Clinical trial NCT00963105
Conditions: Relapsed or Refractory Chronic Lymphocytic Leukemia
Sponsor: Celgene
Start date: 2009-10-19; Completion date: 2017-09-05
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety and effectiveness of different dose regimens of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Detailed description:

Arms: arm 1: Participants received a starting dose of 5 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability.

Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug arm 2: Participants received a starting dose of 10 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability.

Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug arm 3: Participants received a starting dose of 15 mg lenalidomide orally once a day. Lenalidomide dose was escalated by 5 mg in a step-wise manner every 28 days up to a maximum dose of 25 mg daily based on tolerability.

Participants continued receiving study drug until disease progression or unacceptable toxicity, unless they withdrew consent or had other reasons to discontinue from study drug
Interventions: intervention 1: lenalidomide
Intervention descriptions: intervention 1: Depending on the starting dose, subjects will be allocated in a double-blind fashion to three different regimens and will escalate every 28 days, based on individual subject tolerability, as follows:

* Treatment Arm 1: 5 mg →10 mg →15 mg →20 mg →25 mg/daily
* Treatment Arm 2: 10 mg →15 mg →20 mg →25 mg/daily
* Treatment Arm 3: 15 mg →20 mg →25 mg/daily Subjects will continue treatment until disease progression or unacceptable toxicity

Protocol documents:
Prot_000.pdf: 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
1
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
TITLE PAGE 
A PHASE 2, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
PARALLEL-GROUP STUDY OF THE SAFETY AND EFFICACY OF 
DIFFERENT LENALIDOMIDE (REVLIMID®) DOSE REGIMENS IN 
SUBJECTS WITH RELAPSED OR REFRACTORY B-CELL CHRONIC 
LYMPHOCYTIC LEUKEMIA
STUDY DRUG:
Lenalidomide
PROTOCOL NUMBER:
CC-5013-CLL-009
EudraCT NUMBER
2009-009836-54
DATE FINAL:
09 March 2009
AMENDMENT #1 
10 June 2009
AMENDMENT #2
11 February 2010
AMENDMENT #3
9 December 2010
AMENDMENT #4
12 May 2011
AMENDMENT #5
AMENDMENT #6
9  November 2011
15 April 2015
___________{See appended electronic signature page}___________
Signature of Celgene Therapeutic Area Head
__________
  _____________________
Printed Name of Celgene Therapeutic Area Head
Date Signed __________________
                   dd mmm yyyy 
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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Celgene Corporation
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2
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
[include if applicable]
Signature of Coordinating Principal Investigator
dd mmm yyyy
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, IRB/EC 
procedures, instructions from Celgene representatives, the Declaration of Helsinki, ICH 
Good Clinical Practice guidelines, and the applicable parts of the United States Code of 
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Celgene Corporation
Confidential and Proprietary
3
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
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Site Number________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
IRB/EC procedures, instructions from Celgene representatives, the Declaration of 
Helsinki, ICH Good Clinical Practice guidelines, and the applicable parts of the United 
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Celgene Corporation
Confidential and Proprietary
4
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
1.
STUDY CONTACT INFORMATION
Table 1:
Celgene Emergency Contact Information
Role in Study
Name
Address and Telephone Number
Celgene International Sàrl
Celgene R&D
Route de Perreux 1
2017 Boudry, Switzerland
Telephone:  
Email:  
 
Celgene International Sàrl
Celgene R&D
Route de Perreux 1
2017 Boudry, Switzerland
Telephone:  
Mobile:  
Email:  
Drug Safety Contact
**Contact 
information for the 
local reporting of 
SAEs will be 
provided in a 
separate document.
Global Drug Safety
International 
Celgene Corporation
Telephone:  
Fax:  
E-mail: drugsafety@celgene.com
Celgene Global Drug Safety
Celgene International Sàrl
Route de Perreux 1
2017 Boudry, Switzerland
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Celgene Corporation
Confidential and Proprietary
5
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 1:
Celgene Emergency Contact Information (Continued)
Role in Study
Name
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Celgene International Sàrl
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Route de Perreux 1
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Telephone:  
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Telephone: 
 
Mobile: 
 
Email: 
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emergency calls  
Back-up 24 Hour Global Emergency Contact Call Center: +1-877-501-7738
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Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
6
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
2.
SYNOPSIS
Name of Sponsor/Company:  Celgene Corporation
Name of Investigational Product:  lenalidomide
Protocol Number: CC-5013-CLL-009
Protocol Title: A Phase 2, Multi-Center, Randomized, Double-Blind, Parallel-Group Study Of 
The Safety And Efficacy Of Different Lenalidomide (Revlimid®) Dose Regimens In Subjects 
With Relapsed Or Refractory B-Cell Chronic Lymphocytic Leukemia
Indication: For the treatment of patients with B-cell chronic lymphocytic leukemia who have 
failed at least 1 prior therapy
Study Duration:
Subjects may receive study drug until disease 
progression or unacceptable toxicity develops, whichever 
occurs first.
Study will be closed once 80% of the subjects
randomized to the study have progressed or died or up to 
five years after the last subject was randomized, 
whichever occurs later.  All subjects ongoing on study 
drug at the time the study is closed will be transferred to 
lenalidomide on a free basis in agreement with the site 
principal investigator and according to local regulations.
Phase of development:
Phase 2
Objectives
Primary
!
To evaluate the safety of different lenalidomide dose regimens in subjects with 
relapsed or refractory B-cell CLL.  
Secondary
!
To evaluate the efficacy of different lenalidomide dose regimens in subjects with 
relapsed or refractory B-cell CLL.  
Study Endpoints
Primary
!
Safety [type, frequency, and severity of adverse events (AEs) and relationship of 
AEs to lenalidomide]
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
7
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
!
Response rate; International Workshop on Chronic Lymphocytic Leukemia 
(iwCLL) Guidelines for the diagnosis and treatment of CLL (Hallek, 2008)
!
Duration of response 
!
Time to response (TTR)
!
Time to progression (TTP)
!
Event-free survival (EFS)
!
Progression-free survival (PFS)
!
Overall survival (OS)
Exploratory
!
Evaluation of response rate in predefined biologic risk group
!
!
Investigate the relationship between pharmacokinetics (PK) and response 
(biomarkers or clinical outcomes as appropriate)
!
Quality of Life
Study Design
CC-5013-CLL-009 is a phase 2, multi-center, randomized, double-blind, parallel-group
adaptive design study that will evaluate the safety and efficacy of different lenalidomide dose 
regimens administered orally.  All regimens use a stepwise dose escalation scheme with three 
different initial ascending starting dose of 5 mg daily, 10 mg daily and 15 mg daily and then 
escalating in a stepwise manner every 28 days to reach a maximum dose of 25 mg daily based 
on subject tolerability.  Approximately 105 subjects will be enrolled.  Eligible subjects must 
have B-cell CLL that has relapsed after or is refractory to at least one prior CLL treatment 
regimen.  At least one of the prior treatments must have included a purine-analog or 
bendamustine based treatment regimen.  Subjects must have active disease per the iwCLL 
Guidelines for the diagnosis and treatment of CLL (Hallek, 2008).
At the time of randomization, study subjects will be stratified by the following criteria:
!
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regimen [relapsed/refractory as defined per the iwCLL guidelines for diagnosis and 
treatment of CLL (Hallek, 2008)].  If subject has received both, the status post most 
recent purine-analog or bendamustine regimen will be used for stratification.
!
Age < 65 years of age vs. ≥ 65 years of age
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 
initiating study drug as outlined in Table 2.
During screening all subjects will have the following assessments / samples collected:
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
8
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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Vital signs, including height and weight
!
Pregnancy testing as specified in Appendix 21.9
!
Pregnancy and risk counseling as specified in Appendix 21.9
!
Assessment of ECOG performance score
!
Assessments of constitutional symptoms
!
Physical examination to assess the lymph nodes, spleen and liver
!
Clinical staging using Rai and /or Binet as defined per the iwCLL guidelines for 
diagnosis and treatment of CLL (Hallek, 2008) in Appendix 21.4
!
12-lead ECG
!
Peripheral blood smear, bone marrow aspirate and bone marrow biopsy (reference 
samples) for central pathology reviewer (local pathology results will also be 
captured on the eCRFs).
!
Peripheral blood for disease confirmation by immunophenotyping per Hallek, 2008.
!
Peripheral blood sample for complete blood counts (CBCs), serum chemistries and 
thyroid function tests
!
Urine sample for urinalysis
!
Calculated (method of Cockroft-Gault) creatinine clearance (creatinine clearance 
may also be obtained by the 24-hour collection method at the investigator’s 
discretion)
!
Peripheral blood sample for a direct antiglobulin test (DAT)
!
CT scans of the neck, chest, abdomen and pelvis to assess lymphadenopathies
Local/Central Laboratories and Reviewers
Data generated by central laboratories and evaluations performed by central pathology 
reviewer will prevail over locally generated information in the evaluation of the subject’s 
efficacy results.
Laboratory tests that may result in dose interruption and/or modification as specified in Table 5
should also be performed locally to allow for treatment related decisions during subject visits.
At a minimum the following hematology/chemistry assessments must be performed locally:  
hemoglobin, absolute lymphocyte count, absolute neutrophil count and platelet count, 
potassium, calcium, phosphorus, creatinine, total bilirubin, AST/SGOT, ALT/SGPT, and uric 
acid.  
At screening, subjects must meet eligibility criteria based on central lab results.  At Study Day 
1, subjects must meet eligibility criteria based on local or central lab results prior to initiating 
study therapy, however, a re-calculation of creatinine clearance is not required at Study Day 1.
Exploratory Assessments
The following exploratory assessments will be performed in all subjects:
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
9
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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Blood samples for ZAP-70, VH mutational status /TP53 mutation analysis, FISH 
studies for cytogenetic assessment,
 
will be collected at baseline.
 
 
 
 
 
 
 
Subjects will complete quality of life questionnaire (FACT-Leu and EQ-5D questionnaires) at 
time points detailed in Table 2.
Pharmacokinetic assessments
Pharmacokinetic assessments will be performed in up to 40 subjects who provide consent at 
select centers.  Intensive sampling and sparse sampling will be discontinued as of this 
amendment, protocol amendment #6.
Treatment
Subjects must meet all eligibility criteria to be randomized for the study.
Initial randomization
Initially subjects will be randomized (1:1:1) in a double-blind fashion to the 5 mg, 10 mg, and 
15 mg starting dose arms (treatment arm 1, treatment arm 2, and treatment arm 3 respectively).  
The randomization procedure will be accomplished by a validated interactive voice response 
system (IVRS).  Subjects will be stratified at randomization by (i) relapsed vs refractory to 
their last purine-analog or bendamustine based treatment regimen (if subject has received both, 
the status post most recent purine-analog or bendamustine regimen will be used for 
stratification) and (ii) age < 65 years of age vs ∀65 years of age.  The subjects will receive 
lenalidomide once daily in a 28 day cycle and will be escalated every 28 days as tolerated in a 
stepwise manner up to a maximum of 25 mg daily.
Stopping of Treatment Arm(s)
After 18 subjects complete one 28 day cycle, an interim analysis will be conducted to review 
the safety of each starting dose arm(s).  Subsequent interim analyses to review the safety and 
progression rate of each starting dose arm(s) will occur at 13-week intervals.  After review of 
each interim analysis, a treatment arm may be dropped.  At any time accrual to a starting dose 
arm will also be stopped if unacceptable toxicities are observed in that arm.  If a treatment arm 
is dropped then all new subjects will be randomized equally into the remaining arm(s).
Dose Regimens:
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
10
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Depending on the starting dose, subjects will be allocated in a double-blind fashion to three 
different regimens and will escalate every 28 days, based on individual subject tolerability, as 
follows:
!
Treatment Arm 1: 5 mg →10 mg →15 mg →20 mg →25 mg/daily
!
Treatment Arm 2: 10 mg →15 mg →20 mg →25 mg/daily
!
Treatment Arm 3: 15 mg →20 mg →25 mg/daily
For toxicities requiring dose interruption and/or modification see Section 10.2.3. Note that a 
more gradual stepwise dose escalation of lenalidomide (more than one 28 day cycle for each 
dose level) might be needed at the discretion of the treating physician due to adverse events 
that do not require dose reduction or interruption.
Subjects unable to escalate to the 25 mg maximum dose due to toxicity may continue with the 
highest dose achieved in the previous cycle or as indicated in the dose modification section (see 
Section 10.2.3).
Study visits and serial measurements of safety and efficacy will be performed as outlined in 
Table 2.  The severity of adverse events (AEs) will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 with 
the exceptions of hematological toxicities and TLS.  Hematological toxicities will be graded as 
specified in the iwCLL guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia (Hallek, 2008) (Appendix 21.4).  TLS will be graded as specified by the Cairo-
Bishop grading system (Appendix 21.3).
The use of hematopoietic growth factors is permitted.  Treatment with myeloid growth factors 
is strongly encouraged following ASCO guidelines recommendation (Smith, 2006) for dosing 
and administration when the absolute neutrophil count (ANC) is less than 1,000/μL [NOTE: 
per the inclusion criteria, subjects must have an ANC ≥ 1000/μL to be eligible for study entry].  
Subjects will continue in the study and receive study drug until discontinuation from the study 
for any of the following reasons: disease progression; AEs that, in the judgment of the
Investigator, may cause severe or permanent harm or which rule out continuation of study drug, 
subject withdraws consent, subject is lost to follow-up, death, protocol violation that may rule
out continuation of study drug and other reasons that in the judgment of the Investigator may 
rule out continuation of study drug.
For those subjects who discontinue study drug for reasons other than disease progression or 
withdrawal of consent, study visits should continue every 28 days to assess response until 
documentation of disease progression or until a new CLL therapeutic regimen is started, 
whichever comes first.  During these visits only the following assessments will be required: 
hematology, ECOG performance status, evaluation of constitutional symptoms, physical exam 
for liver, spleen and lymph nodes, adverse events, assessment for second primary malignancies,
concomitant medications/therapies, and assessment of response.
For subjects who develop PD characterized by transformation to a more aggressive histology 
[i.e. Richter’s syndrome (lymphomas) or prolymphocytic leukemia], this diagnosis should be 
established by lymph node biopsy whenever possible.
Subjects who are discontinued from the study drug for any reason, except for withdrawal of 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
11
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
consent, will be followed every 12 weeks for survival, secondary primary malignancies and 
subsequent CLL therapies until the study is closed (see Figure 1 Overall Study Schema).
Study will be closed once 80% of the subjects randomized to the study have progressed or died
or up to five years after the last subject was randomized, whichever occurs later.  All subjects 
ongoing on study drug at the time the study is closed will be transferred to lenalidomide on a 
free basis in agreement with the site principal investigator and local regulations.
Response Assessment
Tumor response will be assessed according to the iwCLL guidelines for the diagnosis and 
treatment of CLL (Hallek, 2008), including CR, CRi, nPR, PR, SD and PD.  Evaluation of 
response will be performed after 3 cycles of therapy and every 4 weeks thereafter.
For those subjects who reach PR, CRi or CR, a CT scan of the neck, chest, abdomen and pelvis 
to assess lymphadenopathies will be performed at the PR and CR/CRi confirmation visits (≥ 8 
weeks to ≤ 12 weeks)after all clinical and laboratory response criteria have been met for PR or 
CR/CRi).  Those subjects whose response was down-graded based on the CT scan 
interpretation at the PR or CR/CRi confirmation visit will have the CT scan repeated 4 months 
later at the location where remaining disease has been documented, as long as clinical and 
laboratory response remains present to try to document further improvement.
For those subjects who reach CR or CRi, a bone marrow aspirate and bone marrow biopsy will 
be performed at the CR/CRi confirmation visit (≥ 8 weeks to ≤ 12 weeks after all clinical and 
laboratory response criteria have been met).  If the bone marrow is hypocellular, a repeat 
specimen should be obtained after 4 weeks, provided that the blood counts have recovered. If 
the bone marrow biopsy shows disease involvement (30% or greater lymphocytes, or nodules 
positive for B-CLL cells by immunohistochemistry), an additional bone marrow biopsy and 
aspirate will be taken 4 months later as long as clinical and laboratory response remain in CR 
or CRi response status to try to document further improvement.
MRD status will be evaluated for those subjects who reach CR or CRi. A peripheral blood and 
bone marrow aspirate sample will be collected for MRD analysis by flow cytometry at the 
CR/CRi confirmation visit.
!
If peripheral blood and bone marrow are both MRD-positive, peripheral blood 
samples will be repeated and assessed up to 3 additional times at 8 week intervals to 
try to document MRD negativity in subjects who reach confirmed CR or CRi (see 
Follow-up MRD assessments).
!
If peripheral blood is MRD-negative and bone marrow is MRD-positive, both 
peripheral blood and bone marrow should be retested for MRD negativity after ≥ 12 
weeks. If this repeat bone marrow is MRD-positive, no further testing for MRD 
will be performed.
!
If both the peripheral blood and bone marrow are MRD-negative, peripheral blood 
will be tested every 6 months for assessment of MRD until subject discontinues 
study drug.
Follow-up MRD assessments:
!
If any of the repeat peripheral blood assessments indicate MRD-negativity, a bone 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
12
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
marrow aspirate sample should be collected and retested as soon as possible to 
confirm MRD negativity. 
#
If the bone marrow is MRD-positive, both peripheral blood and bone marrow 
should be retested for MRD negativity after ≥ 12 weeks. If this repeat bone 
marrow is MRD-positive, no further testing for MRD will be performed.
#
If at any time, the bone marrow is MRD-negative, peripheral blood will be 
tested every 6 months for assessment of MRD until subject discontinues study 
drug.
Prophylaxis for Tumor Lysis Syndrome (TLS), infection and thromboembolism and treatment of 
tumor flare reaction (TFR):
TLS and TFR 
TLS prophylaxis, comprising of oral hydration and allopurinol 300 mg/day will be initiated at 
least 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles.  For 
subjects with known allergy to allopurinol prior to study initiation or for those who develop an 
allergy during the course of study, the medical monitor should be contacted.  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 each cycle during the dose escalation period.  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.
Grade 1 TFR may be treated with NSAIDs and TFR ≥ Grade 2 may be treated with 
corticosteroids.  Narcotic analgesics may be added as needed for pain control in subjects 
experiencing ≥ Grade 2 TFR.
Subjects will be monitored for TLS and TFR as follows:
!
On Day 2 and 4 and then weekly (Days 8, 15, 22) for cycle 1 and the first cycle of 
each dose escalation
!
On Day 1, 8 and 15 of cycle 2 (if not dose escalated)
!
At least every 28 days thereafter and as clinically indicated.
Thromboembolic Events Prophylaxis
Lenalidomide may increase the risk of thromboembolic events in subjects who are at high risk 
(high risk is defined for example as a history of a thromboembolic event and/or taking a 
concomitant medication associated with an increased risk for a thromboembolic event and/or a 
known hypercoagulable state regardless of thromboembolic history). All subjects should 
receive anti-thrombotic prophylaxis during study treatment.  For subjects who enter the study 
with a platelet count close to the eligibility criteria of ≥ 50,000/ μL, the medical monitor should 
be contacted to discuss the anti-thrombotic prophylaxis.  The recommended prophylaxis is low-
dose aspirin [ASA] (70-100mg) daily; however, another prophylactic anti-thrombotic therapy 
may be used per investigator’s discretion during study treatment. Choice of the most 
appropriate anti-thrombotic therapy for each subject should be based upon a careful evaluation 
of the different risk factors associated with each therapy, and a corresponding assessment of the 
individual subject’s underlying medical condition.  Selection should be based on the overall 
benefit-to-risk ratio. Use of low molecular weight heparin or warfarin (or equivalent Vitamin K 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
13
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
antagonist) to keep the International Normalization Ratio (INR) in the range of 2-3 or other 
anti-thrombotic therapy according to hospital guidelines or physician preference is acceptable.
If platelets drop below 50,000/μL, the investigator should consider interrupting or adjusting the 
dose of anti-thrombotic therapy. In the event that platelets drop below 20,000/μL and the anti-
thrombotic therapy has not already been interrupted, the investigator should again strongly 
consider interrupting the anti-thrombotic therapy.  In addition, for platelets < 20,000/μL, 
lenalidomide should be interrupted and CBC should be followed every 7 days.  Appropriate 
interventions (i.e., platelet infusion) should be considered where applicable. 
Infection
Prophylactic antibiotics should be considered in subjects 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.
Data Monitoring Committee
An independent external Data Monitoring Committee (DMC) will review safety and efficacy 
data collected during the conduct of the study.  DMC Meetings will occur approximately every 
3 months during enrollment (with the first meeting occurring when ~18 subjects have 
completed their first cycle of treatment) and twice per year thereafter.  In addition, safety data 
will be reviewed in an ongoing manner to assess benefit-to-risk considerations; accrual will be 
stopped to a treatment arm if unacceptable toxicities are observed in that treatment arm.
Response Adjudication Committee
An independent Response Adjudication Committee (RAC) will perform a blinded, independent 
assessment of response (including the development of PD) prior to database lock.  The RAC 
adjudicated response data will be used in the efficacy analysis for the study.
Number of planned subjects
Approximately 105 subjects 
Study Population
Key Inclusion Criteria
!
Must understand and voluntarily sign an informed consent form
!
Age ≥ 18 years at the time of signing the informed consent form
!
Must be able to adhere to the study visit schedule and other protocol requirements
Must have a documented diagnosis of B-cell CLL [iwCLL guidelines for diagnosis and 
treatment of CLL (Hallek, 2008)] meeting at least one of the following criteria:
#
Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia and/or thrombocytopenia
#
Massive (i.e., > 6 cm below the left costal margin) or progressive or 
symptomatic splenomegaly
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
14
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
#
Massive nodes (i.e., > 10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy
#
 
