modifications.  The 
severity of TLS AEs will be graded according to the Cairo-Bishop grading system. 
Amendment #11: 


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Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
After Study Discontinuation: 
Upon discontinuation of study drug, subjects will be followed every 24 weeks for survival, 
information on other CLL treatments, response to next therapy and progression following next 
therapy, and second primary malignancies (reported as SAEs).  Subjects will be followed until 
all subjects in the study have been followed for at least 5 years from the last randomization, 
October 2020 (or have died/become lost to follow-up before 5 years).  
FCBP with regular menstrual cycles discontinued from treatment must have a pregnancy test on 
day 28 after the treatment discontinuation visit. FCBP with irregular cycles discontinued from 
treatment must have a pregnancy test on days 14 and 28 after the treatment discontinuation visit. 
SAEs will continue to be collected for the first 30 days after the treatment discontinuation visit.  
Following 30 days post the treatment discontinuation visit, only SAEs related to maintenance 
therapy will be collected for the study duration.  Second primary malignancies must be reported 
as SAEs.  This includes any second primary malignancy, regardless of causal relationship to 
study medication, occurring at any time for the duration of the study, from the time of signing 
the informed consent up to and including progression free follow-up and survival follow-up.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CC-5013-CLL-002 Amend 11 Final:  16 March 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   


Lenalidomide (CC-5013) 
Protocol CC-5013-CLL-002 
 
  Celgene Corporation 
Confidential and Proprietary 
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CC-5013-CLL-002 Amend 11 Final:  16 March 2018 
9. 
STUDY POPULATION 
9.1. 
Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the study: 
1. Must understand and voluntarily sign an informed consent form. 
2. Must be t18 years at the time of signing the informed consent form. 
3. Must be able to adhere to the study visit schedule and other protocol requirements. 
4. Must have a documented diagnosis of B-cell CLL (IWCLL guidelines for the diagnosis 
and treatment of chronic lymphocytic leukemia 
). 
5. Must have been treated with one of the following in first and/or second line: 
x  a purine analog-containing regimen 
x a bendamustine-containing regimen  
x an anti-CD20 antibody-containing regimen 
x a chlorambucil-containing regimen 
x an alemtuzumab-containing regimen (for those subjects with a 17p deletion) 
6. Must have achieved a minimum response of partial response (PR, nPR, CRi, CR, and 
MRD-negative CR) (IWCLL guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia 
 Appendix 22.4) following completion of second-
line induction therapy prior to randomization (documentation of response status must be 
available).  Second-line induction therapy must be documented to have been of sufficient 
duration.  
7. Must have completed last cycle of second-line induction no less than 8 weeks (56 days) 
and no greater than 20 weeks (140 days) prior to randomization. 
8. Must have an ECOG performance status score of d2. 
9. Females of childbearing potential (FCBP)† must: 
x 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 22.6). This applies even if 
the subject practices complete and continued sexual abstinence. 
 
 
† Definition found in appendices 
 


Lenalidomide (CC-5013) 
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x Either commit to continued abstinence from heterosexual contact (which must be 
reviewed on a monthly basis) or agree to use, and be able to comply with, effective 
contraception without interruption, 28 days prior to starting study drug, during the 
study therapy (including dose interruptions), and for 28 days after discontinuation of 
study therapy (see specifics in Appendix 22.6). 
10. Male subjects must: 
x Commit to continued abstinence from heterosexual contact or 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 22.6) 
x Agree to not donate semen during study drug therapy and for a period after end of 
study drug therapy (see specifics in Appendix 22.6). 
11. All subjects must: 
x Have an understanding that the study drug could have a potential teratogenic risk. 
x Agree to abstain from donating blood while taking study drug therapy and following 
discontinuation of study drug therapy. (See specifics in Appendix 22.6) 
x Agree not to share study medication with another person. 
x All subjects must be counseled about pregnancy precautions and risks of fetal 
exposure.  See Appendix 22.6. 
9.2. 
Subject Exclusion Criteria 
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from participating in the study. 
2. Active infections requiring systemic antibiotics. 
3. 6\VWHPLFLQIHFWLRQWKDWKDVQRWUHVROYHG!PRQWKVSULRUWRLQLWLDWLQJOHQDOLGRPLGH
treatment in spite of adequate anti-infective therapy 
4. Autologous or allogeneic bone marrow transplant as second-line therapy. 
5. Pregnant or lactating females. 
6. Systemic treatment for B-cell CLL in the interval between completing the last cycle of 
second-line induction therapy and randomization. 
7. Participation in any clinical study or having taken any investigational therapy for a 
disease other than CLL within 28 days prior to initiating maintenance therapy. 
8. Known presence of alcohol and/or drug abuse. 
9. Central nervous system involvement as documented by spinal fluid cytology or imaging.  
Subjects who have signs or symptoms suggestive of leukemic meningitis or a history of 
leukemic meningitis must have a lumbar puncture procedure performed within two weeks 
prior to randomization. 


Lenalidomide (CC-5013) 
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10. Prior history of malignancies, other than CLL, unless the subject has been free of the 
GLVHDVHIRU5 years.  Exceptions include the following: 
x Basal cell carcinoma of the skin 
x Squamous cell carcinoma of the skin 
x Carcinoma in situ of the cervix 
x Carcinoma in situ of the breast 
x Incidental histologic finding of prostate cancer (tumor-nodes-metastasis [TNM] stage 
of T1a or T1b) 
11. History of renal failure requiring dialysis. 
12. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), and/or 
active Hepatitis C Virus (HCV) infection. 
13. Prior therapy with lenalidomide. 
14. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (Appendix 22.5) 
(subjects may be enrolled upon correction of electrolyte abnormalities). 
15. Any of the following laboratory abnormalities: 
x Calculated (method of Cockroft-Gault) creatinine clearance <60 mL/min. 
x Absolute neutrophil count (ANC) <1,000ȝL (1.0 X 109/L) 
x Platelet count <50,000/ȝ/50 X 109/L) 
x Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase 
(SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase 
(SGPT) ![XSSHUOLPLWRIQRUPDO8/1 
x 6HUXPWRWDOELOLUXELQ!PJG/ (with the exception of Gilbert’s Syndrome) 
16. Grade 4 rash due to prior thalidomide treatment 
17. Uncontrolled hyperthyroidism or hypothyroidism 
18. Venous thromboembolism within one year 
19. tGrade-2 neuropathy 
20. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia 
21. Disease transformation (active) (ie, Richter’s Syndrome, prolymphocytic leukemia) 
22. Known allergy to allopurinol for subjects assessed with PR following their second-line 
induction therapy. 
23. Prisoners. 
24. More than 2 prior lines of CLL therapy. 


Lenalidomide (CC-5013) 
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10. 
DESCRIPTION OF TREATMENT 
10.1. 
Description of Study Drug 
Celgene Corporation will supply lenalidomide 2.5 mg, 5 mg, and 10 mg capsules for oral 
administration.  Subjects dose reduced to 7.5 mg dose level (as outlined in Section 10.2.1) will 
receive one 5.0 mg capsule and one 2.5 mg capsule daily. 
Study drug will be packaged in bottles containing study capsules for 28 days.  Subjects assigned 
to active treatment will receive 28 days of active drug (with the exception of those subjects de-
escalated to 2.5 mg every other day).   
Celgene Corporation will no longer supply blinded allopurinol 300 mg and matching placebo 
(Amendment #10). 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment immediately.  
Celgene Corporation will no longer supply lenalidomide (Amendment #11). 
10.1.1. 
Randomization 
Randomization will be accomplished by an IVRS to ensure timely registration and 
randomization.  Designated research personnel at the investigational sites will be assigned 
password protected, coded identification numbers, which gives them authorization to call into the 
IVRS to enroll subjects.  The system will present a menu of questions by which the research 
personnel will identify the subject and confirm eligibility. When all questions have been 
answered, including questions regarding the results of pregnancy tests for FCBP, the IVRS will 
assign a subject number and study drug to the eligible subject. IVRS will fax a confirmation of 
registration and drug assignment for each subject to the site and Celgene.   Subjects will be 
randomized (1:1) to receive lenalidomide or placebo.  Subjects will be stratified at randomization 
by: 1) their response to second-line induction therapy (PR, nPR, CRi or CR versus 
MRD-QHJDWLYH&5DJHYHUVXV!\HDUVDQGpresence of at least one of the 
following poor prognostic factors:  11q deletion, 17p deletion, unmutated IgVH, or ȕ0!
mg/L (Yes versus No versus Unknown).   
Site staff are to contact Celgene at each visit for study drug assignment, to register dose 
reductions or escalations, and at discontinuation from treatment.  Confirmation of each call will 
be faxed to the site. 
10.2. 
Treatment Assignments 
Lenalidomide  
Oral lenalidomide 2.5 mg capsule once daily on Days 1 through 28 of the first 28-day cycle.  
If the 2.5 mg dose is well tolerated, subjects should be escalated starting at the second cycle 
to 5 mg capsule once daily on Days 1 through 28 of each 28-day cycle to disease progression.  
If a subject develops a Grade 1 or 2 adverse event, the drug may be interrupted until 
resolution, however the subject must complete one full cycle at the 2.5 mg dose level prior to 
escalation to the 5 mg dose level. 


Lenalidomide (CC-5013) 
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Following 5 continuous cycles at the 5 mg dose level, subjects who are tolerating the 5 mg 
dose level may be escalated to 10.0 mg once daily on days 1 through 28 of each 28-day cycle 
up to disease progression. 
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
10.2.1. 
Dose Modification or Interruption 
Subjects will be evaluated for AEs at each visit with the NCI CTCAE (Version 3.0) used as a 
guide for the grading of severity with the exceptions recommended by the IWCLL guidelines for 
the diagnosis and treatment of chronic lymphocytic leukemia 
 as listed below*: 
Table 4: 
Grading Scale for Hematological Toxicity in CLL Studies 
Grade# 
Decrease in Platelets* or Hb° (nadir) 
From Pretreatment value (%) 
Absolute neutrophil count/ȝL@ (nadir) 
0 
No change to 10% 
 
1 
11% - 24% 
DQG 
2 
25% - 49% 
DQG 
3 
50% - 74% 
DQG 
4 
 
< 500 
* Platelet counts must be below normal levels for grades 1-4.  If, at any level of decrease the platelet count is 
ȝ/WKLVZLOOEHFRQVLGHUHGJUDGHWR[LFLW\XQOHVVDVHYHUHRUOLIH-threatening decrease in the initial 
SODWHOHWFRXQWHJȝ/ZDVSUHVHQWSUHWUHDWPHQWLQZKLFKFDVHWKHSDWLHQWLVQRWHYDOXDEOHIRUWR[LFLW\
referable to platelet counts. 
° Hb levels must be below normal levels for grades 1-4.  Baseline and subsequent Hb determinations must be 
performed before any given transfusions.  The use of erythropoietin is irrelevant for the grading of toxicity, but 
should be documented. 
# Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal.  Death occurring as a result of toxicity at any 
level of decrease from pretreatment will be recorded as grade 5. 
@ If the absolute neutrophil count (ANC) reaches less than 1,0ȝ/LWVKRXOGEHMXGJHGWREHJUDGHWR[LFLW\
Other decreases in the white blood cell count, or in circulating granulocytes, are not to be considered, since a 
decrease in the white blood cell count is a desired therapeutic end point.  A gradual decrease in granulocytes is not 
a reliable index in CLL for stepwise grading of toxicity.  The use of G-CSF is irrelevant for the grading toxicity, 
but should be documented. 
In addition, TLS will be graded as specified by the Cairo-Bishop grading system (Appendix 
22.5). 6XEMHFWVPHHWLQJFULWHULDRIODERUDWRU\7/6RU*UDGH7/6ZLOOEHKRVSLWDOL]HG (per 
investigator’s discretion for laboratory TLS), provided with vigorous intravenous hydration and 
appropriate therapy (ie, rasburicase where available) as needed to reduce hyperuricemia, until 
correction of electrolyte abnormalities.  In the case of laboratory TLS and Grade 1 TLS, 
lenalidomide will be continued at the same dose without interruption or dose reduction. Subjects 
ZLWK*UDGH7/6ZLOOKDYHWKHLUGRVHLQWHUUXSWHGDQGZLOOUHVXPHOHQDOLGRPLGHDWWKHQH[W
lower dose level when electrolyte abnormalities are corrected (ie, Grade 0). If lenalidomide is 


Lenalidomide (CC-5013) 
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resumed prior to the start of the subsequent cycle, chemistry tests should be performed every 
other day for the first week following initiation of lenalidomide. 
If a subject develops toxicity (Table 6), the dose may be reduced as outlined in Table 5. 
Table 5: 
Dose Reduction Steps 
Lenalidomide 
Dose 
2.5 mg every day x 28 
days of a 28-day cycle 
5 mg every day x 28 days 
of a 28-day cycle  
10 mg every day x 28 
days of a 28-day cycle  
Dose Reduction – 1 
2.5 mg every other day 
x 28 days of a 28-day 
cycle 
2.5 mg every day x 28 
days of a 28-day cycle 
7.5 mg every day x 28 
days of a 28- day cycle 
Dose Reduction – 2 
n/a 
2.5 mg every other day x 
28 days of a 28-day cycle 
5 mg every day x 28 days 
of a 28- day cycle 
Dose Reduction – 3 
n/a 
n/a 
2.5 mg every day x 28 
days of a 28- day cycle 
Dose Reduction – 4 
n/a 
n/a 
2.5 mg every other day x 
28 days of a 28-day cycle 
SubjectVH[SHULHQFLQJD*UDGHQRQ-hematologic AE will have their study drug held until 
resolution of the AE as described in Table 6: Dose Reduction and Modification Guidelines.  
Subjects with a hematologic AE will modify study drug dosing as outlined in Table 6. 
Subjects who cannot tolerate 2.5 mg every other day x 28 days of a 28-day cycle are to be 
discontinued from study drug and followed for survival as outlined in Table 2. 
Table 6: 
Dose Reduction and Modification Guidelines 
NCI CTCAE Toxicity Grade 
Action 
Neutropenia  
ANC < 400/uL 
 
x 
Interrupt study drug therapy 
x 
Resume study drug (decrease one dose level) when 
ANC recovers to t 500/uL 
Thrombocytopenia 
< 20,000/uL 
 
x 
Interrupt study drug therapy 
x 
Resume study drug (decrease one dose level) when 
platelet count recovers to ! 25,000/uL 
Syndromes 
 
Tumor Flare 
Grade 3 or 4 
x 
Interrupt study drug therapy and initiate therapy with 
NSAIDs, narcotic analgesics or prednisone 
x 
Resume study drug (decrease one dose level) when 
symptoms resolve to d Grade 2 
Desquamating (blistering) rash  
x 
Discontinue study drug 
Non- desquamating rash 
 
Grade 3 
x 
Interrupt study drug therapy.  


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Protocol CC-5013-CLL-002 
 
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NCI CTCAE Toxicity Grade 
Action 
x 
Resume study drug when the rash resolves to *UDGH
1 (decrease one dose level) 
Grade 4 
x 
Discontinue study drug  
Table 6: 
Dose Reduction and Modification Guidelines (Continued) 
NCI CTCAE Toxicity Grade 
Action 
Neuropathy 
 
Grade 3 
x 
If Grade 3, interrupt study drug therapy. 
x 
Resume study drug when the neuropathy resolves to 
Grade 1 (decrease one dose level) 
Grade 4 
x 
If Grade 4, discontinue study drug  
Venous thrombosis/embolism  
Grade 3 
x 
Hold (interrupt) dose and start anticoagulation; 
x 
Resume study drug when adequately anticoagulated 
(maintain dose level). 
Hyperthyroidism or hypothyroidism 
 
x 
Interrupt study drug and initiate appropriate medical 
therapy. 
x 
Resume study drug when appropriately controlled 
(maintain dose level). 
Serum Creatinine 
 
Grade 1  
**It is possible for subjects entering 
WKHVWXG\ZLWKDFUHDWLQLQHFOHDUDQFH
60 ml/min and a serum creatinine at 
the upper limit of normal to show 
slight fluctuations of the serum 
creatinine above the upper limit of 
normal.  It is left at the investigator’s 
discretion to measure the creatinine 
clearance for those subjects to 
evaluate whether a dose adjustment is 
needed. 
x 
Interrupt study drug 
x 
Evaluate subject weekly x 3 weeks  
x 
If during those 3 weeks, the creatinine level  
ZRUVHQHGDWDQ\WLPHWR!*UDGHpermanently 
discontinue and follow for PD 
x 
If at the end of the third week the creatinine level has 
improved to < Grade 1, resume study drug (maintain 
dose level)  
x 
If at the end of the third week the creatinine level  has 
stabilized at Grade 1, resume study drug (decrease 
one dose level)  
x 
Following resumption of study drug, evaluate subject 
weekly x 2 weeks to ensure creatinine level does not 
worsen; if creatinine level again worsens during those 
2 weeks, permanently discontinue and follow for PD 
Grade 2 
x 
Interrupt study drug 
x 
Evaluate subject weekly x 3 weeks  
x 
If during those 3 weeks, the creatinine level  
ZRUVHQHGDWDQ\WLPHWR!*UDGHpermanently 
discontinue and follow for PD 


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NCI CTCAE Toxicity Grade 
Action 
x 
If at the end of the third week, the creatinine level has 
improved to < Grade 1 resume study drug (maintain 
dose level)  
x 
If at the end of the third week, the creatinine level has 
improved to a Grade 1 or has stabilized at Grade 2, 
resume study drug (decrease one dose level) 
Table 6: 
Dose Reduction and Modification Guidelines (Continued) 
NCI CTCAE Toxicity Grade 
Action 
 
x 
Upon resumption of study drug, evaluate subject 
weekly x 2 weeks to ensure creatinine level does not 
worsen; if creatinine level again worsens during those 
2 weeks, permanently discontinue and follow for PD 
Grade 3 
x 
Interrupt study drug 
x 
Evaluate subject weekly x 3 weeks  
x 
If during those 3 weeks, the creatinine level  
ZRUVHQHGDWDQ\WLPHWR!*UDGH or if dialysis is 
indicated, permanently discontinue and follow for PD 
x 
If at the end of the third week, the creatinine level has 
LPSURYHGWR*UDGHUHVXPHVWXG\GUXJGHFUHDVH
one dose level)  
x 
Upon resumption of study drug, evaluate subject 
weekly x 2 weeks to ensure creatinine level does not 
worsen; if creatinine level again worsens during those 
2 weeks, permanently discontinue and follow for PD 
x 
If at the end of the third week, the creatinine level has 
not improved to < Grade 3, permanently discontinue 
and follow for PD 
Grade 4 
OR 
if dialysis is indicated 
x 
Permanently discontinue and follow for PD 
Cairo-Bishop Toxicity Grade 
 
&OLQLFDO7/6*UDGH 
x 
Interrupt lenalidomide therapy. 
x 
May resume lenalidomide when the TLS resolves to < 
Grade 1 (decrease one dose level) 


Lenalidomide (CC-5013) 
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Table 6: 
Dose Reduction and Modification Guidelines (Continued) 
NCI CTCAE Toxicity Grade 
Action 
Chemistry value 
Action 
Lenalidomide Dose Modification 
x 
$/7!DQG[8/1 
AND 
x 
6HUXPWRWDOELOLUXELQPJG/
(~1.5 x ULN) 
x 
Continue current 
dose level 
x 
Test at next 
scheduled visit 
x 
None Required – continue 
current dose level. 
x 
$/7!DQG[8/1 
 
AND 
 
x 
6HUXPWRWDOELOLUXELQ!PJG/
(~1.5 x ULN) 
x 
Temporarily 
Discontinue 
lenalidomide  
x 
Re-test weekly until 
ALT and total 
bilirubin return to 
baseline 
x 
Resume the same dose of 
lenalidomide if recovery from 
the event is  d 14 days.   
x 
,IUHFRYHU\RFFXUV!GD\V
EXWGD\VWKHOHQDOLGRPLGH
dose should be decreased by 
one dose level, and weekly 
testing of liver functions 
should occur during that cycle.   
x 
If the event does not repeat, 
dose escalation or re-escalation 
may continue according to the 
protocol.  
x 
If the values do not return to 
baseline within 28 days, the 
medical monitor must be 
notified. 
x 
$/7![8/1 
 
AND/OR 
 
x 
6HUXPWRWDOELOLUXELQ!mg/dL 
(~1.5 x ULN) 
x 
Temporarily 
Discontinue 
lenalidomide  
x 
Re-test weekly until 
ALT and total 
bilirubin return to 
baseline 
x 
Resume the same dose of 
lenalidomide if recovery from 
the event is  d 14 days.  
x 
,IUHFRYHU\RFFXUV!GD\V
EXWGD\VWKHOHQDOLGomide 
dose should be decreased by 
one dose level, and weekly 
testing of liver functions 
should occur during that cycle.  
x 
If the event does not repeat, 
dose escalation or re-escalation 
may continue according to the 
protocol.   
x 
If the values do not return to 
baseline within 28 days, the 
medical monitor must be 
notified. 


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Table 6: 
Dose Reduction and Modification Guidelines (Continued) 
NCI CTCAE Toxicity Grade 
Action 
Other lenalidomide-related non-
hematologic AEs 
t Grade 3 
x 
Interrupt lenalidomide therapy. 
x 
May resume lenalidomide 
when the adverse event 
UHVROYHVWR*UDGHGHFUHDVH
one dose level or maintain dose 
level per the investigator’s 
discretion) 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
 the ANC is ȝ/ 
 the platelet count is ȝ/ 
 any other lenalidomide-related non-hematologic adverse event that may have 
occurred has resolved as indicated in Table 6. 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and 
a new cycle will not be initiated until the toxicity has resolved as described above. 
Dose interruptions/reductions are permitted for Grade 1 or 2 adverse events at the investigator’s 
discretion. 
If a study drug interruption has lasted for 5 weeks, the investigator should contact the medical 
monitor to discuss whether the subject should be continued on the study. 
Site staff are to contact Celgene to record new dose level and obtain new study drug assignment.  
If the treatment has been withheld and the next treatment cycle is delayed beyond 29 days after 
Day 1 of the prior treatment cycle, then Day 1 of the next treatment cycle will be defined as the 
first day that the treatment is resumed.  If dose reduction occurs within a cycle, subjects will be 
given a new 28-day supply bottle, subjects should begin taking study drug at the current cycle 
day (ie, if reduction occurs on Cycle Day 16, then the subject will take study drug from the new 
bottle for the remainder of the cycle).  Subjects will be required to return empty bottle or any 
unused drug prior to new drug being dispensed. 
Dose re-escalation is permitted if the subject is able to complete 2 full cycles at the reduced dose 
level without experiencing a DLT or other toxicity deemed to be unacceptable by the investigator 
or subject.  In the event the dose reduction is implemented due to Grade 4 neutropenia, subjects 
may be re-escalated after one full cycle at the lower dose level if the neutropenia resolves to a 
Grade 2 or better by the end of the cycle and no other DLT is observed.  If that dose level is 
again not tolerated, the subject should be de-escalated to the dose below and remain at that 
tolerated dose level for the rest of the study. 
Allopurinol Dose Adjustment Guidelines: 
Allopurinol should be permanently discontinued for any adverse reaction deemed possibly 
related to allopurinol administration.  


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For a Grade 1 or 2 rash, allopurinol should be discontinued prior to study drug to try to 
determine causality.  If the rash does not improve, the study drug should be adjusted per the 
investigator’s discretion. 
For a Grade 3 or 4 rash, allopurinol should be discontinued and study drug adjusted as outlined 
in Table 6.   
In the event of development of renal impairment, allopurinol should be discontinued and study 
drug adjusted as outlined in Table 6. 
For all other AEs, study drug should be adjusted as outlined above. 
10.3. 
Blinding 
This is now an open-label protocol.  Therefore the dose of study drug will be identified on the 
package labeling (Amendment #10). 
10.4. 
Emergency Unblinding 
This is now an open-label protocol.  Therefore the dose of study drug will be identified on the 
package labeling (Amendment #10).  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.6. 
Discontinuation from Treatment 
The following events are considered sufficient reasons for discontinuing a subject from study 
drug: 
x AEs that, in the judgment of the Investigator, may cause severe or permanent harm or 
which rule out continuation of study drug. 
x Disease progression with or without histologic transformation 
x Subject withdraws consent 


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x Subject lost to follow-up 
x Death 
x Protocol violation 
The reason for discontinuation should be recorded in the CRF and in the subject’s medical 
records. Celgene is to be notified of all discontinuations from study drug. 


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11. 
EMERGENCY PROCEDURES 
11.1. 
Emergency Contact 
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page). 
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page).  This global 
Emergency Call Center is available 24 hours and 7 days a week.  The representatives are 
responsible for obtaining your call-back information and contacting the on call Celgene/CRO 
Medical Monitor, who will then contact you promptly. 
Note:  The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 


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12. 
STUDY DRUG MATERIALS AND MANAGEMENT 
12.1. 
Supplier(s) 
Celgene Corporation will supply lenalidomide capsules. 
Celgene Corporation will no longer supply blinded allopurinol and matching placebo 
(Amendment #10). 
Celgene Corporation will no longer supply lenalidomide (Amendment #11). 
12.2. 
Dosage Form 
Lenalidomide will be supplied as 2.5 mg, 5 mg, and 10 mg capsules for oral administration.  
Subjects dose reduced to 7.5 mg dose level (as outlined in Section 10.2.1) will receive one 5.0 
mg capsule and one 2.5 mg capsule daily. 
12.3. 
Dosage Regimen 
Subjects will be randomized (1:1) via IVRS to receive the following: 
x Oral lenalidomide 2.5 mg capsule once daily on days 1-28 of the first 28 day cycle 
and if tolerated should be escalated starting with the second cycle to a 5 mg capsule 
once daily on days 1-28 of a 28 day cycle up to disease progression. 
Following 5 continuous cycles at the 5 mg dose level, subjects who are tolerating the 
5 mg dose level may be escalated to 10 mg once daily on days 1 through 28 of each 
28-day cycle up to disease progression. 
x Oral placebo capsule once daily every day for a 28 day cycle up to disease 
progression.  The placebo treatment arm is discontinued in amendment #10. 
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
12.4. 
Study Drug Packaging and Labeling 
Celgene Corporation will supply lenalidomide 2.5 mg, 5 mg, and 10 mg capsules for oral 
administration.  Subjects dose reduced to 7.5 mg dose level (as outlined in Section 10.2.1) will 
receive one 5.0 mg capsule and one 2.5 mg capsule daily. 
The lenalidomide study drug will be packaged in 28-count bottles.    
The label for study drug supplied by Celgene will bear Celgene’s name and address, the protocol 
number, EudraCT number (where required), product name, dosage form, and strength, 
medication identification/kit number, 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 and/or applicable 


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Subjects requiring dose reduction within a treatment cycle must return to the study site and 
return the empty bottles or any unused drug and a new bottle will be dispensed.  Subjects will be 
given a new 28-day supply bottle and should begin taking study drug at the current cycle day. 
12.5. 
Study Drug Receipt and Storage 
The Investigator(s) is responsible for taking an inventory of each shipment of study drug 
received, and comparing it with the accompanying study drug shipping order form.  The 
Investigator(s) will verify the accuracy of the information on the form and call Celgene to 
register the study medication received at the site. 
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 package label. 
12.6. 
Record of Administration 
Accurate recording of all study drug administration (including dispensing and dosing) will be 
made in the appropriate section of the subject’s CRF and source documents. 
12.7. 
Study Drug Accountability 
The Investigator(s) or designee(s) is responsible for accounting for all study drug that is issued to 
and returned by the subject during the course of the study. 
12.8. 
Study Drug Handling and Disposal 
FCBP should not handle or administer study drug unless they are wearing gloves. All patients 
should not extensively handle or open study drug capsules and should maintain storage of 
capsules in the packaging until ingestion. 
In investigational studies, study drug 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 patients.  Once 
trained these healthcare staff will counsel patients prior to study drug being dispensed to ensure 
that the patient has complied with all requirements including use of birth control and pregnancy 
testing (FCBP) and that the patient understands the risks associated with lenalidomide.  This step 
will be documented with a completed lenalidomide Education and Counseling Guidance 
Document (Appendix 22.6), and no drug will be dispensed until this step occurs. Counseling 
includes verification with the patient that required pregnancy testing was performed and results 
were negative. A Lenalidomide Information Sheet (Appendix 22.6) will be supplied with each 
study drug dispense.  
Celgene will instruct the Investigator(s) on the return or destruction of unused study drug.  If any 
study drug is lost or damaged, its disposition should be documented in the subject’s CRF and 
source documents.  Celgene will provide instructions for the return of study drug supplies at the 
end of the study. 


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13. 
ASSESSMENT OF EFFICACY 
13.1. 
Assessments 
x Survival/Date of death 
13.2. 
Methods and Timing of Efficacy Assessments 
Serial measurements of efficacy will be performed at baseline and at scheduled intervals 
throughout the duration of the study as outlined in Table 2.  All scheduled visits will have a ± 3 
day window unless otherwise stated. 


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14. 
ASSESSMENT OF SAFETY 
14.1. 
Assessments 
x Clinical laboratory evaluations: 
 Hematology: white blood cell (WBC), hemoglobin (HGB), hematocrit (HCT), 
platelet count, absolute neutrophil count (ANC), and absolute lymphocyte count 
(ALC) 
 Chemistry: calculated (method of Cockroft-Gault) creatinine clearance (screening 
only), potassium, calcium, phosphorus, creatinine, alkaline phosphatase, total 
bilirubin, AST/SGOT, ALT/SGPT, and uric acid 
x Pregnancy testing for FCBP: serum or urine beta-human chorionic gonadotropin 
hormone ȕ-HCG) pregnancy testing with a sensitivity of at least 25 mIU/mL is to be 
done on FCBP only 
 FCBP should be monitored during the course of the study and after the end of 
study therapy to: 
o Ensure that pregnancy tests are performed during the course of the study and 
after end of study therapy and are negative (see specifics in Appendix 22.6). 
o Ensure the patient continues to practice abstinence or remains on adequate 
contraception (see specifics in Appendix 22.6). 
o If a FCBP becomes pregnant treatment should be stopped and the patient 
referred to the appropriate physician 
x Male patients should be monitored during the course of the study and 28 days after 
the end of study therapy to: 
 Ensure they commit to continued abstinence from heterosexual contact or 
continue to use a condom during sexual contact with a FCBP 
 If a female partner of a male patient becomes pregnant she should be referred to 
an appropriate physician 
 
 
x AEs by NCI CTCAE Version 3.0 with modifications recommended by the IWCLL 
guidelines for the diagnosis and treatment of chronic lymphocytic leukemia 
 
 
x Second primary malignancies will be monitored as events of interest and should be 
included as part of the assessment of adverse events throughout the course of the 
study.  Investigators are to report any second primary malignancies as serious adverse 
events regardless of causal relationship to 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 survival follow up phase.   