#
A minimum of any one of the following disease-related symptoms must be 
present:
#
Unintentional weight loss ≥ 10% within the previous 6 months
#
Significant fatigue (i.e., ECOG PS 2; cannot work or unable to perform 
usual activities)
#
Fevers of greater than 100.5° F or 38.0° C for 2 or more weeks without other 
evidence of infection
#
Night sweats for more than 1 month without evidence of infection
#
Must be relapsed or refractory to at least 1 prior regimen for treatment of CLL 
[relapsed / refractory as defined per the iwCLL guidelines for diagnosis and 
treatment of CLL (Hallek, 2008)].  At least one of the prior treatments must 
have included a purine-analog or bendamustine based treatment regimen
#
Relapsed is defined as a subject who has previously achieved the criteria of a 
complete remission (CR) or partial remission (PR), but after a period of ≥6 
months, demonstrates evidence of disease progression
#
Refractory is defined as treatment failure [e.g. Stable disease (SD), non
response, or progressive disease] or disease progression within 6 months to the 
last antileukemic therapy
!
Must have an Eastern Cooperative Oncology Group (ECOG) performance status 
score of ≤2.  
!
Females of childbearing potential (FCBP) must:
#
Have a negative medically supervised pregnancy test prior to starting study 
drug.  She must agree to ongoing pregnancy testing during study therapy and 
after discontinuation of study drug as specified in Appendix 21.9.  This applies 
even if the subject practices complete and continued sexual abstinence.
#
Either commit to continued abstinence from heterosexual intercourse (which 
must be reviewed on a monthly basis) or agree to use, and be able to comply 
with, effective contraception without interruption, prior to starting study drug, 
during study drug therapy, and after discontinuation of study drug as specified 
in Appendix 21.9.
!
Male subjects must:
#
Agree to use a condom during sexual contact with a FCBP, even if they have 
had a vasectomy, during study drug therapy and after discontinuation of study 
drug as specified in Appendix 21.9.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
15
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
#
Agree to not donate semen or sperm during study drug therapy and after 
discontinuation of study drug as specified in Appendix 21.9.
!
All subjects must:
#
Have an understanding that the study drug could have a potential teratogenic 
risk
#
Agree to abstain from donating blood during study drug therapy and after 
discontinuation of study drug as specified in Appendix 21.9.
#
Agree not to share study drug with another person
#
Be counseled about pregnancy precautions and risks of fetal exposure as 
specified in Appendix 21.9.
Key Exclusion Criteria
!
Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form
!
Active infections requiring systemic antibiotics
!
Systemic treatment for B-cell CLL within 28 days of initiation of lenalidomide 
treatment
!
Alemtuzumab therapy within 60 days of initiating lenalidomide treatment
!
Prior therapy with lenalidomide
!
History of grade 4 rash due to prior thalidomide treatment
!
Planned autologous or allogeneic bone marrow transplantation
!
Pregnant or lactating females
!
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 initiating study drug
!
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
#
Carcinoma in situ of the bladder
#
Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
!
History of renal failure requiring dialysis
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
16
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
!
Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or 
Hepatitis C Virus (HCV) infection
!
Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (subjects may 
be enrolled upon correction of electrolyte abnormalities)
!
Any of the following laboratory abnormalities:
#
Calculated (method of Cockroft-Gault) creatinine clearance of <60 mL/min 
(creatinine clearance may also be obtained by the 24-hour collection method at 
the investigator’s discretion)
#
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 > 1.5 x ULN
!
Uncontrolled hyperthyroidism or hypothyroidism
!
Venous thromboembolism within 12 months
!
≥ Grade-2 neuropathy
!
Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
!
Disease transformation [i.e. Richter’s Syndrome (lymphomas) or prolymphocytic 
leukemia]
!
Participation in any clinical study or having taken any investigational therapy within 
28 days prior to initiating lenalidomide therapy
!
Known presence of alcohol and/or drug abuse
Investigational product, dosage and mode of administration:
Celgene Corporation will supply lenalidomide 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg 
capsules for oral administration.  Subjects will receive 28 days of lenalidomide per cycle.
Study drug will be packaged in bottles containing study capsules for 28 days.  
Assessments
Efficacy
!
Physical Exam (lymph nodes, spleen and liver measurement)
!
Complete blood count (CBC) and differential
!
Immunophenotyping of peripheral blood lymphocytes
!
Histopathology (bone marrow aspirate/biopsy)
!
Assessment for MRD by flow cytometry (peripheral blood and bone marrow 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
17
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
aspirate)
!
Computed tomography (CT) scans
!
ECOG Performance Status
!
Assessment of constitutional symptoms (weight loss, fever, night sweats, fatigue)
Safety
!
Vital signs
!
Clinical laboratory evaluations
!
Pregnancy testing
!
Electrocardiogram (ECG)
!
Concomitant medications
!
AEs by NCI CTCAE Version 3.0, with modifications recommended by the iwCLL 
guidelines for the diagnosis and treatment of CLL (Hallek, 2008), and by the Cairo-
Bishop grading system for TLS
!
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. Subjects will be followed until 80% of 
the subjects have progressed or died or up to five years after the last subject was 
randomized, whichever occurs later.
Exploratory
!
FISH analyses, VH mutational status assessment, TP53 mutation, 
 
, ZAP-70 
 expression by flow cytometry
!
!
Beta-2 Microglobulin (β2M)
!
Plasma PK (in up to 40 subjects who provide consent at select centers)
!
!
Quality of Life as measured by FACT-Leu questionnaire and EQ-5D
Statistical Analysis
Overview
This study will be conducted using a randomized Bayesian schedule-administration design that 
jointly models toxicity/disease progression outcomes using an extension method.  The object of 
interest is to determine if a particular treatment administration schedule is superior to other 
competing schedules.
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
18
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
The approximate sample size will be 105 subjects, 35 per arm, barring early stopping.
Operationally the study will proceed as follows:  Subjects will be randomized to one of the 
three treatment arms.  The first interim analysis (toxicity only) will be performed once 18 
subjects complete one 28-day cycle. 
 
 Subsequent 
interim analyses will occur at 13-week intervals to monitor both combined toxicity and disease 
progression.  Depending on the calculated posterior probability of toxicity and disease 
progression, any one of the three treatment arms may be dropped for excessive toxicity or 
progression rate.
Safety Analysis
All subjects who receive at least 1 dose of study drug will be included in the safety analyses.  
AEs, vital sign measurements, clinical laboratory information, and concomitant medications 
will be tabulated and summarized for each treatment arm during therapy.  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 MedDRA terms and by NCI 
CTCAE Version 3.0, with modifications recommended by the iwCLL guidelines for the 
diagnosis and treatment of CLL (Hallek, 2008), and by the Cairo-Bishop grading system for 
TLS.  Time to first dose reduction will be summarized for each regimen.
Death and clinically important AEs (including TFR, TLS, 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.
Efficacy Analysis
Efficacy analyses will be performed on the intent-to-treat (ITT) population that includes all 
subjects randomized.
Response, duration of response, TTR, TTP, EFS, PFS, and OS will be summarized.  The 
Kaplan-Meier procedure will be used to characterize the time-to-event curves in these analyses 
when there is censoring.
Exploratory Analysis
 
  
Pharmacokinetics Analysis
If the data are sufficient, noncompartmental PK parameters, such as Tmax, Cmax, AUC, CL/F, 
and t1/2, will be estimated.  Descriptive statistics will be provided for plasma concentrations and 
PK parameters.  Lenalidomide concentration data obtained from all visits may be used to 
develop the population PK model.  The relationship between pharmacokinetics and response 
(biomarkers or clinical outcomes as appropriate) will be explored.
Analysis and Reporting
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Lenalidomide (CC-5013)
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Celgene Corporation
Confidential and Proprietary
19
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
In addition to the interim analyses focusing on toxicities and disease progression, efficacy 
analyses will be performed when 80% of the subjects have progressed or died, or five years 
after the last subject was randomized, whichever occurs later.  
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Lenalidomide (CC-5013)
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Celgene Corporation
Confidential and Proprietary
20
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Figure 1:
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
21
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 2:
Schedule of Assessments
Procedurea
Screen-
ing ≤28 
days 
prior 
to Day 
1
Study 
Day 1
Days 2 and 
4 for Cycle 
1 and the 
first cycle 
at 
Dose Level
+1,+2,+3,+4
+/- 1 day
Days 8, 15, 22 
of Cycle 1 
and first 
cycle at 
Dose Level
+1, +2,+3, +4
Days 8 and 
15 of Cycle 2
+/- 2 days
Every 28 
days
(4 wks)b, c
(1st day 
of each 
cycle)
At time of 
clinical 
manifestation 
of TFR
At time of 
clinical 
resolution 
of TFR
CR/CRi/ 
PR 
confirma-
tion visit
Treat-
ment 
discon-
tinuationc
Every 12 
weeks
(+/- 7 
days) 
until 
study 
closure
ICF/Inclusion/Exclusion
X
--
--
--
--
--
--
--
--
--
Clinical staging for CLL (Rai or 
Binet classification)
X
--
--
--
--
--
--
--
--
--
Medical history 
 