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14.2. 
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 Table 2.  All scheduled visits will have a ± 3 
day window unless otherwise stated.  Abnormalities will be captured as adverse events.  The 
adverse event of flare reaction, which may mimic disease progression, may render the efficacy 
assessments not evaluable at the corresponding visit(s).  Cause of death is to be recorded in the 
CRF and the subject’s medical record. 
14.3. 
Recording and Reporting of Adverse Events 
The recording and reporting of adverse events is described in Appendix 22.1. 


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16. 
STATISTICAL ANALYSES 
16.1. 
Statistical Overview 
The objective of the statistical analysis will be to compare the efficacy and safety of 
lenalidomide versus placebo as maintenance therapy in subjects with relapsed or refractory 
B-cell chronic lymphocytic leukemia (CLL) having achieved PR or better after second-line 
therapy. 
Overall survival (OS) will be the primary endpoint for the protocol following amendment #10.  
This analysis will be performed at the completion of the study.  It is estimated that at least 160 
subjects across both treatment arms have died at the time of analysis (yielding 80% power to 
detect a 61.3% improvement in median OS for a two-sided test at 0.025 level allowing for one 
interim analysis).   
16.2. 
Study Population Definitions 
16.2.1. 
Intent-to-Treat Population 
The primary efficacy analysis will be performed on the intent-to-treat (ITT) population, which 
will include all subjects who were randomized. 
16.2.2. 
Safety Population 
All randomized subjects who receive any study drug will be included in the safety analyses. 
16.2.3. 
Subgroup Analyses 
In addition to analyses that include all subjects, analyses will be performed to compare 
treatments within the following stratification subgroups: 
x Response to second-line induction chemotherapy (PR, CRi or CR versus 
MRD-negative CR) 
x $JH\HDUVYHUVXV!\HDUV 
x Presence of at least one of the following poor prognostic factors:  11q deletion, 17p 
deletion, unmutated IgVH or ȕ0!PJ/ (Yes versus No versus Unknown) 
Additional subgroups may be examined, as needed based on regulatory and clinical requests. 
16.3. 
Efficacy Evaluation 
16.3.1. 
Primary Endpoint 
Overall Survival (OS) 
Overall survival is calculated as the time from randomization to death from any cause.  OS will 
be censored at the last date that the subject was known to be alive for subjects who were alive at 
the time of analysis and for subjects who were lost to follow-up before death was documented. 


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The analysis of OS will include survival information for all randomized subjects.  Subjects who 
discontinued from the treatment phase of the study and who had possibly received other 
anti-cancer therapies and then subsequently died will be included in the analysis as death.  
However, sensitivity analyses will be performed in which these subjects will be censored at the 
date of the first dose date of the anti-cancer therapy. 
16.3.2. 
Secondary Endpoint 
Progression Free Survival 2 (PFS2) 
PFS is defines as the time from randomization to the second objective disease progression, or 
death from any cause, whichever occurs first.  Patients alive and for whom a second objective 
disease progression has not been observed should be censored at the last time known to be alive 
and without second objective disease progression.  In situations where OS and PFS2 cannot 
reliably be determined, it may be possible to rule out significant lack of efficacy of further 
treatments by looking at the outcome of the next line therapy.  For this analysis, an event is 
defined as second objective disease progression, or death from any cause, or the start of the CLL 
therapy after next line treatment, whichever occurred first (EMEA guideline 13 DEC 2012).  
Various schemes will be assessed for missing data imputation if needed. 
16.3.3. 
Efficacy Analyses 
Kaplan-Meier product limit methods will be used to estimate the survivorship functions for the 
time-to-event endpoints (eg, OS, and PFS2).  A two-sided log-rank test stratified by the 3 strata 
used in the randomization will be used as the primary analytic method to compare survivorship 
functions for time-to-event variables in the 2 treatment groups.  In terms of the survivorship 
functions for each treatment group, the hypotheses of interest were: 
H0:  FA(t) =  FP(t) for all t 
Versus 
H1:  FP(t)  FA(t) for all t 
where FP is the survivorship function for placebo and FA is the survivorship function for 
lenalidomide. 
Median OS will be estimated using Kaplan-Meier estimates, and the 95% confidence intervals 
(CI) will be computed using the method of Brookmeyer and Crowley.  Hazard ratio will be 
calculated using Cox model stratified for the 3 strata (ie, response to second-line induction 
chemotherapy, age, and presence of at least one prognostic factor) to account for the stratified 
randomization.  The Cox model will also be used to identify prognostic factors. 
Cross-tabulations will be provided by treatment group to summarize improvements from the best 
response during induction therapy. 
16.4. 
Background and Demographic Characteristics 
Subjects’ age, weight, height, and other continuous demographic and baseline variables will be 
summarized using descriptive statistics (mean, standard deviation, minimum, and maximum), 
while performance status, gender, race, and other categorical variables will be summarized with 
frequency tabulations for each treatment group separately and pooled over both treatment 


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regimens. Medical history data will be summarized using frequency tabulations for each 
treatment arm separately and pooled over both arms. Individual subject listings will be provided. 
Homogeneity of these variables will be assessed by one-way analysis of variance for continuous 
measures and Fisher’s exact test for categorical measures. 
16.5. 
Study Drug 
Dosage statistics (mean, median, mode, standard deviation and final dose, dose at each 
evaluation) will be provided.  Reasons for discontinuation will be summarized. 
 
 
 
 
 
16.7. 
Safety Evaluation 
All subjects who receive at least one dose of study medication will be included in the safety 
analyses. 
Adverse events (AE) will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. The severity of the toxicities will be graded according to the 
NCI CTCAE version 3.0 whenever possible. 
The adverse event of infection will also be analyzed according to the grading system as 
recommended by the IWCLL guidelines for the diagnosis and treatment of CLL 
 
(Appendix 22.4). 
AE frequency will be tabulated by body system, MedDRA preferred term for each treatment 
regimen during the Treatment Phase.  In the by-subject analysis, a subject having the same event 
more than once will be counted only once.  AEs will be summarized by worst NCI CTCAE 
version 3.0 grade.  AEs leading to death or to discontinuation from treatment, events classified as 
NCI CTCAE version 3.0 Grade 3 or higher, study-drug-related events, serious adverse events 
(SAEs), and events of interest (including second primary malignancies) will be summarized 
separately. 
Laboratory data will be graded according to NCI CTCAE version 3.0 severity grade.  Cross 
tabulations will be provided to summarize frequencies of abnormalities. 
For vital sign and body weight data, means, medians, standard deviations, minimum, and 
maximum values will be provided. 
Graphical displays will be provided where useful to assist in the interpretation of results. 


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16.9. 
Sample Size and Power Considerations 
For OS, a 61.3% improvement in median survival from randomization, from 3 years for placebo 
to 4.83 years on lenalidomide is considered clinically relevant.  The OS is assumed to be 
exponential with a constant failure (hazard) rate.  When the total number of events is 
approximately 160 over both treatment arms, then a two-sided log-rank test with an overall 
significance level of 0.025 (allowing for one interim analysis) would have 80% power to detect a 
hazard rate ratio of 0.62 (that is, if the survival curves are exponential, to detect a 61.3% 
difference in the median OS in the 2 arms). To ensure timely completion of the study, 320 
subjects will be enrolled, 160 in each treatment arm.  Enrollment will close once 320 subjects are 
randomized or 160 adjudicated PFS events are reached, whichever comes first. 


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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1. 
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(s) and the staff.   Prior to enrolling subjects into the 
study, a Celgene representative will review the protocol, CRFs, procedures for obtaining 
informed consent, record keeping, and reporting of AEs with the Investigator(s).  Monitoring 
will include on-site visits with the Investigator(s) and his/her staff as well as any appropriate 
communications by mail, fax, or telephone.  At each monitoring visit, the facilities, study drug 
storage area, CRFs, subject’s source documents, and all other study documentation will be 
inspected/reviewed by the Celgene representative for adherence to the protocol and Good 
Clinical Practice. 
The monitor will review CRFs for completion and accuracy.  Accuracy will be checked by 
performing source data verification at each site visit that is a direct comparison of the entries 
made onto the CRF against the appropriate source documentation.  Any resulting discrepancies 
will be reviewed with the Investigator(s) and/or his/her staff.  Any necessary corrections will be 
made directly to the CRFs or via queries by the Investigator(s) and/or his/her staff. Monitoring 
procedures require that informed consents, adherence to inclusion/exclusion criteria, and 
documentation of SAEs and the proper recording be verified.  Additional monitoring activities 
may be outlined in a study-specific monitoring plan. 
17.2. 
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 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 subject participation for audits 
and inspections by Institutional Review Board/Independent Ethic Committees (IRB/IECs), 
regulatory authorities (eg, FDA, EMA, Health Canada) 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. 
17.3. 
Investigator(s) Responsibilities 
Investigator responsibilities are set out in the International Conference on Harmonisation (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. 


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The Investigator(s) is responsible for keeping a record of all subjects who sign an Informed 
Consent Form and are screened for entry into the study.  For those subjects who fail screening, 
the reason(s) for exclusion must be recorded in the subject’s source documents and in the IVRS 
system. 
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 subject’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 subject’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 subject’s records (eg, 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 subject’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. 


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18. 
REGULATORY CONSIDERATIONS 
18.1. 
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 (Appendix 22.2).  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 subjects, 
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 subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved by 
Celgene and the IRB/IEC prior to use. 
18.2. 
Protocol Amendments 
Any amendment to this protocol that seems appropriate, as the study progresses (eg, 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.  Celgene does not require that 
amendments that are administrative in nature receive IRB/IEC approval, but will be submitted to 
the IRB/IEC for information purposes.  If local IRB/IEC procedures require approval of 
administrative amendments, then study sites should follow local IRB/IEC regulations. 
18.3. 
Informed Consent 
The Investigator(s) must obtain informed consent of a subject 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 subject’s entry into the study and of 
the informed consent process should be recorded in the subject’s source documents.  The original 
consent form, signed and dated by the subject and by the person consenting the subject prior to 
the subject’s entry into the study, must be maintained in the Investigator’s study files and a copy 
given to the subject.  In addition, if a protocol is amended and it impacts on the content of the 
informed consent, the informed consent must be revised.  Subjects 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 subject and by the person 
consenting the subject must be maintained in the Investigator’s study files and a copy given to 
the subject. 
18.4. 
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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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
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, CRFs, source documents, original documents, data, 
records (eg, 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, filed and retained. 
19.2. 
Data Management 
Data will be entered into the clinical database as per Celgene SOPs. These data will be 
electronically verified through use of on-line checks during data entry, and through 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, in the form of a 
Data Clarification Form (DCF).  Resolutions to these issues will be reflected in the database.  An 
audit trail within the system will track all changes made to the data.  A quality control audit will 
be performed per Celgene SOP(s). 
19.3. 
Retention of Records 
The investigator(s) must maintain records of all study documents and supporting information 
relating to the conduct of the study.  This documentation includes, but is not limited to, 
protocols, case report forms, advertising for subject participation, adverse event reports, subject 
source data, correspondence with health authorities and IRBs/IECs, informed consent forms, 
investigator(s) curricula vitae, monitoring visit logs, laboratory reference ranges, laboratory 
certification or quality control procedures, and laboratory director curriculum vitae.  Subject 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 must be consulted if the 
investigator(s) wishes to assign the study files to someone else, remove them to another location 
or is unable to retain them for a specified period. 
For studies conducted in the United States under a US Investigational New Drug (IND), the 
investigator(s) must retain the study records for a minimum of 2 years after a marketing 
application for the indication is 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 (ie, the IND) is discontinued, and FDA is notified of 
that fact.  For IND studies conducted outside the US, the investigator(s), must retain study 
records for the time period described above or according to local laws or requirements, 
whichever is longer.  The monitor will inform the investigator(s) of the dates for retention.  All 
study documents should be made available if required by relevant health authorities.  For studies 
not conducted under the US IND, the investigator(s) 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 


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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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20. 
PREMATURE DISCONTINUATION OF THE STUDY 
20.1. 
Single Site 
The responsible clinical Investigator as well as Celgene have 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: 
x Unsatisfactory enrollment with respect to quantity or quality 
x Inaccurate or incomplete data collection 
x Falsification of records 
x Failure to adhere to the study protocol 
20.2. 
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 (eg, IRB/IEC, 
regulatory authorities, etc.). 


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22. 
APPENDICES 
22.1. 
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 subject during the course of a study.  It may be a new 
intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment 
of the subject’s health, including laboratory test values (as specified by the criteria below), 
regardless of etiology. Any medical condition that was present 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 an AE.  A diagnosis or syndrome should be 
recorded on the AE page of the electronic Case Report Form rather than the individual signs or 
symptoms of the diagnosis or syndrome. 
All AEs will be recorded by the Investigator(s) from the time of signing of informed consent 
form to 30 days after the treatment discontinuation visit.  All AEs that lead to study 
discontinuation should be followed until resolution or stabilization.  AEs will be recorded on the 
AE page of the CRF and in the subject’s source documents. 
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: 
x Results in discontinuation from the study. 
x Requires treatment, modification/interruption of study drug dose, or any other 
therapeutic intervention. 
x Is judged by the Investigator(s) to be of significant clinical importance. 
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. 
Please note that all Grade 3 hematologic lab abnormalities must be reported as an Adverse 
Event on the AE page of the CRF.   
Serious adverse event 
A serious adverse event (SAE) is any AE which: 
x Results in death 
x Is life-threatening (ie, in the opinion of the Investigator[s] the subject is at immediate 
risk of death from the AE) 
x Requires inpatient hospitalization or prolongation of existing hospitalization 
x Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions) 
x Is a congenital anomaly/birth defect 


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x Constitutes an important medical event 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious. 
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events.  This includes any second primary malignancy, regardless of causal 
relationship to study medication, occurring at any time for the duration of the study, from the 
time of signing the ICF up to and including any follow-up, observation and/or survival follow-up 
period.  In this study, subjects will be followed until all subjects in the study have been followed 
for at least 5 years from the last randomization, October 2020  (or have died/become lost to 
follow-up before 5 years).  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 of the diagnosis of the second primary malignancy 
must be provided at the time of reporting as a serious adverse event (eg, any confirmatory 
histology or cytology results).    
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. 
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 subject’s symptoms according to National 
Cancer Institute (NCI) Common Terminology Criteria (CTCAE, Version 3.0) with the 
exceptions recommended by the IWCLL guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia 
  AEs will be evaluated for severity according to the 
following scale: 
Grade 1 = Mild 
Grade 2 = Moderate 
Grade 3 = Severe 
Grade 4 =  Life Threatening or disabling AE 
Grade 5 =  Death 


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The following exceptions will be made as recommended by the IWCLL guidelines for the 
diagnosis and treatment of chronic lymphocytic leukemia 
 as listed below*: 
Grade# 
Decrease in Platelets* or Hb° (nadir) 
From Pretreatment value (%) 
Absolute neutrophil count/ȝL@ (nadir) 
0 
No change to 10% 
 
1 
11% - 24% 
DQG 
2 
25% - 49% 
DQG 
3 
50% - 74% 
DQG 
4 
 
< 500 
* Platelet counts must be below normal levels for grades 1-4.  If, at any level of decrease the platelet count is < 
ȝ/WKLVZLOOEHFRQVLGHUHGJUDGHWR[LFLW\XQOHVVDVHYHUHRUOLIH-threatening decrease in the initial 
SODWHOHWFRXQWHJȝ/ZDVSUHVHQWSUHWUHDWPHQWLQZKLFKFDVHWKHSDtient is not evaluable for toxicity 
referable to platelet counts. 
° Hb levels must be below normal levels for grades 1-4.  Baseline and subsequent Hb determinations must be 
performed before any given transfusions.  The use of erythropoietin is irrelevant for the grading of toxicity, but 
should be documented. 
# Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal.  Death occurring as a result of toxicity at any 
level of decrease from pretreatment will be recorded as grade 5. 
@ If the absoluWHQHXWURSKLOFRXQW$1&UHDFKHVOHVVWKDQȝ/LWVKRXOGEHMXGJHGWREHJUDGHWR[LFLW\
Other decreases in the white blood cell count, or in circulating granulocytes, are not to be considered, since a 
decrease in the white blood cell count is a desired therapeutic end point.  A gradual decrease in granulocytes is not 
DUHOLDEOHLQGH[LQ&//IRUVWHSZLVHJUDGLQJRIWR[LFLW\,IWKH$1&ZDVOHVVWKDQȝ/SULRUWRWKHUDS\WKH
patient is not evaluable for toxicity referable to the ANC.  The use of G-CSF is irrelevant for the grading toxicity, 
but should be documented. 
Grade 4 hematologic abnormalities are expected in patients with CLL, and are also observed in 
patients receiving lenalidomide. During the conduct of CC-5013-CLL-002, all Grade 4 
laboratory abnormalities will be reported to Celgene Drug Safety as SAEs at the discretion of the 
investigator and recorded in the CRF as SAEs, however those that are not deemed by the 
investigator to be part of a diagnosis or syndrome will not reported to the Health Authorities in 
an expedited manner.  Laboratory values will be captured within the study database and will be 
reviewed on an ongoing basis by the sponsor and (provided that it is determined that any 
observed individual abnormalities or patterns of abnormalities do not warrant prompt 
communication to Health Authorities) will be reported to Health Authorities in periodic safety 
reports. 
Please note that all Grade 3 hematologic lab abnormalities must be reported as an Adverse 
Event on the AE page of the CRF.   
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 


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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. 
Monitoring and reporting of adverse events 
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. 
Immediate reporting of serious adverse events 
Any AE that meets the criterion for a SAE requires the completion of a 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 subject’s treatment discontinuation visit, and those made known to the 
investigator(s) at anytime that are suspected of being related to study drug. 
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events.  This includes any second primary malignancy, regardless of causal 
relationship to study medication, occurring at any time for the duration of the study, from the 
time of signing the ICF up to and including any follow-up, observation and/or survival follow-up 
period.  In this study, subjects will be followed until all subjects in the study have been followed 
for at least 5 years from the last randomization, October 2020 (or have died/become lost to 
follow-up before 5 years).  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 of the diagnosis of the second primary malignancy 
must be provided at the time of reporting as a serious adverse event (eg, any confirmatory 
histology or cytology results).    
Grade 4 hematologic abnormalities are expected in patients with CLL, and are also observed in 
patients receiving lenalidomide.  The investigator will use their judgement to classify the 
seriousness of laboratory abnormality events.  Laboratory values will be captured within the 
study database and will be reviewed on an ongoing basis by the sponsor and (provided that it is 
determined that any observed individual abnormalities or patterns of abnormalities do not 
warrant prompt communication to Heath Authorities) will be reported to Health Authorities in 
periodic safety reports. 
The SAE must be reported (ie, within 24 hours of the Investigators’ knowledge of the event) to 
the Celgene 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 the Safety Monitor (see below for 
contact information). 


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The SAE report should provide a detailed description of the SAE and include copies of hospital 
records and other relevant documents.  If a subject 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 subject’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). 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject or the female partner of a male subject occurring while the 
subject is on study drug, or within 28 days of the treatment discontinuation visit, are considered 
immediately reportable events.  Study drug is to be discontinued immediately and the subject 
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 the Celgene Safety Monitor 
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 subject until completion of the pregnancy, and must 
notify Celgene Safety of the outcome of the pregnancy as a follow-up to the initial SAE report. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (ie, 
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 (ie, report the event 
to Celgene Safety by facsimile within 24 hours of the Investigator’s knowledge of the event). 
In the case of a live “normal” birth, the Celgene Safety Monitor should be advised by telephone 
and 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 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 subject’s continued 
participation in the study will be determined by the Investigator(s) and the Celgene Medical 
Monitor. 
Expedited Reporting of Adverse Events 


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For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
reported events suspected of being related to lenalidomide based on the Investigator Brochure. 
Celgene Global Drug Safety will use the German Summary of Product Characteristics (SmPC) 
as the safety reference document for allopurinol. 
For countries within the European Union, Celgene will report in an expedited manner to 
Regulatory Authorities and Ethics Committees concerned, AEs in accordance with the Detailed 
Guidance on 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: 
x Any AE associated with the use of study drug in this study or in other studies that is 
both serious and unexpected, ie, suspected unexpected serious adverse reaction 
(SUSAR).  Note that such cases from blinded studies will be unblinded for reporting 
purposes. 
x Any finding from tests in laboratory animals that suggests a significant risk for 
human study subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
Where required by local legislation, 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 19.3 for records retention information). 


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22.2. 
Declaration of Helsinki 
Celgene operates in accordance with the general ethical principles outlined in the Declaration of 
Helsinki. 


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22.3. 
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 our work of a light or sedentary nature, eg, light housework, 
office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair 
5 
Dead 


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22.6. 
Pregnancy Prevention Risk Management Plans 
22.6.1. 
Lenalidomide Pregnancy Prevention Risk Management Plan 
22.6.1.1. Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials 
Appendix 22.6.1 applies to all patients receiving lenalidomide therapy.  The following 
Pregnancy Risk Minimisation Plan documents are included in this appendix:  
1) Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods (Section 22.6.2);  
2) Lenalidomide Education and Counseling Guidance Document (Section 22.6.2.1);    
3) Lenalidomide Information Sheet (Section 22.6.2.2). 
 
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods document (Section 22.6.2) provides the following 
information: 
x Potential risks to the fetus associated with lenalidomide exposure 
x Definition of Female of Childbearing Potential 
x Pregnancy testing requirements for patients receiving Lenalidomide who are females 
of childbearing potential 
x Acceptable birth control methods for both female of childbearing potential and male 
patients receiving Lenalidomide in the study  
x Requirements for counseling of all study patients receiving Lenalidomide about 
pregnancy precautions and the potential risks of fetal exposure to lenalidomide 
2. The Lenalidomide Education and Counseling Guidance Document (Section 22.6.2.1) 
must be completed and signed by either a trained counselor or the Investigator at the 
participating clinical center prior to each dispensing of lenalidomide study treatment. A 
copy of this document must be maintained in the patient records. 
3. The Lenalidomide Information Sheet (Section 22.6.2.2) will be given to each patient 
receiving lenalidomide study therapy. The patient must read this document prior to 
starting lenalidomide study treatment and each time they receive a new supply of study 
drug. 


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22.6.2. 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods 
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.  The teratogenic effect of lenalidomide in 
humans cannot be ruled out.  Therefore, a risk minimization plan to prevent pregnancy must be 
observed. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has 
not undergone a hysterectomy or bilateral oophorectomy or 2) 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). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following 
are met (ie, all females of childbearing potential must be counseled concerning the following 
risks and requirements prior to the start of lenalidomide study therapy):  
x She understands the potential teratogenic risk to the unborn child 
x She understands the need for effective contraception, without interruption, 4 weeks 
before starting study treatment, throughout the entire duration of study treatment, 
dose interruption and 28 days after the end of study treatment 
x She should be capable of complying with effective contraceptive measures 
x 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 
x She understands the need to commence the study treatment as soon as study drug is 
dispensed following a negative pregnancy test 
x She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol (Section 22.6.2) 
x She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
The investigator must ensure that for females of childbearing potential: 
x Complies with the conditions for pregnancy risk minimization, including 
confirmation that she has an adequate level of understanding 
x Acknowledge the aforementioned requirements 


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For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (ie, all females NOT of childbearing potential must be counseled concerning 
the following risks and requirements prior to the start of lenalidomide study therapy):  
x She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
Traces of lenalidomide have been found in semen.  Male patients 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 study therapy): 
x Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a female of childbearing potential 
x 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 female of childbearing 
potential.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 
contact during the following time periods related to this study: 1) for at least 28 days before 
starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 
28 days after study treatment discontinuation. 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:   
x Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (birth control pills, injections, implants) 
 Tubal ligation 
 Partner’s vasectomy 
x Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
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 patients with neutropenia.  


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Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Before starting study drug 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to 
starting study drug.  The first pregnancy test must be performed within 10 to 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 study doctor has verified 
that the results of these pregnancy tests are negative. 
Male Patients: 
Must practice complete abstinence or agree to use a condom during sexual contact with a 
pregnant female or a female of childbearing potential while participating in the study, during 
dose interruptions and for at least 28 days following study drug discontinuation, even if he has 
undergone a successful vasectomy. 
During study participation and for 28 days following study drug discontinuation  
Female Patients: 
x FCBP 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 on study, at 
study discontinuation, and at day 28 following study drug discontinuation. If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 
28 days and then every 14 days while on study, at study discontinuation, and at days 
14 and 28 following study drug discontinuation. 
x At each visit, the Investigator must confirm with the FCBP that she is continuing to 
use two reliable methods of birth control. 
x 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 study patient, study drug must be immediately 
discontinued.  
x Pregnancy testing and counseling must be performed if a patient misses her period or 
if her pregnancy test or her menstrual bleeding is abnormal.  Study drug treatment 
must be discontinued during this evaluation. 
x Females must agree to abstain from breastfeeding during study participation and for 
at least 28 days after study drug discontinuation. 
Male Patients: 
x Counseling about the requirement for complete abstinence or condom use during 
sexual contact with a pregnant female or a female of childbearing potential and the 


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potential risks of fetal exposure to lenalidomide must be conducted at a minimum of 
every 28 days.  
x If pregnancy or a positive pregnancy test does occur in the partner of a male study 
patient during study participation, the investigator must be notified immediately. 
Additional precautions 
x Patients should be instructed never to give this medicinal product to another person 
and to return any unused capsules to the study doctor at the end of treatment. 
x Female patients should not donate blood during therapy and for at least 28 days 
following discontinuation of study drug. 
x Male patients should not donate blood, semen or sperm during therapy or for at least 
28 days following discontinuation of study drug. 
x Only enough study drug for one cycle of therapy may be dispensed with each cycle of 
therapy.  
 
 


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22.6.2.1. Lenalidomide Education and Counseling Guidance Document   
To be completed prior to each dispensing of study drug. 
Protocol Number: ____________________________________________ 
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
(Check the appropriate box to indicate risk category) 
Female:    Ƒ 
If female, check one: 
 FCBP (Female of childbearing potential): sexually mature female who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy 
(the surgical removal of both ovaries) or 2) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at 
least 24 consecutive months (ie, has had menses at any time during the preceding 24 
consecutive months) 
 NOT FCBP 
Male:  
  Ƒ 
 
Do Not Dispense study drug if: 
x The patient is pregnant. 
x No pregnancy tests were conducted for a FCBP. 
x The patient states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence of heterosexual contact) [at least 28 days prior to 
therapy, during therapy and during dose interruption]. 
FCBP: 
1. I verified that the required pregnancy tests performed are negative. 
2. I counseled FCBP regarding the following: 
x Potential risk of fetal exposure to lenalidomide:  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.  The teratogenic potential of 
lenalidomide in humans cannot be ruled out.  FCBP must agree not to become 
pregnant while taking lenalidomide.  
x Using TWO reliable methods of birth control at the same time or complete abstinence 
from heterosexual contact [at least 28 days prior to therapy, during therapy, during 
dose interruption and 28 days after discontinuation of study drug]. 
x That even if she has amenorrhea she must comply with advice on contraception.  


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x Use of one highly effective method and one additional method of birth control AT 
THE SAME TIME. The following are examples of highly effective and additional 
effective methods of contraception: 
 Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
 Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
x Pregnancy tests before and during treatment, even if the patient agrees not to have 
reproductive heterosexual contact.  Two pregnancy tests will be performed prior to 
receiving study drug, one within 10 to 14 days and the second within 24 hours of the 
start of study drug. 
x Frequency of pregnancy tests to be done: 
 Every week during the first 28 days of this study and a pregnancy test every 28 
days during the patient’s participation in this study if menstrual cycles are regular 
or every 14 days if cycles are irregular.  
 If the patient missed a period or has unusual menstrual bleeding. 
 When the patient is discontinued from the study and at day 28 after study drug 
discontinuation 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 study drug discontinuation. 
x Stop taking study drug immediately in the event of becoming pregnant and to call 
their study doctor as soon as possible. 
x NEVER share study drug with anyone else. 
x Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
x Do not breastfeed a baby while participating in this study and for at least 28 days after 
study drug discontinuation. 
x Do not break, chew, or open study drug capsules. 
x Return unused study drug to the study doctor. 
3. Provide Lenalidomide Information Sheet to the patient. 


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FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT LEAST 24 CONSECUTIVE 
MONTHS, A HYSTERECTOMY, OR BILATERAL OOPHORECTOMY): 
1. I counseled the female NOT of child bearing potential regarding the following: 
x Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP) 
x NEVER share study drug with anyone else. 
x Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
x Do not break, chew, or open study drug capsules. 
x Return unused study drug capsules to the study doctor. 
2. Provide Lenalidomide Information Sheet to the patient. 
MALE: 
1. I counseled the Male patient regarding the following: 
x Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP). 
x To engage in complete abstinence or use a condom when engaging in sexual contact 
(including those who have had a vasectomy) with a pregnant female or a female of 
childbearing potential, while taking study drug, during dose interruptions and for 28 
days after stopping study drug. 
x Males should notify their study doctor when their female partner becomes pregnant 
and female partners of males taking study drug should be advised to call their 
healthcare provider immediately if they get pregnant. 
x NEVER share study drug with anyone else. 
x Do not donate blood, semen or sperm while taking study drug and for 28 days after 
stopping study drug. 
x Do not break, chew, or open study drug capsules. 
x Return unused study drug capsules to the study doctor.  
2. Provide Lenalidomide Information Sheet to the patient. 
 
Investigator/Counselor Name (Print): ____________________  
  (circle applicable) 
 
Investigator/Counselor Signature: _______________________  
Date: _____/_____/_____ 
  (circle applicable) 
**Maintain a copy of the Education and Counseling Guidance Document in the patient records.**  


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22.6.2.2. Lenalidomide Information Sheet  
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
Please read this Lenalidomide Information Sheet before you start taking study drug 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.  Lenalidomide has not been tested in pregnant 
women but may also cause birth defects.  Findings from a monkey study indicate that 
lenalidomide caused birth defects in the offspring of female monkeys who received the 
drug during pregnancy.   
If you are a female who is able to become pregnant: 
x Do not take study drug if you are pregnant or plan to become pregnant 
x You must practice complete abstinence or use two reliable, separate forms of 
effective birth control at the same time:  
 for 28 days before starting study drug 
 while taking study drug 
 during dose interruptions of study drug 
 for 28 days after stopping study drug  
x You must have pregnancy testing done at the following times: 
 within 10 to 14 days and again 24 hours prior to the first dose of study drug 
 weekly for the first 28 days 
 every 28 days after the first month or every 14 days if you have irregular 
menstrual periods 
 if you miss your period or have unusual menstrual bleeding 
 28 days after the last dose of study drug (14 and 28 days after the last dose if 
menstrual periods are irregular) 
x Stop taking study drug if you become pregnant during treatment 
 If you suspect you are pregnant at any time during the study, you must stop study 
drug immediately and immediately inform your study doctor.  Your study doctor 
will report all cases of pregnancy to Celgene Corporation 
x Do not breastfeed while taking study drug  


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x The study doctor will be able to advise you where to get additional advice on 
contraception.   
If you are a female not of childbearing potential: 
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: 
Lenalidomide is detected in trace quantities in human semen. The risk to the foetus in 
females of childbearing potential whose male partner is receiving lenalidomide is 
unknown at this time. 
x Male patients (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 study drug 
 During dose interruptions of study drug   
 For 28 days after you stop taking study drug 
x Male patients should not donate sperm or semen while taking study drug and for 
28 days after stopping study drug. 
x 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 get pregnant.   
2. Restrictions in sharing study drug and donating blood: 
x Do not share study drug with other people. It must be kept out of the reach of 
children and should never be given to any other person. 
x Do not donate blood while you take study drug and for 28 days after stopping study 
drug. 
x Do not break, chew, or open study drug capsules. 
x You will get no more than a 28-day supply of study drug at one time. 
x Return unused study drug 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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– SUMMARY OF CHANGES – 
AMENDMENT NO. 11 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL-GROUP STUDY OF THE EFFICACY AND SAFETY 
OF LENALIDOMIDE (REVLIMID®) AS MAINTENANCE THERAPY FOR 
PATIENTS WITH B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA 
FOLLOWING SECOND-LINE THERAPY  
(THE CONTINUUM TRIAL) 
 
INVESTIGATIONAL PRODUCT (IP): 
 
Lenalidomide 
PROTOCOL NUMBER: 
 
CC-5013-CLL-002 
ORIGINAL DATE: 
 
15 Jan 2008 
AMENDMENT No. 11 DATE: 
 
16 March 2018 
EudraCT NUMBER: 
 
2007-0016-26-27 
IND NUMBER:  
 
060100 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
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 


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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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A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP 
STUDY OF THE EFFICACY AND SAFETY OF 
LENALIDOMIDE (REVLIMID®) AS MAINTENANCE 
THERAPY FOR PATIENTS WITH B-CELL CHRONIC 
LYMPHOCYTIC LEUKEMIA FOLLOWING SECOND-
LINE THERAPY  
(THE CONTINUUM TRIAL) 
STUDY DRUG: 
 Lenalidomide 
PROTOCOL NUMBER: 
 CC-5013-CLL-002 
EUDRACT NUMBER: 
 2007-001626-27 
DATE FINAL: 
 15 January 2008 
AMENDMENT 
#11: 
 
 16 March 2018 
 
 
 
              
 
 
 
 
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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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Original Protocol:  15 January 2008 
Amendment #1:  12 August 2008 
Amendment #2:  23 September 2008 
Amendment #3:  17 October 2008 
Amendment #4:  6 May 2009 
Amendment #5:  28 June 2010  
Amendment #6:  4 May 2011 
Amendment #7:  7 October 2011 
Amendment #8:  4 October 2012 
Amendment #9:  24 April 2015 
Amendment #10:  13 May 2016 
Amendment #11:  16 March 2018 
 
 
 
 
Signature of Coordinating Principal Investigator 
 
dd/mmm/yy 
 
 
 
Printed Name of Coordinating Principal Investigator 
and Title 
 
 
Site Number________ 
By my signature, I agree to supervise and oversee the conduct of this study and to 
ensure its conduct is in compliance with the protocol, informed consent, Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, International Conference on 
Harmonisation (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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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Original Protocol:  15 January 2008 
Amendment #1:  12 August 2008 
Amendment #2:  23 September 2008 
Amendment #3:  17 October 2008 
Amendment #4:  6 May 2009 
Amendment #5:  28 June 2010 
Amendment #6:  4 May 2011 
Amendment #7:  7 October 2011 
Amendment #8:  4 October 2012 
Amendment #9:  24 April 2015 
Amendment #10:  13 May 2016 
Amendment #11:  16 March 2018 
 
 
 
 
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/IEC 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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adverse events (SAEs), and any new SAEs or AEs related to study procedures or prior 
maintenance therapy.   
Subjects randomized to the placebo arm and currently on treatment at the time of Amendment 
#10 and patients who previously discontinued from the study drug and will be followed every 
24 weeks for survival, subsequent CLL therapies, response to next therapy and progression 
following next therapy, and second primary malignancies.  Subjects will be followed until all 
subjects in the study have been followed for at least 5 years from the last randomization, 
October 2020 (or have died/become lost to follow-up before 5 years).  
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
Screening 
Subjects will sign informed consent prior to undergoing any study-related procedures. 
Screening assessments for protocol eligibility will be performed within 28 days prior to 
randomization as outlined in Table 2: Schedule of Assessments.  Subjects who develop PD 
during screening will not be eligible to enroll into this study. 
All subjects will undergo both bone marrow aspirate and bone marrow biopsy procedures 
during screening.  MRD status will be assessed by peripheral blood and bone marrow flow 
cytometry at entry into the study for those subjects who achieved a complete response (CR) to 
second-line induction therapy.  Peripheral blood flow cytometry will be performed for all 
subjects at entry to confirm disease diagnosis by immunophenotyping and to perform immune 
cell (NK and T cell) analyses.  If subjects enter the study with MRD negativity, the disease 
diagnosis will be confirmed based on prior flow cytometry (documentation needed).  MRD 
status, immunophenotyping, and immune cell analyses will be performed at a central 
laboratory.   
A peripheral blood sample for direct antiglobulin test (DAT) will be collected during screening 
and analyzed at a central laboratory. 
Before randomization, subjects will be tested for cytogenetics by FISH, IgVH mutational status, 
and β2M.  The β2M test will be performed during screening using a peripheral blood sample 
and analyzed at a central laboratory. 
FISH and IgVH testing will be performed prior to second line, during second line, in the 
interval between second-line therapy, and screening or during the screening period using a 
peripheral blood sample.  Because test results cannot be obtained during screening or between 
second line and screening in some subjects who achieve a good response due to the limited 
number of remaining CLL cells, we recommend conducting the FISH and IgVH tests preferably 
prior to second line or during second line.   
Samples for FISH and IgVH will be analyzed at a central laboratory. 
If tests do not yield results, subjects can be randomized and stratified based on historical data. 
Those subjects for whom results were not obtainable pre-randomization and for whom no 
historical data were available will be enrolled and grouped separately. 
During screening, CT scans of the chest, abdomen and pelvis will also be performed for all 
subjects; in particular, they will be used to document the status (PR or CR) of subjects entering 
the study.   
If, during the screening period, the subject has a correctable event that prevents randomization 
and the event cannot be corrected within the 28 day screening period, the subject may be re-


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screened; however, the CT scans and bone marrow aspirate and biopsy will not need to be 
repeated if those tests were implemented within 56 days prior to randomization and the 
subject’s clinical status remains the same. 
Randomization 
Randomization must occur no less than 8 weeks (56 days) and no greater than 20 weeks (140 
days) from the last day of the last cycle of second-line induction therapy received by the 
subject in order for the subject to be eligible for enrollment into this study.  Subjects meeting 
all eligibility criteria will be randomized (1:1) in a double-blind manner to receive maintenance 
therapy with either lenalidomide or placebo up to disease progression.  The randomization 
procedure will be accomplished by a validated interactive voice response system (IVRS).  
Subjects will be stratified at randomization by: 1) their response to second-line induction 
therapy (PR, nPR, CRi or CR versus MRD-negative CR); 2) age (≤ 70 versus > 70 years); and 
3) presence of at least one of the following poor prognostic factors:  11q deletion, 17p deletion, 
unmutated IgVH or β2M > 4.0 mg/L (Yes versus No versus Unknown).   
Maintenance Therapy 
Study treatment for each subject begins on the same day the subject undergoes randomization.  
Study visits and serial measurements of safety and efficacy during maintenance therapy will be 
performed as outlined in Table 2.  Lenalidomide is administered orally.  Subjects will receive 
lenalidomide 2.5 mg once daily on Days 1 through 28 of the first 28-day cycle.  If the 2.5 mg 
dose is well tolerated (subject does not experience any Grade 3 or 4 study drug-related 
toxicities or any other toxicity [Grade 1 or 2] found to be unacceptable by the investigator or 
the subject), subjects should be escalated starting at the second cycle to 5 mg once daily on 
Days 1 through 28 of each 28-day cycle up to disease progression or 
 
  If a subject develops a Grade 1 or 2 adverse event, the drug may be 
interrupted until resolution, however the subject must complete one full cycle at the 2.5 mg 
dose level prior to escalation to the 5 mg dose level. 
Subjects who complete 5 continuous cycles at the 5 mg dose level without experiencing any 
Grade 3 or 4 study drug-related toxicities and without experiencing any other toxicity (Grade 1 
or 2) found to be unacceptable by the investigator may be escalated to 10 mg once daily on 
Days 1 through 28 of each 28-day cycle up to disease progression 
 
 
Dose interruptions/reductions are permitted for Grade 1 or 2 adverse events at the 
investigator’s discretion.  A guideline for the reduction of the dose of lenalidomide for dose-
limiting toxicity (DLT) is provided (see Section 10.2.1).  Dose re-escalation is permitted if the 
subject is able to complete 2 full cycles at the reduced dose level without experiencing a DLT 
or other toxicity deemed to be unacceptable by the investigator or subject.  In the event the 
dose reduction is implemented due to Grade 4 neutropenia, subjects may be re-escalated after 
one full cycle at the lower dose level if the neutropenia resolves to a Grade 2 or better by the 
end of the cycle and no other DLT is observed.  If that dose level is again not tolerated, the 
subject should be de-escalated to the dose below and remain at that tolerated dose level for the 
rest of the study. 
Subjects randomized to the lenalidomide treatment arm will continue to receive study 
lenalidomide maintenance therapy until PD develops 
 
  Progressive disease is characterized by at least one of the following: 
• 
Lymphadenopathy.  Progression of lymphadenopathy discovered by physical 
examination.  Disease progression occurs if one of the following events is 
observed: 


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- Appearance of any new lesion such as enlarged lymph nodes (> 1.5 cm), 
splenomegaly, hepatomegaly or other organ infiltrates. 
- An increase by 50% or more in greatest determined diameter of any previous 
site.   
• 
An increase in the previously noted enlargement of the liver or spleen by 50% or 
more or the de novo appearance of hepatomegaly or splenomegaly. 
• 
An increase in the number of blood lymphocytes by 50% or more with at least 
5,000 B lymphocytes per μL. 
• 
Transformation to a more aggressive histology (eg, Richter’s syndrome).  
Whenever possible, this diagnosis should be established by lymph node biopsy. 
• 
Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to 
CLL 
• 
During therapy:  cytopenias may occur as a side effect of many therapies and 
should be assessed according to Table 4.  During therapy, cytopenias cannot be 
used to define disease progression. 
• 
Post treatment:  The progression of any cytopenia (unrelated to autoimmune 
cytopenia), as documented by a decrease of hemoglobin levels by more than 2 
g/dL or to less than 10 g/dL, or by a decrease of platelet counts by more than 50% 
or to less than 100,000/μL, which occurs at least 3 months after treatment, defines 
disease progression, if the marrow biopsy demonstrates an infiltrate of clonal CLL 
cells. 
Tumor response, including PD, will be assessed according to the International Workshop on 
Chronic Lymphocytic Leukemia (IWCLL) guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia 
.  The severity of AEs will be graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 3.0 with modifications as noted in Section 10.2.1 of the protocol. 
Local hematology and chemistry tests will be performed for patient management/treatment 
decisions. 
Bone marrow aspirate and biopsy specimens obtained from each subject will be reviewed 
centrally prior to randomization. All repeat bone marrow aspirate and biopsy assessment will 
be completed at the discretion of the investigators and assessed locally.  The bone marrow 
aspirate and biopsy assessment is removed as part of protocol amendment #10.   
The CT scans of the chest, abdomen and pelvis will be performed for all subjects at baseline.  
All repeat CT scan assessment will be completed at the discretion of the investigator and 
assessed locally.  The CT scan assessment is removed as part of protocol amendment #10.  
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
 
Prophylaxis for Tumor Lysis Syndrome (TLS), thromboembolism and infection and treatment 
of tumor flare reaction (TFR) 
TLS prophylaxis, comprising of oral hydration and allopurinol 300 mg/day will be initiated 3 
days prior to starting maintenance therapy and for a minimum of the first treatment cycle at 


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each dose level for those subjects entering the study with a PR to their second-line induction 
therapy.  Subjects with a known allergy to allopurinol and a PR will be excluded from 
the study.  Please refer to Section 10.2.1 for further guidance on allopurinol modification in 
the event of an adverse event.  If a subject is taking allopurinol for a condition other than for 
TLS prophylaxis, the subject should be continued on the allopurinol prescribed by their 
physician and the dose titrated to 300 mg/day.  If, at any time, the allopurinol being taken for 
reasons other than TLS prophylaxis is discontinued and prophylaxis is still required per 
protocol, the subject should be administered commercial allopurinol.  To maintain fluid intake, 
subjects must be instructed to drink 8 to 10 eight ounce (240 mL) glasses of water each day for 
the first 14 days of Cycle 1 and the first cycle of each dose escalation.  Hydration levels should 
be adjusted according to age and clinical status, and lowered if the subject’s cardiovascular 
status indicates the possibility of volume overload.  At the investigator’s discretion, allopurinol 
prophylaxis may be omitted for subjects entering the study with a CR; however subjects must 
be advised of the need for adequate hydration as outlined above. 
Grade 1 TFR may be treated with non-steroidal anti-inflammatory drugs (NSAIDs) (ie, 
ibuprofen 400-600 mg orally every 4-6 hours as needed) and TFR ≥ Grade 2 should be treated 
with corticosteroids.  Narcotic analgesics may be added as needed for pain control in subjects 
experiencing ≥ Grade 2 tumor flare. 
Subjects will be monitored for TLS and TFR on Days 1, 8 and 15 for cycle 1.  Monitoring for 
TLS and TFR will continue on every 28 days thereafter and as clinically indicated. 
It is recommended that subjects receive low dose aspirin (75 mg to 100 mg) as prophylactic 
anti-thrombotic treatment while on study drug, however the use of aspirin should only be 
implemented after careful evaluation of the hemorrhagic risk and determination that the subject 
is at limited risk.  The investigator may use other anti-coagulation prophylactic therapies (ie, 
low-molecular weight (LMW) heparin, warfarin, etc.) at their discretion based on the subjects 
pre-disposing risk factors for thromboembolism (ie, subjects with a history of a 
thromboembolic event and/or taking a concomitant medication associated with an increased 
risk for a thromboembolic event and/or known hypercoagulable state regardless of 
thromboembolic history). 
Aspirin should be interrupted if the platelet count drops below 50,000/μL. 
Prophylactic antibiotics should be considered in patients with neutropenia.  In addition, 
subjects who were on prophylactic treatment for infection while on alemtuzumab therapy 
should continue prophylactic treatment for at least 6 months following the discontinuation of 
alemtuzumab therapy and can be enrolled into the study while continuing prophylactic therapy.  
Subjects with an active infection requiring systemic antibiotics and subjects with a systemic 
infection that has not resolved > 2 months prior to initiating lenalidomide treatment in spite of 
adequate anti-infective therapy are excluded from entering the study. 
Treatment and Dose Modification for Tumor Lysis Syndrome (TLS) 
Subjects meeting criteria of laboratory TLS or ≥ Grade 1 TLS according to the Cairo-Bishop 
definition and grading system should be treated as follows: 
• 
Subjects must be hospitalized for ≥ Grade 1 TLS.  For laboratory TLS, hospitalization 
is left to the investigator’s discretion. 
• 
The following should be provided:  vigorous hydration and appropriate therapy (ie, 
rasburicase where available) as needed to reduce hyperuricemia, until correction of 
electrolyte abnormalities. 
• 
In cases of laboratory TLS and Grade 1 TLS, lenalidomide will be continued at the 
same dose without interruption or dose reduction.  Dose escalation to the next 


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consecutive dose level will be permitted when laboratory TLS is resolved and Grade 1 
TLS is resolved to Grade 0. 
• 
Subjects with ≥ Grade 2 TLS will have their dose interrupted and will resume 
lenalidomide at the next lower dose when electrolyte abnormalities are corrected (ie, 
Grade 0) as specified in the Dose Modification and Interruption section of the protocol.  
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. 
• 
When those subjects that have been dose reduced complete two full cycles without 
meeting criteria for laboratory TLS or ≥ Grade 1 TLS or experiencing toxicities, re-
escalation to their maximum dose level or to the next higher dose level is permitted. 
A total of 320 subjects will be enrolled (160 subjects/treatment arm) in order to detect a 61.3% 
improvement (hazard ratio of 0.62) in median OS and PFS in the lenalidomide treatment group 
compared to placebo-treated subjects with 80% statistical power (see Section 16).  Enrollment 
will close once 320 subjects are randomized or 160 adjudicated PFS events are reached, 
whichever comes first. 
Please refer to Figure 1 for an overall summary of the study design. 
Analysis and Reporting: 
The final analysis on OS will be performed and reported when 160 subjects have died (ie, 
when full information necessary to have 80% power for OS is achieved). 
Data Monitoring Committee 
An external independent Data Monitoring Committee will evaluate safety and efficacy data in 
an ongoing, periodic manner to assess benefit-to-risk considerations.  Since the study will be 
unblinded, the Data Monitoring Committee will not be utilized beginning with protocol 
amendment #10.  Safety reviews will be performed by Celgene annually for the remainder of 
the study. 
Response Adjudication Committee 
An independent Response Adjudication Committee will perform a blinded, independent 
assessment of response (including the development of PD) prior to the interim analysis 
database lock. Since the placebo arm is discontinued, the Response Adjudication Committee 
will not be utilized beginning with protocol amendment #10. 
Number of planned subjects: 320 (160 subjects per treatment arm) 
Enrollment will close once 320 subjects are randomized or 160 adjudicated PFS events are 
reached, whichever comes first. 
Study Population  
Key Inclusion Criteria 
1. Must understand and voluntarily sign an informed consent form. 
2. Age ≥ 18 years at the time of signing the informed consent form. 
3. Must be able to adhere to the study visit schedule and other protocol requirements. 
4. Must have a documented diagnosis of B-cell CLL (IWCLL guidelines for the diagnosis 
and treatment of chronic lymphocytic leukemia, 
). 
5. Must have been treated with one of the following in first and/or second line: 


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• 
a purine analog-containing regimen 
• 
a bendamustine-containing regimen  
• 
an anti-CD20 antibody-containing regimen 
• 
a chlorambucil-containing regimen 
• an alemtuzumab-containing regimen (for those subjects with a 17p deletion) 
6. Must have achieved a minimum response of partial response (PR, nPR, CRi, CR, and 
MRD-negative CR) (IWCLL guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia, 
 Appendix 22.4) following completion of 
second-line induction therapy prior to randomization (documentation of response 
status must be available).  Second-line induction therapy must be documented to have 
been of sufficient duration. 
7. Must have completed last cycle of second-line induction no less than 8 weeks (56 
days) and no greater than 20 weeks (140 days) prior to randomization. 
8. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score 
of ≤2. 
9. 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 22.6). This applies 
even if the subject practices complete and continued sexual abstinence. 
• 
Either commit to continued abstinence from heterosexual contact (which must be 
reviewed on a monthly basis) or agree to use, and be able to comply with, effective 
contraception without interruption, 28 days prior to starting study drug, during the 
study therapy (including dose interruptions), and for 28 days after discontinuation 
of study therapy, (see specifics in Appendix 22.6). 
10. Male subjects must: 
• 
Commit to continued abstinence from heterosexual contact or 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 22.6). 
• 
Agree to not donate semen during study drug therapy and for a period after end of 
study drug therapy (see specifics in Appendix 22.6). 
11. All subjects must: 
• 
Have an understanding that the study drug could have a potential teratogenic risk. 
 
 
† Definition found in appendices 
 


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• 
Agree to abstain from donating blood while taking study drug therapy and 
following discontinuation of study drug therapy (See specifics in Appendix 22.6). 
• 
Agree not to share study medication with another person. 
• 
All subjects must be counseled about pregnancy precautions and risks of fetal 
exposure (See Appendix 22.6). 
Key Exclusion Criteria 
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study. 
2. Active infections requiring systemic antibiotics. 
3. Systemic infection that has not resolved > 2 months prior to initiating lenalidomide 
treatment in spite of adequate anti-infective therapy 
4. Autologous or allogeneic bone marrow transplant as second-line therapy. 
5. Pregnant or lactating females. 
6. Systemic treatment for B-cell CLL in the interval between completing the last cycle of 
second-line induction therapy and randomization. 
7. Participation in any clinical study or having taken any investigational therapy for a 
disease other than CLL within 28 days prior to initiating maintenance therapy. 
8. Known presence of alcohol and/or drug abuse. 
9. Central nervous system (CNS) involvement as documented by spinal fluid cytology or 
imaging.  Subjects who have signs or symptoms suggestive of leukemic meningitis or a 
history of leukemic meningitis must have a lumbar puncture procedure performed 
within two weeks prior to randomization. 
10. Prior history of malignancies, other than CLL, unless the subject 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 histologic finding of prostate cancer (tumor-nodes-metastasis [TNM] 
stage of T1a or T1b) 
11. History of renal failure requiring dialysis. 
12. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) 
and/or active Hepatitis C Virus (HCV) infection. 
13. Prior therapy with lenalidomide. 
14. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (Appendix 22.5) 
(subjects may be enrolled upon correction of electrolyte abnormalities). 
15. Any of the following laboratory abnormalities: 
• 
Calculated (method of Cockroft-Gault) creatinine clearance of <60 mL/min 
• 
Absolute neutrophil count (ANC) < 1,000/μL (1.0 X 109/L) 
• 
Platelet count < 50,000/μL (50 X 109/L) 
• 
Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase 
(SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase 
(SGPT) > 3.0 x upper limit of normal (ULN) 


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• 
Serum total bilirubin > 2.0 mg/dL (with the exception of Gilbert’s Syndrome) 
16. Grade 4 rash due to prior thalidomide treatment. 
17. Uncontrolled hyperthyroidism or hypothyroidism. 
18. Venous thromboembolism within one year. 
19. ≥ Grade-2 neuropathy. 
20. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia. 
21. Disease transformation (active) (ie, Richter’s Syndrome, prolymphocytic leukemia). 
22. Known allergy to allopurinol for subjects assessed with PR following their second-line 
induction therapy. 
23. Prisoners. 
24. More than 2 prior lines of CLL therapy. 
Investigational product, dosage and mode of administration:  Celgene Corporation will 
supply lenalidomide 2.5 mg, 5 mg, and 10 mg capsules  for oral administration.  Subjects dose 
reduced to 7.5 mg dose level (as outlined in Section 10.2.1) will receive one 5.0 mg capsule 
and one 2.5 mg capsule daily. 
Study drug will be packaged in bottles containing study capsules for 28 days.  
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately.   Celgene will discontinue supply of lenalidomide as a part of Protocol 
Amendment #11.   


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Assessments: 
Efficacy: 
• 
Survival/Date of death 
Safety: 
• 
Clinical laboratory evaluations 
• 
Pregnancy testing 
 
 
• 
AEs by NCI CTCAE Version 3.0, with modifications recommended by the 
IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia 
 (Appendix 22.4) 
• 
Second primary malignancies will be monitored as events of interest and should be 
included as part of the assessment of adverse events throughout the course of the 
study.  Investigators are to report any second primary malignancies as serious 
adverse events regardless of causal relationship to 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 survival follow-up phase  
 
 
 
 
 
 
Statistical Analysis: 
Overview: 
The objective of the statistical analysis will be to compare the efficacy and safety of 
lenalidomide versus placebo as maintenance therapy in subjects with relapsed or refractory B-
cell chronic lymphocytic leukemia (CLL) having achieved PR or better after second-line 
therapy. 
Overall Survival (OS) will be the primary endpoint for the study following protocol 
amendment #10. 
Sample Size: 
For OS, a 61.3% improvement in median survival from randomization, from 3 years for 
placebo to 4.84 years on lenalidomide is considered clinically relevant.  The OS distribution is 
assumed to be exponential with a constant failure (hazard) rate.  At the conclusion of the study 
a two-sided log-rank test with an overall significance level of 0.025 would have 80% power to 
detect a hazard rate ratio of 0.62. To ensure timely completion of the study, 320 subjects will 
be enrolled, 160 in each treatment arm.  Enrollment will close once 320 subjects are 
randomized or 160 adjudicated PFS events are reached, whichever comes first. 
Demographic, Disposition, Study Medication:   
The baseline characteristics of subjects enrolled in each arm will be summarized.  An 
accounting will be made of the study course for all subjects who received study drug for each 
arm and, in particular, the number of subjects who expired or withdrew during treatment will 
be specified and reasons for withdrawal categorized.  
Efficacy Analysis: 
Efficacy analyses will be performed on the intent-to-treat (ITT) population that includes all 
subjects randomized.  


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Overall Survival (OS) will be the primary endpoint for the study following protocol 
amendment #10. 
Exploratory analyses will be performed to investigate relationships between biomarker 
expression/cytogenetic characteristics, age and overall survival.  Cytogenetic response will be 
evaluated in that subset of subjects who have follow-up cytogenetics.   
Safety Analysis: 
All subjects who receive at least 1 dose of study medication will be included in the safety 
analyses. AEs, clinical laboratory information, and concomitant medications will be tabulated 
and summarized.  Subject incidence rates of all AEs (including serious, Grade 3, Grade 4, 
treatment-related [with and without discontinuation] and events requiring the discontinuation 
of investigational product), will be tabulated by system class, preferred term, and severity using 
Medical Dictionary for Regulatory Activities (MedDRA) terms and NCI CTCAE Version 3.0 
severity grades with modifications. (Section 10.2.1).  Time to first dose reduction will be 
summarized.  The adverse event of infection will also be analyzed according to the grading 
system as recommended by the IWCLL guidelines for the diagnosis and treatment of CLL 
 (Appendix 22.4). 
Death and clinically important AEs (including tumor flare, tumor lysis, second primary 
malignancies, and thrombosis) will also be summarized. 
All other measurements will be summarized using means, standard deviations, medians, 
minimum, and maximum.  Graphical displays will be provided where useful in the 
interpretation of results. 
 




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Table 2 
Schedule of Assessments (Continued) 
 
Maintenance Therapy 
After Treatment Discontinuation 
Procedurea 
Screening <28 days 
prior to Day 1 
Study Day 1 
Every 28 days  
(4 weeks) 
Tx discontinuation 
Survival Follow-uppost disease 
progression:b 
Every 24 weeks 
(+/- 7 days) 
Tumor lysis monitoring and 
prophylaxis (allopurinol 
administration) and tumor flare 
reaction monitoringn 
X 
X 
X 
-- 
-- 
Study drug administrationo 
-- 
X 
X 
-- 
-- 
Adverse eventsb,p 
X 
X 
X 
X 
-- 
Assessment of Second Primary 
Malignanciesq 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Assessment of responser 
-- 
-- 
X 
X 
-- 
Survivalb 
-- 
-- 
-- 
-- 
X 
 
ALC = absolute lymphocyte count; ANC = absolute neutrophil count; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CLL = chronic 
lymphocytic leukemia; CR = complete response; CRi = complete response with incomplete bone marrow recovery; CRF = case report form; CT = computed 
tomography; DAT = direct antiglobulin test; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group;  FISH = fluorescence in-situ 
hybridization; HCT = hematocrit; HGB = hemoglobin; ICF = informed consent form; NK = natural killer; nPR = nodular partial response; PD = progressive 
disease; PR = partial response; SAE = serious adverse event; WBC = white blood cell; ZAP-70 = Zeta-chain Associated Protein kinase 70 
a All study procedures should be performed within ± 3 days of the scheduled visit unless otherwise stated. 
b Subjects who discontinued from the study drug will be followed for survival, subsequent CLL therapies, response to next therapy and progression following 
next therapy, and second primary malignancies at each of these visits.  Subjects will be followed until all subjects in the study have been followed for at least 5 
years from last subject randomized, October 2020, (or have died/become lost to follow-up before 5 years). 
c Females of childbearing potential (FCBP) must have a medically supervised pregnancy test (serum or urine with sensitivity of at least 25 mIU/mL).  FCBP 
must have 2 negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting study drug. The first pregnancy test must be performed within 10 to 
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 (see Appendix 22.6).  For additional information on 
the frequency and schedule of pregnancy testing, see the document entitles “Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods” in Appendix 22.6.  For requirements regarding: 1) counselling and education of patients, including the reading of 


Lenalidomide (CC-5013) 
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the “Lenalidomide Information Sheet” by the patient; 2) reliable contraception methods; and 3) retention of Risk Management Plan documents 
concerning the pregnancy prevention program, see Appendix 22.6. 
d All male and FCBP patients must be counselled about pregnancy precautions and risks of fetal exposure.  All patients must also be counselled against sharing 
study drug and donating blood during and within 28 days of discontinuing study drug (see Appendix 22.6. for frequency). 
e Physical examination of lymphadenopathies, the spleen and liver will be performed at screening, Study Day 1, and at the treatment discontinuation visit.  
Lymph node evaluation will record the diameter, in two dimensions, of the largest palpable nodes in each of the following sites: cervical, axillary, 
supraclavicular, inguinal, and femoral. 
f Vital signs include:  temperature, pulse, blood pressure, weight, and height (height to be measured at baseline only) 
g Hematology includes WBC, HGB, HCT, platelet count, ANC, and ALC. 
h Chemistry includes potassium, calcium, phosphorus, creatinine, alkaline phosphatase, total bilirubin, AST/SGOT, ALT/SGPT, and uric acid. 
i β2M will be analysed during screening and, in selected sites, after one and two years of treatment and later if appropriate.  
j DAT (direct antiglobulin test) will be performed at screening and analyzed at the central laboratory.  The DAT test must be repeated if the investigator suspects 
haemolytic anemia during the course of the study. 
k ECG will be performed at baseline and at treatment discontinuation and interpreted locally. 
l Peripheral blood for FISH, ZAP 70, IgVH mutational status analyses and storage will be drawn during screening and analysed at a central laboratory.  
m NK and T cell analyses will be performed at screening.  
n Tumor lysis prophylaxis, consisting of oral hydration and allopurinol 300 mg/day, will be administered for 3 days prior to starting treatment and for at least 
the first cycle of each dose level. At the investigator’s discretion, allopurinol prophylaxis may be omitted for subjects entering the study with a CR; however 
subjects must be advised of the need for adequate hydration. 
o Study drug to be dispensed in 28-day cycles.  Subjects should be instructed to return the bottle every 28 days. 
p Adverse events that lead to study discontinuation should be followed until resolution or stabilization.  Serious adverse events should be monitored for 30 days 
after treatment discontinuation.  All SAEs should be followed until resolution or stabilization.  Any SAE deemed by the investigator to be related to study drug 
should be reported and followed until resolution. 
q Second primary malignancies will be monitored as events of interest and must be reported as serious adverse events.  This includes any second primary 
malignancy, 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 survival follow-up period.  Subjects will be followed until all subjects in the study have been followed for at least 5 years from 
randomization (or died/become lost to follow-up before 5 years).  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 (eg, any confirmatory histology or cytology results, X-rays, CT scans, etc.). 
r Investigators to provide assessment of CR, CRi, nPR, PR, and PD based on laboratory, physical exam, and if appropriate bone marrow aspirate/biopsy and CT 
scan findings.  To confirm a complete response, subjects must have maintained no evidence of disease for > 8 weeks and partial response must be maintained 
for ≥8 weeks as per the IWCLL guidelines for the diagnosis and treatment of chronic lymphocytic leukemia (Hallek, 2008). 
 