X
--
--
--
--
--
--
--
--
--
Pregnancy testd
Xd
Xd
--
--
Xd
--
--
--
Xd
--
Pregnancy and risk counseling
Xe
Xe
--
--
Xe
--
--
--
Xe
--
ECOG Performance Status
X
X
--
--
X
--
--
--
X
--
Evaluation of constitutional 
symptoms
X
X
--
--
X
--
--
--
X
--
Physical examination to assess 
lymph nodes, spleen and liverf
X
X
--
--
X
--
--
--
X
--
Vital signs including weight, height 
(at screening only)g
X
X
X
X
X
--
--
--
X
--
CT scansh
X
--
--
--
--
--
--
Xh
Xh
--
ECG (12 lead)i
X
--
--
--
X 
(starting at 
C3D1 then 
every 84 
days 
thereafter)
--
--
--
X
--
TLS monitoring and prophylaxis 
and TFR monitoringj
X
X
X
X
X
--
--
--
--
--
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
22
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 2:
Schedule of Assessments (Continued)
Procedurea
Screen-
ing ≤28 
days 
prior 
to Day 
1
Study 
Day 1
Days 2 and 
4 for Cycle 
1 and the 
first cycle 
at 
Dose Level 
+1,+2,+3,+4
+/- 1 day
Days 8, 15, 22 
of Cycle 1 
and first 
cycle at 
Dose Level 
+1, +2,+3, +4
Days 8 and 
15 of Cycle 2
+/- 2 days
Every 28 
days
(4 wks)b, c
(1st day 
of each 
cycle)
At time of 
clinical 
manifestation 
of TFR
At time of 
clinical 
resolution 
of TFR
CR/CRi/ 
PR 
confirma-
tion visit
Treat-
ment 
discon-
tinuationc
Every 12 
weeks
(+/- 7 
days) 
until 
study 
closure
Hematologyk
X
X
X
X
X
--
--
--
X
--
Chemistryl
X
X
X
X
X
--
--
--
X
--
Urinalysism
X
X
X
X
X
--
--
--
X
--
Calculated (method of Cockroft-
Gault) creatinine clearance (24-hour 
collection method may also be used 
at the investigator’s discretion)l
X
--
--
--
--
--
--
--
--
--
Direct antiglobulin (DAT) testn
X
--
--
--
--
--
--
--
--
--
Thyroid function testo
X
--
--
--
X 
(starting at 
C3D1 then 
every 84 
thereafter)
--
--
--
X
--
Bone marrow aspirate, biopsy, 
peripheral blood slidesp
Xp
Xp
--
--
--
--
--
Xp
(CR/CRi 
only)
--
--
Disease diagnosis confirmation 
)q
--
X 
--
--
--
--
--
--
--
--
MRD evaluationr
--
--
--
--
--
--
--
Xr
(CR/CRi 
only)
--
--
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
23
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 2:
Schedule of Assessments (Continued)
Procedurea
Screen-
ing ≤28 
days 
prior 
to Day 
1
Study 
Day 1
Days 2 and 
4 for Cycle 
1 and the 
first cycle 
at 
Dose Level 
+1,+2,+3,+4
+/- 1 day
Days 8, 15, 22 
of Cycle 1 
and first 
cycle at 
Dose Level 
+1, +2,+3, +4
Days 8 and 
15 of Cycle 2
+/- 2 days
Every 28 
days
(4 wks)b, c
(1st day 
of each 
cycle)
At time of 
clinical 
manifestation 
of TFR
At time of 
clinical 
resolution 
of TFR
CR/CRi/ 
PR 
confirma-
tion visit
Treat-
ment 
discon-
tinuationc
Every 12 
weeks
(+/- 7 
days) 
until 
study 
closure
FACT-Leu and EQ-5D 
questionnaire
--
X
--
--
X 
(starting at 
C3D1 then 
every 56 
days 
thereafter)
--
--
--
X
--
Study drug administrations
--
X
--
--
X
--
--
--
X
--
Adverse eventst
X
X
X
X
X
--
--
--
X
--
Assessment of Second Primary 
Malignancyu
X
X
X
X
X
--
--
--
X
X
Concomitant medication/therapiesw
X
X
X
X
X
--
--
--
X
X
Assessment of responsev
--
--
--
--
Xu
--
--
--
X
--
Survivalw
--
--
--
--
--
--
--
--
--
X
Beta-2 Microglobulin (β2M)x
--
X
--
--
--
--
--
--
--
--
ZAP-70 expressiony
--
X
--
--
--
--
--
--
--
--
VH mutational status/ TP53 
mutationy
--
X
--
--
--
--
--
--
--
--
Cytogenetic analysis (FISH)y
--
X
--
--
--
--
--
--
--
--
a. All study procedures should be performed within ± 3 days of the scheduled visit unless otherwise stated.
b. These assessments must be performed every 28 days (±3days).  If a Day 1 for any cycle is delayed, an unscheduled visit should be performed, if required, to 
ensure these assessments are performed at least every 28 days (±3days) during the study.
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
24
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
c. For those subjects who discontinue study drug for reasons other than disease progression or withdrawal of consent, study visits should continue every 28 days 
to assess response until documentation of disease progression or until a new CLL therapeutic regimen is started, whichever comes first.  During these visits 
for these subjects only the following assessments are required: hematology, ECOG performance status, evaluation of constitutional symptoms, physical exam 
for liver, spleen and lymph nodes, adverse events, assessment for second primary malignancies, concomitant medications/therapies and assessment of 
response.  
d. Females of childbearing potential (FCBP) must have a medically supervised pregnancy test (serum or urine with sensitivity of at least 25 mIU/mL) per the 
frequency specified in Appendix 21.9 Pregnancy Prevention Risk Minimization Plans
e. All male and FCBP subjects must be counseled about pregnancy precautions and risks of fetal exposure as detailed in Appendix 21.9 Pregnancy Prevention 
Risk Minimization Plans.
f.
Physical examination of the lymph nodes, spleen and liver will be performed at screening, Study Day 1 and every 28 days thereafter and at the treatment 
discontinuation visit.  Lymph node evaluation will record the bi-dimensional diameter of the largest palpable nodes in each of the following sites:  cervical, 
axillary, supraclavicular, inguinal and femoral.  The size of the liver and spleen will be assessed by palpation and recorded.
g. Vital signs include:  temperature, pulse, blood pressure, weight and height (height to be measured during screening only).
h. CT scans of the neck, chest, abdomen and pelvis to assess lymphadenopathies will be performed during screening and at the PR and CR/CRi confirmation 
visits (≥8 weeks - ≤ 12 weeks after all clinical and laboratory response criteria have been met for PR or CR/CRi) and for all subjects, except those who 
discontinue due to PDs, at the treatment discontinuation visit.  At screening, if medically justified, the possibility of not repeating the CT Scan when 
previously performed within 56 days of randomization will be evaluated by the Celgene Medical Monitor on a case by case basis. Those subjects whose 
response was down-graded based on the CT scan interpretation at the PR or CR/CRi confirmation visit will have the CT scan repeated 4 months later at the 
location where remaining disease has been documented as long as clinical and laboratory response remains present to try to document further improvement..
i.
ECG will be performed and interpreted locally.  After the screening ECG, the next ECG will be done at Cycle 3 Day 1, and then every 12 weeks while on 
study drug, and at treatment discontinuation.
j.
TLS prophylaxis, comprising of oral hydration and allopurinol 300 mg/day will be initiated at least 3 days prior to starting study drug and for a minimum of 
the first 3 treatment cycles.  For subjects with known allergy to allopurinol prior to study initiation or for those who develop an allergy during the course of 
study therapy, the medical monitor should be contacted.  To maintain fluid intake, subjects should be instructed to drink 8-10 eight ounce glasses of water 
each day for the first 14 days of each cycle during the dose escalation period.  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.
k. Hematology: Local lab assessments include HGB, ANC, ALC and platelet count.  At screening, subject must meet eligibility criteria based on central lab 
results.  At Study Day 1, subject must meet eligibility criteria based on local or central lab results prior to initiating study therapy
l.
Chemistry: Local lab assessments include potassium, calcium, phosphorus, creatinine, total bilirubin, AST/SGOT, ALT/SGPT, and uric acid.  At screening, 
subject must meet eligibility criteria based on central lab results.  At Study Day 1, subject must meet eligibility criteria based on local or central lab results 
prior to initiating study therapy, however, a re-calculation of creatinine clearance is not required at Study Day 1.
m. Urinalysis:  Local laboratory assessments will include ketones, sediments and specific gravity.  
n. DAT (direct antiglobulin test) will be performed at screening and analyzed at the central laboratory.  The DAT test should be repeated if the investigator 
suspects hemolytic anemia during the course of the study. Analysis of DAT will be completed by local laboratory as part of this amendment, protocol 
amendment #6.
o. TSH (thyroid-stimulating hormone), free T3, and free T4 levels will be assessed at screening, Cycle 3 Day 1 and every 12 weeks while on study drug and at 
treatment discontinuation.  All samples will be analyzed centrally.  Collection of TSH samples is discontinued as of this amendment, protocol amendment #6.
p. A peripheral blood, bone marrow aspirate and bone marrow biopsy slide will be prepared and submitted to the central pathology reviewer for all subjects 
during screening or at cycle 1 day 1and at the CR/CRi confirmation visit.  At screening, if medically justified, the possibility of not repeating the bone 
marrow aspirate/biopsy when previously performed within 56 days of randomization will be evaluated by the Celgene Medical Monitor on a case by case 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
25
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
basis if sufficient and appropriate samples are available for submission to the central pathology reviewer.  For those subjects who reach CR or CRi, a 
peripheral blood, bone marrow aspirate and bone marrow biopsy slide will be prepared and submitted to the local pathology reviewer at the CR/CRi 
confirmation visit (≥ 8 weeks - ≤ 12 weeks after all clinical and laboratory response criteria have been met).  If the bone marrow is hypocellular, a repeat 
specimen should be obtained after 4 weeks, provided that the blood counts have recovered.  If the bone marrow biopsy shows disease involvement (30% or 
greater lymphocytes, or nodules positive for B-CLL cells by immunohistochemistry), an additional bone marrow biopsy and aspirate will be taken 4 months 
later as long as clinical and laboratory response remain to document further improvement.  All bone marrow and aspirate samples will also be analyzed 
locally and this data will be captured on the eCRFs.
q. Peripheral blood for disease diagnosis confirmation (by immunophenotyping as per Hallek, 2008) 
 will be drawn at Study Day 
1 for all subjects. All samples will be analyzed centrally.  
 
r.
Initial MRD assessment: MRD status will be evaluated for those subjects who reach CR or CRi. A peripheral blood and bone marrow aspirate sample will 
be collected for MRD analysis by flow cytometry at the CR/CRi confirmation visit (≥8 weeks - ≤ 12 weeks after all clinical and laboratory response criteria 
have been met for CR/CRi).  If peripheral blood and bone marrow are both MRD-positive, peripheral blood samples will be repeated and assessed up to 3 
additional times at 8 week intervals to try to document MRD negativity in subjects who reach confirmed CR or CRi (see Follow-up MRD assessments). If 
peripheral blood is MRD-negative and bone marrow is MRD-positive, both peripheral blood and bone marrow should be retested for MRD negativity after ≥ 
12 weeks.  If this repeat bone marrow is MRD-positive, no further testing for MRD will be performed.  If both the peripheral blood and bone marrow are 
MRD-negative, peripheral blood will be tested every 6 months for assessment of MRD until subject discontinues study drug.  All samples will be analyzed 
locally.  Follow-up MRD assessments:  If any of the repeat peripheral blood assessments indicate MRD-negativity, a bone marrow aspirate sample should 
be collected and retested as soon as possible to confirm MRD negativity.  If the bone marrow is MRD-positive, both peripheral blood and bone marrow 
should be retested for MRD negativity after ≥ 12 weeks.  If this repeat bone marrow is MRD-positive, no further testing for MRD will be performed.  If at 
any time, the bone marrow is MRD-negative, peripheral blood will be tested every 6 months for assessment of MRD until subject discontinues study drug.  
All samples will be analyzed locally.  
s. Study drug to be dispensed at Day 1 of each cycle.  Subjects should be instructed to return the study drug at Day 1 of each 28-day cycle.  No more than a 28-
day supply of study drug will be dispensed at a time.
t.
AEs will be reported from the time informed consent is signed to 30 days post last dose of study drug.  AEs that lead to study discontinuation should be 
followed until resolution or stabilization.  For subjects who discontinue study treatment but continue to be followed every 28 days until PD or new CLL 
therapy, AEs will be reported until 30 days post last dose of study drug or until study discontinuation, whichever occurs last.  SAEs will be reported from 
time informed consent form is signed to 30 days post last dose of study drug.  SAEs will be reported at any time post last dose of study drug if it is considered 
related to study drug.
u. Second primary malignancies will be monitored as events of interest and must be reported as serious adverse events regardless of the treatment arm the 
subject is in.  This includes any second primary malignancy, regardless of causal relationship to 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 80% of the subjects 
have progressed or died or up to five years after the last subject was randomized, whichever occurs later.  Events of second primary malignancy are to be 
reported using the SAE report form and must be considered an “Important Medical Event” even if no other serious criteria apply; these events must also be 
documented in the appropriate page(s) of the CRF and subject’s source documents.  Documentation on the diagnosis of the second primary malignancy must 
be provided at the time of reporting as a serious adverse event (e.g., any confirmatory histology or cytology results, X-rays, CT scans, etc.).
v. Investigators to provide assessment of CR, CRi, nPR, PR, SD, and PD based on laboratory, physical exam, assessment of constitutional symptoms and if 
appropriate CT scan findings (CT scans are to be performed at baseline and to confirm PR or CR/CRi).  For confirmed PR, nPR or CR/CRi, response must be 
maintained for ≥ 8 weeks as per the iwCLL guidelines for the diagnosis and treatment of CLL (Hallek, 2008) Tumor response will be assessed according to 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
26
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
the iwCLL guidelines (Hallek, 2008) for the diagnosis and treatment of CLL (Hallek, 2008), including CR, CRi, nPR, PR, SD, and PD.  Evaluation of 
response will be performed after 3 cycles of therapy and every 4 weeks thereafter.
w. Subjects who develop PD or disease transformation [Richter’s syndrome (lymphomas) or prolymphocytic leukaemia], at any time, or who choose to 
discontinue study participation for any reason, or who begin a new CLL therapeutic regimen will be discontinued from the study and will be followed for 
survival, assessment for second primary malignancies and subsequent CLL therapies until 80% of the subjects have progressed or died or up to five years 
after the last subject was randomized, whichever occurs later.
x. Blood samples for β2M will be collected at baseline.  
 
All Samples will be analyzed centrally.  
 
y. Blood samples for ZAP-70, VH mutational status / TP53 mutation analysis and FISH studies for cytogenetic assessment (CCND1/IgH fusion, 11q, 17 p, 13 q, 
and Trisomy 12) will be collected at Study Day 1 pre-dose.  
 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
27
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
3.
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
1.
STUDY CONTACT INFORMATION .....................................................................4
2.
SYNOPSIS...............................................................................................................6
3.
TABLE OF CONTENTS........................................................................................27
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................34
5.
INTRODUCTION..................................................................................................38
5.1.
Chronic Lymphocytic Leukemia.............................................................................38
5.2.
Lenalidomide..........................................................................................................40
5.3.
Background and rationale for lenalidomide in chronic lymphocytic leukemia .........40
5.3.1.
Background ............................................................................................................40
5.3.2.
Clinical studies .......................................................................................................41
5.3.2.1.
Relapsed/refractory CLL ........................................................................................41
5.3.2.2.
Previously untreated symptomatic CLL ..................................................................43
5.3.2.3.
Study CC-5013-CLL-001 .......................................................................................44
5.3.3.
Rationale for study CC-5013-CLL-009...................................................................45
6.
STUDY OBJECTIVES...........................................................................................46
6.1.
Primary Objective...................................................................................................46
6.2.
Secondary Objectives .............................................................................................46
7.
STUDY ENDPOINTS............................................................................................47
7.1.
Primary...................................................................................................................47
7.2.
Secondary...............................................................................................................47
7.3.
Exploratory.............................................................................................................47
8.
OVERALL STUDY DESIGN ................................................................................48
8.1.
Design Rationale ....................................................................................................48
8.1.1.
Study Design ..........................................................................................................48
8.1.2.
Adaptive Study Design...........................................................................................48
8.1.3.
Randomization........................................................................................................48
8.1.4.
Duration of Treatment ............................................................................................49
8.1.5.
Study Population ....................................................................................................49
8.1.6.
Dose and dose interval............................................................................................49
8.1.7.
Safety.....................................................................................................................49
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.1.3.
.1.3.
8.1.4.
.1.4.


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Protocol CC-5013-CLL-009
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8.1.8.
Efficacy..................................................................................................................50
8.1.9.
Independent Data Monitoring Committee ...............................................................51
8.1.10.
Pharmacokinetics....................................................................................................51
8.1.11.
Exploratory Biomarkers..........................................................................................51
8.1.12.
Other Outcomes......................................................................................................52
9.
STUDY POPULATION.........................................................................................53
9.1.
Subject Inclusion Criteria .......................................................................................53
9.2.
Subject Exclusion Criteria ......................................................................................54
10.
DESCRIPTION OF TREATMENT........................................................................57
10.1.
Description of Study Drug......................................................................................57
10.2.
Treatment Assignments ..........................................................................................57
10.2.1.
Randomization........................................................................................................57
10.2.2.
Treatment ...............................................................................................................58
10.2.3.
Dose Modification or Interruption...........................................................................58
10.3.
Emergency Unblinding...........................................................................................65
10.4.
Prior/Concomitant Medications ..............................................................................65
10.4.1.
Prophylaxis and/or Treatment for TLS, TFR, Neutropenia, and 
Thromboembolic Events.........................................................................................66
10.4.1.1.
Tumor Lysis Syndrome (TLS) Prophylaxis.............................................................66
10.4.1.2.
Tumor Flare Reaction (TFR) Treatment..................................................................66
10.4.1.3.
Neutropenia Supportive Treatment .........................................................................66
10.4.1.4.
Infection Prophylaxis..............................................................................................66
10.4.1.5.
Thromboembolic Events Prophylaxis......................................................................67
10.4.1.6.
Other ......................................................................................................................67
10.4.1.7.
Prohibited Concomitant Therapy ............................................................................67
10.5.
Discontinuation from Treatment .............................................................................67
11.
STUDY DRUG MATERIALS AND MANAGEMENT .........................................69
11.1.
Supplier(s)..............................................................................................................69
11.2.
Dosage Form..........................................................................................................69
11.3.
Dosage Regimen.....................................................................................................69
11.4.
Study Drug Packaging and Labeling.......................................................................69
11.5.
Study Drug Receipt and Storage .............................................................................69
11.6.
Record of Administration .......................................................................................70
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CC-5013-CLL-009 Amendment 6 Final 15Apr2015
11.7.
Study Drug Accountability .....................................................................................70
11.8.
Study Drug Handling and Disposal.........................................................................70
12.
ASSESSMENT OF EFFICACY.............................................................................71
12.1.
Assessments ...........................................................................................................71
12.2.
Methods and Timing of Efficacy Assessments........................................................71
13.
ASSESSMENT OF SAFETY.................................................................................74
13.1.
Assessments ...........................................................................................................74
13.2.
Methods and Timing of Safety Assessments ...........................................................75
13.3.
Recording and Reporting of Adverse Events...........................................................75
14.
OTHER ASSESSMENTS.......................................................................................76
14.1.
Assessments Following Treatment Discontinuation ................................................76
14.2.
Assessment of Pharmacokinetics ............................................................................76
14.3.
Assessment of Exploratory Biomarkers ..................................................................77
14.4.
Assessment of Other Outcomes ..............................................................................77
15.
STATISTICAL ANALYSES..................................................................................79
15.1.
Overview................................................................................................................79
15.2.
Study Population Definitions ..................................................................................80
15.2.1.
Intent-to-Treat Population.......................................................................................80
15.2.2.
Safety Population....................................................................................................80
15.2.3.
Subgroup Analyses.................................................................................................80
15.3.
Efficacy Evaluation ................................................................................................81
15.4.
Regression Analyses...............................................................................................82
15.5.
Background and Demographic Characteristics........................................................82
15.6.
Study Drug .............................................................................................................82
15.7.
Concomitant Therapy .............................................................................................83
15.8.
Safety Evaluation....................................................................................................83
15.9.
Interim Analyses.....................................................................................................83
15.10.
Sample Size and Power Considerations...................................................................84
15.11.
Other Topics...........................................................................................................84
15.11.1.
Pharmacokinetics Analysis: ....................................................................................84
15.11.2.
Exploratory Analysis ..............................................................................................84
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................85
16.1.
Monitoring .............................................................................................................85
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
30
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
16.2.
Audits and Inspections............................................................................................85
16.3.
Investigator(s) Responsibilities ...............................................................................85
17.
REGULATORY CONSIDERATIONS...................................................................87
17.1.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................87
17.2.
Protocol Amendments.............................................................................................87
17.3.
Informed Consent ...................................................................................................87
17.4.
Subject Confidentiality ...........................................................................................88
18.
DATA HANDLING AND RECORDKEEPING.....................................................89
18.1.
Data/Documents .....................................................................................................89
18.2.
Data Management...................................................................................................89
18.3.
Retention of Records ..............................................................................................89
19.
PREMATURE DISCONTINUATION OF THE STUDY .......................................91
19.1.
Single Site ..............................................................................................................91
19.2.
Study as a Whole....................................................................................................91
20.
REFERENCES.......................................................................................................92
21.
APPENDICES........................................................................................................96
21.1.
Adverse Event ........................................................................................................96
21.2.
Declaration of Helsinki.........................................................................................101
21.3.
Cairo-Bishop Definition and Grading of Tumor Lysis Syndrome (Cairo, 
2004)....................................................................................................................102
21.4.
Grading of Hematological Toxicity (Hallek, 2008) ...............................................103
21.5.
ECOG Performance Status Scale ..........................................................................104
21.6.
Clinical Staging of CLL Patients...........................................................................105
21.6.1.
Rai staging system (modified) (Rai, 1987)............................................................105
21.6.2.
Binet staging system (Binet, 1981) .......................................................................105
21.7.
FACT-Leu Questionnaire .....................................................................................106
21.8.
EQ-5D Health Questionnaire ................................................................................109
21.9.
Pregnancy Prevention Risk Minimization Plans....................................................111
21.9.1.
Lenalidomide Pregnancy Prevention Risk Management Plan................................111
21.9.1.1.
Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials.......111
21.9.1.2.
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods........................................................................112
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
31
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.9.1.3.
Lenalidomide Education and Counseling Guidance Document .............................116
21.9.1.4.
Lenalidomide Information Sheet...........................................................................119
21.10.
Randomized Bayesian Schedule-Administration Design.......................................121
21.10.1.
Overview..............................................................................................................121
21.10.2.
Background ..........................................................................................................121
21.10.3.
Design of Study....................................................................................................122
21.10.4.
Decision Rules......................................................................................................123
21.10.5.
Operating Characteristics of Simulation Study......................................................124
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12