 
 


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Figure 1: 
Schema of Events 
 
 
                                                                                                                                 
                                                                                    
 
 
 
 
                                                                                                                                                                                                   
                                           
 
  
 
 
 
                                                                                                                                                    
                                                                                                                                                                   
                    
                                                                                                             
 
 
 
CLL= chronic lymphocytic leukemia, CR = complete response, CRi = complete response with incomplete bone marrow recovery, MRD = Minimal residual 
disease; nPR = nodular partial response, PO = oral, PD = progressive disease, PR = partial response, QD = every day
Screen 
PR, nPR, 
CRi, CR, or 
MRD-
negative 
CR 
Randomize to: 
Cycle 1:  2.5 mg 
po qd on days 1-
28 
Starting at cycle 
2 (if 2.5 mg well 
tolerated):  5 mg 
po qd on days 1-
28 every 28 days 
up to disease 
progression  
After 5 cycles at 
the 5 mg dose, if 
MRD-negativity 
is not achieved 
and 5 mg dose is 
tolerated, 
escalate to 10 
mg po qd on 
days 1-28 every 
28 days up to 
disease 
progression 
or 
placebo PO QD 
on Days 1-28 
every 28 days up 
PD or disease 
transformation: 
Discontinue 
study drug 
PR, nPR, CRi, CR or 
MRD-negative CR: 
Continue study drug 
up to disease 
progression or 
unacceptable 
toxicity 
Placebo patients 
will discontinue 
study drug in 
Amendment #10 
 
Follow for survival, 
subsequent CLL 
treatment regimens, 
and second primary 
malignancies,    
Lenalidomide 
patients will 
discontinue 
study drug in 
Amendment #11 


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4. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
 
 
2. 
SYNOPSIS .................................................................................................................11 
3. 
TABLE OF CONTENTS ...........................................................................................27 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................33 
 
 
 
 
 
 
6. 
STUDY OBJECTIVES ..............................................................................................47 
6.1. 
Primary Objective .......................................................................................................47 
6.2. 
Secondary Objective ...................................................................................................47 
7. 
STUDY ENDPOINTS ................................................................................................48 
7.1. 
Primary .......................................................................................................................48 
7.2. 
Secondary ...................................................................................................................48 
 
 
8. 
INVESTIGATIONAL PLAN .....................................................................................49 
8.1. 
Overall Study Design ..................................................................................................49 
 
 
9. 
STUDY POPULATION .............................................................................................64 
9.1. 
Subject Inclusion Criteria ...........................................................................................64 
9.2. 
Subject Exclusion Criteria ..........................................................................................65 
10. 
DESCRIPTION OF TREATMENT ...........................................................................67 
10.1. 
Description of Study Drug ..........................................................................................67 
10.1.1. 
Randomization ............................................................................................................67 
10.2. 
Treatment Assignments ..............................................................................................67 
10.2.1. 
Dose Modification or Interruption ..............................................................................68 
10.3. 
Blinding ......................................................................................................................74 
10.4. 
Emergency Unblinding ...............................................................................................74 
 
 
 
 


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10.6. 
Discontinuation from Treatment .................................................................................75 
11. 
EMERGENCY PROCEDURES ................................................................................77 
11.1. 
Emergency Contact .....................................................................................................77 
12. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................78 
12.1. 
Supplier(s) ...................................................................................................................78 
12.2. 
Dosage Form ...............................................................................................................78 
12.3. 
Dosage Regimen .........................................................................................................78 
12.4. 
Study Drug Packaging and Labeling ..........................................................................78 
12.5. 
Study Drug Receipt and Storage .................................................................................79 
12.6. 
Record of Administration ...........................................................................................79 
12.7. 
Study Drug Accountability .........................................................................................79 
12.8. 
Study Drug Handling and Disposal ............................................................................79 
13. 
ASSESSMENT OF EFFICACY ................................................................................80 
13.1. 
Assessments ................................................................................................................80 
13.2. 
Methods and Timing of Efficacy Assessments ..........................................................80 
14. 
ASSESSMENT OF SAFETY .....................................................................................81 
14.1. 
Assessments ................................................................................................................81 
14.2. 
Methods and Timing of Safety Assessments ..............................................................82 
14.3. 
Recording and Reporting of Adverse Events .............................................................82 
 
 
 
 
 
 
16. 
STATISTICAL ANALYSES .....................................................................................84 
16.1. 
Statistical Overview ....................................................................................................84 
16.2. 
Study Population Definitions ......................................................................................84 
16.2.1. 
Intent-to-Treat Population ..........................................................................................84 
16.2.2. 
Safety Population ........................................................................................................84 
16.2.3. 
Subgroup Analyses .....................................................................................................84 
16.3. 
Efficacy Evaluation ....................................................................................................84 
16.3.1. 
Primary Endpoint ........................................................................................................84 
16.3.2. 
Secondary Endpoint ....................................................................................................85 
16.3.3. 
Efficacy Analyses .......................................................................................................85 




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22.6. 
Pregnancy Prevention Risk Management Plans .......................................................120 
22.6.1. 
Lenalidomide Pregnancy Prevention Risk Management Plan ..................................120 
22.6.1.1. 
Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials .......120 
22.6.2. 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods ...........................................................................121 
22.6.2.1. 
Lenalidomide Education and Counseling Guidance Document ...............................125 
22.6.2.2. 
Lenalidomide Information Sheet ..............................................................................128 
 
 
 


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LIST OF TABLES 
 
 
Table 2: 
Schedule of Assessments ............................................................................................23 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................33 
Table 4: 
Grading Scale for Hematological Toxicity in CLL Studies .......................................68 
Table 5: 
Dose Reduction Steps .................................................................................................69 
Table 6: 
Dose Reduction and Modification Guidelines ............................................................69 
 
 
 
 
 
 
 
 
 
 


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LIST OF FIGURES 
Figure 1: 
Schema of Events .......................................................................................................26 
 
 


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5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 3: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALT (SGPT) 
Alanine transaminase (serum glutamate 
pyruvic transaminase) 
ANC 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
Aspartate transaminase (serum glutamic 
oxaloacetic transaminase) 
ATC 
Anatomic Therapeutic Chemical  
β2M 
Beta-2 Microglobulin 
β –HCG 
Beta-human chorionic gonadotropin hormone 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLL 
Chronic lymphocytic leukemia 
Clb 
Chlorambucil 
CNS 
Central nervous system 
CR 
Complete response 
Cri 
Complete response with incomplete bone 
marrow recovery 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
DAT 
Direct antiglobulin test 
DCF 
Data Clarification Form 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency  


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Abbreviation or Specialist Term 
Explanation 
EU 
European Union 
Table 3: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Explanation 
F 
Fludarabine 
FC 
Fludarabine and Cyclophosphamide 
FCBP 
Female of childbearing potential 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in Situ Hybridization 
GClb 
Obinutuzumab and Chlorambucil 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HGB 
Hemoglobin 
HCT 
Hematocrit 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgVh 
Immunoglobulin Heavy-chain Variable-region 
IL-6 
Interleukin 6 
IL-10 
Interleukin 10 
IMiD 
Immunomodulatory drug 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
IVRS 
Interactive Voice Response System 
IWCLL 
International Workshop on Chronic 
Lymphocytic Leukemia 
LMW 
Low-molecular weight 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation or Specialist Term 
Explanation 
MRD 
Minimal residual disease 
NCI CTCAE  
National Cancer Institute Common 
Terminology Criteria for Adverse Events  
 
Table 3: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Explanation 
NCI-WG 
National Cancer Institute Working Group 
criteria for chronic lymphocytic leukemia 
NK cells 
Natural killer cells 
nPR 
Nodular partial response 
NSAID 
Non-steroidal anti-inflammatory drug 
ORR 
Overall response rate 
OS 
Overall Survival 
PCR 
Pentostatin, cyclophosphamide, and rituximab 
PD 
Progressive disease 
PFS 
Progression free survival 
PFS2 
Progression free survival 2 
PR 
Partial Response 
RClb 
Rituxan and Chlorambucil 
RIC 
Reduced intensity conditioning 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Serum-Glutamic-Oxaloacetic Transaminase 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse 
reaction 
TFR 
Tumor flare reaction 
TLS 
Tumor lysis syndrome 
TNF α 
Tumor necrosis factor alpha 
TNM 
Tumor-nodes-metastasis 
ULN 
Upper limit of normal 
US 
United States 


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Abbreviation or Specialist Term 
Explanation 
VEGF 
Vascular endothelial growth factor 
VTE 
Venous thromboembolism 
WBC 
White blood cell count 
WG 
Working Group 
 
Table 3: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Explanation 
WHO 
World Health Organization 
ZAP 70 
Zeta-Chain-Associated Protein Kinase 70 






















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7. 
STUDY OBJECTIVES  
7.1. 
Primary Objective 
• To compare the efficacy of lenalidomide versus placebo maintenance therapy 
7.2. 
Secondary Objective 
• To evaluate the safety of lenalidomide versus placebo maintenance therapy 




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9. 
INVESTIGATIONAL PLAN 
9.1. 
Overall Study Design  
CC-5013-CLL-002 is a phase 3, multicenter, randomized, placebo-controlled, parallel-group 
study that will compare the efficacy and safety of oral lenalidomide maintenance therapy to that 
of placebo in subjects with B-cell CLL who achieved at least partial response (PR) with second-
line therapy.  The primary efficacy objective of this study is to demonstrate superiority of 
lenalidomide over placebo in prolonging OS due to continued therapy, for all subjects, including 
subjects with or without poor prognostic factors, subjects of various ages and subjects with PR, 
nodular partial response (nPR), complete response with incomplete bone marrow recovery (CRi), 
complete response (CR), and minimal residual disease (MRD)-negative CR.  All subjects 
randomized to the lenalidomide arm, including those subjects who do not improve their response 
(PR, nPR, CRi, or CR) and subjects who do not have the opportunity to improve their response 
further (MRD-negative CR) will be treated up to disease progression 
 
with the objective to demonstrate prolongation of OS. 
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
Eligible subjects must have been treated with a purine analog-, a bendamustine-, an anti-CD20 
antibody-, or a chlorambucil-based regimen in first and/or second line and must have achieved at 
least PR to second-line induction therapy of sufficient duration. Alemtuzumab- containing 
regimens will also be allowed for those patients with 17p deletion.  Subjects who achieve stable 
disease (SD) only or who develop progressive disease (PD) at any time during induction therapy 
will not be eligible for participation in this study. 
Approximately, three hundred twenty (320) subjects with PR, nPR, CRi, CR or MRD-negative 
CR will be enrolled and randomized (1:1) into two arms:  placebo daily or lenalidomide 2.5 mg 
daily on days 1-28 of the first cycle.  If the 2.5 mg dose level is well tolerated, escalation to 5 mg 
daily on days 1-28 of each 28-day cycle is permitted starting with the second cycle.  If a subject 
develops a Grade 1 or 2 adverse event, the drug may be interrupted until resolution, however the 
subject must complete one full cycle at the 2.5 mg dose level prior to escalation to the 5 mg dose 
level.  For those subjects who tolerate the 5 mg dose without unacceptable toxicity, escalation to 
10 mg daily on days 1-28 of each 28-day cycle after 5 continuous cycles at 5 mg will be 
permitted.  Each treatment arm will be stratified according to 1) the response to second-line 
induction therapy (PR, nPR, CRi or CR versus MRD-negative CR); 2) age (≤ 70 versus > 70 
years); and 3) presence of at least one of the following poor prognostic factors:  11q deletion, 
17p deletion, unmutated IgVH or β2M > 4.0 mg/L (Yes versus No versus Unknown). 
The subjects randomized to the lenalidomide treatment will continue to receive lenalidomide up 
to PD 
.  For those subjects who discontinue therapy for 
reasons other than PD (ie, unacceptable toxicity) they will transition to the survival follow-up 
period.  


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Subjects who discontinued from the study drug will be followed every 24 weeks for survival, 
subsequent CLL therapies, response to next therapy and progression following next therapy, and 
second primary malignancies.  Subjects will be followed until all subjects in the study have been 
followed for at least 5 years from the last randomization, October 2020, (or have died/become 
lost to follow up before 5 years).     
Screening: 
Potential study subjects will be screened for protocol eligibility within 28 days prior to 
randomization as outlined in Table 2.  Please refer to Figure 1. 
During the screening process for potentially protocol-eligible subjects, complete blood counts 
(CBCs), serum chemistries, thyroid function tests, quantitative immunoglobulin tests, a 12-lead 
electrocardiogram (ECG), physical exam to assess lymphadenopathies, the spleen and the liver, 
vital signs (with weight), Eastern Cooperative Oncology Group (ECOG) performance status, and 
evaluation of constitutional symptoms will be performed. 
Bone marrow biopsies and aspirates are to be performed on all subjects at screening.  A central 
review of the bone marrow aspirate and biopsy specimens will be performed to confirm disease 
status.  Subjects who develop PD during screening will not be eligible to enroll into this study.  
Peripheral blood will be sent to a central laboratory for flow cytometry for all subjects for 
disease diagnosis confirmation (by immunophenotyping), to perform immune cell (NK and T 
cell) analyses and for subjects entering the study with a CR for determination of MRD status. If 
peripheral blood is MRD negative, a bone marrow flow cytometry will be implemented. If 
subjects enter the study with MRD negativity, the disease diagnosis will be confirmed based on 
prior flow cytometry (documentation needed). 
A peripheral blood sample for a direct antiglobulin test (DAT) will be collected and analyzed at a 
central laboratory. 
Before randomization, subjects will be tested for cytogenetics by FISH, IgVH mutational status, 
and β2M.  The β2M test will be performed during screening using a peripheral blood sample and 
analyzed at a central laboratory. 
FISH and IgVH testing will be performed prior to second line, during second line, in the interval 
between second-line therapy and screening or during the screening period using a peripheral 
blood sample.  Because test results cannot be obtained during screening or between second line 
and screening in some subjects who achieve a good response due to the limited number of 
remaining CLL cells, we recommend conducting the FISH and IgVH tests preferably prior to 
second line or during second line.   
Samples for FISH and IgVH will be analyzed at a central laboratory. 
If tests do not yield results, subjects can be randomized and stratified based on historical data. 
Those subjects for whom results were not obtainable pre-randomization and for whom no 
historical data were available will be enrolled and grouped separately. 
An additional peripheral blood sample will be collected at baseline and stored at -70° at a central 
laboratory until the completion of the study; subjects will be re-consented if additional testing is 
to be performed. 


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Computed tomography (CT) scans of the chest, abdomen, and pelvis will be performed at 
baseline for all subjects to document the subject’s status (PR or CR).   
If, during the screening period, the subject has a correctable event that prevents randomization 
and the event cannot be corrected within the 28 day screening period, the subject may be 
re-screened; however, the CT scans and bone marrow aspirate and biopsy will not need to be 
repeated if those tests were implemented within 56 days prior to randomization and the subject’s 
clinical status remains the same. 
Females of childbearing potential (FCBP) must have two negative pregnancy tests performed at 
the study site prior to initiating lenalidomide therapy. The first pregnancy test will be performed 
within 10-14 days prior to randomization and the second test within 24 hours prior to starting 
study drug.  FCBP must agree to birth control requirements as outlined in Appendix 22.6 during 
the following time periods related to this study: 1) for at least 28 days before starting study drug; 
2) while participating in the study; and 3) at least 28 days after the treatment discontinuation 
visit.  FCBP must be referred to a qualified provider of contraceptive methods, if needed.  Males 
must commit to continued abstinence from heterosexual contact or agree to use appropriate 
contraceptive methods during any sexual contact with FCBP during study participation and for at 
least 28 days following the treatment discontinuation visit as outlined in Appendix 22.6.  Male 
subjects must agree to abstain from donating blood, semen or sperm during study participation 
and for at least 28 days after the treatment discontinuation visit.  Subjects must be counseled 
about pregnancy precautions and the potential risk of fetal exposure. 
Randomization: 
Randomization must occur no less than 8 weeks (56 days) and no greater than 20 weeks (140 
days) from the last day of the last cycle of second-line induction therapy received by the subject 
in order for the subject to be eligible for enrollment into this study.  Subjects meeting all 
eligibility criteria will be randomized (1:1) in a double-blind fashion to receive either 
lenalidomide or placebo.  The randomization procedure will be accomplished by a validated 
interactive voice response system (IVRS) (see Section 10.1.1). Subjects will be stratified at 
randomization by: 1) their response to second-line induction therapy (PR, nPR, CRi or CR versus 
MRD-negative CR); 2) age (≤ 70 versus > 70 years); and 3) presence of at least one of the 
following poor prognostic factors:  11q deletion, 17p deletion, unmutated IgVH or β2M > 4.0 
mg/L (Yes versus No versus Unknown).   
Maintenance Therapy: 
Study treatment for each subject begins on the same day the subject undergoes randomization.  
Lenalidomide is administered orally.  Subjects will receive lenalidomide 2.5 mg once daily on 
Days 1 through 28 of the first 28-day cycle.  If the 2.5 mg dose is well tolerated (subject does not 
experience any Grade 3 or 4 study drug-related toxicities or any other toxicity [Grade 1 or 2] 
found to be unacceptable by the investigator or the subject), subjects should be escalated starting 
at the second cycle to 5 mg once daily on Days 1 through 28 of each 28-day cycle up to disease 
progression 
.  If a subject develops a Grade 1 or 2 
adverse event, the drug may be interrupted until resolution, however the subject must complete 
one full cycle at the 2.5 mg dose level prior to escalation to the 5 mg dose level. 


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Subjects who complete 5 continuous cycles at the 5 mg dose level without experiencing any 
Grade 3 or 4 study drug-related toxicities and without experiencing any other toxicity (Grade 1 
or 2) found to be unacceptable by the investigator may be escalated to 10 mg once daily on Days 
1 through 28 of each 28-day cycle up to disease progression 
 
 
Dose de-escalation to 7.5 mg from 10 mg and to 5 mg from 7.5 mg and to 2.5 mg from 5 mg and 
to 2.5 mg every other day from 2.5 mg will be permitted for those subjects who experience a 
Grade 3 or 4 study drug-related toxicity or any other Grade 1 or 2 toxicity found to be 
unacceptable by the investigator or subject. 
Dose interruptions are also permitted for Grade 1 or 2 adverse events at the investigator’s 
discretion.  A guideline for the reduction of the dose of lenalidomide for dose-limiting toxicity 
(DLT) is provided (see Section 10.2.1). 
Dose re-escalation is permitted if the subject is able to complete 2 full cycles at the reduced dose 
level without experiencing a DLT or other toxicity deemed to be unacceptable by the investigator 
or subject.  In the event the dose reduction is implemented due to Grade 4 neutropenia, subjects 
may be re-escalated after one full cycle at the lower dose level if the neutropenia resolves to a 
Grade 2 or better by the end of the cycle and no other DLT is observed.  If that dose level is 
again not tolerated, the subject should be de-escalated to the dose below and remain at that 
tolerated dose level for the rest of the study. 
Study visits and serial measurements of safety and efficacy will be performed as outlined in 
Table 2. 
Females of childbearing potential must have a pregnancy test (conducted by the study site) 
within 24 hours prior to starting study drug; the subject may not receive study drug until the 
Investigator has verified that the pregnancy test is negative. Pregnancy testing for FCBP will 
continue throughout the study as outlined in Table 2 and Appendix 22.6.   
Counseling regarding blood, eggs and ovum donation, and contraceptive use and the potential 
risks of fetal exposure should be performed as outlined in Appendix 22.6. 
FCBP should be monitored during the course of the study and after the end of study therapy to: 
• Ensure that pregnancy tests are performed during the course of the study and after end 
of study therapy and are negative (see specifics in Appendix 22.6). 
• Ensure the subject continues to practice abstinence or remains on adequate 
contraception (see specifics in Appendix 22.6). 
If a FCBP becomes pregnant, treatment should be stopped and the subject referred to the 
appropriate physician. 
Male subjects should be monitored during the course of the study and after the end of study 
therapy to: 
• Ensure they commit to continued abstinence from heterosexual contact or continue to 
use a condom during sexual contact with a FCBP. 


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• If a female partner of a male subject becomes pregnant she should be referred to the 
appropriate physician. 
CBCs will be monitored on Days 1, 8, and 15 of cycle 1, on Day 1 of each cycle thereafter, and 
at the treatment discontinuation visit.  In the event of Grade 4 hematologic toxicity, monitoring 
of CBCs will continue weekly until resolution to grade 3 or better.  It is recommended to utilize 
myeloid and erythroid growth factors as per the American Society of Clinical Oncology (ASCO) 
guidelines.  The use of myeloid growth factors is encouraged when the absolute neutrophil count 
(ANC) is less than 1,000/μL. 
If a subject develops Grade 4 neutropenia or thrombocytopenia, the drug will be withheld until 
the toxicity has recovered to Grade 3 or better.  The drug may then be restarted at one dose level 
lower.  If the treatment has been withheld and the next cycle is delayed beyond 29 days after day 
1 of the prior treatment cycle, then day 1 of the next treatment cycle will be defined as the first 
day that the treatment is resumed. 
Serum chemistries will be performed on Days 1, 8, and 15 of cycle 1, on Day 1 of each cycle 
thereafter, and at the treatment discontinuation visit.   
Scheduled laboratory studies (CBCs, chemistries) will be sent to the site’s local laboratory for 
analysis purposes.  
The DAT test must be repeated if the investigator suspects haemolytic anemia and will be 
analysed centrally during the course of the study. 
ECOG Performance Status will be measured at the treatment discontinuation visit. 
Evaluation of constitutional symptoms will be performed at the treatment discontinuation visit. 
Vitals signs will be monitored at the treatment discontinuation visit.  A physical examination to 
assess in particular lymphadenopathies, spleen and liver will be performed at the treatment 
discontinuation visit. 
An ECG will be performed at the treatment discontinuation visit. 
Investigators will assess subjects for response every 28 days and at the treatment discontinuation 
visit.  Investigators will provide an assessment of CR (MRD-negative or MRD-positive), CRi, 
nPR, PR, and PD based on laboratory, physical exam, and if appropriate local assessments for 
CT scan findings, flow cytometry and bone marrow aspirate and biopsy.  To confirm a CR, 
subjects must have maintained no evidence of disease for ≥ 8 weeks and PR must be maintained 
for ≥ 8 weeks as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
guidelines for the diagnosis and treatment of chronic lymphocytic leukemia 
   
FCBP must have a pregnancy test at the treatment discontinuation visit. 
Subjects will receive study maintenance therapy until PD develops; any disease transformation 
will need to be documented by lymph node biopsies for Richter’s syndrome and percent of 
peripheral blood or bone marrow prolymphocytes for prolymphocytic leukemia.  Progressive 
disease is characterized by at least one of the following: 
• Lymphadenopathy.   Progression of lymphadenopathy discovered by physical 
examination.  Disease progression occurs if one of the following events is observed: 


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− Appearance of any new lesion such as enlarged lymph nodes (> 1.5 cm), 
splenomegaly, hepatomegaly or other organ infiltrates. 
− An increase by 50% or more in greatest determined diameter of any previous site.   
• An increase in the previously noted enlargement of the liver or spleen size by 50% or 
more or the de novo appearance of hepatomegaly or splenomegaly. 
• An increase in the number of blood lymphocytes by 50% or more with at least 5,000 
B lymphocytes per μL. 
• Transformation to a more aggressive histology (eg, Richter’s syndrome).  Whenever 
possible, this diagnosis should be established by lymph node biopsy. 
• Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to 
CLL. 
• During therapy:  cytopenias may occur as a side effect of many therapies and should 
be assessed according to Table 4.  During therapy, cytopenias cannot be used to 
define disease progression. 
• Post treatment:  The progression of any cytopenia (unrelated to autoimmune 
cytopenia), as documented by a decrease of hemoglobin levels by more than 2 g/dL 
or to less than 10 g/dL, or by a decrease of platelet counts by more than 50% or to 
less than 100,000/μL, which occurs at least 3 months after treatment, defines disease 
progression, if the marrow biopsy demonstrates an infiltrate of clonal CLL cells. 
Prophylaxis for TLS, thromboembolism and infection and treatment of tumor flare reaction 
(TFR): 
TLS prophylaxis, comprising of oral hydration and allopurinol 300 mg/day will be initiated 3 
days prior to starting maintenance therapy and for a minimum of the first treatment cycle at each 
dose level for those subjects entering the study with a PR to their second-line induction therapy.  
Subjects with a known allergy to allopurinol with a response of PR  will be excluded from the 
study.  Please refer to Section 10.2.1 for further guidance on allopurinol modification in the 
event of an adverse event.  If a subject is taking allopurinol for a condition other than for TLS 
prophylaxis, the subject should be continued on the allopurinol prescribed by their physician and 
the dose titrated to 300 mg/day.  If, at any time, the allopurinol being taken for reasons other than 
TLS prophylaxis is discontinued and prophylaxis is still required per protocol, the subject should 
be administered commercial allopurinol.  To maintain fluid intake, subjects must be instructed to 
drink 8 to 10 eight ounce (240 mL) glasses of water each day for the first 14 days of cycle 1 and 
the first cycle of each dose escalation.  Hydration levels should be adjusted according to age and 
clinical status, and lowered if the subject’s cardiovascular status indicates the possibility of 
volume overload.  At the investigator’s discretion, allopurinol prophylaxis may be omitted for 
subjects entering the study with a CR;  however subjects must be advised of the need for 
adequate hydration as outlined above. 
Grade 1 TFR may be treated with non-steroidal anti-inflammatory drug (NSAIDs) (ie, ibuprofen 
400-600 mg orally every 4-6 hours as needed) and TFR ≥ Grade 2 should be treated with 


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corticosteroids.  Narcotic analgesics may be added as needed for pain control in subjects 
experiencing ≥ Grade 2 tumor flare. 
Subjects will be monitored for TLS and TFR on Days 1, 8, and 15 for cycle 1 and the first cycle 
of each dose escalation.  Monitoring for TLS and TFR will continue on Days 1 and 15 for the 
second cycle of each dose level, at least every 28 days thereafter, and as clinically indicated. 
It is recommended that subjects receive low dose aspirin (75 mg to 100 mg) as prophylactic 
anti-thrombotic treatment while on study drug, however the use of aspirin should only be 
implemented after careful evaluation of the hemorrhagic risk and determination that the subject 
is at limited risk.  The investigator may use other anti-coagulation prophylactic therapies (ie, 
low-molecular weight (LMW) heparin, warfarin, etc.) at their discretion based on the subjects 
pre-disposing risk factors for thromboembolism (ie, subjects with a history of a thromboembolic 
event and/or taking a concomitant medication associated with an increased risk for a 
thromboembolic event and/or known hypercoagulable state regardless of thromboembolic 
history). 
Aspirin should be interrupted if the platelet count drops below 50,000/μL. 
Prophylactic antibiotics should be considered in patients with neutropenia.  In addition, subjects 
who were on prophylactic treatment for infection while on alemtuzumab therapy should continue 
prophylactic treatment for at least 6 months following the discontinuation of alemtuzumab 
therapy and can be enrolled into the study while continuing prophylactic therapy.  Subjects with 
an active infection requiring systemic antibiotics and subjects with a systemic infection that has 
not resolved > 2 months prior to initiating lenalidomide treatment in spite of adequate 
anti-infective therapy are excluded from entering the study. 
Treatment and Dose Modification for Tumor Lysis Syndrome (TLS): 
Subjects meeting criteria of laboratory TLS or ≥ Grade 1 TLS according to the Cairo-Bishop 
definition and grading system should be treated as follows: 
• Subjects must be hospitalized for ≥ Grade 1 TLS.  For laboratory TLS, hospitalization 
is left to the investigator’s discretion. 
• The following should be provided:  vigorous hydration and appropriate therapy (ie, 
rasburicase where available) therapy as needed to reduce hyperuricemia, until 
correction of electrolyte abnormalities. 
• In cases of laboratory TLS and Grade 1 TLS, lenalidomide will be continued at the 
same dose without interruption or dose reduction.  Dose escalation to the next 
consecutive dose level will be permitted when laboratory TLS is resolved and Grade 
1 TLS is resolved to Grade 0. 
• Subjects with ≥ Grade 2 TLS will have their dose interrupted and will resume 
lenalidomide at the next lower dose when electrolyte abnormalities are corrected (ie, 
Grade 0) as specified in the Dose Modification and Interruption section of the 
protocol.  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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10. 
STUDY POPULATION 
10.1. 
Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the study: 
1. Must understand and voluntarily sign an informed consent form. 
2. Must be ≥18 years at the time of signing the informed consent form. 
3. Must be able to adhere to the study visit schedule and other protocol requirements. 
4. Must have a documented diagnosis of B-cell CLL (IWCLL guidelines for the diagnosis 
and treatment of chronic lymphocytic leukemia 
]). 
5. Must have been treated with one of the following in first and/or second line: 
•  a purine analog-containing regimen 
• a bendamustine-containing regimen  
• an anti-CD20 antibody-containing regimen 
• a chlorambucil-containing regimen 
• an alemtuzumab-containing regimen (for those subjects with a 17p deletion) 
6. Must have achieved a minimum response of partial response (PR, nPR, CRi, CR, and 
MRD-negative CR) (IWCLL guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia 
 Appendix 22.4) following completion of second-
line induction therapy prior to randomization (documentation of response status must be 
available).  Second-line induction therapy must be documented to have been of sufficient 
duration.  
7. Must have completed last cycle of second-line induction no less than 8 weeks (56 days) 
and no greater than 20 weeks (140 days) prior to randomization. 
8. Must have an ECOG performance status score of ≤2. 
9. 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 22.6). This applies even if 
the subject practices complete and continued sexual abstinence. 
 
 
† Definition found in appendices 
 


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• Either commit to continued abstinence from heterosexual contact (which must be 
reviewed on a monthly basis) or agree to use, and be able to comply with, effective 
contraception without interruption, 28 days prior to starting study drug, during the 
study therapy (including dose interruptions), and for 28 days after discontinuation of 
study therapy (see specifics in Appendix 22.6). 
10. Male subjects must: 
• Commit to continued abstinence from heterosexual contact or 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 22.6) 
• Agree to not donate semen during study drug therapy and for a period after end of 
study drug therapy (see specifics in Appendix 22.6). 
11. All subjects 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 following 
discontinuation of study drug therapy. (See specifics in Appendix 22.6) 
• Agree not to share study medication with another person. 
• All subjects must be counseled about pregnancy precautions and risks of fetal 
exposure.  See Appendix 22.6. 
10.2. 
Subject Exclusion Criteria 
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from participating in the study. 
2. Active infections requiring systemic antibiotics. 
3. Systemic infection that has not resolved > 2 months prior to initiating lenalidomide 
treatment in spite of adequate anti-infective therapy 
4. Autologous or allogeneic bone marrow transplant as second-line therapy. 
5. Pregnant or lactating females. 
6. Systemic treatment for B-cell CLL in the interval between completing the last cycle of 
second-line induction therapy and randomization. 
7. Participation in any clinical study or having taken any investigational therapy for a 
disease other than CLL within 28 days prior to initiating maintenance therapy. 
8. Known presence of alcohol and/or drug abuse. 
9. Central nervous system involvement as documented by spinal fluid cytology or imaging.  
Subjects who have signs or symptoms suggestive of leukemic meningitis or a history of 
leukemic meningitis must have a lumbar puncture procedure performed within two weeks 
prior to randomization. 


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10. Prior history of malignancies, other than CLL, unless the subject 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 histologic finding of prostate cancer (tumor-nodes-metastasis [TNM] stage 
of T1a or T1b) 
11. History of renal failure requiring dialysis. 
12. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), and/or 
active Hepatitis C Virus (HCV) infection. 
13. Prior therapy with lenalidomide. 
14. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (Appendix 22.5) 
(subjects may be enrolled upon correction of electrolyte abnormalities). 
15. Any of the following laboratory abnormalities: 
• Calculated (method of Cockroft-Gault) creatinine clearance <60 mL/min. 
• Absolute neutrophil count (ANC) <1,000/μL (1.0 X 109/L) 
• Platelet count <50,000/μL (50 X 109/L) 
• Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase 
(SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase 
(SGPT) > 3.0 x upper limit of normal (ULN) 
• Serum total bilirubin >2.0 mg/dL (with the exception of Gilbert’s Syndrome) 
16. Grade 4 rash due to prior thalidomide treatment 
17. Uncontrolled hyperthyroidism or hypothyroidism 
18. Venous thromboembolism within one year 
19. ≥Grade-2 neuropathy 
20. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia 
21. Disease transformation (active) (ie, Richter’s Syndrome, prolymphocytic leukemia) 
22. Known allergy to allopurinol for subjects assessed with PR following their second-line 
induction therapy. 
23. Prisoners. 
24. More than 2 prior lines of CLL therapy. 


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11. 
DESCRIPTION OF TREATMENT 
11.1. 
Description of Study Drug 
Celgene Corporation will supply lenalidomide 2.5 mg, 5 mg, and 10 mg capsules for oral 
administration.  Subjects dose reduced to 7.5 mg dose level (as outlined in Section 10.2.1) will 
receive one 5.0 mg capsule and one 2.5 mg capsule daily. 
Study drug will be packaged in bottles containing study capsules for 28 days.  Subjects assigned 
to active treatment will receive 28 days of active drug (with the exception of those subjects de-
escalated to 2.5 mg every other day).   
Celgene Corporation will no longer supply blinded allopurinol 300 mg and matching placebo 
(Amendment #10). 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment immediately.  
Celgene Corporation will no longer supply lenalidomide (Amendment #11). 
11.1.1. 
Randomization 
Randomization will be accomplished by an IVRS to ensure timely registration and 
randomization.  Designated research personnel at the investigational sites will be assigned 
password protected, coded identification numbers, which gives them authorization to call into the 
IVRS to enroll subjects.  The system will present a menu of questions by which the research 
personnel will identify the subject and confirm eligibility. When all questions have been 
answered, including questions regarding the results of pregnancy tests for FCBP, the IVRS will 
assign a subject number and study drug to the eligible subject. IVRS will fax a confirmation of 
registration and drug assignment for each subject to the site and Celgene.   Subjects will be 
randomized (1:1) to receive lenalidomide or placebo.  Subjects will be stratified at randomization 
by: 1) their response to second-line induction therapy (PR, nPR, CRi or CR versus 
MRD-negative CR); 2) age (≤ 70 versus > 70 years); and 3) presence of at least one of the 
following poor prognostic factors:  11q deletion, 17p deletion, unmutated IgVH, or β2M > 4.0 
mg/L (Yes versus No versus Unknown).   
Site staff are to contact Celgene at each visit for study drug assignment, to register dose 
reductions or escalations, and at discontinuation from treatment.  Confirmation of each call will 
be faxed to the site. 
11.2. 
Treatment Assignments 
Lenalidomide  
Oral lenalidomide 2.5 mg capsule once daily on Days 1 through 28 of the first 28-day cycle.  
If the 2.5 mg dose is well tolerated, subjects should be escalated starting at the second cycle 
to 5 mg capsule once daily on Days 1 through 28 of each 28-day cycle to disease progression 
.  If a subject develops a Grade 1 or 2 adverse event, 
the drug may be interrupted until resolution, however the subject must complete one full 
cycle at the 2.5 mg dose level prior to escalation to the 5 mg dose level. 


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Following 5 continuous cycles at the 5 mg dose level, subjects who are tolerating the 5 mg 
dose level may be escalated to 10.0 mg once daily on days 1 through 28 of each 28-day cycle 
up to disease progression 
 
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
11.2.1. 
Dose Modification or Interruption 
Subjects will be evaluated for AEs at each visit with the NCI CTCAE (Version 3.0) used as a 
guide for the grading of severity with the exceptions recommended by the IWCLL guidelines for 
the diagnosis and treatment of chronic lymphocytic leukemia 
 as listed below*: 
Table 4: 
Grading Scale for Hematological Toxicity in CLL Studies 
Grade# 
Decrease in Platelets* or Hb° (nadir) 
From Pretreatment value (%) 
Absolute neutrophil count/μL@ (nadir) 
0 
No change to 10% 
≥ 2,000 
1 
11% - 24% 
≥1,500 and < 2,000 
2 
25% - 49% 
≥1,000 and < 1,500 
3 
50% - 74% 
≥ 500 and < 1,000 
4 
≥ 75% 
< 500 
* Platelet counts must be below normal levels for grades 1-4.  If, at any level of decrease the platelet count is 
<20,000/μL, this will be considered grade 4 toxicity, unless a severe or life-threatening decrease in the initial 
platelet count (eg, 20,000/μL) was present pretreatment, in which case the patient is not evaluable for toxicity 
referable to platelet counts. 
° Hb levels must be below normal levels for grades 1-4.  Baseline and subsequent Hb determinations must be 
performed before any given transfusions.  The use of erythropoietin is irrelevant for the grading of toxicity, but 
should be documented. 
# Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal.  Death occurring as a result of toxicity at any 
level of decrease from pretreatment will be recorded as grade 5. 
@ If the absolute neutrophil count (ANC) reaches less than 1,000/μL, it should be judged to be grade 3 toxicity.  
Other decreases in the white blood cell count, or in circulating granulocytes, are not to be considered, since a 
decrease in the white blood cell count is a desired therapeutic end point.  A gradual decrease in granulocytes is not 
a reliable index in CLL for stepwise grading of toxicity.  The use of G-CSF is irrelevant for the grading toxicity, 
but should be documented. 
In addition, TLS will be graded as specified by the Cairo-Bishop grading system (Appendix 
22.5). Subjects meeting criteria of laboratory TLS or ≥ Grade 1 TLS, will be hospitalized (per 
investigator’s discretion for laboratory TLS), provided with vigorous intravenous hydration and 
appropriate therapy (ie, rasburicase where available) as needed to reduce hyperuricemia, until 
correction of electrolyte abnormalities.  In the case of laboratory TLS and Grade 1 TLS, 
lenalidomide will be continued at the same dose without interruption or dose reduction. Subjects 
with ≥ Grade 2 TLS, will have their dose interrupted and will resume lenalidomide at the next 
lower dose level when electrolyte abnormalities are corrected (ie, Grade 0). If lenalidomide is 


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resumed prior to the start of the subsequent cycle, chemistry tests should be performed every 
other day for the first week following initiation of lenalidomide. 
If a subject develops toxicity (Table 6), the dose may be reduced as outlined in Table 5. 
Table 5: 
Dose Reduction Steps 
Lenalidomide 
Dose 
2.5 mg every day x 28 
days of a 28-day cycle 
5 mg every day x 28 days 
of a 28-day cycle  
10 mg every day x 28 
days of a 28-day cycle  
Dose Reduction – 1 
2.5 mg every other day 
x 28 days of a 28-day 
cycle 
2.5 mg every day x 28 
days of a 28-day cycle 
7.5 mg every day x 28 
days of a 28- day cycle 
Dose Reduction – 2 
n/a 
2.5 mg every other day x 
28 days of a 28-day cycle 
5 mg every day x 28 days 
of a 28- day cycle 
Dose Reduction – 3 
n/a 
n/a 
2.5 mg every day x 28 
days of a 28- day cycle 
Dose Reduction – 4 
n/a 
n/a 
2.5 mg every other day x 
28 days of a 28-day cycle 
Subjects experiencing a ≥ Grade 3 non-hematologic AE will have their study drug held until 
resolution of the AE as described in Table 6: Dose Reduction and Modification Guidelines.  
Subjects with a hematologic AE will modify study drug dosing as outlined in Table 6. 
Subjects who cannot tolerate 2.5 mg every other day x 28 days of a 28-day cycle are to be 
discontinued from study drug and followed for survival as outlined in Table 2. 
Table 6: 
Dose Reduction and Modification Guidelines 
NCI CTCAE Toxicity Grade 
Action 
Neutropenia  
ANC < 400/uL 
 
• 
Interrupt study drug therapy 
• 
Resume study drug (decrease one dose level) when 
ANC recovers to ≥ 500/uL 
Thrombocytopenia 
< 20,000/uL 
 
• 
Interrupt study drug therapy 
• 
Resume study drug (decrease one dose level) when 
platelet count recovers to > 25,000/uL 
Syndromes 
 
Tumor Flare 
Grade 3 or 4 
• 
Interrupt study drug therapy and initiate therapy with 
NSAIDs, narcotic analgesics or prednisone 
• 
Resume study drug (decrease one dose level) when 
symptoms resolve to ≤ Grade 2 
Desquamating (blistering) rash  
• 
Discontinue study drug 
Non- desquamating rash 
 
Grade 3 
• 
Interrupt study drug therapy.  


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NCI CTCAE Toxicity Grade 
Action 
• 
Resume study drug when the rash resolves to ≤ Grade 
1 (decrease one dose level) 
Grade 4 
• 
Discontinue study drug  
Table 6: 
Dose Reduction and Modification Guidelines (Continued) 
NCI CTCAE Toxicity Grade 
Action 
Neuropathy 
 
Grade 3 
• 
If Grade 3, interrupt study drug therapy. 
• 
Resume study drug when the neuropathy resolves to ≤ 
Grade 1 (decrease one dose level) 
Grade 4 
• 
If Grade 4, discontinue study drug  
Venous thrombosis/embolism  
≥ Grade 3 
• 
Hold (interrupt) dose and start anticoagulation; 
• 
Resume study drug when adequately anticoagulated 
(maintain dose level). 
Hyperthyroidism or hypothyroidism 
 
• 
Interrupt study drug and initiate appropriate medical 
therapy. 
• 
Resume study drug when appropriately controlled 
(maintain dose level). 
Serum Creatinine 
 
Grade 1  
**It is possible for subjects entering 
the study with a creatinine clearance ≥ 
60 ml/min and a serum creatinine at 
the upper limit of normal to show 
slight fluctuations of the serum 
creatinine above the upper limit of 
normal.  It is left at the investigator’s 
discretion to measure the creatinine 
clearance for those subjects to 
evaluate whether a dose adjustment is 
needed. 
• 
Interrupt study drug 
• 
Evaluate subject weekly x 3 weeks  
• 
If during those 3 weeks, the creatinine level  
worsened at any time to > Grade 1, permanently 
discontinue and follow for PD 
• 
If at the end of the third week the creatinine level has 
improved to < Grade 1, resume study drug (maintain 
dose level)  
• 
If at the end of the third week the creatinine level  has 
stabilized at Grade 1, resume study drug (decrease 
one dose level)  
• 
Following resumption of study drug, evaluate subject 
weekly x 2 weeks to ensure creatinine level does not 
worsen; if creatinine level again worsens during those 
2 weeks, permanently discontinue and follow for PD 
Grade 2 
• 
Interrupt study drug 
• 
Evaluate subject weekly x 3 weeks  
• 
If during those 3 weeks, the creatinine level  
worsened at any time to > Grade 2, permanently 
discontinue and follow for PD 


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NCI CTCAE Toxicity Grade 
Action 
• 
If at the end of the third week, the creatinine level has 
improved to < Grade 1 resume study drug (maintain 
dose level)  
• 
If at the end of the third week, the creatinine level has 
improved to a Grade 1 or has stabilized at Grade 2, 
resume study drug (decrease one dose level) 
Table 6: 
Dose Reduction and Modification Guidelines (Continued) 
NCI CTCAE Toxicity Grade 
Action 
 
• 
Upon resumption of study drug, evaluate subject 
weekly x 2 weeks to ensure creatinine level does not 
worsen; if creatinine level again worsens during those 
2 weeks, permanently discontinue and follow for PD 
Grade 3 
• 
Interrupt study drug 
• 
Evaluate subject weekly x 3 weeks  
• 
If during those 3 weeks, the creatinine level  
worsened at any time to > Grade 3, or if dialysis is 
indicated, permanently discontinue and follow for PD 
• 
If at the end of the third week, the creatinine level has 
improved to ≤ Grade 2 resume study drug (decrease 
one dose level)  
• 
Upon resumption of study drug, evaluate subject 
weekly x 2 weeks to ensure creatinine level does not 
worsen; if creatinine level again worsens during those 
2 weeks, permanently discontinue and follow for PD 
• 
If at the end of the third week, the creatinine level has 
not improved to < Grade 3, permanently discontinue 
and follow for PD 
Grade 4 
OR 
if dialysis is indicated 
• 
Permanently discontinue and follow for PD 
Cairo-Bishop Toxicity Grade 
 
Clinical TLS ≥ Grade 2 
• 
Interrupt lenalidomide therapy. 
• 
May resume lenalidomide when the TLS resolves to < 
Grade 1 (decrease one dose level) 


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Table 6: 
Dose Reduction and Modification Guidelines (Continued) 
NCI CTCAE Toxicity Grade 
Action 
Chemistry value 
Action 
Lenalidomide Dose Modification 
• 
ALT > 3.0 and ≤ 5.0 x ULN 
AND 
• 
Serum total bilirubin ≤ 2.0 mg/dL 
(~1.5 x ULN) 
• 
Continue current 
dose level 
• 
Test at next 
scheduled visit 
• 
None Required – continue 
current dose level. 
• 
ALT > 3.0 and ≤ 5.0 x ULN  
 
AND 
 
• 
Serum total bilirubin > 2.0 mg/dL 
(~1.5 x ULN) 
• 
Temporarily 
Discontinue 
lenalidomide  
• 
Re-test weekly until 
ALT and total 
bilirubin return to 
baseline 
• 
Resume the same dose of 
lenalidomide if recovery from 
the event is  ≤ 14 days.   
• 
If recovery occurs > 14 days 
but ≤ 28 days, the lenalidomide 
dose should be decreased by 
one dose level, and weekly 
testing of liver functions 
should occur during that cycle.   
• 
If the event does not repeat, 
dose escalation or re-escalation 
may continue according to the 
protocol.  
• 
If the values do not return to 
baseline within 28 days, the 
medical monitor must be 
notified. 
• 
ALT  >5.0 x ULN 
 
AND/OR 
 
• 
Serum total bilirubin > 2.0 mg/dL 
(~1.5 x ULN) 
• 
Temporarily 
Discontinue 
lenalidomide  
• 
Re-test weekly until 
ALT and total 
bilirubin return to 
baseline 
• 
Resume the same dose of 
lenalidomide if recovery from 
the event is  ≤ 14 days.  
• 
If recovery occurs > 14 days 
but ≤ 28 days, the lenalidomide 
dose should be decreased by 
one dose level, and weekly 
testing of liver functions 
should occur during that cycle.  
• 
If the event does not repeat, 
dose escalation or re-escalation 
may continue according to the 
protocol.   
• 
If the values do not return to 
baseline within 28 days, the 
medical monitor must be 
notified. 


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Table 6: 
Dose Reduction and Modification Guidelines (Continued) 
NCI CTCAE Toxicity Grade 
Action 
Other lenalidomide-related non-
hematologic AEs 
≥ Grade 3 
• 
Interrupt lenalidomide therapy. 
• 
May resume lenalidomide 
when the adverse event 
resolves to ≤ Grade 2 (decrease 
one dose level or maintain dose 
level per the investigator’s 
discretion) 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
− the ANC is ≥ 500/μL; 
− the platelet count is ≥ 25,000/μL; 
− any other lenalidomide-related non-hematologic adverse event that may have 
occurred has resolved as indicated in Table 6. 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and 
a new cycle will not be initiated until the toxicity has resolved as described above. 
Dose interruptions/reductions are permitted for Grade 1 or 2 adverse events at the investigator’s 
discretion. 
If a study drug interruption has lasted for 5 weeks, the investigator should contact the medical 
monitor to discuss whether the subject should be continued on the study. 
Site staff are to contact Celgene to record new dose level and obtain new study drug assignment.  
If the treatment has been withheld and the next treatment cycle is delayed beyond 29 days after 
Day 1 of the prior treatment cycle, then Day 1 of the next treatment cycle will be defined as the 
first day that the treatment is resumed.  If dose reduction occurs within a cycle, subjects will be 
given a new 28-day supply bottle, subjects should begin taking study drug at the current cycle 
day (ie, if reduction occurs on Cycle Day 16, then the subject will take study drug from the new 
bottle for the remainder of the cycle).  Subjects will be required to return empty bottle or any 
unused drug prior to new drug being dispensed. 
Dose re-escalation is permitted if the subject is able to complete 2 full cycles at the reduced dose 
level without experiencing a DLT or other toxicity deemed to be unacceptable by the investigator 
or subject.  In the event the dose reduction is implemented due to Grade 4 neutropenia, subjects 
may be re-escalated after one full cycle at the lower dose level if the neutropenia resolves to a 
Grade 2 or better by the end of the cycle and no other DLT is observed.  If that dose level is 
again not tolerated, the subject should be de-escalated to the dose below and remain at that 
tolerated dose level for the rest of the study. 
Allopurinol Dose Adjustment Guidelines: 
Allopurinol should be permanently discontinued for any adverse reaction deemed possibly 
related to allopurinol administration.  






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• Subject lost to follow-up 
• Death 
• Protocol violation 
The reason for discontinuation should be recorded in the CRF and in the subject’s medical 
records. Celgene is to be notified of all discontinuations from study drug. 


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12. 
EMERGENCY PROCEDURES 
12.1. 
Emergency Contact 
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page). 
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page).  This global 
Emergency Call Center is available 24 hours and 7 days a week.  The representatives are 
responsible for obtaining your call-back information and contacting the on call Celgene/CRO 
Medical Monitor, who will then contact you promptly. 
Note:  The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 


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13. 
STUDY DRUG MATERIALS AND MANAGEMENT 
13.1. 
Supplier(s) 
Celgene Corporation will supply lenalidomide capsules. 
Celgene Corporation will no longer supply blinded allopurinol and matching placebo 
(Amendment #10). 
Celgene Corporation will no longer supply lenalidomide (Amendment #11). 
13.2. 
Dosage Form 
Lenalidomide will be supplied as 2.5 mg, 5 mg, and 10 mg capsules for oral administration.  
Subjects dose reduced to 7.5 mg dose level (as outlined in Section 10.2.1) will receive one 5.0 
mg capsule and one 2.5 mg capsule daily. 
13.3. 
Dosage Regimen 
Subjects will be randomized (1:1) via IVRS to receive the following: 
• Oral lenalidomide 2.5 mg capsule once daily on days 1-28 of the first 28 day cycle 
and if tolerated should be escalated starting with the second cycle to a 5 mg capsule 
once daily on days 1-28 of a 28 day cycle up to disease progression or October 2020, 
whichever comes first. 
Following 5 continuous cycles at the 5 mg dose level, subjects who are tolerating the 
5 mg dose level may be escalated to 10 mg once daily on days 1 through 28 of each 
28-day cycle up to disease progression or October 2020, whichever comes first. 
• Oral placebo capsule once daily every day for a 28 day cycle up to disease 
progression.  The placebo treatment arm is discontinued in amendment #10. 
Amendment #11: 
Subjects currently on lenalidomide treatment will discontinue lenalidomide treatment 
immediately and complete the Treatment Discontinuation assessment.  The subjects will then 
transition to the survival follow-up period. 
13.4. 
Study Drug Packaging and Labeling 
Celgene Corporation will supply lenalidomide 2.5 mg, 5 mg, and 10 mg capsules for oral 
administration.  Subjects dose reduced to 7.5 mg dose level (as outlined in Section 10.2.1) will 
receive one 5.0 mg capsule and one 2.5 mg capsule daily. 
The lenalidomide study drug will be packaged in 28-count bottles.    
The label for study drug supplied by Celgene will bear Celgene’s name and address, the protocol 
number, EudraCT number (where required), product name, dosage form, and strength, 
medication identification/kit number, 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 and/or applicable 


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Subjects requiring dose reduction within a treatment cycle must return to the study site and 
return the empty bottles or any unused drug and a new bottle will be dispensed.  Subjects will be 
given a new 28-day supply bottle and should begin taking study drug at the current cycle day. 
13.5. 
Study Drug Receipt and Storage 
The Investigator(s) is responsible for taking an inventory of each shipment of study drug 
received, and comparing it with the accompanying study drug shipping order form.  The 
Investigator(s) will verify the accuracy of the information on the form and call Celgene to 
register the study medication received at the site. 
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 package label. 
13.6. 
Record of Administration 
Accurate recording of all study drug administration (including dispensing and dosing) will be 
made in the appropriate section of the subject’s CRF and source documents. 
13.7. 
Study Drug Accountability 
The Investigator(s) or designee(s) is responsible for accounting for all study drug that is issued to 
and returned by the subject during the course of the study. 
13.8. 
Study Drug Handling and Disposal 
FCBP should not handle or administer study drug unless they are wearing gloves. All patients 
should not extensively handle or open study drug capsules and should maintain storage of 
capsules in the packaging until ingestion. 
In investigational studies, study drug 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 patients.  Once 
trained these healthcare staff will counsel patients prior to study drug being dispensed to ensure 
that the patient has complied with all requirements including use of birth control and pregnancy 
testing (FCBP) and that the patient understands the risks associated with lenalidomide.  This step 
will be documented with a completed lenalidomide Education and Counseling Guidance 
Document (Appendix 22.6), and no drug will be dispensed until this step occurs. Counseling 
includes verification with the patient that required pregnancy testing was performed and results 
were negative. A Lenalidomide Information Sheet (Appendix 22.6) will be supplied with each 
study drug dispense.  
Celgene will instruct the Investigator(s) on the return or destruction of unused study drug.  If any 
study drug is lost or damaged, its disposition should be documented in the subject’s CRF and 
source documents.  Celgene will provide instructions for the return of study drug supplies at the 
end of the study. 


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14. 
ASSESSMENT OF EFFICACY 
14.1. 
Assessments 
• Survival/Date of death 
14.2. 
Methods and Timing of Efficacy Assessments 
Serial measurements of efficacy will be performed at baseline and at scheduled intervals 
throughout the duration of the study as outlined in Table 2.  All scheduled visits will have a ± 3 
day window unless otherwise stated. 


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15. 
ASSESSMENT OF SAFETY 
15.1. 
Assessments 
• Clinical laboratory evaluations: 
− Hematology: white blood cell (WBC), hemoglobin (HGB), hematocrit (HCT), 
platelet count, absolute neutrophil count (ANC), and absolute lymphocyte count 
(ALC) 
− Chemistry: calculated (method of Cockroft-Gault) creatinine clearance (screening 
only), potassium, calcium, phosphorus, creatinine, alkaline phosphatase, total 
bilirubin, AST/SGOT, ALT/SGPT, and uric acid 
• Pregnancy testing for FCBP: serum or urine beta-human chorionic gonadotropin 
hormone (β-HCG) pregnancy testing with a sensitivity of at least 25 mIU/mL is to be 
done on FCBP only 
− FCBP should be monitored during the course of the study and after the end of 
study therapy to: 
o Ensure that pregnancy tests are performed during the course of the study and 
after end of study therapy and are negative (see specifics in Appendix 22.6). 
o Ensure the patient continues to practice abstinence or remains on adequate 
contraception (see specifics in Appendix 22.6). 
o If a FCBP becomes pregnant treatment should be stopped and the patient 
referred to the appropriate physician 
• Male patients should be monitored during the course of the study and 28 days after 
the end of study therapy to: 
− Ensure they commit to continued abstinence from heterosexual contact or 
continue to use a condom during sexual contact with a FCBP 
− If a female partner of a male patient becomes pregnant she should be referred to 
an appropriate physician 
• Concomitant medications 
• AEs by NCI CTCAE Version 3.0 with modifications recommended by the IWCLL 
guidelines for the diagnosis and treatment of chronic lymphocytic leukemia 
 
 
• Second primary malignancies will be monitored as events of interest and should be 
included as part of the assessment of adverse events throughout the course of the 
study.  Investigators are to report any second primary malignancies as serious adverse 
events regardless of causal relationship to 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 survival follow up phase.   


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15.2. 
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 Table 2.  All scheduled visits will have a ± 3 
day window unless otherwise stated.  Abnormalities will be captured as adverse events.  The 
adverse event of flare reaction, which may mimic disease progression, may render the efficacy 
assessments not evaluable at the corresponding visit(s).  Cause of death is to be recorded in the 
CRF and the subject’s medical record. 
15.3. 
Recording and Reporting of Adverse Events 
The recording and reporting of adverse events is described in Appendix 22.1. 




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17. 
STATISTICAL ANALYSES 
17.1. 
Statistical Overview 
The objective of the statistical analysis will be to compare the efficacy and safety of 
lenalidomide versus placebo as maintenance therapy in subjects with relapsed or refractory 
B-cell chronic lymphocytic leukemia (CLL) having achieved PR or better after second-line 
therapy. 
Overall survival (OS) will be the primary endpoint for the protocol following amendment #10.  
This analysis will be performed at the completion of the study.  It is estimated that at least 160 
subjects across both treatment arms have died at the time of analysis (yielding 80% power to 
detect a 61.3% improvement in median OS for a two-sided test at 0.025 level allowing for one 
interim analysis).   
17.2. 
Study Population Definitions 
17.2.1. 
Intent-to-Treat Population 
The primary efficacy analysis will be performed on the intent-to-treat (ITT) population, which 
will include all subjects who were randomized. 
17.2.2. 
Safety Population 
All randomized subjects who receive any study drug will be included in the safety analyses. 
17.2.3. 
Subgroup Analyses 
In addition to analyses that include all subjects, analyses will be performed to compare 
treatments within the following stratification subgroups: 
• Response to second-line induction chemotherapy (PR, CRi or CR versus 
MRD-negative CR) 
• Age (≤ 70 years versus > 70 years) 
• Presence of at least one of the following poor prognostic factors:  11q deletion, 17p 
deletion, unmutated IgVH or β2M > 4.0 mg/L (Yes versus No versus Unknown) 
Additional subgroups may be examined, as needed based on regulatory and clinical requests. 
17.3. 
Efficacy Evaluation 
17.3.1. 
Primary Endpoint 
Overall Survival (OS) 
Overall survival is calculated as the time from randomization to death from any cause.  OS will 
be censored at the last date that the subject was known to be alive for subjects who were alive at 
the time of analysis and for subjects who were lost to follow-up before death was documented. 