('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
32
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
LIST OF TABLES
Table 1:
Celgene Emergency Contact Information..................................................................4
Table 2:
Schedule of Assessments........................................................................................21
Table 3:
Abbreviations and Specialist Terms........................................................................34
Table 4:
Dose Regimen by Treatment Arm...........................................................................58
Table 5:
Dose Reduction and Modification Guidelines for Lenalidomide .............................59
Table 6:
Dose Reduction Steps for Lenalidomide .................................................................65
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
33
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
LIST OF FIGURES
Figure 1:
Overall Study Schema ............................................................................................20
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
34
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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
ANOVA/ANCOVA
Analysis of Variance/Covariance
AST (SGOT)
Asparate transaminase (serum glutamic 
oxaloacetic transaminase)
ATC
Anatomic Therapeutic Chemical 
β2M
Beta-2 Microglobulin
∃-HCG
Beta-human chorionic gonadotropin hormone
BUN
Blood urea nitrogen
CBC
Complete blood count
CFR
Code of Federal Regulations
CI
Confidence Interval
CrCl
Creatinine Clearance
CLL
Chronic lymphocytic leukemia
CMV
Cytomegalovirus
CNS
Central nervous system
CR
Complete response
CRi
Complete response with incomplete bone 
marrow recovery
eCRF
Electronic case report form
CR MRD+
Complete response – Minimal residual disease 
positive
CR MRD-
Complete response – Minimal residual disease 
negative
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse 
Events
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Lenalidomide (CC-5013)
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Celgene Corporation
Confidential and Proprietary
35
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 3:
Abbreviations and Specialist Terms (Continued)
Abbreviation or Specialist Term
Explanation
DAT
Direct Antiglobulin Test
DCF
Data Clarification Form
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
DVT
Deep vein thrombosis
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EE
Efficacy Evaluable Population
EFS
Event-free survival
EMA
European Medicines Agency
EQ-5D
EuroQol 
F
Fludarabine
FACT-Leu
Functional Assessment of Cancer Therapy-
Leukemia
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
FISH
Fluorescence in Situ Hybridization
FNA
Fine Needle Aspirate
GCP
Good Clinical Practice
GCSF
Granulocyte colony-stimulating factor
HGB
Hemoglobin
HCT
Hematocrit
HIV
Human immunodeficiency virus
HRQL
Human Related Quality of Life
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
VH
Immunoglobulin Heavy-chain Variable-region
IL-6
Interleukin 6
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Lenalidomide (CC-5013)
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Celgene Corporation
Confidential and Proprietary
36
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 3:
Abbreviations and Specialist Terms (Continued)
Abbreviation or Specialist Term
Explanation
IMiD
Immunomodulatory drug
IMP
Investigational Medicinal Product
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
Intent to Treat
IV
Intravenous
IVRS
Interactive Voice Response System
iwCLL
International Workshop on CLL
LDH
Lactate dehydrogenase
 
LN
Lymph node
MDS
Myelodysplastic syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Minimal residual disease
MTD
Maximum-tolerated dose
MTDEL
Maximum tolerated dose escalation level 
NCI CTCAE 
National Cancer Institute Common 
Terminology Criteria for Adverse Events 
NCI-WG
National Cancer Institute Working Group 
criteria for chronic lymphocytic leukemia
NK cells
Natural killer cells
NOS
Not otherwise specified
NSAID
Non-steroidal anti-inflammatory drug
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive disease
PFS
Progression free survival
PK
Pharmacokinetic
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Lenalidomide (CC-5013)
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Celgene Corporation
Confidential and Proprietary
37
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 3:
Abbreviations and Specialist Terms (Continued)
Abbreviation or Specialist Term
Explanation
PR
Partial Response
PS
Performance Status
RAC
Response Adjudication Committee
RBC
Red blood cell
RIC
Reduced intensity conditioning
SAE
Serious adverse event
SC
Subcutaneous
SCID
severe combined immunodeficiency 
SCT
Stem cell transplantation
SD
Stable disease
SGOT
Serum-Glutamic-Oxaloacetic Transaminase
SLL
Small Lymphocytic Lymphoma
SOP
Standard Operating Procedure
TFR
Tumor Flare Reaction
TLS
Tumor Lysis Syndrome
TNF-%
Tumor necrosis factor alpha
TNM
Tumor-nodes-metastasis 
TP53
Tumor protein 53
TSH
Thyroid stimulating hormone
TTE
Time to event
TTF
Time to treatment failure
TTP
Time to progression
TTR
Time to response
VEGF
Vascular Endothelial Growth Factor
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
38
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
5.
INTRODUCTION
5.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia is the most prevalent adult leukemia among Caucasians.  It 
affects mainly elderly individuals with the median age at presentation of 72 years, but up to one 
third of newly diagnosed patients are under the age of 65 years (Leukemia and Lymphoma 
Society, 2008).  It is an incurable lymphoproliferative malignancy manifested by progressive 
accumulation of morphologically mature but functionally incompetent lymphocytes in the blood, 
bone marrow, and lymphoid tissues.  The clinical course of CLL ranges from indolent disease 
(Rai 0, Binet A) with long-term survival over 12 years to aggressive disease (Rai III/IV, Binet C) 
with median survival of 2 years (Montserrat, 1995).
Multiple, randomized, Phase 3 studies have attempted to identify treatments that improve overall 
survival (OS).  Chlorambucil, approved by the FDA in March 1957, is a well-tolerated oral agent 
that can induce partial remissions (PR) in advanced stage CLL patients and has been in use for 
many decades.  In early stage CLL patients, the French Co-operative group on CLL (Dighiero, 
1998) reported that early therapy with alkylator-based therapy did not improve survival 
compared to observation alone. Due to the availability of newer treatment options demonstrating 
improved efficacy, chlorambucil is not considered the optimal first-line treatment choice by 
physicians in the United States.  However, the drug is still considered a valid treatment option for 
elderly patients and those with comorbidities that preclude treatment with more aggressive 
treatment regimens.
Fludarabine is approved by the FDA (April 1991) as a second-line agent.  Clinical studies of 
fludarabine have shown superior overall response rates, complete response rates, and progression 
free survival, but no improvement in overall survival was noted (Rai, 2000) (Catovsky, 2007)  In 
recent years, data from several phase 2/3 clinical studies in which fludarabine was combined 
with cyclophosphamide and/or rituximab demonstrated high response rates and long progression-
free survivals, with increased toxicity compared to chlorambucil, but as yet have not shown a 
survival benefit (O’Brien, 2001) (Byrd, 2003) (Wierda, 2005) (Eichhorst, 2006) (Tam, 2007).
In September 2007, alemtuzumab was also approved as first line therapy of B-cell CLL.  In an 
open-label, randomized (1:1) study of 297 patients, the patients receiving alemtuzumab 
experienced longer PFS compared to those randomized to receive chlorambucil (median PFS 
14.6 months vs. 11.7 months respectively).  The overall response rates (ORR) were 83% and 
55% (p < 0.0001) and the CR rates were 24% and 2% (p < 0.0001) (Hillmen, 2007).
In March 2008, bendamustine was approved for the treatment of patients with chronic 
lymphocytic leukemia.  The labeling states “Efficacy relative to first line therapies other than
chlorambucil has not been established”.  The study comparing bendamustine, 100 mg/m2 IV on 
days 1 and 2 every 28 days, to chlorambucil, 0.8 mg/kg/day orally on days 1 and 15 every 28 
days, was conducted in 301 patients (153 on bendamustine and 148 on chlorambucil) with Binet 
stage B or C (Rai stages I-IV) requiring treatment.  The ORR was 59% for bendamustine vs 26% 
for chlorambucil (p < 0.0001) with 8% vs <1% CRs for bendamustine and chlorambucil arms, 
respectively.  The median PFS was 18 months for bendamustine vs 6 months for chlorambucil (p 
< 0.0001) (TREANDA package insert, 2008).  Since receiving FDA approval in 2008, market 
blood, 
blood, 
isease
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
39
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
research data demonstrate increased bendamustine usage in first line and in the 
relapsed/refractory setting either as a single-agent or in combination with rituximab.
Based on these data and the indolent clinical course of many CLL patients, the current medical 
practice for most early stage CLL patients is that of “watchful waiting.” For those CLL patients 
with advanced stage disease who require treatment, initial treatment selection is largely based on 
age, performance status and co-morbid conditions and is either chlorambucil monotherapy,
fludarabine-based or bendamustine-based combination regimens.
Many CLL patients relapse after initial therapy.  Second-line treatment and subsequent 
treatments often consist of purine-analog-based treatment regimens.  Eighty-five percent of 
patients previously responsive to fludarabine respond to re-treatment with the same agent but the 
response rate falls to 12% in patients who were refractory to previous fludarabine therapy when 
re-treated with fludarabine single agent (Thomas, 1998), and between 39% to 58% in patients re-
treated with fludarabine combined therapy (fludarabine with cyclophosphamide, or 
cyclophosphamide and rituximab) (O’Brien, 2001) (Wierda, 2005).  Patients who become 
refractory or resistant to purine analogues containing regimens have a poor prognosis and limited 
therapeutic options.
On 07 May 2007, alemtuzumab was initially approved for patients previously treated with 
alkylating agents and refractory to fludarabine.  In a study of 93 heavily pretreated fludarabine 
refractory patients a response rate of 33% (2% CR) was achieved, with the median time to 
progression for responders of 9.5 months and a median overall survival of 16 months for all 
patients and 32 months for responders (Keating, 2002).  Subjects in this study with at least one 
lymph node > 5 cm (bulky lymphadenopathy) achieved a 12% PR and 0% CR.  Toxicity with 
alemtuzumab therapy was not negligible and included infusion-related toxicity (81%), 
immunosuppression, and infections (55%) with reactivation of cytomegalovirus seen in 7 
patients.
On 19 September 2007, alemtuzumab’s accelerated approval was converted to a full approval 
with a revised indication, “as a single agent for the treatment of B-cell chronic lymphocytic 
leukemia (B-CLL)”.  In an open-label, randomized (1:1) study of 297 patients, the patients who 
received alemtuzumab experienced longer PFS compared to those randomized to receive 
chlorambucil (median PFS 14.6 months vs. 11.7 months, respectively).  The ORRs were 83% 
and 55% (p < 0.0001), and the CR rates were 24% and 2% (p < 0.0001).  Despite the approval, 
use of alemtuzumab as a treatment for previously untreated patients remains very limited.
Although alemtuzumab has demonstrated efficacy in the fludarabine-refractory CLL population, 
several studies have shown that patients that have CLL bulky disease (i.e lymphadenopathy 
greater than 5 cm) are poor responders to alemtuzumab therapy (Keating, 2002) (Fiegl, 2006) 
(Osterborg, 1997). A recent historical review by Tam et al (Tam, 2007) underlines that 
fludarabine refractory CLL patients who have bulky lymphadenopathy constitute a high unmet 
medical need despite the availability of new salvage therapy in the last decades which include
purine analogues combinations and monocloncal antibodies.
On 26 October 2009 the U.S. Food and Drug Administration granted accelerated approval to 
ofatumumab (Arzerra™) for the treatment of patients with chronic lymphocytic leukemia (CLL) 
refractory to fludarabine and alemtuzumab. The approval was based on a clinically meaningful 
and durable overall response rate (ORR) observed in a single-arm, multicenter trial in 154 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
40
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
patients with relapsed or refractory CLL. Accelerated approval was based on the results of a pre-
specified subgroup of 59 patients who were refractory to both fludarabine and alemtuzumab.
Drug refractoriness was defined as failure to achieve at least a partial response to, or disease 
progression within 6 months of the last dose of fludarabine or alemtuzumab. The primary 
efficacy outcome was durable ORR as determined by the 1996 National Cancer Institute 
Working Group (NCIWG) Guidelines for CLL.
5.2.
Lenalidomide
Lenalidomide (REVLIMID®; Celgene Corp., NJ, USA) is a member of a class of pharmaceutical 
compounds known as immunomodulatory drugs (IMiDsP®
P).  It offers potential benefit over the 
first commercially available IMiD, thalidomide, in terms of both safety and efficacy in human 
subjects (Galustian, 2004) (Tohnya, 2004).  The key to its therapeutic potential lies in the fact 
that it has multiple mechanisms of action, which act to produce both anti-inflammatory and anti-
tumor effects.  These effects are thought to be contextual in that they depend on both the cell 
type and the triggering stimulus.  To date, lenalidomide has been associated with TNF-α 
inhibitory, T cell costimulatory, and antiangiogenic activities (Galustian, 2004).
REVLIMID® has been approved by multiple global Health Authorities (including the FDA, but 
excluding the EU) for the treatment of patients with transfusion dependent anemia due to Low-
or Intermediate-1-risk myelodysplastic syndrome associated with a deletion 5q cytogenetics 
abnormality with or without other cytogenetic abnormalities.
REVLIMID® has also been approved by multiple global Health Authorities (notably including 
the US and EU) in combination with dexamethasone, for patients with previously treated 
multiple myeloma. 
Lenalidomide is being investigated as treatment for various oncologic indications, including 
multiple myeloma, non-Hodgkin’s lymphomas, and solid tumors.  It is also being explored as a 
treatment for inflammatory conditions.  While many of the studies are ongoing, results from 
controlled and uncontrolled studies in subjects with MDS and MM are available.
5.3.
Background and rationale for lenalidomide in chronic lymphocytic 
leukemia
5.3.1.
Background
The cellular interplay between the microenvironment and the malignant CLL clone and the 
decreased sensitivity of B-CLL cells to apoptotic signal is thought to play an important role in 
the pathophysiology and development of CLL disease (Ghia, 2005).  CLL cells can secrete 
various prosurvival cytokines (TNF-α, IL-6 and VEGF) and modulate their receptor expression 
in a paracrine/autocrine growth loop manner (Hoffbrand, 1993).
Lenalidomide has been reported to inhibit TNF-α production, modulate cytokine production and 
also to have immunomodulatory properties that are thought to be critical for the activity of this 
drug in chronic lymphocytic leukemia (Corral, 1996) (Corral, 1999).  Lenalidomide co-
stimulates T-cells and enhances antitumor immunity, which is mediated by T-helper-1 type 
cytokines, such as interferon-γ and interleukin-2 (IL-2); it also enhances other innate immune 
utical
ica
er the
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and
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dependent 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
41
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
cells such as natural killer cells, which can increase tumor cell death (Bartlett, 2004) (Hayashi, 
2005).
Additional experiments performed in vitro confirmed the ability of lenalidomide to increase NK-
cell mediated killing of primary B-CLL tumor cells in both a PBMC co-culture model and NK 
mediated antibody-dependent cellular cytotoxicity (ADCC) model (Wu, 2008)( Lapalombella, 
2008).  Co-treatment of B-CLL cells and NK cells with lenalidomide was shown to enhance
rituximab-mediated ADCC in vitro, however a greater enhancement was observed when B-CLL 
cells were not pre-treated with lenalidomide suggesting that alternative sequencing strategies 
might be also beneficial when combining the two drugs in a clinical setting (Lapalombella, 
2008).  Interestingly, lenalidomide also synergized with rituximab to promote animal survival in 
a severe combined immunodeficiency (SCID) mouse-disseminated lymphoma xenograph model.  
Lenalidomide treatment enhanced rituximab’s NK cell antitumor activity, and resulted in the in 
vivo expansion of murine NK cells, suggesting a role for the co-stimulatory properties of this 
agent in this model (Hernandez- Ilizaliturri, 2005).
The potential ability of lenalidomide to enhance immune cell recognition in CLL was also 
reported in a recent work by Ramsay et al. (Ramsay, 2008) demonstrating that lenalidomide can 
modulate the actin cytoskeleton and improve the defect in B-CLL cells and T-cells immune 
synapse formation and function. 
Additional work is underway to better elucidate lenalidomide’s mechanism of action in CLL and 
its ability to modulate the cellular interplay between the microenvironment and the malignant 
CLL clone.
5.3.2.
Clinical studies 
5.3.2.1.
Relapsed/refractory CLL
Initial clinical studies were conducted with thalidomide, a less potent immune modulator than 
lenalidomide also capable of inhibiting TNF-α, that has known anti-angiogenic properties.  
Thalidomide was studied in combination with fludarabine in previously untreated CLL (Chanan-
Khan, 2005).  Although this study investigated the efficacy and safety of the combination 
regimen of fludarabine and thalidomide, the design of the study called for the administration of 
thalidomide alone for the first 7 days of therapy, after which fludarabine was added.  Antitumor 
effects, manifested as reduction on the peripheral blood lymphocyte count, occurred within 7 
days of starting thalidomide, prior to institution of fludarabine, suggesting that thalidomide alone 
has anti-CLL activity.
Based on the observations made with thalidomide, single-agent lenalidomide was studied in 
relapsed/refractory CLL (Chanan-Khan, 2006a) (Ferrajoli, 2008).  Chanan-Khan treated patients 
with relapsed/refractory CLL with lenalidomide (25mg x 21 d q 28 days).  Patients with stable 
disease (SD) or better response were continued on therapy for a maximum of 12 months while 
those with progressive disease (PD) were to receive monthly rituximab (375mg/m2) added to 
lenalidomide.  Forty-five patients were enrolled.  Median age was 64 years (range: 47 to 75 
years), and advanced Rai stage (III or IV) disease was noted in 64%.  The median number of 
prior therapies given was three (range:  1 to 10 therapies), with 51% of the patients refractory to 
fludarabine.  Using an intent-to-treat analysis, major responses were seen in 26 patients (57.7%; 
95% CI, 32% to 62%) with six patients (13.3%) achieving a CR, including 5 (11%) molecular 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
42
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
CRs, and 20 (44.4%) achieving a PR.  Antitumor activity of lenalidomide was evident as early as 
day 8 of treatment with 24 (70.5%) of 34 patients (34 patients who had day 1 ALC of >5000 
cells/uL and day 8 ALC available) demonstrating a decrease in their peripheral blood absolute 
lymphocyte count (ALC).  Clinical responses (CR or PR) were observed in 40% of the patients 
with del (11)(q23) adverse cytogenetics and in 40% of patients with bulky disease.  The median 
PFS of all patients enrolled was 19.4 months (range 1.2-31.8) (Chanan-Khan, 2007).  Fatigue 
(83%) and flare reaction (tender swelling of lymph nodes and/or rash) (58%) were the most
common non-hematologic AEs reported.  Other important AEs reported were tumor lysis 
syndrome (5%); Grade 3 and 4 thrombocytopenia (45%), and Grade 3 and 4 neutropenia (70%).  
Pulmonary embolism was reported in two patients (5%).
Ferrajoli treated patients with relapsed/refractory CLL with lenalidomide administered daily for 
28 days out of 28 day cycles up to disease progression.  All patients received lenalidomide at 10 
mg daily for 28 days followed by titration upward by 5 mg increments every 28 days to a 
maximum dose of 25 mg daily.  Forty-four (44) patients have been enrolled and were evaluated 
for response.  The median daily dose of lenalidomide tolerated by the patients was 10 mg.  The 
median age was 64 years (range:  49 to 86 years), the median number of prior treatments was 5 
(range:  1 to 15), and the median β2M at entry was 4.3 mg/dL (1.6 to 10.1).  Fifty nine percent of 
the patients carried unfavorable genomic abnormalities (17p or 11q23 deletions) and 66% had 
unmutated VH.  Twelve patients (27%) were refractory to fludarabine.  Responses according to 
NCI-WG criteria assessed after 3 months of treatment based on an intent-to-treat analysis 
showed that 14 patients (32%) had achieved a response [3 CR (7%), 1 nodular PR (2%), 10 PR 
(23%)].  Time to best response was 6 months in 11 patients and 9 months in 3 patients.  The 
median response duration has not been reached.  Eleven patients (25%) had stable disease (SD) 
or clinical improvement and were able to continue on treatment past the third month, and 17 
patients (39%) progressed and two patients died of early infectious complication.  Thirty two 
patients (73%) are alive with a median follow up of 14 months.  Myelosuppression was the most 
common toxicity with in the courses, 41% ∀Grade 3 neutropenia and 16% Grade 3 
thrombocytopenia.  TFR was observed in 12% of the courses (Grade & 2 in 10% and Grade ∀3 
in 2%), with a greater incidence (53%) in patients with lymph nodes larger than 5 cm.  Grade ∀3 
fatigue and diarrhea were reported in 1% and 2% of the courses, respectively.
TFR was a frequent adverse event reported in both studies and was well managed with non 
steroidal anti-inflammatory agents (NSAIDs) and/or corticosteroids or in some case narcotic 
analgesics.  In Chanan-Khan’s study (Chanan-Khan, 2006b), out of the 45 patients treated with 
lenalidomide, no TFR prophylaxis was given to the first 29 patients (Group A).  Subsequently, 
16 patients received prophylaxis with prednisone 20 mg po qd x 5 days followed by 10 mg po qd 
x 5 days starting on Day 1 of treatment (Group B).  The prophylaxis did not decrease the 
incidence of TFR (83% [Group A] vs. 81% [Group B]).  TFR ≥ Grade 2 was seen in 31% of 
Group A and 6% of Group B.  It thus appears that steroid prophylaxis decreases the severity of 
the reaction, but not the overall incidence.  In the group of patients who developed tumor flare, 4 
CRs were achieved, all in patients who had experienced ≥ Grade 2 tumor flare reaction in 
comparison to 19 patients with ≤ PR who had experienced a median tumor flare severity Grade 1 
(Chanan-Khan, 2006a).  These preliminary data seem to indicate that patients who develop a 
more severe flare reaction may also achieve a better remission.  However, in Ferrajoli et al. study 
the occurrence of a tumor flare reaction did not predict for a higher response rate with an overall 
response of 38% and 34% in patients with and without a TFR (Ferrajoli, 2008).
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
43
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Additional single-center clinical studies investigating other dose regimens in relapsed/refractory 
CLL are in progress.
5.3.2.2.
Previously untreated symptomatic CLL
In addition, two studies were conducted in previously untreated symptomatic CLL subjects
(Chen, 2008), (Ferrajoli, 2008).
Chen treated previously untreated symptomatic CLL subjects with single agent lenalidomide.  
The starting dose for lenalidomide was initially 10 mg daily with weekly 5mg dose escalations to 
the target dose of 25 mg daily x 21 days every 28 day cycle.  Toxic events in the first 2 subjects 
(TLS requiring dialysis; neutropenic sepsis) led to a study halt with DSMB review, and 
subsequent protocol amendments to reduce both the starting and target doses (2.5 mg and 10 mg, 
respectively, days 1-21), slow the dose escalation rate (2.5 mg cycle 1, 5 mg cycle 2, 10 mg 
cycle 3 and thereon), extend allopurinol TLS prophylaxis to a minimum of 3 cycles, and increase 
frequency of TLS lab monitoring.  Deep vein thrombosis (DVT) prophylaxis with low dose 
aspirin was mandated.  Steroids were allowed for management of TFR symptoms as needed.  
Twenty-five (25) subjects have been enrolled on the amended protocol.  The median age is 60 
(range 33-78), 10 subjects (40%) were Rai stage III-IV, bulky nodes were present in 9 subjects 
(36%), organomegaly in 23 pts (92%).  Twenty-three (23) subjects have received at least 1 cycle 
and are evaluable for toxicity.  Ten (10) subjects (43%) developed grade 3-4 neutropenia during 
at least 1 cycle (at doses 2.5-10 mg) which was the most common cause for dose 
reductions/interruptions.  Six (6) subjects have required intermittent GCSF support (none 
requiring routine use).  Three (3) subjects (13%) developed grade 3-4 thrombocytopenia (without 
bleeding).  The most common non-hematologic toxicities were:  Fatigue (74%), non-
desquamating rash (48%), all were reported as grade 1-2.  Infections (43%) were mostly minor 
non-neutropenic respiratory/sinus/skin infections.  TFR occurred in 18 subjects (78%).  Although 
most subjects experienced TFR in the first week on study, many also continued to experience 
flare symptoms with subsequent cycles (30.6% of all 186 cycles).  Most tumor flare symptoms 
resolved spontaneously but eight subjects required steroids on at least one occasion with prompt 
resolution.  Four (4) subjects were hospitalized for febrile neutropenia and/or pneumonia.  No 
further TLS has been noted.  Seventeen (17) subjects have completed at least 3 cycles and are 
evaluable for response.  Eleven (11) subjects (65%) have achieved a PR, 6 SD (35%), and none 
have progressed.  Responses were reached at a median of 4 cycles (range 2-15).  Although 
dramatic lymphocyte reductions were seen as early as week 1 (lenalidomide dose 2.5 mg/d), 
rebound during cycle days 22-28 off-drug were common.  Two subjects have withdrawn from 
the study due to lack of response after 10 cycles (SD) and prolonged Grade 3-4 neutropenia and 
thrombocytopenia, respectively.  The median daily tolerated dose is 10 mg with 26% of subjects 
requiring dose reductions to 5 mg (most due to cytopenias).
Ferrajoli used lenalidomide as initial treatment of elderly subjects with CLL.  Subjects were 
eligible for this study if age 65 or older and met requirements for treatment according to the 1996 
NCI-WG guidelines.  All subjects received lenalidomide at 5 mg daily for the first 56 days.  The 
lenalidomide dose could then be titrated up by 5 mg increments every 28 days to reach a 
maximum dose of 25 mg daily.  Allopurinol 300 mg daily was given from day 1-14 as TLS 
prophylaxis.  Sixty patients were enrolled into the study.  All 60 patients were evaluable for 
response and toxicity. Median age was 71 years (range, 66-85).  The overall response (OR) rate 
was 60%. 5 patient (8%) achieved a complete response (CR), 5 (8%) a nodular partial response 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
44
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
(nPR) and 26 (43%) a PR. Median time to treatment failure was not yet reached with a median 
follow-up of 19 months.  Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 
35%, 4%, and <1% of cycles; Grade 3-4 infections were reported in 7% of patients. There were 
no cases of Grade 3 or Grade 4 tumor lysis or tumor flare reactions, 30 (50%) patients 
experienced Grade 1 or Grade 2 tumor flare. (Badoux 2010).
5.3.2.3.
Study CC-5013-CLL-001
Based on these initial data in patients with relapsed/refractory CLL, a large multicenter phase 2 
study (CC-5013-CLL-001) was initiated to investigate two lenalidomide dose regimens, 10 mg 
daily and 25 mg x 21 days q 28 days, and confirm the efficacy and safety of lenalidomide in the 
treatment of relapsed/refractory CLL.  The study did not include a dose escalation period.  After 
18 patients were enrolled into the CC-5013-CLL-001 study, four patients developed TLS of 
varying severity associated with concomitant TFR characterized by severe back and bone pain, 
with onset during the first 15 days of treatment in the first cycle of treatment.  Metabolic 
abnormalities and/or renal dysfunction resolved with supportive therapy in 2 patients, however 2 
patients died.
Similar TFR and TLS reactions have been observed with other active and immune modulating 
agents in CLL (Yang,1999) (Byrd, 2007) mostly occurring in early phases of treatment.  The use 
of low dose-intensity regimens at the initiation of therapy, aggressive TLS prophylaxis, and 
increased patient monitoring decreased the incidence of TLS during treatment with these 
therapies.  TFR during lenalidomide therapy has been observed in both CLL and small 
lymphocytic lymphoma (SLL) patients.  TFR and TLS were also observed in two phase 2 studies 
that recently reported the effects of lenalidomide in patients with relapsed or refractory CLL 
(Chanan-Khan, 2006a) (Ferrajoli, 2007).  In the Chanan-Khan et al. study TFR occurred in 58% 
of patients (Grade & 2 in 50% and Grade ∀3 in 8%) and TLS occurred in 5% of the patients (all 
Grade 3).  The second study by Ferrajoli et al. reported 37 % TFR (Grade & 2 in 30% and Grade 
∀3 in 7% of patients) and no TLS.  Notably, the Chanan-Khan et al. study used a starting dose of 
25 mg of lenalidomide given orally once daily on days 1-21 of each 28-day cycle whereas 
Ferrajoli et al. used a dose escalation scheme starting with 10 mg given for 21 days in the first 
cycle 28 day cycle followed by titration upward by 5 mg increments every 28 days to a 
maximum dose of 25 mg daily.
TFR in lenalidomide-treated CLL patients in clinical studies has usually been Grade 1-2 and has 
been well managed with non-steroidal anti-inflammatory agents or steroids.
The CC-5013-CLL-001 protocol was amended into a phase 1/2 study where the safety of several 
lenalidomide doses was investigated.  In this study patients with prior treatment with an 
alkylating agent and who have failed fludarabine were started on 2.5 mg of lenalidomide daily, 
followed by slow intra-patient dose escalation to 5 mg after 28 days as tolerated (Wendtner, 
2010).  Doses were then escalated as tolerated by 5 mg every 28 days by initial cohorts of 6 
patients, until the maximum tolerated dose escalation level (MTDEL) was defined or a maximum 
dose of 25 mg daily.  Patients were treated until disease progression, and all patients received 
TLS prophylaxis with hydration starting 3 days prior to lenalidomide treatment and continuing 
for at least the first 3 cycles.  The redesigned phase I study enrolled 52 patients with a median 
age of 65 (range, 37–80) and bulky disease (>5 cm) in 70%. Patients were heavily pretreated 
with a median of 4 prior therapies (range,1–14); 54% were fludarabine refractory (no-
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
45
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
response/relapse ≤ 6 mo), 42% had prior FCR or PCR and 21% had prior alemtuzumab. The TLS 
prevention strategy resulted in only 2 (3.8%) cases of TLS, both observed at 2.5 mg/daily (1 
patient with Grade 2 and another with lab TLS).  Grade 3/4 tumor flare occurred in 5 (9.6%) 
patients and was managed with NSAIDs or low-dose steroids. The most common Grade 3/4 
adverse events (AEs) included neutropenia (65%) and thrombocytopenia (33%). Febrile 
neutropenia occurred in 4 (8%) patients. Grade 3/4 infections were observed in 21 (40%) 
patients; 10 (19%) patients developed pneumonia and 3 developed sepsis; 2 cases of sepsis-
related death at day 37 and 94 of therapy were also noted but deemed unrelated to study drug by 
the investigators. Reasons for study discontinuation included disease progression (37%), AE’s 
(29%), consent withdrawal (15%), death (4%), other reasons (10%).  For 16 (31%) patients, 2.5 
mg/daily was the maximum dose reached and 22 (42%) patients were unable to escalate beyond
5 mg/daily.  Grade 4 neutropenia was the primary reason for delay in dose escalation. By intent-
to-treat (ITT) analysis, 6 patients (12%) had a partial response (NCI-WG 1996), 30 patients 
(58%) had stable disease and 13 patients (25%) progressed; 3 patients were non-evaluable. 
Median duration of treatment was 3.1 months (range, 0.07-18.4) and the median time to response 
was 4.3 months (range, 2.8-7.4). Responses were observed at 10 mg/daily (n=3), at 15 mg/daily
(n=1), and at 20 mg/daily (n=2); Median PFS (ITT) was 5.5 months and median PFS for 
responders was 12 months. Three patients still remain on therapy and were transferred to 
commercial lenalidomide. (Data on file at Celgene)
5.3.3.
Rationale for study CC-5013-CLL-009
Patients with purine-analog or bendamustine relapsed/refractory CLL have limited therapeutic 
options and the addition of novel agents with alternative mechanisms of action are needed.  
Several studies have been conducted with lenalidomide in relapsed/refractory CLL and have 
demonstrated a good activity; however an optimal starting dose remains to be determined.  Three 
different starting dose regimens of 5 mg daily, 10 mg daily and 15 mg daily respectively will be 
evaluated in CC-5013-CLL-009.  These starting doses are based on a review by an independent 
external data monitoring committee (DMC) and an expert steering committee review of the 
safety and efficacy results of CC-5013-CLL-001 and other investigator initiated studies.  These 
studies have demonstrated a consistent, manageable, comparable toxicity profile for subjects 
beginning therapy at either the 2.5 mg, 5 mg or 10 mg starting doses when adequate prophylaxis 
measures for TLS are implemented (increased duration of allopurinol prophylaxis with increased 
hydration, and increased monitoring of electrolytes with correction of electrolyte abnormalities 
prior to the initiation of study drug) (Ferrajoli, 2008) (Chen, 2008).  Data also indicate that 
starting therapy at lenalidomide doses higher than 2.5 mg daily may provide superior efficacy.  
In light of these data, Celgene consulted expert clinicians; these experts supported a reduction in 
the number of dose escalation steps and thought a minimum efficacious dose to be in the range 
of 10 to 15 mg in relapsed CLL.  As a result, CC-5013-CLL-009 was developed to study starting 
dose of 5 mg, 10 mg and 15 mg followed by a step-wise dose escalation to a maximum dose of 
25 mg daily as tolerated to allow for fewer escalations to reach a higher dose.
This study will be conducted in accordance with “good clinical practice” (GCP) and all 
applicable regulatory requirements, including, where applicable, the 2008 version of the 
Declaration of Helsinki (see Appendix 21.2).
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
46
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
6.
STUDY OBJECTIVES
6.1.
Primary Objective
!
To evaluate the safety of different lenalidomide dose regimens in subjects with 
relapsed or refractory B-cell CLL.
6.2.
Secondary Objectives
!
To evaluate the efficacy of different lenalidomide dose regimens in subjects with 
relapsed or refractory B-cell CLL.
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
47
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
7.
STUDY ENDPOINTS
7.1.
Primary
!
Safety [type, frequency, and severity of adverse events (AEs) and relationship of AEs 
to lenalidomide]
7.2.
Secondary
!
Response rate; International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 
Guidelines for the diagnosis and treatment of CLL (Hallek, 2008)
!
Duration of response 
!
Time to response (TTR)
!
Time to progression (TTP)
!
Event-free survival (EFS)
!
Progression-free survival (PFS)
!
Overall survival (OS)
7.3.
Exploratory
!
Evaluation of response rate in predefined biologic risk group
!
!
Investigate the relationship between pharmacokinetics (PK) and response (biomarkers 
or clinical outcomes as appropriate)
!
Quality of Life
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
48
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
8.
OVERALL STUDY DESIGN
8.1.
Design Rationale
8.1.1.
Study Design
CC-5013-CLL-009 is a phase 2, multicenter, randomized, double-blind, parallel-group adaptive 
design study that will evaluate the safety and efficacy of different lenalidomide dose regimens 
administered orally in subjects with relapsed or refractory B-Cell Chronic Lymphocytic 
Leukemia.  All regimens use an intra-patient stepwise dose escalation scheme with three 
different initial ascending starting dose of 5 mg daily, 10 mg daily and 15 mg daily and then 
escalating in a stepwise manner every 28 days to reach a maximum dose of 25 mg daily based on 
subject tolerability.  Approximately 105 subjects will be enrolled.
8.1.2.
Adaptive Study Design
The CC-5013-CLL-009 phase 2 study will compare different treatment regimens (starting dose 
of 5 mg, 10 mg and 15 mg daily, followed by an intra-patient escalation up to a maximum of 25 
mg daily) using a Bayesian approach to evaluate both efficacy and toxicity.  This adaptive design 
will consider joint efficacy (progression rate) and toxicity outcomes to stop randomization of less 
promising arms (Bekele, 2008b).  At any time accrual to a starting dose arm will be stopped if 
unacceptable toxicities are observed in that arm.
8.1.3.
Randomization
Based on consideration of the Bayesian approach the following randomization schema will be 
followed:
!
Initially subjects will be randomized (1:1:1) in a double-blind fashion to the 5 mg, 10 
mg, and 15 mg starting dose arms (treatment arm 1, treatment arm 2, and treatment 
arm 3 respectively).  
!
After 18 subjects complete one 28 day cycle, an interim analysis will be conducted to 
review the safety of each starting dose arm(s).  Subsequent interim analyses to review 
the safety and progression rate of each starting dose arm(s) will occur at 13-week 
intervals.  After review of each interim analysis, a treatment arm may be dropped.  At 
any time accrual to a starting dose arm will also be stopped if unacceptable toxicities 
are observed in that arm.  If a treatment arm is dropped then all new subjects will be 
randomized equally into the remaining arm(s).
Stratification
To minimize potential imbalances within treatment groups due to select patient characteristics 
that may impact outcomes, study subjects will be stratified by the following criteria at 
randomization:
!
Relapsed versus refractory to their last purine-analog or bendamustine based 
treatment regimen [relapsed/refractory as defined per the iwCLL guidelines for 
diagnosis and treatment of CLL (Hallek, 2008)].  If a subject has had prior purine-
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
49
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
analog based and bendamustine based regimen, the stratification will be based on 
subject’s status post most recent regimen.
!
Age < 65 years of age versus ≥ 65 years of age
8.1.4.
Duration of Treatment
Subjects will receive study drug until PD or unacceptable toxicity develops.  The continuation of 
lenalidomide treatment duration until disease progression is supported by Chanan-Khan and 
Ferrajoli studies which report that patients with relapsed CLL that have received lenalidomide 
therapy for more than one year continue to improve their response to treatment (Chanan-Khan, 
2006a) (Chanan Khan, 2007) (Ferrajoli, 2008).  In the Chanan-Khan study the median time to 
best response was 5.9 months (range 1.6 to 18.3 months).  In the Ferrajoli study time to best 
response was 6 months in 11 patients and 9 months in 3 patients.  
8.1.5.
Study Population
Eligible subjects must have B-cell CLL that has relapsed after or is refractory to at least one prior 
CLL treatment regimen.  At least one of the prior treatments must have included a purine-analog
or bendamustine based treatment regimen.
8.1.6.
Dose and dose interval
Depending on the starting dose, subjects will be allocated in a double-blind fashion to three 
different regimens and will escalate every 28 days, based on individual subject tolerability, as 
follows:
!
Treatment Arm 1:  5 mg →10 mg →15 mg →20 mg →25 mg/daily
!
Treatment Arm 2:  10 mg →15 mg →20 mg →25 mg/daily
!
Treatment Arm 3:  15 mg →20 mg →25 mg/daily
Toxicities requiring dose interruption and/or modification are described in Section 10.2.3.
The rationale for the dosing for this study is discussed in Section 5.3.3 Rationale for CC-5013-
CLL-009 study.
Blinding
To minimize bias for both safety and efficacy parameters based on a subject’s treatment regimen, 
the study was a double-blinded trial.  The blind was removed once all patients had completed 3 
cycles of treatment.
8.1.7.
Safety
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 of hematological toxicities and TLS.  
Hematological toxicities will be graded as specified in the iwCLL guidelines for the diagnosis 
and treatment of chronic lymphocytic leukemia (Hallek, 2008) (Appendix 21.4).  TLS will be 
graded as specified by the Cairo-Bishop grading system (Appendix 21.3).
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 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
50
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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 period.  Subjects will be 
followed until 80% of the subjects have progressed or died or up to five years after the last 
subject was randomized, whichever occurs later.
8.1.8.
Efficacy 
Tumor response will be assessed according to the iwCLL guidelines for the diagnosis and 
treatment of CLL (Hallek, 2008), including CR, CRi, nPR, PR, SD, and PD.  Evaluation of 
response will be performed after 3 cycles of therapy and every 4 weeks thereafter.
For those subjects who reach PR, CRi or CR, a CT scan of the neck, chest, abdomen and pelvis 
to assess lymphadenopathies will be performed at the PR and CR/CRi confirmation visits (≥8 
weeks to ≤ 12 weeks after all clinical and laboratory response criteria have been met for PR or 
CR/CRi).  Those subjects whose response was down-graded based on the CT scan interpretation 
at the PR or CR/CRi confirmation visit will have the CT scan repeated 4 months later at the 
location where remaining disease has been documented, as long as clinical and laboratory 
response remains present to try to document further improvement.
For those subjects who reach CR or CRi, a bone marrow aspirate and bone marrow biopsy will
be performed at the CR/CRi confirmation visit (≥ 8 weeks to ≤ 12 weeks after all clinical and 
laboratory response criteria have been met).  If the bone marrow is hypocellular, a repeat 
specimen should be obtained after 4 weeks, provided that the blood counts have recovered. If 
the bone marrow biopsy shows disease involvement (30% or greater lymphocytes, or nodules 
positive for B-CLL cells by immunohistochemistry), an additional bone marrow biopsy and 
aspirate will be taken 4 months later as long as clinical and laboratory response remain to 
document further improvement.
MRD status will be evaluated for those subjects who reach CR or CRi. A peripheral blood and 
bone marrow aspirate sample will be collected for MRD analysis by flow cytometry at the 
CR/CRi confirmation visit.
!
If peripheral blood and bone marrow are both MRD-positive, peripheral blood 
samples will be repeated and assessed up to 3 additional times at 8 week intervals to 
try to document MRD negativity in subjects who reach confirmed CR or CRi (see 
Follow-up MRD assessments).
!
If peripheral blood is MRD-negative and bone marrow is MRD-positive, both 
peripheral blood and bone marrow should be retested for MRD negativity after ≥ 12 
weeks. If this repeat bone marrow is MRD-positive, no further testing for MRD will 
be performed.
!
If both the peripheral blood and bone marrow are MRD-negative, peripheral blood 
will be tested every 6 months for assessment of MRD until subject discontinues study 
drug.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
51
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Follow-up MRD assessments:
!
If any of the repeat peripheral blood assessments indicate MRD-negativity, a bone 
marrow aspirate sample should be collected and retested as soon as possible to 
confirm MRD negativity. 
#
If the bone marrow is MRD-positive, both peripheral blood and bone marrow 
should be retested for MRD negativity after ≥ 12 weeks. If this repeat bone 
marrow is MRD-positive, no further testing for MRD will be performed.
#
If at any time, the bone marrow is MRD-negative, peripheral blood will be tested 
every 6 months for assessment of MRD until subject discontinues study drug.
Response Adjudication Committee
An independent Response Adjudication Committee (RAC) will perform a blinded, assessment of 
response (including assessment of SD and of PD) prior to database lock.  The RAC adjudicated 
response data will be used in the efficacy analysis for the study.
8.1.9.
Independent Data Monitoring Committee
An independent external Data Monitoring Committee (DMC) will review safety and efficacy 
data collected during the conduct of the study. DMC Meetings will occur approximately every 3
months during enrollment and no less than twice per year thereafter.  In addition, safety data will 
be reviewed in an ongoing manner to assess benefit-to-risk considerations; accrual will be 
stopped if unacceptable toxicities are observed in a treatment arm.
8.1.10.
Pharmacokinetics
Pharmacokinetic (PK) studies will be performed in up to 40 subjects.  Following the enrollment 
of 90 subjects, participation in the PK sub-study will be mandatory for all additional subjects 
enrolled.  Intensive sampling and sparse sampling will be discontinued as of this amendment, 
protocol amendment #6.  Lenalidomide concentration data obtained from all visits may be used 
to develop the population PK model.  The relationship between pharmacokinetics and response 
(biomarkers or clinical outcomes as appropriate) will be explored.
8.1.11.
Exploratory Biomarkers
Rationale
Biomarkers are objectively measured indicators of biological or pathogenic processes, or 
pharmacologic responses to a therapeutic intervention.  In CLL, there is particular interest in the 
molecular changes that may identify disease subtypes, stage of disease, or predict high-risk 
disease or disease progression.
 