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The analysis of OS will include survival information for all randomized subjects.  Subjects who 
discontinued from the treatment phase of the study and who had possibly received other 
anti-cancer therapies and then subsequently died will be included in the analysis as death.  
However, sensitivity analyses will be performed in which these subjects will be censored at the 
date of the first dose date of the anti-cancer therapy. 
17.3.2. 
Secondary Endpoint 
Progression Free Survival 2 (PFS2) 
PFS is defines as the time from randomization to the second objective disease progression, or 
death from any cause, whichever occurs first.  Patients alive and for whom a second objective 
disease progression has not been observed should be censored at the last time known to be alive 
and without second objective disease progression.  In situations where OS and PFS2 cannot 
reliably be determined, it may be possible to rule out significant lack of efficacy of further 
treatments by looking at the outcome of the next line therapy.  For this analysis, an event is 
defined as second objective disease progression, or death from any cause, or the start of the CLL 
therapy after next line treatment, whichever occurred first (EMEA guideline 13 DEC 2012).  
Various schemes will be assessed for missing data imputation if needed. 
17.3.3. 
Efficacy Analyses 
Kaplan-Meier product limit methods will be used to estimate the survivorship functions for the 
time-to-event endpoints (eg, OS, and PFS2).  A two-sided log-rank test stratified by the 3 strata 
used in the randomization will be used as the primary analytic method to compare survivorship 
functions for time-to-event variables in the 2 treatment groups.  In terms of the survivorship 
functions for each treatment group, the hypotheses of interest were: 
H0:  FA(t) =  FP(t) for all t 
Versus 
H1:  FP(t) ≠ FA(t) for all t 
where FP is the survivorship function for placebo and FA is the survivorship function for 
lenalidomide. 
Median OS will be estimated using Kaplan-Meier estimates, and the 95% confidence intervals 
(CI) will be computed using the method of Brookmeyer and Crowley.  Hazard ratio will be 
calculated using Cox model stratified for the 3 strata (ie, response to second-line induction 
chemotherapy, age, and presence of at least one prognostic factor) to account for the stratified 
randomization.  The Cox model will also be used to identify prognostic factors. 
Cross-tabulations will be provided by treatment group to summarize improvements from the best 
response during induction therapy. 
17.4. 
Background and Demographic Characteristics 
Subjects’ age, weight, height, and other continuous demographic and baseline variables will be 
summarized using descriptive statistics (mean, standard deviation, minimum, and maximum), 
while performance status, gender, race, and other categorical variables will be summarized with 
frequency tabulations for each treatment group separately and pooled over both treatment 






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18. 
QUALITY CONTROL AND QUALITY ASSURANCE 
18.1. 
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(s) and the staff.   Prior to enrolling subjects into the 
study, a Celgene representative will review the protocol, CRFs, procedures for obtaining 
informed consent, record keeping, and reporting of AEs with the Investigator(s).  Monitoring 
will include on-site visits with the Investigator(s) and his/her staff as well as any appropriate 
communications by mail, fax, or telephone.  At each monitoring visit, the facilities, study drug 
storage area, CRFs, subject’s source documents, and all other study documentation will be 
inspected/reviewed by the Celgene representative for adherence to the protocol and Good 
Clinical Practice. 
The monitor will review CRFs for completion and accuracy.  Accuracy will be checked by 
performing source data verification at each site visit that is a direct comparison of the entries 
made onto the CRF against the appropriate source documentation.  Any resulting discrepancies 
will be reviewed with the Investigator(s) and/or his/her staff.  Any necessary corrections will be 
made directly to the CRFs or via queries by the Investigator(s) and/or his/her staff. Monitoring 
procedures require that informed consents, adherence to inclusion/exclusion criteria, and 
documentation of SAEs and the proper recording be verified.  Additional monitoring activities 
may be outlined in a study-specific monitoring plan. 
18.2. 
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 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 subject participation for audits 
and inspections by Institutional Review Board/Independent Ethic Committees (IRB/IECs), 
regulatory authorities (eg, FDA, EMA, Health Canada) 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. 
18.3. 
Investigator(s) Responsibilities 
Investigator responsibilities are set out in the International Conference on Harmonisation (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. 


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The Investigator(s) is responsible for keeping a record of all subjects who sign an Informed 
Consent Form and are screened for entry into the study.  For those subjects who fail screening, 
the reason(s) for exclusion must be recorded in the subject’s source documents and in the IVRS 
system. 
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 subject’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 subject’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 subject’s records (eg, 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 subject’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. 


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19. 
REGULATORY CONSIDERATIONS 
19.1. 
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 (Appendix 22.2).  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 subjects, 
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 subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved by 
Celgene and the IRB/IEC prior to use. 
19.2. 
Protocol Amendments 
Any amendment to this protocol that seems appropriate, as the study progresses (eg, 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.  Celgene does not require that 
amendments that are administrative in nature receive IRB/IEC approval, but will be submitted to 
the IRB/IEC for information purposes.  If local IRB/IEC procedures require approval of 
administrative amendments, then study sites should follow local IRB/IEC regulations. 
19.3. 
Informed Consent 
The Investigator(s) must obtain informed consent of a subject 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 subject’s entry into the study and of 
the informed consent process should be recorded in the subject’s source documents.  The original 
consent form, signed and dated by the subject and by the person consenting the subject prior to 
the subject’s entry into the study, must be maintained in the Investigator’s study files and a copy 
given to the subject.  In addition, if a protocol is amended and it impacts on the content of the 
informed consent, the informed consent must be revised.  Subjects 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 subject and by the person 
consenting the subject must be maintained in the Investigator’s study files and a copy given to 
the subject. 
19.4. 
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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20. 
DATA HANDLING AND RECORDKEEPING 
20.1. 
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, CRFs, source documents, original documents, data, 
records (eg, 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, filed and retained. 
20.2. 
Data Management 
Data will be entered into the clinical database as per Celgene SOPs. These data will be 
electronically verified through use of on-line checks during data entry, and through 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, in the form of a 
Data Clarification Form (DCF).  Resolutions to these issues will be reflected in the database.  An 
audit trail within the system will track all changes made to the data.  A quality control audit will 
be performed per Celgene SOP(s). 
20.3. 
Retention of Records 
The investigator(s) must maintain records of all study documents and supporting information 
relating to the conduct of the study.  This documentation includes, but is not limited to, 
protocols, case report forms, advertising for subject participation, adverse event reports, subject 
source data, correspondence with health authorities and IRBs/IECs, informed consent forms, 
investigator(s) curricula vitae, monitoring visit logs, laboratory reference ranges, laboratory 
certification or quality control procedures, and laboratory director curriculum vitae.  Subject 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 must be consulted if the 
investigator(s) wishes to assign the study files to someone else, remove them to another location 
or is unable to retain them for a specified period. 
For studies conducted in the United States under a US Investigational New Drug (IND), the 
investigator(s) must retain the study records for a minimum of 2 years after a marketing 
application for the indication is 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 (ie, the IND) is discontinued, and FDA is notified of 
that fact.  For IND studies conducted outside the US, the investigator(s), must retain study 
records for the time period described above or according to local laws or requirements, 
whichever is longer.  The monitor will inform the investigator(s) of the dates for retention.  All 
study documents should be made available if required by relevant health authorities.  For studies 
not conducted under the US IND, the investigator(s) 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 


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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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21. 
PREMATURE DISCONTINUATION OF THE STUDY 
21.1. 
Single Site 
The responsible clinical Investigator as well as Celgene have 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 
• Inaccurate or incomplete data collection 
• Falsification of records 
• Failure to adhere to the study protocol 
21.2. 
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 (eg, IRB/IEC, 
regulatory authorities, etc.). 










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23. 
APPENDICES 
23.1. 
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 subject during the course of a study.  It may be a new 
intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment 
of the subject’s health, including laboratory test values (as specified by the criteria below), 
regardless of etiology. Any medical condition that was present 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 an AE.  A diagnosis or syndrome should be 
recorded on the AE page of the electronic Case Report Form rather than the individual signs or 
symptoms of the diagnosis or syndrome. 
All AEs will be recorded by the Investigator(s) from the time of signing of informed consent 
form to 30 days after the treatment discontinuation visit.  All AEs that lead to study 
discontinuation should be followed until resolution or stabilization.  AEs will be recorded on the 
AE page of the CRF and in the subject’s source documents. 
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. 
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. 
Please note that all ≥ Grade 3 hematologic lab abnormalities must be reported as an Adverse 
Event on the AE page of the CRF.   
Serious adverse event 
A serious adverse event (SAE) is any AE which: 
• Results in death 
• Is life-threatening (ie, in the opinion of the Investigator[s] the subject 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 
subject’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 


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• Constitutes an important medical event 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious. 
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events.  This includes any second primary malignancy, regardless of causal 
relationship to study medication, occurring at any time for the duration of the study, from the 
time of signing the ICF up to and including any follow-up, observation and/or survival follow-up 
period.  In this study, subjects will be followed until all subjects in the study have been followed 
for at least 5 years from the last randomization, October 2020  (or have died/become lost to 
follow-up before 5 years).  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 of the diagnosis of the second primary malignancy 
must be provided at the time of reporting as a serious adverse event (eg, any confirmatory 
histology or cytology results).    
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. 
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 subject’s symptoms according to National 
Cancer Institute (NCI) Common Terminology Criteria (CTCAE, Version 3.0) with the 
exceptions recommended by the IWCLL guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia 
  AEs will be evaluated for severity according to the 
following scale: 
Grade 1 = Mild 
Grade 2 = Moderate 
Grade 3 = Severe 
Grade 4 =  Life Threatening or disabling AE 
Grade 5 =  Death 


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The following exceptions will be made as recommended by the IWCLL guidelines for the 
diagnosis and treatment of chronic lymphocytic leukemia 
as listed below*: 
Grade# 
Decrease in Platelets* or Hb° (nadir) 
From Pretreatment value (%) 
Absolute neutrophil count/μL@ (nadir) 
0 
No change to 10% 
≥ 2,000 
1 
11% - 24% 
≥1,500 and < 2,000 
2 
25% - 49% 
≥1,000 and < 1,500 
3 
50% - 74% 
≥ 500 and < 1,000 
4 
≥ 75% 
< 500 
* Platelet counts must be below normal levels for grades 1-4.  If, at any level of decrease the platelet count is < 
20,000/μL, this will be considered grade 4 toxicity, unless a severe or life-threatening decrease in the initial 
platelet count (eg, 20,000/μL) was present pretreatment, in which case the patient is not evaluable for toxicity 
referable to platelet counts. 
° Hb levels must be below normal levels for grades 1-4.  Baseline and subsequent Hb determinations must be 
performed before any given transfusions.  The use of erythropoietin is irrelevant for the grading of toxicity, but 
should be documented. 
# Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal.  Death occurring as a result of toxicity at any 
level of decrease from pretreatment will be recorded as grade 5. 
@ If the absolute neutrophil count (ANC) reaches less than 1,000/μL, it should be judged to be grade 3 toxicity.  
Other decreases in the white blood cell count, or in circulating granulocytes, are not to be considered, since a 
decrease in the white blood cell count is a desired therapeutic end point.  A gradual decrease in granulocytes is not 
a reliable index in CLL for stepwise grading of toxicity.  If the ANC was less than 1,000/μL prior to therapy, the 
patient is not evaluable for toxicity referable to the ANC.  The use of G-CSF is irrelevant for the grading toxicity, 
but should be documented. 
Grade 4 hematologic abnormalities are expected in patients with CLL, and are also observed in 
patients receiving lenalidomide. During the conduct of CC-5013-CLL-002, all Grade 4 
laboratory abnormalities will be reported to Celgene Drug Safety as SAEs at the discretion of the 
investigator and recorded in the CRF as SAEs, however those that are not deemed by the 
investigator to be part of a diagnosis or syndrome will not reported to the Health Authorities in 
an expedited manner.  Laboratory values will be captured within the study database and will be 
reviewed on an ongoing basis by the sponsor and (provided that it is determined that any 
observed individual abnormalities or patterns of abnormalities do not warrant prompt 
communication to Health Authorities) will be reported to Health Authorities in periodic safety 
reports. 
Please note that all ≥ Grade 3 hematologic lab abnormalities must be reported as an Adverse 
Event on the AE page of the CRF.   
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 


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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. 
Monitoring and reporting of adverse events 
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. 
Immediate reporting of serious adverse events 
Any AE that meets the criterion for a SAE requires the completion of a 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 subject’s treatment discontinuation visit, and those made known to the 
investigator(s) at anytime that are suspected of being related to study drug. 
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events.  This includes any second primary malignancy, regardless of causal 
relationship to study medication, occurring at any time for the duration of the study, from the 
time of signing the ICF up to and including any follow-up, observation and/or survival follow-up 
period.  In this study, subjects will be followed until all subjects in the study have been followed 
for at least 5 years from the last randomization, October 2020 (or have died/become lost to 
follow-up before 5 years).  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 of the diagnosis of the second primary malignancy 
must be provided at the time of reporting as a serious adverse event (eg, any confirmatory 
histology or cytology results).    
Grade 4 hematologic abnormalities are expected in patients with CLL, and are also observed in 
patients receiving lenalidomide.  The investigator will use their judgement to classify the 
seriousness of laboratory abnormality events.  Laboratory values will be captured within the 
study database and will be reviewed on an ongoing basis by the sponsor and (provided that it is 
determined that any observed individual abnormalities or patterns of abnormalities do not 
warrant prompt communication to Heath Authorities) will be reported to Health Authorities in 
periodic safety reports. 
The SAE must be reported (ie, within 24 hours of the Investigators’ knowledge of the event) to 
the Celgene 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 the Safety Monitor (see below for 
contact information). 


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The SAE report should provide a detailed description of the SAE and include copies of hospital 
records and other relevant documents.  If a subject 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 subject’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). 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject or the female partner of a male subject occurring while the 
subject is on study drug, or within 28 days of the treatment discontinuation visit, are considered 
immediately reportable events.  Study drug is to be discontinued immediately and the subject 
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 the Celgene Safety Monitor 
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 subject until completion of the pregnancy, and must 
notify Celgene Safety of the outcome of the pregnancy as a follow-up to the initial SAE report. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (ie, 
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 (ie, report the event 
to Celgene Safety by facsimile within 24 hours of the Investigator’s knowledge of the event). 
In the case of a live “normal” birth, the Celgene Safety Monitor should be advised by telephone 
and 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 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 subject’s continued 
participation in the study will be determined by the Investigator(s) and the Celgene Medical 
Monitor. 
Expedited Reporting of Adverse Events 


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For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
reported events suspected of being related to lenalidomide based on the Investigator Brochure. 
Celgene Global Drug Safety will use the German Summary of Product Characteristics (SmPC) 
as the safety reference document for allopurinol. 
For countries within the European Union, Celgene will report in an expedited manner to 
Regulatory Authorities and Ethics Committees concerned, AEs in accordance with the Detailed 
Guidance on 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, ie, 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 that suggests a significant risk for 
human study subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
Where required by local legislation, 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 19.3 for records retention information). 


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23.2. 
Declaration of Helsinki 
Celgene operates in accordance with the general ethical principles outlined in the Declaration of 
Helsinki. 


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23.3. 
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 our work of a light or sedentary nature, eg, light housework, 
office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair 
5 
Dead 




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23.6. 
Pregnancy Prevention Risk Management Plans 
23.6.1. 
Lenalidomide Pregnancy Prevention Risk Management Plan 
23.6.1.1. Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials 
Appendix 22.6.1 applies to all patients receiving lenalidomide therapy.  The following 
Pregnancy Risk Minimisation Plan documents are included in this appendix:  
1) Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth 
Control Methods (Section 22.6.2);  
2) Lenalidomide Education and Counseling Guidance Document (Section 22.6.2.1);    
3) Lenalidomide Information Sheet (Section 22.6.2.2). 
 
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods document (Section 22.6.2) provides the following 
information: 
• Potential risks to the fetus associated with lenalidomide exposure 
• Definition of Female of Childbearing Potential 
• Pregnancy testing requirements for patients receiving Lenalidomide who are females 
of childbearing potential 
• Acceptable birth control methods for both female of childbearing potential and male 
patients receiving Lenalidomide in the study  
• Requirements for counseling of all study patients receiving Lenalidomide about 
pregnancy precautions and the potential risks of fetal exposure to lenalidomide 
2. The Lenalidomide Education and Counseling Guidance Document (Section 22.6.2.1) 
must be completed and signed by either a trained counselor or the Investigator at the 
participating clinical center prior to each dispensing of lenalidomide study treatment. A 
copy of this document must be maintained in the patient records. 
3. The Lenalidomide Information Sheet (Section 22.6.2.2) will be given to each patient 
receiving lenalidomide study therapy. The patient must read this document prior to 
starting lenalidomide study treatment and each time they receive a new supply of study 
drug. 


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23.6.2. 
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods 
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.  The teratogenic effect of lenalidomide in 
humans cannot be ruled out.  Therefore, a risk minimization plan to prevent pregnancy must be 
observed. 
Criteria for females of childbearing potential (FCBP) 
This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has 
not undergone a hysterectomy or bilateral oophorectomy or 2) 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). 
Counseling 
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following 
are met (ie, all females of childbearing potential must be counseled concerning the following 
risks and requirements prior to the start of lenalidomide study therapy):  
• She understands the potential teratogenic risk to the unborn child 
• She understands the need for effective contraception, without interruption, 4 weeks 
before starting study treatment, throughout the entire duration of study treatment, 
dose interruption and 28 days after the end of study treatment 
• She should 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 the study treatment as soon as study drug is 
dispensed following a negative pregnancy test 
• She understands the need and accepts to undergo pregnancy testing based on the 
frequency outlined in this protocol (Section 22.6.2) 
• She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
The investigator must ensure that for females of childbearing potential: 
• Complies with the conditions for pregnancy risk minimization, including 
confirmation that she has an adequate level of understanding 
• Acknowledge the aforementioned requirements 


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For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (ie, all females NOT of childbearing potential must be counseled concerning 
the following risks and requirements prior to the start of lenalidomide study therapy):  
• She acknowledges that she understands the hazards and necessary precautions 
associated with the use of lenalidomide 
Traces of lenalidomide have been found in semen.  Male patients 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 study therapy): 
• Understand the potential teratogenic risk if engaged in sexual activity with a pregnant 
female or a female of childbearing potential 
• 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 female of childbearing 
potential.   
Contraception 
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable 
forms of contraception simultaneously or to practice complete abstinence from heterosexual 
contact during the following time periods related to this study: 1) for at least 28 days before 
starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 
28 days after study treatment discontinuation. 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. FCBP must be referred to a qualified provider of 
contraceptive methods if needed. The following are examples of highly effective and additional 
effective methods of contraception:   
• Highly effective methods: 
− Intrauterine device (IUD) 
− Hormonal (birth control pills, injections, implants) 
− Tubal ligation 
− Partner’s vasectomy 
• Additional effective methods: 
− Male condom 
− Diaphragm 
− Cervical Cap 
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 patients with neutropenia.  


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Pregnancy testing 
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for females of childbearing potential, including females of childbearing potential who 
commit to complete abstinence, as outlined below. 
Before starting study drug 
Female Patients: 
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to 
starting study drug.  The first pregnancy test must be performed within 10 to 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 study doctor has verified 
that the results of these pregnancy tests are negative. 
Male Patients: 
Must practice complete abstinence or agree to use a condom during sexual contact with a 
pregnant female or a female of childbearing potential while participating in the study, during 
dose interruptions and for at least 28 days following study drug discontinuation, even if he has 
undergone a successful vasectomy. 
During study participation and for 28 days following study drug discontinuation  
Female Patients: 
• FCBP 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 on study, at 
study discontinuation, and at day 28 following study drug discontinuation. If 
menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 
28 days and then every 14 days while on study, at study discontinuation, and at days 
14 and 28 following study drug discontinuation. 
• At each visit, the Investigator must confirm with the FCBP that she is continuing to 
use two reliable methods of birth control. 
• 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 study patient, study drug must be immediately 
discontinued.  
• Pregnancy testing and counseling must be performed if a patient misses her period or 
if her pregnancy test or her menstrual bleeding is abnormal.  Study drug treatment 
must be discontinued during this evaluation. 
• Females must agree to abstain from breastfeeding during study participation and for 
at least 28 days after study drug discontinuation. 
Male Patients: 
• Counseling about the requirement for complete abstinence or condom use during 
sexual contact with a pregnant female or a female of childbearing potential and the 


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potential risks of fetal exposure to lenalidomide 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 study 
patient during study participation, the investigator must be notified immediately. 
Additional precautions 
• Patients should be instructed never to give this medicinal product to another person 
and to return any unused capsules to the study doctor at the end of treatment. 
• Female patients should not donate blood during therapy and for at least 28 days 
following discontinuation of study drug. 
• Male patients should not donate blood, semen or sperm during therapy or for at least 
28 days following discontinuation of study drug. 
• Only enough study drug for one cycle of therapy may be dispensed with each cycle of 
therapy.  
 
 


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23.6.2.1. Lenalidomide Education and Counseling Guidance Document   
To be completed prior to each dispensing of study drug. 
Protocol Number: ____________________________________________ 
Patient Name (Print): __________________ DOB: _____/_____/_____ (mm/dd/yyyy) 
(Check the appropriate box to indicate risk category) 
Female:    □ 
If female, check one: 
 FCBP (Female of childbearing potential): sexually mature female who: 1) has not 
undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy 
(the surgical removal of both ovaries) or 2) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at 
least 24 consecutive months (ie, has had menses at any time during the preceding 24 
consecutive months) 
 NOT FCBP 
Male:  
  □ 
 
Do Not Dispense study drug if: 
• The patient is pregnant. 
• No pregnancy tests were conducted for a FCBP. 
• The patient states she did not use TWO reliable methods of birth control (unless 
practicing complete abstinence of heterosexual contact) [at least 28 days prior to 
therapy, during therapy and during dose interruption]. 
FCBP: 
1. I verified that the required pregnancy tests performed are negative. 
2. I counseled FCBP regarding the following: 
• Potential risk of fetal exposure to lenalidomide:  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.  The teratogenic potential of 
lenalidomide in humans cannot be ruled out.  FCBP must agree not to become 
pregnant while taking lenalidomide.  
• Using TWO reliable methods of birth control at the same time or complete abstinence 
from heterosexual contact [at least 28 days prior to therapy, during therapy, during 
dose interruption and 28 days after discontinuation of study drug]. 
• That even if she has amenorrhea she must comply with advice on contraception.  


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• Use of one highly effective method and one additional method of birth control AT 
THE SAME TIME. The following are examples of highly effective and additional 
effective methods of contraception: 
− Highly effective methods: 
o Intrauterine device (IUD) 
o Hormonal (birth control pills, injections, implants) 
o Tubal ligation 
o Partner’s vasectomy 
− Additional effective methods: 
o Male condom 
o Diaphragm 
o Cervical Cap 
• Pregnancy tests before and during treatment, even if the patient agrees not to have 
reproductive heterosexual contact.  Two pregnancy tests will be performed prior to 
receiving study drug, one within 10 to 14 days and the second within 24 hours of the 
start of study drug. 
• Frequency of pregnancy tests to be done: 
− Every week during the first 28 days of this study and a pregnancy test every 28 
days during the patient’s participation in this study if menstrual cycles are regular 
or every 14 days if cycles are irregular.  
− If the patient missed a period or has unusual menstrual bleeding. 
− When the patient is discontinued from the study and at day 28 after study drug 
discontinuation 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 study drug discontinuation. 
• Stop taking study drug immediately in the event of becoming pregnant and to call 
their study doctor as soon as possible. 
• NEVER share study drug with anyone else. 
• Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
• Do not breastfeed a baby while participating in this study and for at least 28 days after 
study drug discontinuation. 
• Do not break, chew, or open study drug capsules. 
• Return unused study drug to the study doctor. 
3. Provide Lenalidomide Information Sheet to the patient. 


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FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT LEAST 24 CONSECUTIVE 
MONTHS, A HYSTERECTOMY, OR BILATERAL OOPHORECTOMY): 
1. I counseled the female NOT of child bearing potential regarding the following: 
• Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP) 
• NEVER share study drug with anyone else. 
• Do not donate blood while taking study drug and for 28 days after stopping study 
drug. 
• Do not break, chew, or open study drug capsules. 
• Return unused study drug capsules to the study doctor. 
2. Provide Lenalidomide Information Sheet to the patient. 
MALE: 
1. I counseled the Male patient regarding the following: 
• Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP). 
• To engage in complete abstinence or use a condom when engaging in sexual contact 
(including those who have had a vasectomy) with a pregnant female or a female of 
childbearing potential, while taking study drug, during dose interruptions and for 28 
days after stopping study drug. 
• Males should notify their study doctor when their female partner becomes pregnant 
and female partners of males taking study drug should be advised to call their 
healthcare provider immediately if they get pregnant. 
• NEVER share study drug with anyone else. 
• Do not donate blood, semen or sperm while taking study drug and for 28 days after 
stopping study drug. 
• Do not break, chew, or open study drug capsules. 
• Return unused study drug capsules to the study doctor.  
2. Provide Lenalidomide Information Sheet to the patient. 
 
Investigator/Counselor Name (Print): ____________________  
  (circle applicable) 
 
Investigator/Counselor Signature: _______________________  
Date: _____/_____/_____ 
  (circle applicable) 
**Maintain a copy of the Education and Counseling Guidance Document in the patient records.**  


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23.6.2.2. Lenalidomide Information Sheet  
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
Please read this Lenalidomide Information Sheet before you start taking study drug 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.  Lenalidomide has not been tested in pregnant 
women but may also cause birth defects.  Findings from a monkey study indicate that 
lenalidomide caused birth defects in the offspring of female monkeys who received the 
drug during pregnancy.   
If you are a female who is able to become pregnant: 
• Do not take study drug if you are pregnant or plan to become pregnant 
• You must practice complete abstinence or use two reliable, separate forms of 
effective birth control at the same time:  
− for 28 days before starting study drug 
− while taking study drug 
− during dose interruptions of study drug 
− for 28 days after stopping study drug  
• You must have pregnancy testing done at the following times: 
− within 10 to 14 days and again 24 hours prior to the first dose of study drug 
− weekly for the first 28 days 
− every 28 days after the first month or every 14 days if you have irregular 
menstrual periods 
− if you miss your period or have unusual menstrual bleeding 
− 28 days after the last dose of study drug (14 and 28 days after the last dose if 
menstrual periods are irregular) 
• Stop taking study drug if you become pregnant during treatment 
− If you suspect you are pregnant at any time during the study, you must stop study 
drug immediately and immediately inform your study doctor.  Your study doctor 
will report all cases of pregnancy to Celgene Corporation 
• Do not breastfeed while taking study drug  


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• The study doctor will be able to advise you where to get additional advice on 
contraception.   
If you are a female not of childbearing potential: 
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: 
Lenalidomide is detected in trace quantities in human semen. The risk to the foetus in 
females of childbearing potential whose male partner is receiving lenalidomide is 
unknown at this time. 
• Male patients (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 study drug 
− During dose interruptions of study drug   
− For 28 days after you stop taking study drug 
• Male patients should not donate sperm or semen while taking study drug and for 
28 days after stopping study drug. 
• 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 get pregnant.   
2. Restrictions in sharing study drug and donating blood: 
• Do not share study drug 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 study drug and for 28 days after stopping study 
drug. 
• Do not break, chew, or open study drug capsules. 
• You will get no more than a 28-day supply of study drug at one time. 
• Return unused study drug capsules to your study doctor.   
Additional information is provided in the informed consent form and you can ask your study 
doctor for more information. 
 