 
 
 
 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
52
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
 
Predictive Markers
Currently there are a number of biological markers useful in identifying subsets of CLL that have 
shortened time to treatment or increased risk of disease progression. These markers are: VH
mutational status, ZAP-70 expression, 
, Beta-2 Microglobulin (β2M), and 
genomic variations identifiable by FISH (del 13q, del 11q, del 17p, trisomy 12).  These classic 
prognostic markers will be evaluated in this study. 
 
8.1.12.
Other Outcomes
Quality of life data will be collected as detailed in Table 2 using the FACT-Leu and EQ-5D 
questionnaires.
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
53
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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. 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 diagnosis and 
treatment of CLL (Hallek, 2008)] meeting at least one of the following criteria:
!
Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia and/or thrombocytopenia
!
Massive (i.e. > 6 cm below the left costal margin) or progressive or symptomatic 
splenomegaly
!
Massive nodes (i.e., > 10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy
!
!
A minimum of any one of the following disease-related symptoms must be present:
#
Unintentional weight loss ≥ 10% within the previous 6 months
#
Significant fatigue (i.e., ECOG PS 2; cannot work or unable to perform usual 
activities)
#
Fevers of greater than 100.5° F or 38.0° C for 2 or more weeks without other 
evidence of infection
#
Night sweats for more than 1 month without evidence of infection
5. Must be relapsed or refractory to at least 1 prior regimen for treatment of CLL [relapsed / 
refractory as defined per the iwCLL guidelines for diagnosis and treatment of CLL 
(Hallek, 2008)].  At least one of the prior treatments must have included a purine-analog
or bendamustine based regimen
!
Relapsed is defined as a subject who has previously achieved the criteria of a 
complete remission (CR) or partial remission (PR), but after a period of ≥6 months, 
demonstrates evidence of disease progression
!
Refractory is defined as treatment failure [e.g. Stable disease (SD), nonresponse, or 
progressive disease] or disease progression within 6 months to the last antileukemic 
therapy
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
54
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
6. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 
≤2.
7. Females of childbearing potential (FCBP) must:
!
Have a negative medically supervised pregnancy test prior to starting study drug.  She 
must agree to ongoing pregnancy testing during study drug therapy, and after 
discontinuation of study drug as specified in Appendix 21.9.  This applies even if the 
subject practices complete and continued sexual abstinence.
!
Either commit to continued abstinence from heterosexual intercourse (which must be 
reviewed on a monthly basis) or agree to use, and be able to comply with, effective 
contraception without interruption, prior to starting study drug, during study drug 
therapy, and after discontinuation of study drug as specified in Appendix 21.9.
8. Male subjects must:
!
Agree to use a condom during sexual contact with a FCBP, even if they have had a 
vasectomy, during study drug therapy and after discontinuation of study drug as 
specified in Appendix 21.9.
!
Agree to not donate semen or sperm during study drug therapy and after 
discontinuation of study drug as specified in Appendix 21.9.
9. All subjects must:
!
Have an understanding that the study drug could have a potential teratogenic risk
!
Agree to abstain from donating blood during study drug therapy and after 
discontinuation of study drug as specified in Appendix 21.9.
!
Agree not to share study drug with another person
!
Be counseled about pregnancy precautions and risks of fetal exposure as specified in 
Appendix 21.9.
9.2.
Subject Exclusion Criteria
Subjects must not meet any of the following exclusion criteria to be eligible for enrollment 
into the study:
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from signing the informed consent form
2. Active infections requiring systemic antibiotics
3. Systemic treatment for B-cell CLL within 28 days of initiation of lenalidomide treatment
4. Alemtuzumab therapy within 60 days of initiating lenalidomide treatment
5. (removed in protocol amendment #3)
6. Prior therapy with lenalidomide
7. History of grade 4 rash due to prior thalidomide treatment
8. Planned autologous or allogeneic bone marrow transplantation
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
55
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
9. Pregnant or lactating females
10. 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 initiating study drug
11. 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
#
Carcinoma in situ of the bladder
#
Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
12. History of renal failure requiring dialysis
13. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or 
Hepatitis C Virus (HCV) infection
14. Evidence of TLS per the Cairo-Bishop definition of laboratory TLS (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 
(creatinine clearance may also be obtained by the 24-hour collection method at 
the investigator’s discretion)
#
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 > 1.5 x ULN
16. Uncontrolled hyperthyroidism or hypothyroidism
17. Venous thromboembolism within 12 months
18. ≥ Grade-2 neuropathy
19. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
20. Disease transformation [i.e. Richter’s Syndrome (lymphomas) or prolymphocytic 
leukemia]
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
56
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21. Participation in any clinical study or having taken any investigational therapy within 28 
days prior to initiating lenalidomide therapy
22. Known presence of alcohol and/or drug abuse
&(/*(1(35235,(7$5<,1)250$7,21


('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
57
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
10.
DESCRIPTION OF TREATMENT 
10.1.
Description of Study Drug
Celgene Corporation will supply lenalidomide 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg 
capsules for oral administration.  Subjects will receive 28 days of lenalidomide per cycle.
Study drug will be packaged in bottles containing study capsules for 28 days.
10.2.
Treatment Assignments
10.2.1.
Randomization
Randomization will be accomplished by a validated interactive voice response system (IVRS) to 
ensure timely registration and randomization.  Designated site staff 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 site staff will identify 
the subject and confirm eligibility. When all questions have been answered, 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.
Initially subjects will be randomized (1:1:1) in a double-blind fashion to the 5 mg, 10 mg, and 15 
mg starting dose arms (treatment arm 1, treatment arm 2, and treatment arm 3 respectively).  
Subjects will be stratified at randomization by:
#
relapsed vs. refractory to their last purine-analog or bendamustine based treatment 
regimen (if subject has received both, the status post most recent purine-analog or 
bendamustine treatment regimen will be used for stratification) and
#
age < 65 years of age vs. ∀65 years of age
After 18 subjects complete one 28 day cycle, an interim analysis will be conducted to review the 
safety of each starting dose arm(s).  Subsequent interim analyses to review the safety and 
progression rate of each starting dose arm(s) will occur at 13-week intervals.  After review of 
each interim analysis, a treatment arm may be dropped.  At any time accrual to a starting dose 
arm will also be stopped if unacceptable toxicities are observed in that arm.  If a treatment arm is 
dropped then all new subjects will be randomized equally into the remaining arm(s).
Site staff must contact Celgene at each visit for study drug assignment.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
58
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
10.2.2.
Treatment
Depending on the starting dose, each subject will be allocated in a double-blind fashion to three 
different regimens and will escalate every 28 days, based on individual subject tolerability, as 
follows:
Table 4:
Dose Regimen by Treatment Arm
Dose level
Lenalidomide dose (oral administration)
Schedule
Treatment Arm 1
5 mg starting dose arm
Treatment Arm 2
10 mg starting dose arm
Treatment Arm 3
15 mg starting 
dose arm
Dose level +4
25 mg daily
25 mg daily
25 mg daily
28 days
Dose level +3
20 mg daily
25 mg daily
25 mg daily
28 days
Dose level +2
15 mg daily
20 mg daily
25 mg daily
28 days
Dose level +1
10 mg daily
15 mg daily
20 mg daily
28 days
Dose level 0
5 mg daily
10 mg daily
15 mg daily
28 days 
For toxicities requiring dose interruption and/or modification (see Section 10.2.3), a more 
gradual stepwise dose escalation of lenalidomide (more than one 28 day cycle for each dose 
level) might be needed at the discretion of the treating physician due to adverse events that do 
not require dose reduction or interruption.
Subjects unable to escalate to the 25 mg maximum dose due to toxicity may continue with the 
highest dose achieved in the previous cycle or as indicated in Section 10.2.3 Dose Modification 
or Interruption.
10.2.3.
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 of hematological toxicities and TLS.  
Hematological toxicities will be graded according to iwCLL guidelines for the diagnosis and 
treatment of chronic lymphocytic leukemia (Hallek, 2008) (Appendix 21.4).  TLS will be graded 
as specified by the Cairo-Bishop grading system (Appendix 21.3).
If a subject develops toxicity (see Table 5 Dose Reduction and Modification Guidelines), the 
dose may be reduced as outlined in Table 6 Dose Reduction Steps for Lenalidomide.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
59
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 5:
Dose Reduction and Modification Guidelines for Lenalidomide
Toxicity
Severity
Action
Neutropenia
ANC < 500/μL
#
Dose should be held (once first result of ANC showing 
decrease below 500/μL is present)
#
An additional CBC sample may be drawn at the 
investigator’s discretion within 24 hours of the ANC 
decrease, prior to interruption of lenalidomide therapy, 
to re-monitor the ANC and confirm ANC < 500/μL
#
If the ANC is ≥ 500/μL (Grade 4 neutropenia not 
confirmed), the same dose of lenalidomide may be 
continued without interruption or dose reduction
#
If ANC is confirmed to be < 500/μL or confirmation is 
not required per the investigator’s discretion:
#
Interrupt lenalidomide therapy
#
Follow CBC every 7 days
#
Resume lenalidomide (decrease one dose 
level) when ANC recovers to ∀500/μL 
#
Use of growth factors (i.e. G-CSF) is permitted at the 
investigator’s discretion
#
Re-escalation to the next consecutive dose level is 
permitted as follows:
#
If subject restarts dosing at one dose level 
lower on Day 1 to Day 14 of a cycle, and 
completes the remainder of that cycle at this 
lower dose without occurrence of toxicities 
requiring dose interruption/reduction, then 
the subject may be dose re-escalated by one-
dose level starting at Day 1 of the 
subsequent cycle.
#
If subject restarts dosing at one dose level 
lower on Day 15 to Day 28 of a cycle, and 
completes the remainder of that cycle and 
the subsequent cycle at this lower dose 
without occurrence of toxicities requiring 
dose interruption/reduction, then the subject 
may be dose re-escalated by one-dose level 
starting at Day 1 of the following cycle.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
60
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 5:
Dose Reduction and Modification Guidelines for Lenalidomide (Continued)
Toxicity
Severity
Action
Febrile 
Neutropenia
ANC < 1,000/μL 
with fever 
(temperature ≥ 
38.5°C)
#
Interrupt lenalidomide therapy
#
Follow CBC every 7 days
#
Use of growth factors (G-CSF, GM-CSF) is permitted at 
the investigator’s discretion
#
Resume lenalidomide (decrease one dose level) when 
febrile neutropenia has resolved with ANC ≥ 500/μL
#
Re- escalation to the next consecutive dose level is 
permitted as follows:
#
If subject restarts dosing at one dose level 
lower on Day 1 to Day 14 of a cycle, and 
completes the remainder of that cycle at this 
lower dose without occurrence of toxicities 
requiring dose interruption/reduction, then 
the subject may be dose re-escalated to next 
consecutive-dose level starting at Day 1 of 
the subsequent cycle.
#
If subject restarts dosing at one dose level 
lower on Day 15 to Day 28 of a cycle, and 
completes the remainder of that cycle and 
the subsequent cycle at this lower dose 
without occurrence of toxicities requiring 
dose interruption/reduction, then the subject 
may be dose re-escalated to next 
consecutive-dose level starting at Day 1 of 
the following cycle.
Thrombocytopenia
Platelets 
< 20,000/ μL
#
Interrupt lenalidomide therapy
#
Follow CBC every 7 days
#
Resume lenalidomide (decrease one dose level) when 
platelet count recovers to ≥ 25,000/μL
#
Re-escalation to the next consecutive dose level is 
permitted if the subject completes one full cycle without 
occurrence of toxicities requiring dose 
interruption/reduction. 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
61
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 5:
Dose Reduction and Modification Guidelines for Lenalidomide (Continued)
Toxicity
Severity
Action
Tumor Flare
Grade 3 or 4
#
Interrupt lenalidomide therapy and initiate therapy with 
corticosteroids, NSAIDs and/or narcotics
#
Resume lenalidomide (decrease one dose level) when 
symptoms resolve to & Grade 1
#
Re-escalation to the next consecutive dose level is 
permitted at Day 1 of the subsequent cycle when Tumor 
Flare resolves to ≤ Grade 1.
Desquamating 
(blistering) rash
Any
#
Permanently discontinue lenalidomide and follow for 
PD
Non-
desquamating rash
Grade 3
#
Interrupt lenalidomide therapy.
#
Resume lenalidomide when the rash resolves to ≤ Grade 
1 (decrease one dose level)
Non-
desquamating rash
Grade 4
#
Permanently discontinue lenalidomide and follow for 
PD
Neuropathy
Grade 3
#
Interrupt lenalidomide therapy. 
#
Resume lenalidomide when the neuropathy resolves to ≤ 
Grade 1 (decrease one dose level)
Neuropathy
Grade 4
#
Permanently discontinue lenalidomide and follow for 
PD
Venous 
thrombosis/emboli
sm
≥ Grade 3
#
Hold (interrupt) dose and start anticoagulation;
#
Resume lenalidomide at investigator’s discretion 
(maintain dose level).
Hyperthyroidism 
or hypothyroidism
Any
#
Interrupt lenalidomide and initiate appropriate medical 
therapy.
#
Resume lenalidomide at investigator’s discretion 
(maintain dose level).
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
62
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 5:
Dose Reduction and Modification Guidelines for Lenalidomide (Continued)
Toxicity
Severity
Action
Serum Creatinine
Grade 2 
(> 1.5 - 3.0 x 
ULN)
OR 
Grade 3 
(> 3.0 - 6.0 x 
ULN)
#
Interrupt lenalidomide
#
Evaluate subject weekly (minimum) until the serum 
creatinine return to baseline 
#
If serum creatinine resolves to < Grade 1 resume 
lenalidomide (decrease one dose level) 
#
If serum creatinine has stabilized to grade 1 after a 
minimum of 3 weeks of dose interruption resume 
lenalidomide at the investigator’s discretion (decrease 
one dose level) 
#
If serum creatinine has not stabilized to ≤ grade 1 after 5 
weeks of dose interruption:
#
Permanently discontinue lenalidomide and 
follow for PD at the investigator’s discretion 
OR
#
Contact the Celgene Medical Monitor to 
discuss subject status
#
If the serum creatinine worsens at any time to > Grade 3, 
or if dialysis is indicated, permanently discontinue 
lenalidomide and follow for PD 
#
Upon resumption of lenalidomide, evaluate subject 
weekly x 2 weeks to ensure the serum creatinine does 
not worsen; if the serum creatinine again worsens during 
those 2 weeks, permanently discontinue and follow for 
PD
Serum Creatinine
Grade 4 (> 6.0 x 
ULN)
OR
if dialysis is 
indicated
#
Permanently discontinue lenalidomide and follow for 
PD
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
63
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 5:
Dose Reduction and Modification Guidelines for Lenalidomide (Continued)
Toxicity
Severity
Action
TLS
Laboratory TLS 
or Grade 1 TLS
#
Same dose of lenalidomide will be continued without 
interruption or dose reduction at the investigator’s 
discretion.
#
Hospitalize subjects with Grade 1 TLS, (hospitalization 
for laboratory TLS will be per investigator’s discretion)
#
Provide with vigorous intravenous hydration and 
rasburicase therapy as needed to reduce hyperuricemia, 
until correction of electrolyte abnormalities.
#
Dose escalation to the next consecutive dose level is 
permitted when laboratory TLS is resolved and Grade 1 
TLS is resolved to Grade 0.
TLS
≥ Grade 2
#
Interrupt lenalidomide therapy.
#
Resume lenalidomide (at the next lower dose level) 
when the TLS resolves to Grade 0.
#
If lenalidomide is resumed prior to the start of the 
subsequent cycle, a chemistry test should be performed 
every other day for the first week following re-initiation 
of lenalidomide.
#
Re-escalation to the next consecutive dose level is 
permitted after completion of one full cycle without 
laboratory TLS or ≥ Grade 1 TLS, or occurrence of 
toxicities requiring dose interruption/reduction. 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
64
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 5:
Dose Reduction and Modification Guidelines for Lenalidomide (Continued)
Toxicity
Severity
Action
Liver Function 
Tests (LFTs)
ALT > 3.0 and ≤ 
5.0 x ULN and 
serum total 
bilirubin ≤ 1.5 x 
ULN 
#
Continue current dose level
#
Test at next scheduled visit 
Liver Function 
Tests (LFTs)
ALT > 3.0 and ≤ 
5.0 x ULN and a 
serum total 
bilirubin > 1.5 x 
ULN
OR
ALT > 5.0 x 
ULN
OR 
Serum total 
bilirubin > 1.5 x 
ULN
#
Interrupt lenalidomide therapy.
#
Evaluate ALT and serum total bilirubin weekly until 
both return to baseline levels
#
Resume lenalidomide when ALT and serum total 
bilirubin return to baseline.
#
Maintain dose level if recovery from event occurs ≤ 14 
days from initial test result.
#
Decrease by one dose level if recovery from event is 
prolonged > 14 days but ≤ 28 days from initial test 
result. Continue to monitor weekly LFTs during this 
cycle.  If the event does not repeat, dose escalation or re-
escalation may continue according to protocol.  
Medical monitor must be notified if values do not return to 
baseline within 28 days of the initial event.
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)
Lenalidomide dose may be interrupted/modified per the investigator’s discretion for any 
AE (any Grade) not outlined in Table 5.
Dose escalation or re-escalation may begin on the scheduled Day 1 of a new cycle according to 
the protocol guidelines if toxicities requiring dose interruption and/or modification have resolved 
as specified in Table 5.
If there is a dose interruption during a cycle that lasts beyond Day 28 of the cycle, the subject 
must still have assessments as per Table 2 every 28 days.  An unscheduled visit may be 
conducted to meet this requirement.
If a study drug interruption has lasted for 5 weeks (35 days), the investigator should contact the 
medical monitor to discuss whether the subject should be continued on the study.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
65
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Table 6:
Dose Reduction Steps for Lenalidomide
Dose level
Lenalidomide dose (oral administration)
Schedule
Treatment Arm 1
5 mg starting dose arm
Treatment Arm 2
10 mg starting dose arm
Treatment Arm 3
15 mg starting 
dose arm
Dose level +4 a
25 mg daily
25 mg dailyb
25 mg dailyc
28 days
Dose level +3 a
20 mg daily
25 mg daily
25 mg dailyc
28 days
Dose level +2 a
15 mg daily
20 mg daily
25 mg daily
28 days
Dose level +1a
10 mg daily
15 mg daily
20 mg daily
28 days
Dose level 0
5 mg daily
10 mg daily
15 mg daily
28 days 
Dose level -1
2.5 mg daily
5 mg daily
10 mg daily
28 days
Dose level -2
2.5 mg every other day
2.5 mg daily
5 mg daily
28 days
Dose level -3d
2.5 mg 2x per week 
2.5 mg every other day
2.5 mg daily
28 days
Dose level -4d
Not Applicable
2.5 mg 2x per week
2.5 mg every other 
day
28 days
a.  If a subject is at Dose Levels +1, +2, +3 or +4, a maximum of 5 consecutive dose reductions are allowed.  If a 6th
consecutive dose reduction is required, the subject will be discontinued from the study.
b.  For the 10 mg starting dose arm, if a dose reduction is required at Dose Level +4 (25 mg daily), the subject will 
be dose reduced directly to Dose level +2 (20 mg daily).  This will be counted as one dose reduction.
c.  For the 15 mg starting dose arm, if a dose reduction is required at Dose Level +3 (25 mg daily)or Dose Level +4 
(25 mg daily), the subject will be dose reduced directly to Dose level +1 (20 mg daily).  This will be counted as 
one dose reduction.
d.  If a dose reduction is required at Dose Level -4 (or at dose level -3 in the 5 mg starting dose arm) subject will be 
discontinued from the study.
Site staff must contact Celgene to obtain new study drug bottle for a patient.  If the treatment has 
been withheld and the next cycle is delayed beyond 29 days after Day 1 of the prior cycle, then 
Day 1 of the next cycle will be defined as the first day that the treatment is resumed.
Subjects requiring dose reduction within a treatment cycle must return to the study site and
return the empty bottle or any unused drug and a new bottle will be dispensed.  Subjects will be 
required to return the empty bottle or any unused drug prior to new drug being dispensed.  
Subjects should take study drug from the new bottle for the remainder of the cycle (i.e. if 
reduction occurs on Cycle Day 16, then the subject will take study drug for days 16 though 28).
10.3.
Emergency Unblinding
This is now an open label protocol.  Therefore the dose of study drug will be identified on the 
package labeling.
10.4.
Prior/Concomitant Medications
All medications (prescription and non-prescription), treatments and therapies taken from 28 days 
prior to Cycle 1 Day 1 through the last dose of study drug, must be recorded on the eCRF.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
66
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
10.4.1.
Prophylaxis and/or Treatment for TLS, TFR, Neutropenia, and 
Thromboembolic Events
10.4.1.1.
Tumor Lysis Syndrome (TLS) Prophylaxis 
TLS prophylaxis, comprising of oral hydration and allopurinol 300 mg/day will be initiated at 
least 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles.  For 
subjects with known allergy to allopurinol prior to study initiation or for those who develop an 
allergy during the course of study, the medical monitor should be contacted.  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 each cycle during the dose escalation period.  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.
Subjects will be monitored for TLS as follows:
!
On Day 2 and 4 and then weekly (Days 8, 15, 22) for cycle 1 and the first cycle of 
each dose escalation
!
On Day 1, 8 and 15 of cycle 2 (if not dose escalated)
!
At least every 28 days thereafter and as clinically indicated.
10.4.1.2.
Tumor Flare Reaction (TFR) Treatment
Grade 1 TFR may be treated with NSAIDs and TFR ≥ Grade 2 may be treated with 
corticosteroids.  Narcotic analgesics may be added as needed for pain control in subjects 
experiencing ≥ Grade 2 TFR.
Subjects will be monitored for TFR as follows:
!
On Day 2 and 4 and then weekly (Days 8, 15, 22) for cycle 1 and the first cycle of 
each dose escalation
!
On Day 1, 8 and 15 of Cycle 2
!
At least every 28 days thereafter and as clinically indicated.
10.4.1.3.
Neutropenia Supportive Treatment
The use of hematopoietic growth factors is permitted.  Treatment with myeloid growth factors is 
strongly encouraged following ASCO guidelines recommendation (Smith, 2006) for dosing and 
administration when the absolute neutrophil count (ANC) is less than 1,000/μL [NOTE: per the 
inclusion criteria, subjects must have an ANC ≥1000/μL to be eligible for study entry].
10.4.1.4.
Infection Prophylaxis
Prophylactic antibiotics should be considered in subjects 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.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
67
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
10.4.1.5.
Thromboembolic Events Prophylaxis
Lenalidomide may increase the risk of thromboembolic events in subjects who are at high risk 
(high risk is defined for example as a history of a thromboembolic event and/or taking a 
concomitant medication associated with an increased risk for a thromboembolic event and/or a 
known hypercoagulable state regardless of thromboembolic history). All subjects should receive 
anti-thrombotic prophylaxis during study treatment.  For subjects who enter the study with a 
platelet count close to the eligibility criteria of ≥ 50,000/ μL, the medical monitor should be 
contacted to discuss the anti-thrombotic prophylaxis.  The recommended prophylaxis is low-dose 
aspirin [ASA] (70-100mg) daily; however, another prophylactic anti-thrombotic therapy may be 
used per investigator’s discretion during study treatment. Choice of the most appropriate anti-
thrombotic therapy for each subject should be based upon a careful evaluation of the different 
risk factors associated with each therapy, and a corresponding assessment of the individual 
subject’s underlying medical condition.  Selection should be based on the overall benefit-to-risk 
ratio. Use of low molecular weight heparin or warfarin (or equivalent Vitamin K antagonist) to 
keep the International Normalization Ratio (INR) in the range of 2-3 or other anti-thrombotic 
therapy according to hospital guidelines or physician preference is acceptable.
If platelets drop below 50,000/μL, the investigator should consider interrupting or adjusting the 
dose of anti-thrombotic therapy.  In the event that platelets drop below 20,000/μL and the anti-
thrombotic therapy has not already been interrupted, the investigator should again strongly 
consider interrupting the anti-thrombotic therapy.  In addition, for platelets < 20,000/μL, 
lenalidomide should be interrupted and CBC should be followed every 7 days.  Appropriate 
interventions (i.e., platelet infusion) should be considered where applicable. 
10.4.1.6.
Other
Other therapies considered necessary for the subject’s well being may be administered at the 
discretion of the Investigator.  These therapies may include antibiotics, analgesics, 
antihistamines, or other medications as well as growth factors and transfusions of red blood cells, 
platelets, or fresh frozen plasma given to assist in the management of complications associated 
with chronic lymphocytic leukemia or its therapy.
10.4.1.7.
Prohibited Concomitant Therapy
Concomitant use of other CLL therapy or investigational therapies while the subject is on study 
drug is prohibited.
10.5.
Discontinuation from Treatment
The following events are considered sufficient reasons for discontinuing a subject from study 
drug:
!
AEs that, in the judgment of the Investigator, may cause severe or permanent harm or 
which rule out continuation of study drug.
!
Disease progression
!
Subject withdraws consent
!
Subject lost to follow-up
se
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
68
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
!
Death
!
Protocol violation
!
Other
The reason for discontinuation should be recorded in the eCRF and in the subject’s medical 
records. Celgene is to be notified of all discontinuations from study drug.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
69
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
11.
STUDY DRUG MATERIALS AND MANAGEMENT
11.1.
Supplier(s)
Celgene Corporation will supply lenalidomide capsules.
11.2.
Dosage Form
Lenalidomide will be supplied as 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg capsules for 
oral administration.
11.3.
Dosage Regimen
Subjects will be randomized (1:1:1) via IVRS in a double blind fashion to receive three different 
starting dose of lenalidomide (5 mg daily versus 10 mg daily versus 15 mg daily) on days 1-28 of 
the first 28 day cycle. Subjects will then escalate every 28 days, based on individual subject 
tolerability, as follow (see Table 4).
!
Treatment Arm 1: 5 mg →10 mg →15 mg →20 mg →25 mg/daily
!
Treatment Arm 2: 10 mg →15 mg →20 mg →25 mg/daily
!
Treatment Arm 3: 15 mg →20 mg →25 mg/daily
11.4.
Study Drug Packaging and Labeling
The lenalidomide study drug will be packaged in bottles and each bottle will contain supplies for 
28 days.  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.
Daily dispensing of capsules will be clearly defined on the bottle. Subjects requiring dose 
reduction within a treatment cycle must return to the study site and return the empty bottle or any 
unused drug and a new bottle will be dispensed.  Subjects will be required to return the empty 
bottle or any unused drug prior to new drug being dispensed.  Subjects should take study drug 
from the new bottle for the remainder of the cycle (i.e. if reduction occurs on Cycle Day 16, then 
the subject will take study drug for days 16 though 28).
11.5.
Study Drug Receipt and Storage
The Investigator(s) or designee(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) or designee(s) will verify the accuracy of the information on the form and 
register receipt in the study drug supply system.  The investigator must contact Celgene 
regarding any discrepancies.
At the study site, all investigational study drugs will be stored in a locked, safe area to prevent 
unauthorized access.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
70
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
The study drug should be stored as directed on package label.
11.6.
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 eCRF and source documents.
11.7.
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.
11.8.
Study Drug Handling and Disposal
FCBP should not handle or administer lenalidomide unless they are wearing gloves. All subjects 
should not extensively handle or open lenalidomide 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 the 
counseling of subjects.  Once trained, these healthcare staff will counsel subjects prior to 
lenalidomide being dispensed to ensure that the subject has complied with all requirements 
including use of birth control and pregnancy testing (FCBP) and that the subject understands the 
risks associated with lenalidomide.  This step will be documented with a completed lenalidomide 
Education and Counseling Guidance Document (Appendix 21.9), and no lenalidomide will be 
dispensed until this step occurs.  Counseling includes verification with the subject that required 
pregnancy testing was performed and results were negative. A Lenalidomide Information Sheet 
(Appendix 21.9) will be supplied each time lenalidomide is dispensed.  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 eCRF and source documents.  
Celgene will provide instructions for the return of study drug supplies at the end of the study.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
71
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
12.
ASSESSMENT OF EFFICACY
12.1.
Assessments
!
Physical Exam (lymph nodes, spleen and liver measurement)
!
Complete blood count (CBC) and differential
!
ECOG Performance Status
!
Assessment of constitutional symptoms (weight loss, fever, night sweats, fatigue)
!
Computed tomography (CT) scans
!
Histopathology (bone marrow aspirate/biopsy)
!
Assessment for MRD by flow cytometry (peripheral blood and bone marrow aspirate)
!
In addition, the following will be performed at screening:
#
Clinical staging using Rai and/or Binet as defined by the iwCLL guidelines for 
the diagnosis and treatment of CLL (Hallek, 2008)
#
Immunophenotyping of peripheral blood lymphocytes
12.2.
Methods and Timing of Efficacy Assessments
Serial measurements of efficacy will be performed 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.  Data generated by central laboratories and evaluations performed by central 
pathology reviewers will prevail over locally generated information in the evaluation of the 
subject’s efficacy results.  Laboratory tests that may result in dose interruption and/or 
modification as specified in Table 5 should also be performed locally to allow for treatment 
related decisions during subject visits.
At a minimum the following hematology/chemistry assessments must be performed locally:  
hemoglobin, absolute lymphocyte count, absolute neutrophil count and platelet count, potassium, 
calcium, phosphorus, creatinine, total bilirubin, AST/SGOT, ALT/SGPT, and uric acid.  
At screening, subjects must meet eligibility criteria based on central lab results.  At Study Day 1, 
subjects must meet eligibility criteria based on local or central lab results prior to initiating study 
therapy, however, a re-calculation of creatinine clearance is not required at Study Day 1.
Clinical response evaluations
The following assessments for evaluation of clinical response will be performed as specified in 
Table 2
!
Physical Exam (lymph nodes, spleen and liver measurement)
!
Complete blood count (CBC) and differential
!
ECOG Performance Status
!
Assessment of constitutional symptoms (weight loss, fever, night sweats, fatigue)
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
72
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
CT Scan
For those subjects who reach PR, CRi or CR, a CT scan of the neck, chest, abdomen and pelvis 
to assess lymphadenopathies will be performed at the PR and CR/CRi confirmation visits (≥8 
weeks to ≤ 12 weeks after all clinical and laboratory response criteria have been met for PR or 
CR/CRi).  Those subjects whose response was down-graded based on the CT scan interpretation 
at the PR or CR/CRi confirmation visit will have the CT scan repeated 4 months later at the 
location where remaining disease has been documented, as long as clinical and laboratory 
response remains present to try to document further improvement..  A CT scan of the neck, chest, 
abdomen and pelvis will be performed for all subjects, except those who discontinue due to PDs, 
at the treatment discontinuation visit.
The average dose of radiation exposure for a subject during CT scan of neck, chest, abdomen and 
pelvis is approximately 20 mSv for a 70 kg patient.  However, the actual amount of radiation 
exposure for each subject will vary depending on, but not limited to, the size of the subject and 
type of CT equipment used for the assessment.
Histopathology (bone marrow aspirate/biopsy)
For those subjects who reach CR or CRi, a bone marrow aspirate and bone marrow biopsy will 
be performed at the CR/CRi confirmation visit (≥ 8 to ≤ 12 weeks after all clinical and laboratory 
response criteria have been met).  If the bone marrow is hypocellular, a repeat specimen should 
be obtained after 4 weeks, provided that the blood counts have recovered. If the bone marrow 
biopsy shows disease involvement (30% or greater lymphocytes, or nodules positive for B-CLL 
cells by immunohistochemistry), an additional bone marrow biopsy and aspirate will be taken 4 
months later as long as clinical and laboratory response remain to document further 
improvement.
Evaluation of MRD status
MRD status will be evaluated for those subjects who reach CR or CRi. A peripheral blood and 
bone marrow aspirate sample will be collected for MRD analysis by flow cytometry at the 
CR/CRi confirmation visit.  The MRD samples will be analyzed by a local laboratory.
!
If peripheral blood and bone marrow are both MRD-positive, peripheral blood 
samples will be repeated and assessed up to 3 additional times at 8 week intervals to 
try to document MRD negativity in subjects who reach confirmed CR or CRi (see 
Follow-up MRD assessments).
!
If peripheral blood is MRD-negative and bone marrow is MRD-positive, both 
peripheral blood and bone marrow should be retested for MRD negativity after ≥ 12 
weeks. If this repeat bone marrow is MRD-positive, no further testing for MRD will 
be performed.
!
If both the peripheral blood and bone marrow are MRD-negative, peripheral blood 
will be tested every 6 months for assessment of MRD until subject discontinues study 
drug or the study ends.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
73
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Follow-up MRD assessments:
!
If any of the repeat peripheral blood assessments indicate MRD-negativity, a bone 
marrow aspirate sample should be collected and retested as soon as possible to 
confirm MRD negativity. 
#
If the bone marrow is MRD-positive, both peripheral blood and bone marrow 
should be retested for MRD negativity after ≥ 12 weeks. If this repeat bone 
marrow is MRD-positive, no further testing for MRD will be performed.
#
If at any time, the bone marrow is MRD-negative, peripheral blood will be tested 
every 6 months for assessment of MRD until subject discontinues study drug or 
the study ends.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
74
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
13.
ASSESSMENT OF SAFETY
13.1.
Assessments
!
Vital signs: pulse, blood pressure, temperature, weight and height (height at screening 
only)
!
The following clinical laboratory assessments will be analyzed locally:
#
Hematology: hemoglobin (HGB), platelet count, absolute neutrophil count 
(ANC), absolute lymphocyte count (ALC)
#
Blood chemistry: potassium, calcium, phosphorus, creatinine, total bilirubin, 
AST/SGOT, ALT/SGPT and uric acid
#
Urinalysis:  ketones, sediments and specific gravity
#
Calculated (method of Cockroft-Gault) creatinine clearance (creatinine clearance 
may also be obtained by the 24-hour collection method at the investigator’s 
discretion)
#
At screening, subject must meet eligibility criteria based on central lab results.  At 
Study Day 1, subject must meet eligibility criteria based on local or central lab 
results prior to initiating study therapy.
!
Pregnancy testing / counseling as per Appendix 21.9
!
12-lead ECGs (performed and interpreted locally)
!
Concomitant medications
!
AEs by NCI CTCAE (Version 3.0) used as a guide for the grading of severity with 
the exceptions of hematological toxicities and TLS.  Hematological toxicities will be 
graded as specified in the iwCLL guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia (Hallek, 2008) (Appendix 21.4).  TLS will be graded 
as specified by the Cairo-Bishop grading system (Appendix 21.3).Version 3.0 with 
modification recommended by the iwCLL guidelines for the diagnosis and treatment 
of CLL (Hallek, 2008) and Cairo-Bishop grading system (for TLS).
!
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.  Subjects will be followed until 80% of the 
subjects have progressed or died or up to five years after the last subject was 
randomized, whichever occurs later.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
75
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
13.2.
Methods and Timing of Safety Assessments
Serial measurements of safety will be performed at baseline and at scheduled intervals 
throughout the duration of the study as outlined in Table 2.  All scheduled visits will have a ± 3 
day window unless otherwise stated.  Laboratory tests that may result in dose interruption and/or 
modification as specified in Table 5 should also be performed locally.
13.3.
Recording and Reporting of Adverse Events
The recording and reporting of adverse events is described in Appendix 21.1.
&(/*(1(35235,(7$5<,1)250$7,21