SAP_001.pdf: 
Official Title of Study: 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED, 
PARALLEL- GROUP STUDY OF THE EFFICACY AND SAFETY OF LENALIDOMIDE (REVLIMID ®) 
AS MAINTENANCE THERAPY FOR PATIENTS WITH B-CELL CHRONIC LYMPHOCYTIC 
LEUKEMIA FOLLOWING SECOND-LINE THERAPY (THE CONTINUUM TRIAL) 
 
NCT Number: NCT00774345 
Document Date (Date in which document was last revised): October 16, 2015 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
1 
 
S T A TI S TI C A L A N A L Y SI S P L A N  
 
A P H A S E 3, M U L TI C E N T E R, R A N D O MI Z E D, D O U B L E-
B LI N D, P L A C E B O- C O N T R O L L E D, P A R A L L E L- G R O U P 
S T U D Y O F T H E E F FI C A C Y A N D S A F E T Y O F 
L E N A LI D O MI D E ( R E V LI MI D ® ) A S M AI N T E N A N C E 
T H E R A P Y F O R P A TI E N T S WI T H B -C E L L C H R O NI C 
L Y M P H O C Y TI C L E U K E MI A F O L L O W I N G S E C O N D-
LI N E T H E R A P Y  
( T H E C O N TI N U U M T RI A L) 
 
S T U D Y D R U G : 
 C C - 5 0 1 3 
P R O T O C O L N U M B E R : 
 C L L - 0 0 2 
D A T E FI N A L : 
 Oct o ber 1 6, 2 0 1 5  
 
 
  
 
 
 
 
 
C O N FI D E N TI A L  
T he i nf or m ati o n c o nt ai ne d i n t his d oc u me nt  is re g ar de d as c o nfi de nti al 
a n d, e xce pt t o t he e xte nt necess ary t o o bt ai n i nf or me d c o nse nt, m ay n ot be 
discl ose d t o a n ot her p arty u nless s uc h discl os ure is re q uire d by l a w or 
re g ul ati o ns. 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 
 
T A B L E O F C O N T E N T S  
 
 
2.  
LI S T O F A B B R E VI A TI O N S  ....................................................................................... 6 
 
 
4.  
O BJ E C TI V E S  ............................................................................................................. 1 2 
5.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 1 3 
5. 1.  
O verall St u d y Desi g n a n d Pla n ................................................................................... 1 3  
5. 2.  
St u d y E n d p oi nts .......................................................................................................... 1 4  
5. 3.  
Data a n d A nal ysis Q ualit y Ass ura nce  ........................................................................ 1 5 
6.  
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................... 1 6 
6. 1.  
Sa m ple Size  ................................................................................................................ 1 6 
6. 2.  
Ra n d o mizati o n a n d Stratificati o n  ............................................................................... 1 6 
6. 3.  
A nal ysis P o p ulati o ns .................................................................................................. 1 6  
6. 3. 1.  
I nte nt-t o-Treat (I T T) P o p ulati o n  ................................................................................. 1 6 
6. 3. 2.  
Safet y P o p ulati o n ........................................................................................................ 1 6  
6. 4.  
Re p orti n g C o n ve nti o ns ............................................................................................... 1 7  
6. 4. 1.  
Ta bles  .......................................................................................................................... 1 7 
6. 4. 2.  
Listi n gs  ....................................................................................................................... 1 8 
6. 4. 3.  
Dates  ........................................................................................................................... 1 8 
7.  
S U BJ E C T DI S P O SI TI O N  .......................................................................................... 2 0 
8.  
D E M O G R A P HI C S A N D B A S E LI N E C H A R A C T E RI S T I C S ................................. 2 1 
9.  
D R U G E X P O S U R E  ................................................................................................... 2 2 
 
 
1 1.  
E F FI C A C Y A N A L Y SI S  ............................................................................................ 2 5 
1 1. 1.  
C o - pri mar y E n d p oi nts a n d A nal ysis ........................................................................... 2 5 
1 1. 1. 1.  
Pr o gressi o n Free S ur vi val  ........................................................................................... 2 5 
1 1. 1. 2.  
O verall S ur vi val ( O S)  ................................................................................................. 2 8 
1 1. 2.  
Sec o n dar y E n d p oi nts a n d A nal ysis ............................................................................ 2 9  
1 1. 2. 1.  
C ha n ge i n T u m or Res p o nse ........................................................................................ 2 9  
1 1. 2. 2.  
D urati o n of I m pr o ve d Res p o nse ................................................................................. 2 9  
1 1. 2. 3.  
Healt h -Relate d Q ualit y of Life ( H R Q L)  ..................................................................... 2 9 
1 1. 2. 4.  
Pr o gressi o n Free S ur vi val 2 ( P F S 2) ........................................................................... 2 9  


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
3 
 
1 1. 3.  
S u b gr o u p A nal ysis ...................................................................................................... 3 0  
 
 
1 2.  
S A F E T Y A N A L Y SI S  ................................................................................................ 3 1 
1 2. 1.  
A d verse E ve nts ........................................................................................................... 3 1  
1 2. 2.  
Cli nical La b orat or y E val uati o ns  ................................................................................. 3 2 
1 2. 3.  
Vital Si g n Meas ure me nts  ............................................................................................ 3 2 
1 2. 4.  
Electr ocar di o gra m ( E C G)  ........................................................................................... 3 2 
1 2. 5.  
Deat hs  ......................................................................................................................... 3 2 
1 3.  
O T H E R T O PI C S  ........................................................................................................ 3 3 
1 3. 1.  
Q ualit y of Life  ............................................................................................................ 3 3 
1 4.  
I N T E RI M A N A L Y SI S ............................................................................................... 3 4 
1 4. 1.  
A d mi nistrati o n of t he I nteri m A nal yses  ..................................................................... 3 4 
1 4. 2.  
St atistical A p pr oac hes f or C o ntr ol of Al p ha a n d Ot her C o nsi derati o ns ..................... 3 4  
 
 
 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
4 
 
LI S T O F T A B L E S  
Ta ble 1:  
A b bre viati o ns a n d S pecialist Ter ms  ............................................................................. 6 
 
 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
5 
 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
6 
 
2.  
LI S T O F A B B R E VI A TI O N S  
T a ble 1: 
A b bre v i ati o ns a n d S peci alist Ter ms 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
A E  
A d v ers e e v e nt  
AL C 
A bs ol ut e l y m p h oc yt e c o u nt  
AL T ( S G P T)  
Al a ni n e tr a ns a mi n as e (s er u m gl ut a m at e 
p yr u vic tr a ns a mi n as e)  
A N C  
A bs ol ut e n e utr o p hil c o u nt  
A S C O 
A m eric a n S oci et y of Cli ni c al O nc ol o g y 
A N O V A/ A N C O V A  
A n al ysis of V ari a nc e/ C o v ari a nc e  
A S T ( S G O T)  
As p ar at e tr a ns a mi n as e (s er u m gl ut a mic 
ox al o ac etic tr a ns a mi n as e)  
A T C  
A n at o mic T h er a p e utic C h e mic al  
β 2 M  
B et a -2 Micr o gl o b uli n  
β - H C G 
B et a -h u m a n c h ori o nic g o n a d otr o pi n h or m o n e  
B U N  
Bl o o d ur e a nitr o g e n  
C B C  
C o m pl et e bl o o d c o u nt  
C F R 
C o d e of F e d er al R e g ul ati o ns  
CI  
C o nfi d e nc e I nt er v al  
CLL 
C hr o nic l y m p h oc ytic l e u k e mi a  
C N S  
C e ntr al n er v o us s yst e m  
C R  
C o m pl et e  r es p o ns e 
C Ri  
C o m pl et e r es p o ns e wit h i nc o m pl et e b o n e 
m arr o w r ec o v er y  
C R F  
C as e r e p ort f or m  
C T  
C o m p ut e d t o m o gr a p h y  
C T C A E  
C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e 
Ev e nts  
D C F  
D at a Cl arific ati o n F or m  
DL T 
D os e -li miti n g t oxicit y 
D M C  
D at a M o nit ori n g C o m mitt e e 
E C G  
El ectr oc ar di o gr a m  
E C O G  
E ast er n C o o p er ati v e O nc ol o g y Gr o u p  


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
7 
 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
E M A  
E ur o p e a n M e dici n es A g e nc y  
F 
Fl u d ar a bi n e  
F A C T-L e u 
F u ncti o n al Ass ess m e nt of C a nc er T h er a p y -
L e u k e mi a 
F C B P 
F e m al e of c hil d b e ari n g p ot e nti al  
F D A 
F o o d a n d Dr u g A d mi nistr ati o n  
FI S H 
Fl u or esc e nc e i n Sit u H y bri diz ati o n  
G C P  
G o o d Cli nic al Pr actic e  
H G B  
H e m o gl o bi n 
H C T 
H e m at ocrit  
HI V  
H u m a n i m m u n o d efici e nc y vir us  
H R QL  
H u m a n R el at e d Q u alit y of Lif e  
I C H 
I nt er n ati o n al C o nf er e nc e o n H ar m o niz ati o n 
I E C 
I n d e p e n d e nt Et hics C o m mitt e e 
I g V h 
I m m u n o gl o b uli n H e a v y-c h ai n V ari a bl e-r e gi o n 
IL- 6 
I nt erl e u ki n 6 
IL-1 0  
I nt erl e u ki n 1 0 
I Mi D 
I m m u n o m o d ul at or y dr u g 
I N D 
I n v esti g ati o n al N e w Dr u g 
I R B 
I nstit uti o n al R e vi e w B o ar d 
I T T 
I nt e nt t o Tr e at 
I V R S 
I nt er acti v e V oic e R es p o ns e S yst e m 
L D H 
L act at e d e h y dr o g e n as e 
M D S  
M y el o d ys pl astic s y n dr o m e  
M e d D R A  
M e dic al Dicti o n ar y f or R e g ul at or y Acti viti es 
M R D  
Mi ni m al r esi d u al dis e as e  
M T D  
M axi m u m -t ol er at e d d os e 
N CI C T C A E  
N ati o n al C a nc er I nstit ut e C o m m o n 
T er mi n ol o g y Crit eri a f or A d v ers e Ev e nts  
N CI -W G  
N ati o n al C a nc er I nstit ut e W or ki n g Gr o u p 
crit eri a f or c hr o nic l y m p h oc ytic l e u k e mi a  


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
8 
 
 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
N K c ells  
N at ur al kill er c ells  
N O S  
N ot ot h er wis e s p ecifi e d  
n P R  
N o d ul ar p arti al r es p o ns e  
N S AI D  
N o n -st eroi d al a nti -i nfl a m m at or y dr u g 
O S  
O v er all S ur vi v al  
P D  
Pr o gr essi v e dis e as e  
P F S 
Pr o gr essi o n fr e e s ur vi v al  
P F S 2  
Pr o gr essi o n fr e e s ur vi v al 2  
P R  
P arti al R es p o ns e  
P S  
P erf or m a nc e St at us  
R B C  
R e d bl o o d c ell  
RI C  
R e d uc e d i nt e nsit y c o n diti o ni n g  
S A E 
S eri o us a d v ers e e v e nt  
S C T 
St e m c ell tr a ns pl a nt ati o n  
S D 
St a bl e dis e as e  
S G O T  
S er u m- Gl ut a mic -Ox al o ac etic Tr a ns a mi n as e  
S O P  
St a n d ar d O p er ati n g Pr oc e d ur e  
S P M  
S ec o n d Pri m ar y M ali g n a nc y  
T N F α  
T u m or n ecr osis f act or al p h a  
T N M  
T u m or -n o d es -m et ast asis  
T S H  
T h yr oi d sti m ul ati n g h or m o n e  
T T F  
Ti m e t o tr e at m e nt f ail ur e  
T T P  
Ti m e t o pr o gr essi o n  
UL N  
U p p er li mit of n or m al  
V E G F  
V asc ul ar e n d ot h eli al gr o wt h f act or  
V E G R - 1 
V asc ul ar e n d ot h eli al gr o wt h f act or  
r ec e pt or 1  
V E G R -2  
V asc ul ar e n d ot h eli al gr o wt h f act or  
r ec e pt or 2 
V T E  
V e n o us  t hr o m b o e m b olis m 
W B C  
W hit e bl o o d c ell c o u nt  
W G  
W or ki n g Gr o u p  
W H O  
W orl d H e alt h Or g a niz ati o n  


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
9 
 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
Z A P 7 0  
Z et a -C h ai n -Ass oci at e d Pr ot ei n Ki n as e  






C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
1 2 
 
4.  
O B J E C TI V E S  
P ri m ar y: 
T o c o m pare t he efficac y of le nali d o mi de vers us place b o as mai nte na nce t hera p y.  
Sec o n d ar y : 
T o e val uate t he safet y of le nali d o mi de vers us place b o as mai nte na nce t hera p y.  


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
1 3 
 
5.  
I N V E S TI G A TI O N A L P L A N 
5. 1.  
O ver all St u d y Desi g n a n d Pl a n  
C C - 5 0 1 3-C L L - 0 0 2 is a p hase 3, m ultice nter, ra n d o mize d, d o u ble - bli n d, place b o-c o ntr olle d, 
parallel -gr o u p st u d y t hat will c o m pare t he efficac y a n d safet y of oral le nali d o mi de mai nte na nce 
t hera p y t o t hat of place b o mai nte na nce t hera p y i n s u bjects wit h B-cell C L L w h o ac hie ve d at least 
par tial res p o nse ( P R) wit h sec o n d li ne t hera p y.   
T he sc he d ule of a ssess me nts f or t his st u d y is i ncl u de d i n Ta ble 3  of t he pr ot oc ol. T he  st u d y 
c o nsists of 2 p hases f or eac h st u d y s u bject: mai nte na nce t hera p y a n d after st u d y disc o nti n uati o n.  
M ai nte n a nce  Ph ase  
S u bjects w h o meet all eli gi bilit y criteria will be ra n d o mize d ( 1: 1) b y a d o u ble-bli n d  pr oce d ure as 
descri be d i n Secti o n 3.  
St u d y treat me nt f or eac h s u bject be gi ns o n t he sa me da y t he s u bject u n der g oes ra n d o mizati o n.  
Le nali d o mi de a n d place b o are a d mi nist ere d orall y (i de nticall y -matc he d ca ps ules).  S u bjects will 
recei ve le nali d o mi de 2. 5 m g o nce dail y o n Da ys 1 t hr o u g h 2 8 of t he first 2 8-da y c ycle or 
matc hi n g place b o.  If t he 2. 5 m g d ose is well t olerate d (s u bject d oes n ot e x perie nce a n y Gra de 3 
or 4 st u d y dr u g-relate d t o xicities or a n y ot her t o xicit y [ Gra de 1 or 2] f o u n d t o be u nacce pta ble b y 
t he i n vesti gat or or t he s u bject), s u bjects s h o ul d be escalate d starti n g at t he sec o n d c ycle t o 5 m g 
o nce dail y o n Da ys 1 t hr o u g h 2 8 of eac h 2 8- da y c ycle or matc hi n g place b o u p t o disease 
pr o gressi o n.  If a s u bject de vel o ps a Gra de 1 or 2 a d verse e ve nt, t he dr u g ma y be i nterr u pte d 
u ntil res ol uti o n, h o we ver t he s u bject m ust c o m plete o ne f ull c ycle at t he 2. 5 m g d ose le vel pri or 
t o escalati o n t o t he 5 m g d ose le vel. 
S u bjects w h o c o m plete 5 c o nti n u o us c ycles at t he 5 m g d ose le vel wit h o ut ac hie vi n g 
M R D - ne gati ve C R a n d wit h o ut e x perie nci n g a n y Gra de 3 or 4 st u d y dr u g-relate d t o xicities a n d 
wit h o ut e x perie nci n g a n y ot her t o xicit y ( Gra de 1 or 2) f o u n d t o be u nacce pta ble b y t he 
i n vesti gat or ma y be escalate d t o 1 0 m g o nce dail y o n Da ys 1 t hr o u g h 2 8 of eac h 2 8-da y c ycle or 
matc hi n g place b o u p t o disease pr o gressi o n.  
D ose de- escalati o n t o 7. 5  m g fr o m 1 0 m g a n d t o 5 m g fr o m 7. 5  m g a n d t o 2. 5 m g fr o m 5 m g  a n d 
t o 2. 5 m g e ver y ot her da y fr o m 2. 5 m g will be per mitte d f or t h ose s u bjects w h o e x perie nce a 
Gra de 3 or 4 st u d y dr u g-relate d t o xicit y or a n y ot her Gra de 1 or 2 t o xicit y f o u n d t o be 
u nacce pta ble b y t he i n vesti gat or or s u bject.  
D ose i nterr u pti o ns are als o per mitte d f or Gra de 1 or 2 a d verse e ve nts at t he i n vesti gat or’s 
discreti o n.  A g ui deli ne f or t he re d ucti o n of t he d ose of le nali d o mi de/ place b o f or D L T is 
pr o vi de d (see Secti o n  1 0. 2. 1  of t he pr ot oc ol ). 
D ose re -escalati o n is per mitte d if t he s u bject is a ble t o c o m plete 2 f ull c ycles at  t he re d uce d d ose 
le vel wit h o ut e x perie nci n g a D L T or ot her t o xicit y dee me d t o be u nacce pta ble b y t he i n vesti gat or 
or s u bject a n d M R D- ne gati ve C R has n ot bee n ac hie ve d yet.  If t hat d ose le vel is a gai n n ot 
t olerate d, t he s u bject s h o ul d be de-escalate d t o the d ose bel o w a n d re mai n at t hat t olerate d d ose 
le vel f or t he rest of t he st u d y. 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
1 4 
 
St u d y visits a n d serial meas ure me nts of safet y a n d efficac y will be perf or me d as o utli ne d i n 
Ta ble 3  of t he pr ot oc ol . 
S u bjects w h o disc o nti n ue mai nte na nce t hera p y earl y ( d ue t o reas o ns ot her t ha n P D, i ncl u di n g 
u nacce pta ble t o xicit y) will be f oll o we d o n st u d y u ntil P D occ urs.   S u bjects will be assesse d f or 
res p o nse, s u bse q ue nt C L L t hera pies, sec o nd pri mar y mali g na ncies, A Es, rec o ver y fr o m S A Es 
a n d a n y ne w S A Es relate d t o st u d y pr oce d ures or pri or mai nte na nce t hera p y .  S u bjects will als o 
be as ke d t o c o nti n ue t o c o m plete t he F A C T- Le u a n d E Q- 5 D q uesti o n naires e ver y 8 wee ks .  
After St u d y Disc o nti n u ati o n:  
U p o n e x perie nci n g disease pr o gressi o n, s u bjects will be f oll o we d f or s ur vi val, i nf or mati o n o n 
ot her C L L treat me nts, sec o n d pri mar y mali g na ncies (re p orte d as S A Es), h os pitalizati o ns, a n d 
will c o m plete F A C T - Le u a n d E Q-5 D q uesti o n naires at eac h of t hese visits .  Patie nts w h o 
disc o nti n ue fr o m pr o gressi o n f oll o w u p f or reas o ns ot her t ha n pr o gressi o n/ disease tra nsf or mati o n 
(i.e. wit h dra w c o nse nt fr o m m o nt hl y visits, etc) s h o ul d still be f oll o we d f or s ur vi val, a n d if 
p ossi ble, date of pr o gressi o n a n d d oc u me ntati o n of pr o gressi o n s h o ul d be c ollecte d o n t hese 
patie nts w h o e nter t he s ur vi val f o ll o w u p p hase pri or t o pr o gressi o n or disease tra nsf or mati o n.  
S u bjects will be f oll o we d u ntil all s u bjects i n t he st u d y ha ve bee n f oll o we d f or at least 5 years 
fr o m ra n d o mizati o n ( or die d/ bec o me l ost t o f oll o w u p bef ore 5 years) or u ntil at least 1 6 0 deat hs 
ha ve occ urre d, w hic he ver c o mes later.  
5. 2.  
St u d y E n d p oi nts  
F or all t he efficac y e n d p oi nts, t he deter mi nati o n of res p o nses (i ncl u di n g pr o gressi o n of disease) 
is base d o n t he ce ntral a dj u dicati o n c o m mittee ( C A C) re vie w of t he C L L  res p o nse data usi n g 
I W C L L g ui deli nes f or t he dia g n osis a n d treat me nt of c hr o nic l y m p h oc ytic le u ke mia 
 
[ A p pe n di x 2 2. 4  of t he pr ot oc ol ]  
C o - prim ar y E n d p oi nt s 
•  Pr o gressi o n- Free S ur vi val (calc ulate d as t he ti me fr o m ra n d o mizati o n t o t he first 
d oc u me nte d pr o gressi o n c o nfir me d b y a bli n de d, i n de pe n de nt Res p o nse A dj u dicati o n 
C o m mittee or deat h d ue t o a n y ca use d uri n g or after t he treat me nt peri o d, w hic he ver 
occ urs first ) 
•  O verall S ur vi val (calc ulate d as t he ti me fr o m ra n d o mizati o n t o deat h fr o m a n y c a use). 
 
Sec o n d ar y E n d p oi nts  
•  Safet y [t y pe, fre q ue nc y, a n d se verit y of a d verse e ve nts ( A Es) a n d relati o ns hi p of A Es 
t o le nali d o mi de] 
•  T u m or Res p o nse, i ncl u di n g e val uati o n of mi ni mal resi d ual disease ( M R D) b y fl o w 
c yt o metr y  (i m pr o ve me nt of t he q ualit y of res p onse)  
•  D urati o n of res p o nse  
•  Healt h -Relate d Q ualit y of Life ( H R Q L) b y F u ncti o nal Assess me nt of Ca ncer 
T hera p y- Le u ke mia ( F A C T -Le u) a n d E Q - 5 D 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
1 5 
 
•  Pr o gressi o n Free S ur vi val 2 ( P F S 2) 
 
5. 3.  
D at a a n d A n al ysis Q u alit y A ss ur a nce 
T his pr ot oc ol is c o n d ucte d u n der t he s p o ns ors hi p of Cel ge ne C or p orati o n . T he data c ollecti o n 
a n d ma na ge me nt will be perf or me d acc or di n g t o t he  Cel ge ne Sta n dar d O perati n g Pr oce d ures 
( S O P). T he q ualit y of t he a nal yses will be verifie d t hr o u g h a pr o gra m mi n g vali dati o n pr ocess. At 
a mi ni m u m, all ta bles of ke y efficac y a n d safet y varia bles will be vali date d base d o n a n 
i n de pe n de nt pr o gra m mi n g of t hese res ults.  


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
1 6 
 
6.  
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S  
6. 1.  
S a m ple Size  
F or O S, a 6 1. 3 % i m pr o ve me nt i n me dia n s ur vi val fr o m ra n d o mizati o n, fr o m 3 years f or place b o t o 4. 8 4 
ye ars o n le nali d o mi de is c o nsi dere d cli nicall y rele va nt. F or P F S, a 6 1. 3 % i m pr o ve me nt i n me dia n ti me t o 
pr o gressi o n fr o m ra n d o mizati o n, fr o m 2 0 m o nt hs f or place b o t o 3 2. 3  m o nt hs o n le nali d o mi de is 
c o nsi dere d cli nicall y rele va nt. T he O S a n d P F S distri b uti o ns are ass u me d t o be e x p o ne ntial wit h a 
c o nsta nt fail ure ( hazar d) rate. W he n t he t otal n u m ber of e ve nts is a p pr o xi matel y 1 6 0 o ver b ot h treat me nt 
ar ms, t he n a t w o-si de d l o g-ra n k test wit h a n o verall si g nifica nce le vel of 0. 0 2 5 (all o wi n g f or t he c o-
pri mar y e n d p oi nts) w o ul d ha ve 8 0 % p o wer t o detect a hazar d rate rati o of 0. 6 2 . T o e ns ure ti mel y 
c o m pleti o n of t he st u d y, 3 2 0  s u bjects will be e nr olle d, 1 6 0  i n eac h treat me nt ar m. 
6. 2.  
R a n d o miz ati o n a n d Str atific ati o n  
Stratificati o n a n d ra n d o miz ati o n will be perf or me d b y I V R S, an I nteract i ve V oice Res p o nse 
S yste m , t o e ns ure a 1: 1 ce ntral ra n d o mizati o n . S u bjects w h o are eli gi ble f or t he st u d y will be 
ra n d o mize d ( 1: 1) t o recei ve le nali d o mi de or place b o.  S u bjects will be stratifie d at ra n d o mizati o n 
b y: 1) t heir res p o nse t o sec o n d-li ne i n d ucti o n t hera p y ( P R, n P R, C Ri or C R vers us 
M R D -ne gati ve C R); 2) a ge ( ≤ 7 0 vers us > 7 0 years); a n d 3) prese nce of at least o ne of t he 
f oll o wi n g p o or pr o g n ostic fact ors:  1 1 q deleti o n, 1 7 p deleti o n, u n m utate d I g VH  or β 2 M > 4. 0 
m g/ L ( Yes vers us N o vers us U n k n o w n).   
 
6. 3.  
A n al ysis P o p ul ati o ns  
6. 3. 1.  
I nte nt-t o-Tre at (I T T) P o p ul ati o n  
T he I nte nt- t o-Treat  (I T T) p o p ulati o n is defi ne d as all s u bjects w h o are ra n d o mize d, i n de pe n de nt 
of w het her t he y recei ve d st u d y treat me nt or n ot.  T he  I T T p o p ulati o n will be use d f or t he pri mar y 
efficac y a nal ysis.  
S u bject dis p ositi o n, de m o gra p hics, baseli ne c haracteristics, a n d all efficac y a nal yses will be 
base d o n t he I T T p o p ulati o n u nless s pecifie d ot her wise.  All s u bjects i n t he I T T p o p ulati o n will 
be a nal yze d acc or di n g t o t he trea t me nt t he y were ra n d o mize d t o recei ve a n d n ot acc or di n g t o 
w hat t he y act uall y recei ve d, if differe nt.  
6. 3. 2.  
S afet y P o p ul ati o n 
T he safet y p o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o recei ve at least 1 d ose of t he 
st u d y treat me nt (eit her le nali d o mi de or place b o).  
Dr u g e x p os ure a n d all safet y a nal yses (i ncl u di n g a d verse e ve nts, la bs, a n d deat hs) will be base d 
o n t he safet y p o p ulati o n.  S u bjects will be a nal yze d acc or di n g t o t he i nitial treat me nt act uall y 
recei ve d. 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
1 7 
 
6. 4.  
Re p orti n g C o n ve nti o ns  
T he al g orit h ms, i m p u tati o ns, a n d c o n ve nti o ns t hat will ge nerall y a p pl y t o pr o gra m me d 
ma ni p ulati o ns of t he data f or s u m mar y ta b ulati o ns a n d i n di vi d ual s u bject data listi n gs are 
descri be d i n t his secti o n.  
S u m mar y ta bles, listi n gs, a n d a n y s u p p orti ve S A S o ut p ut will i ncl u de a “f o oter” of e x pla nat or y 
n otes t hat will i n dicate, at a mi ni m u m, t he:  
•  Pr o gra m s o urce ( e. g, S A S pr o gra m na me, i ncl u di n g t he pat h, t hat ge nerates t he 
o ut p ut) a n d  
•  Data e xtracti o n date (e. g, t he data base l oc k date).  
T he p ur p ose of t he data e xtracti o n date is t o li n k t he o ut p ut t o a fi nal data base, eit her acti ve or 
arc hi ve d, t hat is write - pr otecte d f or re plicati o n a n d f ut ure refere nce.  A n o ut p ut date will als o 
a p pear o n eac h o ut p ut pa ge a n d will i n dicate t he date t he o ut p ut was ge nerate d b y t he a nal ysis 
pr o gra m.  
6. 4. 1.  
T a bles  
Data i n ta bles will be s u m marize d f or eac h of t he treat me nt gr o u ps  a n d o verall s u bjects w he n 
a p pr o priate. Ta bles will c o ntai n t he n u m ber of s u bjects i n t he a nal ysis p o p ulati o n f or eac h 
c ol u m n a n d t he t otal n u m ber. Prese ntati o ns will be s u m marize d b y c ycle if a p plica ble. I n 
selecte d prese ntati o ns t he e ve nt or assess me nt i n dicati n g t he m ost se vere e ve nt b y N CI C T C A E 
t o xicit y gra de or m ost a b n or mal assess me nt (a nal ysis of t he “ w orst” case) f or eac h s u bject o ver 
t he c o urse of t he st u d y will be s u m marized. 
Ti me p oi nts i n t he s u m maries will reflect t he ti me peri o ds descri be d i n t he pr ot oc ol a n d C R F, 
s uc h as ‘ Baseli ne’, ‘ C ycle 1’, ‘ C ycle 2’, etc.   
A ge will be dis pla ye d i n years a n d relati ve da ys (e. g., st u d y da ys) will be dis pla ye d i n da ys . 
D osi n g e x p os ure a n d treat me nt d urati o ns will als o be dis pla ye d i n da ys; all ot her ti me i nter vals 
will be prese nte d i n wee ks.  
T he f oll o wi n g descri pti ve statistics will be dis pla ye d f or eac h q ua ntitati ve varia ble: n, mea n, 
me dia n, sta n dar d de viati o n ( S De v), mi ni m u m, a n d ma xi m u m.  
Q ualitati ve varia bles will be prese nte d as cate g or y fre q ue ncies a n d perce nta ges. T he 
de n o mi nat or f or calc ulati n g perce nta ges will be eit her t he n u m ber of s u bjects i n t he a nal ysis 
p o p ulati o n or t he n u m ber of n o n- missi n g o bser vati o ns i n t he treat me n t gr o u p f or t he partic ular 
varia ble prese nte d. Visit wi n d o ws will n ot be use d i n t he data a nal yses. T he c ycle n u m ber 
rec or de d o n t he C R F, if a vaila ble, will be use d t o mar k t he data c ollecti o n ti me p oi nts. Act ual 
visit or assess me nt dates will be use d t o c alc ulate i nter vals of ti me.   
If a gi ve n ta ble te m plate s pecifies t he s u m marizati o n of a gi ve n q ualitati ve C R F varia ble a n d n o 
s uc h res p o nse a p pears o n a C R F f or a n y of t he s u bjects i n t he st u d y p o p ulati o n a p pr o priate t o 
t hat ta ble, t he e ntire r o w ma y be delete d fr o m t he s u m mar y rat her t ha n prese nt a r o w of zer oes 
f or t hat res p o nse.   


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
1 8 
 
6. 4. 2.  
Listi n gs  
Data listi n gs will be s orte d b y treat me nt gr o u p (f or u n bli n de d a nal ysis), s u bject n u m ber, a n d 
c ycle n u m ber, if a p plica ble.   
6. 4. 3.  
D ates  
Dates will be dis pla ye d i n d d m m m y y y y f or mat (e. g., 3 0J U N 2 0 0 2).  
Calc ulati o ns usi n g dates will a d here t o t he f oll o wi n g c o n ve nti o ns:  
•  St u d y da ys after t he start da y of st u d y dr u g will be calc ulate d as t he differe nce 
bet wee n t he date of i nterest a n d t he first date of d osi n g of st u d y me dicati o n  (e.g, 
le nali d o mi de) pl us 1 da y. T he ge neralize d calc ulati o n al g orit h m f or relati ve da y: 
S T U D Y D A Y = [( T A R G E T D A T E – D S T A R T) + 1 w here D S T A R T = t he start da y 
of st u d y dr u g].  N ote t hat St u d y Da y 1 is t he first da y of treat me nt of st u d y dr u g.  F or 
st u d y da ys bef ore t he start da y of st u d y dr u g t he al g orit h m is: S T U D Y D A Y = 
( T A R G E T D A T E – D S T A R T).  N e gati ve st u d y da ys are reflecti ve of o bser vati o ns 
o btai ne d d uri n g t he baseli ne/scree ni n g peri o d.   
•  A ge (e x presse d i n da ys) is calc ulate d: A G E = Date of ra n d o mizati o n – D T BI R T H + 
1.  I n practice, a ge will be c o n verte d t o years b y di vi di n g t he differe nce b y 3 6 5. 2 5 
da ys, t he n tr u ncati n g  t o a w h ole n u m ber. 
•  T he c o n versi o n bet wee n wee ks a n d m o nt hs ca n be perf or me d b y usi n g t he f oll o wi n g 
c o n versi o n f or m ula ( wit h o ut tr u ncati o n): 
M O N T H S   = W E E K S  * 7/ 3 0. 4. 
•  Partial dates will be re p orte d as rec or de d  i n t he data listi n gs.  T here will be n o 
i m p utati o n f or missi n g parts of dates, u nless f or t he p ur p ose of 
1.  de ter mi ni n g treat me nt e mer ge nt A Es w hen t he A E start date is partial, or  
2.  differe ntiati n g me dicati o n ta ke n pri or t o t he st u d y treat me nt fr o m c o nc o mita nt 
me dicati o n ta ke n d uri n g t he st u d y w he n t he m e dicati o n start date is partial.  
T he c o n ve nti o n s f or i m p uti n g partial dates f or s uc h p ur p oses are as f oll o ws: 
1.  T he o nset date has year b ut b ot h m o nt h a n d da y missi n g 
•  If t he year of o nset = year of first st u d y dr u g d ose, t he n t he o nset date = First st u d y 
dr u g d ose date. 
•  If t he year of o nset < year of first st u d y dr u g d ose, t he n t he o nset m o nt h = 1 2 a n d t he 
o nset da y =last da y of t he m o nt h.  
•  If t he year of o nset > year of first st u d y dr u g d ose, t he n t he o nset m o nt h = 1 a n d t he 
o nset da y = 1.  
 
2.  T he o nset date has year a n d m o nt h b ut da y missi n g 
•  If t he year a n d m o nt h of o nset = year a n d m o nt h of first st u d y dr u g d ose, t he n t he 
o nset date = first st u dy dr u g d ose date. 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
1 9 
 
•  If t he year of o nset < year of first st u d y dr u g d ose, or t he year of o nset = year of first  
st u d y dr u g d ose b ut t he m o nt h of o nset < t he m o nt h of first st u d y dr u g d ose, t he n t he 
o nset da y = last da y of t he m o nt h.  
•  If t he year of o nset > ye ar of first st u d y dr u g d ose, or t he year of o nset = year of first 
st u d y dr u g d ose b ut t he m o nt h of o nset > m o nt h of first st u d y dr u g d ose, t he n t he 
o nset da y  = first da y of t he m o nt h. 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 0 
 
7.  
S U B J E C T DI S P O SI TI O N  
F or all  s u bjects ra n d o mize d, s u bject dis p ositi o n will be s u m marize d.  S u bject dis p ositi o n 
i ncl u des t he n u m ber of s u bjects i n t he f oll o wi n g cate g ories: 
•  I T T P o p ulati o n 
•  Safet y P o p ulati o n 
Reas o ns f or treat me nt ter mi nati o n will be c ollecte d o n t he C R F a n d will be s u m marize d f or all 
ra n d o mize d s u bjects wit h t he foll o wi n g cate g ories:  
•  A Es t hat, i n t he j u d g me nt of t he I n vesti gat or, ma y ca use se vere or per ma ne nt har m or 
w hic h r ule o ut c o nti n uati o n of st u d y dr u g. 
•  Disease pr o gressi o n wit h or wit h o ut hist ol o gic tra nsf or mati o n  
•  S u bject wit h dra ws c o nse nt 
•  S u bject l ost t o f ol l o w- u p 
•  Deat h  
•  Pr ot oc ol vi olati o n  
A se parate listi n g will be pr o vi de d f or s u bjects n ot treate d. 
 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 1 
 
8.  
D E M O G R A P HI C S A N D B A S E LI N E C H A R A C T E RI S TI C S  
S u bjects’ a ge, wei g ht, a n d ot her c o nti n u o us de m o gra p hic a n d baseli ne varia bles i ncl u di n g 
disease c haracteristics  will b e s u m marize d usi n g descri pti ve statistics ( e. g., mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m a n d ma xi m u m), w hile t he res p o nse t o pre vi o us C L L treat me nt, race 
a n d ot her cate g orical varia bles will be s u m marize d wit h fre q ue nc y ta b ulati o ns f or eac h treat me nt 
ar m se paratel y a n d po ole d o ver all treat me nt ar m s.  C yt o ge netic a b n or malities will be i de ntifie d 
a n d s u m marize d b y treat me nt ar m. 
H o m o ge neit y of t hese varia bles will be assesse d b y t -test f or c o nti n u o us meas ures a n d b y 
Fis her’s e xact test  f or cate g orical measures.  If a n y si g nifica nt differe nces ( p < 0. 1 0 ) are f o u n d 
bet wee n treat me nt ar ms, a d diti o nal e x pl orat or y a nal yses will be perf or me d t o assess t he i m pact 
of t his lac k of baseli ne h o m o ge neit y o n relati ve treat me nt effects.  
S u m maries f or t he de m o gra p hics a n d b aseli ne c haracteristics will be pr o vi de d f or t he I T T 
p o p ulati o n a n d safet y p o p ulati o n se paratel y.  I n di vi d ual s u bject listi n gs will be pr o vi de d.  
Me dical hist or y data will be s u m marize d usi n g fre q ue nc y ta b ulati o ns f or eac h treat me nt ar m b y 
s yste m or ga n class a n d preferre d ter m se paratel y a n d p o ole d o ver all ar ms usi n g t he safet y 
p o p ulati o n. 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 2 
 
9.  
D R U G E X P O S U R E  
T he f oll o wi n g meas ures of dr u g e x p os ure will be a nal yze d f or le nali d o mi de a n d place b o.  
Tre at me nt D ur ati o n 
T he first d ose date of le nali d o mi de or p lace b o is c o nsi dere d t he start date of t he o verall st u d y 
treat me nt. F or eac h c ycle, t he le nali d o mi de/ place b o start date will be c o nsi dere d t he c ycle start 
date a n d t he da y bef ore t hat (after t he 1 st c ycle) will be c o nsi dere d t he e n d da y of t he pre vi o us 
c ycle.  T he  e n d date of t he last c ycle will be calc ulate d as t he start date of last treat me nt c ycle 
pl us 2 7 da ys, u nless s u bject disc o nti n ues st u d y or dies bef ore t he e n d of t he last c ycle, i n w hic h 
case t he e n d date of t he last c ycle will be t he treat me nt disc o nti n u ati o n date or t he deat h date.  
T he o verall st u d y treat me nt e n d date will be t he sa me as t he e n d date of t he last c ycle of t he last 
st u d y dr u g.  T he  o verall treat me nt d urati o n (da y s) is defi ne d as:  
[( T he o verall st u d y treat me nt e n d date) – (t he first st u d y dr u g start date) + 1]  
F or eac h  st u d y dr u g (i.e., le nali d o mi de or place b o), t he treat me nt d urati o n will als o be 
calc ulat e d, a n d defi ne d as : 
  
[( T he e n d of t he last c ycle of t he st u d y dr u g) – (t he first d ose date of t he st u d y dr u g) + 1] 
C u m ul ati ve D ose 
C u m ulat i ve d ose will be calc ulate d f or le nali d o mi de ar m.  T he c u m ulati ve d ose is defi ne d as t he 
s u m of all d oses ta ke n acr oss t he treat me nt peri o d (i n milli gra ms).   
D ose E x p os ure  
D ose e x p os ure will be calc ulate d  f or  le nali d o mi de ar m.  D ose e x p os ure is defi ne d as t he n u m ber 
of da ys o n t he st u d y dr u g d uri n g t he treat me nt p hase (e xcl u di n g t he peri o ds of d ose i nterr u pti o ns. 
A ver a ge D ail y D ose 
A vera ge d ose will be calc ulate d f or le nali d o mi de ar m.  A vera ge dail y d ose is defi ne d as t he 
cu m ulati ve  d ose di vi de d b y d ose ex p o s ure ( m g/ da y).  
D ose Inte nsit y   
D ose i nte nsit y will be calc ulate d f or le nali d o mi de ar m.  D ose i nte nsit y is defi ne d as t he 
cu m ulati ve  d ose di vi de d b y treat me nt d urati o n ( m g/ da y).  
Descri pti ve statistics of treat me nt d urati o n , c u m ulati ve d ose, d ose e x p os u re, a vera ge dail y d ose, 
a n d d ose i nte nsit y , will be prese nte d  b y treat me nt ar m . I n a d diti o n, descri pti ve statistics f or 
treat me nt d urati o n i n wee ks a n d ass ociate d fre q ue nc y ta bles, as well as t he n u m ber of c ycles o n 
st u d y dr u g, will be prese nte d b y treat me nt ar m, f or b ot h i n d ucti o n t hera p y peri o d a n d t he w h ole 
d o u ble- bli n d treat me nt peri o d.  
T he d osi n g statistics as descri be d a b o ve ma y be prese nte d b y c ycle.  
D ose re d ucti o n/i nterr u pti o n a n d re- escalati o n will be s u m marize d . S u m maries will i ncl u de 
s u bjects w ho ha ve at least o ne d ose re d ucti o n/i nterr u pti o n d ue t o A E , ti me t o first d ose 
re d ucti o n/i nterr u pti o n d ue t o A E. A d diti o nal descri pti ve statistics will i ncl u de, s u bjects w h o 
ha ve a sec o n d d ose re d ucti o n/i nterr u pti o n d ue t o A E, d urati o n of first a n d sec o n d d ose 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 3 
 
re d ucti o n/i nterr u pti o n d ue t o A E a n d i nter val bet wee n first a n d sec o n d d ose 
re d ucti o n/i nterr u pti o n d ue t o A E. 
N u m ber of s u bjects w h o reac he d 5 m g at C ycle 2 a n d 1 0 m g at C ycle 7 will als o be s u m marize d.  
As a n e x pl orat or y a nal ysis, t he d osi n g statistic s a b o ve mi g ht  be s u m marize d  b y treat me nt ar m 
a n d st u d y dr u g f or differe nt a ge gr o u ps ( ≤ 7 0  yrs a n d > 7 0  yrs) t o e xa mi ne t he p ossi ble 
differe nce i n d osi n g t olera bilit y b y a ge.  




C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 5 
 
1 1.  
E F FI C A C Y A N A L Y SI S   
Efficac y a nal yses will be perf or me d o n t he i nte nt- t o-treat (I T T) p o p ulati o n t hat i ncl u des all 
s u bjects ra n d o mize d. Pri mar y a nal yses will be perf or me d i n t w o ste ps wit h a B o nferr o ni 
a dj ust me nt use d t o c o ntr ol t he err or rate.  
T he first ste p is t o c o m pare P F S after at least 1 6 0  s u bjects acr oss b ot h treat me nt ar ms ha ve 
pr o gresse d or die d. A n i nteri m a nal ysis f or O S will als o be perf or me d at t his ti me. If t he P F S 
differe nce bet wee n t he t w o treat me nt gr o u ps is si g nifica nt a n d O S res ults d o n ot s h o w a ne gati ve 
effect f or t he le nali d o mi de treat me nt gr o u p, t he n le nali d o mi de treat me nt will be dee me d 
efficaci o us. F urt her m ore, if t he O S i nteri m reac hes t he pre -s pecifie d O’ Brie n-Fle mi n g 
b o u n daries a n d P F S is n ot statisticall y si g nifica nt b ut n ot ne gati ve f or le nali d o mi de, t he n 
le nali d o mi de will be dee me d efficaci o us. T hese a nal yses will be perf or me d b y a n i n de pe n de nt 
statisticia n n ot ass ociate d wit h t he trial.  T he res ults will be s hare d o nl y wit h t he D M C w h o will 
deci de t he f ut ure c o urse of t he st u d y.  S pecificall y, if eit her ( or b ot h) of t he t w o eff icac y 
c o n diti o ns descri be d a b o ve are met, t he n t he D M C c o ul d rec o m me n d t hat t he bli n d be br o ke n 
a n d a nal yses be perf or me d b y t he s p o ns or. 
T he sec o n d ste p will be t he c o m paris o n of O S. T his a nal ysis will be perf or me d w he n at least 1 6 0 
s u bjects acr oss b ot h treat me nt ar ms ha ve die d. T his a nal ysis will be perf or me d re gar dless of t he 
o utc o me of t he a nal ysis of P F S. If n o si g nifica nt differe nces i n P F S are f o u n d d uri n g t he first 
ste p a nal ysis, b ut differe nces are f o u n d i n O S d uri n g t he sec o n d ste p i n fa v or of le nali d o mi de 
treat me nt gr o u p, t he treat me nt will be dee me d efficaci o us. E x pl orat or y a nal ysis o n P F S will als o 
be perf or me d at t his ti me.  
Sec o n dar y a nal yses will be perf or me d t o c haracterize c ha n ge i n t u m or res p o nse, d urati o n of 
i m pr o ve d res p o nse, H R Q L, a n d P FS 2 .  If eit her of t he c o- pri mar y e n d p oi nts is si g nifica nt, a 
fi xe d se q ue nce testi n g pr oce d ure will be use d f or t he sec o n dar y e n d p oi nts wit h t he f oll o wi n g 
or der:  t u m or res p o nse, d urati o n of res p o nse.  T he Ka pla n- Meier pr oce d ure will be use d t o 
c haracterize  t he ti me-t o-e ve nt c ur ves i n t hese a nal yses w he n t here is ce ns ori n g. Stratifie d l o g 
ra n ks tests will be use d t o c o m pare t he ti me-t o-e ve nt c ur ves. A nal ysis of varia nce/c o varia nce 
( A N O V A/ A N C O V A) will be use d t o c o m pare H R Q L a n d E Q- 5 D t otal sc ores a n d s u bsc ores 
acr oss t he t w o treat me nt ar ms. Ot her wise, s u m mar y statistics ( mea n, sta n dar d de viati o n, me dia n, 
mi ni m u m a n d ma xi m u m) a n d rele va nt c o nfi de nce i nter vals will be pr o vi de d. 
1 1. 1.  
C o - pri m ar y E n d p oi nt s a n d A n al ysis  
1 1. 1. 1.  
P r o gressi o n Free S ur vi v al  
Pr o gressi o n- free s ur vi val will be calc ulate d as t he ti me fr o m ra n d o mizati o n t o t he first 
d oc u me nte d pr o gressi o n c o nfir me d b y a bli n de d, i n de pe n de nt Res p o nse A dj u dicati o n C o m mittee 
or deat h d ue t o a n y ca use d uri n g or after t he treat me nt peri o d, w hic he ver occ urs first.  T he 
pr o gres si o n date will be assi g ne d t o t he earliest ti me w he n a n y pr o gressi o n is o bser ve d wit h o ut 
pri or missi n g assess me nts. If wit h dra wal of c o nse nt or l ost t o f oll o w- u p occ urs bef ore 
d oc u me nte d pr o gressi o n or deat h, t he n t hese o bser vati o ns will be ce ns ore d at t he date w he n t he 
last c o m plete t u m or assess me nts deter mi ne d a lac k of pr o gressi o n. 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 6 
 
F or s u bjects w h o d o n ot de vel o p pr o gressi ve disease at t he ti me of a nal ysis, if t he res p o nse fr o m 
t he last visit was ‘ n ot e val ua ble’, t he m ost pri or visit date wit h c o m plete eval uati o n i n dicati n g n o 
pr o gressi ve disease will be use d as t he ce ns or date.  T hese r ules are  base d o n F D A g ui da nce f or 
ca ncer trial e n d p oi nts 
 a n d t he f oll o wi n g ta ble s pecifies t he a p plicati o n of 
t he g uida nce  f or vari o us c o m m o n sit uati o ns f or t he calc ulati o n of P F S. 
Detaile d decisi o n r ules f or t he pri mar y a n d a se nsiti vit y a nal ysis of P F S are s u m marize d i n t he 
f oll o wi n g ta bles:   
T a ble 2:  
Pri m ar y A n al ysis of P F S 
Sit u ati o n  
D ate of Pr o gressi o n or Ce ns ori n g  
Sit u ati o n O utc o me  
N o baseli ne t u m or 
assess me nts  
Ra n d o mizati o n  
Ce ns ore d  
 
Pr o gressi o n d oc u me nte d 
bet wee n  
sc he d ule d visits 
Earliest of:  
•  
Date of p h ysical e xa mi nati o n f or  
l y m p ha de n o pat hies, s plee n a n d li ver 
s h o wi n g: 
o  a p peara nce of ne w 
l y m p ha de n o pat hies or ne w or ga n 
i nfiltrati o n or 
o  i ncrease b y 5 0 % or m ore i n t he 
greatest deter mi ne d dia meters of 
pre vi o usl y e xisti n g 
l y m p ha de n o pat hies 
o  i ncrease b y 5 0 % or m ore i n li ver 
or s plee n size  
•  
Date of la b test s h o wi n g 5 0 % or m ore 
i ncrease i n l y m p h oc ytes 
•  
Date of p ost -treat me nt la b test s h o wi n g 
occ urre nce pr o gressi o n of c yt o pe nia 
attri b uta ble t o C L L  
•  
Date of test c o nfir mi n g tra nsf or mati o n t o a 
m ore a g gressi ve hist ol o g y  
 
Pr o gresse d  
 
N o pr o gressi o n  
Date of last a de q uate assess me nt wit h e vi de nce of 
n o pr o gressi o n  
Ce ns ore d  
St u d y  disc o nti n uati o n 
f or reas o ns ot her t ha n 
disease pr o gressi o n  
Date of last a de q uate assess me nt wit h e vi de nce of 
n o pr o gressi o n  
Ce ns ore d  
Ne w a ntica ncer 
treat me nt starte d wit h n o 
clai m of pr o gressi o n  
Date of last a de q uate assess me nt wit h e vi de nce of 
n o pr o gres si o n pri or t o t he start of ne w a ntica ncer 
treat me nt 
Ce ns ore d  
Deat h bef ore first P D 
assess me nt w hile o n 
Date of deat h  
Pr o gresse d  


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 7 
 
st u d y 
T a ble 2: 
Pri m ar y A n al ysis of P F S ( C o nti n ue d)  
Sit u ati o n  
D ate of Pr o gressi o n or Ce ns ori n g  
Sit u ati o n O utc o me  
Deat h or pr o g ressi o n 
after a n e xte n de d l ost -
t o-f oll o w-u p ti me (t w o 
or m ore misse d 
assess me nts) w hile o n 
st u d y 
Date of last a de q uate assess me nt wit h e vi de nce of n o 
pr o gressi o n  
Ce ns ore d  
Deat h bet wee n a de q uate 
assess me nt visits w hile 
o n st u d y  
Date of deat h  
Pr o gresse d  
De at h wit hi n t w o 
m o nt hs after st u d y 
disc o nti n uati o n  
Date of deat h  
Pr o gresse d  
Deat h be y o n d t w o 
m o nt hs after st u d y 
disc o nti n uati o n  
Date of last a de q uate assess me nt wit h e vi de nce of n o 
pr o gressi o n  
Ce ns ore d  
 
T a ble 3: 
Se nsiti vit y A n al ysis f or P F S  
Sit u ati o n  
D a te of Pr o gressi o n or Ce ns ori n g 
Sit u ati o n O utc o me  
N o baseli ne t u m or 
assess me nts  
Ra n d o mizati o n  
Ce ns ore d  
 
Pr o gressi o n d oc u me nte d 
bet wee n sc he d ule d 
visits  
Date of ne xt sc he d ule d visit  
Pr o gresse d  
 
N o pr o gressi o n  
Date of last a de q uate assess me nt wit h n o e vi de nce of 
pr o gressi o n  
Ce ns ore d  
St u d y  disc o n ti n uati o n 
f or reas o ns ot her t ha n 
disease pr o gressi o n  
Date of last a de q uate assess me nt wit h n o e vi de nce of 
pr o gressi o n d uri n g f oll o w -u p  
Ce ns ore d  
Ne w a ntica ncer 
treat me nt starte d wit h 
n o clai m of pr o gressi o n  
Date of last a de q uate assess me nt wit h n o e vi de nce of 
pr o gressi o n d uri n g f oll o w -u p re gar dless of ne w 
a ntica ncer treat me nt  
Ce ns ore d  
Deat h bef ore first P D 
assess me nt w hile o n 
st u d y  
Date of deat h  
Pr o gresse d  
Deat h bet wee n a de q uate 
assess me nt visits w hile 
o n st u d y  
D ate of deat h  
Pr o gresse d  


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 8 
 
T a ble 3: 
Se nsiti vit y A n al ysis f or P F S  ( C o nti n ue d) 
Sit u ati o n  
D ate of Pr o gressi o n or Ce ns ori n g  
Sit u ati o n O utc o me  
Deat h or pr o gressi o n 
after a n e xte n de d l ost -
t o-f oll o w-u p ti me (t w o 
or m ore misse d 
assess me nts)  w hile o n 
st u d y 
Date of last a de q uate assess me nt wit h n o e vi de nce of 
pr o gressi o n  
Ce ns ore d  
Deat h wit hi n t w o 
m o nt hs after st u d y 
disc o nti n uati o n  
Date of deat h  
Pr o gresse d  
Deat h be y o n d t w o 
m o nt hs after st u d y 
disc o nti n uati o n  
Date of st u d y disc o nti n uati o n visit  
Ce ns ore d  
Ka pla n -Mei er pr o d uct li mit met h o ds will be use d t o esti mate t he s ur vi v ors hi p f u ncti o ns f or t he 
ti me-t o-e ve nt e n d p oi nts (e. g., P F S, ti me t o res p o nse, a n d O S).  A t w o-si de d l o g-ra n k test 
stratifie d b y t he 3 strata use d i n t he ra n d o mizati o n will be use d as t he pri mar y a nal ytic met h o d t o 
c o m pare s ur vi v ors hi p f u ncti o ns f or ti me -t o-e ve nt varia bles i n t he 2 treat me nt gr o u ps.  I n ter ms of 
t he s ur vi v ors hi p f u ncti o ns f or eac h treat me nt gr o u p, t he h y p ot heses of i nterest were: 
H 0:  FA (t) =  FP (t) f or all t 
Vers us  
H 1:  FP (t) ≠ FA (t) f or all t 
w here F P  is t he s ur vi v ors hi p f u ncti o n f or place b o a n d FA  is t he s ur vi v ors hi p f u ncti o n f or 
le nali d o mi de. 
Me dia n P F S will be esti mate d usi n g Ka pla n -Meier esti mates, a n d t he 9 5 % c o nfi de nce i nter vals 
( CI) will be c o m p ute d usi n g t he met h o d of Br o o k me yer a n d Cr o wle y.  Hazar d rati o will be 
calc ulate d usi n g C o x m o del stratifie d f or t he 3 strata (i.e., res p o nse t o sec o n d-li ne i n d ucti o n 
c he m ot hera p y, a ge, a n d prese nce of at least o ne pr o g n ostic fact or ) t o acc o u nt f or t he stratifie d 
ra n d o mizati o n.  T he C o x m o del will als o be use d t o i de ntif y pr o g n ostic fact ors. 
Cr oss -ta b ulati o ns will be pr o vi de d b y treat me nt gr o u p t o s u m marize i m pr o ve me nts fr o m t he best 
res p o nse d uri n g i n d ucti o n t hera p y. 
F or t he pri mar y a nal ysis, t he c o m paris o n of P F S bet wee n t he tr eat me nt ar ms usi n g t he stratifie d 
l o g ra n k test, t he o verall tw o -si de d si g nifica nce le vel is 2. 5%.   
A n u nstratifie d  l o g-ra n k test will als o be perf or me d as a sec o n dar y a nal ysis f or P F S , i n a d diti o n 
t o t he stratifie d a nal ysis descri be d a b o ve. 
1 1. 1. 2.  
O ver all S ur vi v a l ( O S) 
O verall s ur vi val is calc ulate d as t he ti me fr o m ra n d o mizati o n t o deat h fr o m a n y ca use.  O S will 
be ce ns ore d at t he last date t hat t he s u bject was k n o w n t o be ali ve f or s u bjects w h o were ali ve at 
t he ti me of a nal ysis a n d f or s u bjects w h o were l ost t o f oll o w- u p bef ore deat h was d oc u me nte d. 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
2 9 
 
T he a nal ysis of O S will i ncl u de s ur vi val i nf or mati o n f or all ra n d o mize d s u bjects.  S u bjects w h o 
disc o nti n ue d fr o m t he treat me nt p hase of t he st u d y a n d w h o ha d p ossi bl y recei ve d ot her 
a nti-ca ncer t hera pies a n d t he n s u bse q ue ntl y die d will be i ncl u de d i n t he a nal ysis as deat h.  
H o we ver, se nsiti vit y a nal yses will be perf or me d i n w hic h t hese s u bjects will be ce ns ore d at t he 
date of t he first d ose d ate of t he a nti-ca ncer t hera p y.  
O S will be c o m pare d bet wee n treat me nt ar ms u si n g t he stratifie d l o g-ra n k test at 2-si de d 0. 0 2 5 
al p ha le vel.  T he sa me met h o ds use d f or t he P F S a nal ysis will be use d f or t he O S a nal ysis.   
 
1 1. 2.  
Sec o n d ar y E n d p oi nts  a n d A n al ysi s 
1 1. 2. 1.  
C h a n ge i n T u m or Res p o nse  
T u m or res p o nse, i ncl u di n g P D, will be assesse d acc ordi n g t o t he I W C L L g ui deli nes f or t he 
dia g n osis a n d treat me nt of c hr o nic l y m p h oc ytic le u ke mia (Halle k, 2 0 0 8 ).  S u bjects’ t u m or 
res p o nse stat us c ha n ge base d o n t he best res p o nse d uri n g t he treat me nt peri o d relati ve t o t he 
res po nse at baseli ne (i.e., fr o m P R, n P R, C Ri, C R, M R D- ne gati ve C R t o P D, n P R, C Ri, C R, 
M R D -ne gati ve C R) will be c o m pare d i n t he t w o ar ms usi n g Va n Eltere n’s test at a t w o-si de d 
0. 0 5 si g nifica nce le vel stratifie d f or t he 3 strata use d at ra n d o mizati o n.  Res p o nses fr o m s u bjects 
after t he y recei ve d ot her a nti -ca ncer treat me nts will n ot be c o u nte d; h o we ver, t hese s u bjects will 
be i ncl u de d i n t he de n o mi nat or.  Cr oss ta b ulati o ns will be pr o vi de d t o s u m marize res p o nse 
fre q ue nc y c ha n ge c o m pari n g t o baseli ne. 
1 1. 2. 2.  
D ur ati o n of I m pr o ve d Res p o nse  
F or t h ose s u bjects w h o s h o w i m pr o ve me nt fr o m t heir best res p o nse ac hie ve d d uri n g i n d ucti o n 
t hera p y w hile o n st u d y treat me nt (e. g. P R t o C R or C R t o M R D- C R), t he d urati o n of t he 
i m pr o ve d res p o nse will be s u m marize d.  T he d urati o n of i m pr o ve d res p o nse will be calc ulate d at 
t he ti me fr o m first i m pr o ve me nt t o t he ti me of disease pr o gressi o n.  D urati o n of i m pr o ve d 
res p o nse will be ce ns ore d at t he date of last assess me nt s h o wi n g n o w orse ni n g fr o m t he 
i m pr o ve d res p o nse. A t w o-si de d u nstratified l o g ra n k test at 0. 0 5 si g nifica nce le vel will be use d 
t o test t he d urati o n of i m pr o ve d res p o nse bet wee n t he t w o treat me nt ar ms.  
1 1. 2. 3.  
He alt h -Rel ate d Q u alit y of Life ( H R Q L)  
F or Healt h -Relate d Q ualit y of Life ( H R Q L) b y F u ncti o nal Assess me nt of Ca ncer T hera p y -
L e u ke mia ( F A C T - Le u) a n d E Q-5 D, c ha n ges fr o m baseli ne i n o verall sc ore a n d s u b -sc ores will 
be a nal yze d usi n g re peate d meas ures of A N O V A/ A N C O V A usi n g t he baseli ne sc ores as 
c o variates w here a p pr o priate . 
Vari o us sc he mes will be assesse d f or missi n g data i m p uta ti o n if nee de d. 
1 1. 2. 4.  
Pr o gressi o n Free S ur vi v al 2 ( P F S 2)  
 
P F S 2 is d efi n e d as t h e ti m e fr o m r a n d o miz ati o n t o s ec o n d o bj ecti v e dis e as e pr o gr essi o n, or d e at h  
fr o m a n y c a us e, w hic h e v er occ urr e d first. P ati e nts ali v e a n d f or w h o m a s ec o n d o bj ecti v e dis e as e 






C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
3 2 
 
T he a d verse e ve nt of i nfecti o n will als o be a nal yze d acc or di n g t o t he gra di n g s yste m as 
rec o m me n de d b y t he I W C L L g ui deli nes f or t he dia g n osis a n d treat me nt of C L L 
 
( A p pe n di x 2 2. 4). 
 
1 2. 2.  
Cli nic al L a b or at or y E v al u ati o ns  
La b orat or y data will be gra de d acc or di n g t o N CI C T C A E  versi o n 3. 0.  S hift ta bles de m o nstrati n g 
t he c ha n ges fr o m baseli ne t o t he w orst se verit y gra de o bser ve d d uri n g t he treat me nt p hase will 
be dis pla ye d f or eac h treat me nt ar m f or rele va nt la b para meters f or he mat ol o g y, c he mistr y, a n d 
uri nal ysis .     
1 2. 3.  
Vit al Si g n Me as ure me nts  
F or vital si g ns, cr oss -ta b ulati o ns s h o wi n g t he n u m ber of s u bjects wit h val ues bel o w, wit hi n a n d 
a b o ve t he n or mal ra n ges pre- treat me nt vers us p ost-treat me nt will be s u m marize d b y treat me nt 
ar m f or t he treat me nt p hase.  F or wei g ht, mea ns, me dia ns, sta n dar d de viati o ns, mi ni m u m, a n d 
ma xi m u m will be pr o vi de d b y c ycle. 
1 2. 4.  
Electr oc ar di o gr a m ( E C G)  
E C G res ults b y visit will be s u m marize d b y treat me nt ar m. I n a d diti o n, s hift ta bles f or E C G 
e val uati o ns fr o m baseli ne t o t he w orst cate g or y d uri n g t he treat me nt will be pr o vi de d f or eac h 
treat me nt ar m.   
 
1 2. 5.  
De at hs  
Deat hs d uri n g t he treat me nt p hase a n d  wit hi n 3 0  da ys fr o m t he last d ose of st u d y treat me nt will 
be ta b ulate d  b y t he pri mar y ca use of deat h  a n d treat me nt ar ms .  Se parate  s u m mar y ta bles will be 
ma de f or t he deat hs t hat are s us pecte d t o dr u g relate d a n d f or t h ose t hat are c o nsi dere d n o n- dr u g 
relate d. 
T he sa me s u m mar y ta bles will be pr o vi de d f or t he deat hs t hat occ ur d uri n g f oll o w - u p p hase 
se paratel y. 


C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
3 3 
 
1 3.  
O T H E R T O PI C S  
 
1 3. 1.  
Q u alit y of Life  
T he Healt h -Relate d Q ualit y of Life ( H R Q L) o utc o mes assess me nt i ncl u de F u ncti o nal 
Assess me nt of Ca ncer T hera p y -Le u ke mia ( F A C T - Le u) a n d E Q- 5 D.  
T he s u bscale sc ores at eac h assess me nt as well as t he c ha n ges fr o m baseli ne f or p ost -baseli ne 
assess me nts will be s u m marize d a n d c o m pare d bet wee n treat me nt gr o u ps usi n g re peate d 
meas ures of A N O V A/ A N C O V A usi n g t he baseli ne sc ores as c o variates w here a p pr o priate.  I n 
a d diti o n, fre q ue nc y ta bles f or cate g orize d c ha n ge fr o m baseli ne sc ores (I m pr o ve me nt, N o 
C ha n ge, a n d W orse ni n g) will be prese nte d b y treat me nt gr o u p. 
Vari o us sc he mes will be assesse d f or miss i n g data i m p utati o n if nee de d. 
 
 




C C - 5 0 1 3 
 
 
Statistical A nal ysis Pla n Pr ot oc ol C C - 5 0 1 3-C L L - 0 0 2 
Cel ge ne C or p orati o n 
C o nf i de ntial a n d Pr o prietar y 
3 5 
 
I n a d diti o n t o t he l o g-ra n k test c o m pari n g t he 2 ar ms, c o n diti o nal a n d pre dicti ve p o wer will be 
calc ulate d at t his i nteri m a nal ysis, t o get her wit h esti mati o n of t he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val.