('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
76
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
14.
OTHER ASSESSMENTS
14.1.
Assessments Following Treatment Discontinuation
Subjects will continue in the study and receive study drug until discontinuation from the study 
for any of the following reasons: disease progression; AEs that, in the judgment of the 
Investigator, may cause severe or permanent harm or which rule out continuation of study drug, 
subject withdraws consent, subject is lost to follow-up, death, protocol violation that may rule 
out continuation of study drug, other reasons that in the Investigators judgment that may rule out 
continuation of study drug.
For those subjects who discontinue study drug for reasons other than disease progression or 
withdrawal of consent, study visits should continue every 28 days to assess response until 
documentation of disease progression or until a new CLL therapeutic regimen is started, 
whichever comes first.  During these visits only the following assessments will be required: 
hematology, ECOG performance status, evaluation of constitutional symptoms, physical exam 
for liver, spleen and lymph nodes, adverse events, second primary malignancies, concomitant 
medications/therapies, and assessment of response.
For subjects who develop PD characterized by transformation to a more aggressive histology 
[i.e. Richter’s syndrome (lymphomas) or prolymphocytic leukemia], this diagnosis should be 
established by lymph node biopsy whenever possible.
Subjects who are discontinued from the study drug for any reason, except for withdrawal of 
consent, will be followed for survival, second primary malignancies and subsequent CLL 
therapies until the study is closed when 80% of the subjects randomized to the study have 
progressed or died or up to five years after the last subject was randomized, whichever occurs 
later.
14.2.
Assessment of Pharmacokinetics
Collection of pharmacokinetic samples is discontinued as of this amendment, protocol 
amendment #6.  Pharmacokinetic assessments will be performed in up to 40 subjects who 
provide consent at select centers.  Following the enrollment of 90 subjects, participation in the 
PK sub-study will be mandatory for all additional subjects enrolled.  Both intensive and sparse 
PK blood sampling will be performed in these subjects.  All PK samples will be analyzed 
centrally.
Intensive PK sampling
On Cycle 1 Day 1, after an overnight fast, the subjects will receive the dose of lenalidomide 
in the morning at the study site and continue to fast until 3 hours post-dose.  Subjects will 
undergo PK sampling of blood at scheduled time points for up to 8 hours post-dose (see 
Table 2).  On Cycle 1 Day 2, all PK subjects will return to the site to provide a PK blood 
sample at pre-dose (equivalent to 24 hours post Day 1 dose).  The following information 
should be recorded on Cycle 1 Day 1:
!
Actual date and time of dosing
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Actual date and time for the last meal before dosing
Sparse PK sampling
Sparse PK sampling will be performed on Cycle 1 Day 4, Day 8 and Day 22, and Cycle 2
Day 8. Sparse PK sampling will be performed at Days 4, 8 and 22 of the first cycle at Dose 
Levels +1, +2, +3 for each Treatment Arm.  If sparse PK sampling timepoints for the first 
cycle at Dose Levels +1, +2, +3 overlap with the Cycle 2 sparse PK sampling timepoints, 
only one sample is required.  At each of these sparse PK sampling visits, 1 blood sample will 
be collected between 1 and 10 hours (inclusive) after the morning dose. For each subject, 
effort should be made to collect the sample in approximately 1:1 ratio between the interval 1-
5 hours and the interval of 5-10 hours.  On the PK visit days, subjects should take the study 
drug in the morning (preferably prior to their arrival at the study site).  Subjects will not be 
required to fast for these PK visits.
Subjects will be asked to accurately provide the following information and report them to the 
study staff on the PK visit day for sparse PK sampling:
!
Actual date and time of dosing on PK visit days and the day prior to PK visits
!
Actual date and time for the last meal before dosing on PK visit days 
!
Actual date and time for the food eaten within 4 hours after dosing on PK visit days
Actual date and time for blood draws should be recorded.  Lenalidomide concentration in plasma 
will be determined by a validated liquid chromatography-tendem mass spectrometry (LC-
MS/MS) method.
14.3.
Assessment of Exploratory Biomarkers
The following exploratory assessment will be performed as specified in Table 2.
!
Blood samples for β2M will be collected at baseline.  
!
Blood samples for ZAP-70, VH mutational status /TP53 mutation analysis and FISH 
studies for cytogenetic assessment (CCND1/IgH fusion, del 11q, del 17p, del 13q, 
and Trisomy 12), 
 and confirmation of disease diagnosis by flow 
cytometry will be collected at baseline.
 
 
 All samples will be analyzed centrally.
 
 
14.4.
Assessment of Other Outcomes
 
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Lenalidomide (CC-5013)
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Celgene Corporation
Confidential and Proprietary
78
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Quality of Life as measured by FACT-Leu questionnaire (Appendix 21.7) and EQ-5D (Appendix 
21.8) will be assessed at Cycle 1 Day 1, every 8 weeks thereafter and at treatment 
discontinuation.
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
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15.
STATISTICAL ANALYSES
15.1.
Overview
This study will be conducted using a randomized Bayesian schedule-administration design that 
jointly models toxicity/response outcomes using an extension methods developed in (Bekele, 
2004) (Bekele, 2005) (Bekele, 2008a) (Bekele, 2008b).  Schedule-administration (or treatment 
strategy) designs differ from standard treatment designs in that the object of interest is not to 
determine if one treatment is superior to an alternative treatment, but to determine if a particular 
treatment administration schedule is superior to other competing schedules.  In the context of the 
current design Celgene is interested in evaluating whether various intra-patient dose-escalation 
schemes are safe and effective while monitoring safety and efficacy (futility).  Specifically, 
while treatment starts at various doses ranging from very low doses (such as 5 mg/daily) to 
moderately low (15 mg/daily), the goal is to perform intra-patient dose escalation (every 28 days 
as tolerated) until a maximum dose of 25 mg/daily is achieved.  The decision to escalate is based 
on how well the subject tolerates the lower dose levels.  While these dose escalations are taking 
place, toxicity and the progression rate will be monitored.
 
 
 
 
Operationally, the study will proceed as follows:  Subjects will be randomized to one of the three 
treatment arms.  The first interim analysis (toxicity only) will be performed once 18 subjects 
have completed one 28-day cycle.  Subsequent interim analyses will occur at 13-week intervals 
to monitor both combined toxicity and progression rate.  
 
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Celgene Corporation
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80
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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If a treatment arm is dropped then all new subjects will be randomized equally into the remaining 
arms.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15.2.
Study Population Definitions
15.2.1.
Intent-to-Treat Population
The efficacy analysis will be performed on the ITT population, which will include all subjects 
randomized.
15.2.2.
Safety Population
All randomized subjects who receive at least one dose of study drug will be included in the 
safety analyses.
15.2.3.
Subgroup Analyses
In addition to analyses that include all subjects, analyses will be performed to compare 
treatments within the following stratification subgroups:
!
Relapsed vs. refractory to their last purine-analog or bendamustine based treatment 
regimen [relapsed/refractory as defined per the iwCLL guidelines for diagnosis and 
treatment of CLL (Hallek, 2008)].    If a subject has received both, the status post 
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Lenalidomide (CC-5013)
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Celgene Corporation
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81
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most recent purine-analog or bendamustine treatment regimen will be used for 
stratification.
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Age < 65 years of age vs. ≥ 65 years of age
Additional subgroups may be examined, as needed based on regulatory and clinical requests.
15.3.
Efficacy Evaluation
Efficacy analysis will be performed on intent-to-treat population. Adjudicated response will be 
used for these analyses.
Response
Response, including evaluation of minimal residual disease (MRD), will be assessed by iwCLL 
guidelines for diagnosis and treatment of CLL (Hallek, 2008).  The response rate based on the 
best response during the treatment period and the relative proportions in each response category 
will be examined.  Exact test procedures for proportions will be used to compare response rate 
between the treatment arms.  Distributions of the responses into the response categories (CR, 
CRi, nPR, PR, SD, PD) will be provided for each treatment arm.  Response rates 
(CR+CRi+nPR+PR) together with confidence intervals will be provided for each regimen, both 
for the entire population and for the subgroups defined by the stratification factors.
Responses from subjects after they received other anti-cancer treatments will not be counted, 
however, these subjects will be included in the denominator.
Duration of Response
Duration of response is defined as the time from the first visit where PR, CRi, or CR was 
documented to PD.  Duration of response will be censored at the last date that the subject was 
known to be progression-free for: 1) subjects who have not progressed at the time of analysis; 2) 
subjects who have withdrawn consent or are lost to follow-up prior to documentation of 
progression.
A two-sided log rank test stratified by the 3 strata used in the randomization at 0.05 significance 
level will be used to test the duration of response between the two treatment arms.
Time to Response
Time to response is calculated as the time from randomization to the first documented date of 
PR, CRi or CR based on iwCLL guidelines.
Progression-free Survival (PFS)
Progression-free survival is calculated as the time from randomization to the first documented 
progression or death due to any cause during or after the treatment period, whichever occurs 
first.  The progression date will be assigned to the earliest time when any progression is observed 
without prior missing assessments. If withdrawal of consent or loss to follow-up occurs before 
documented progression or death, then these observations will be censored at the date when the 
last complete tumor assessments determined a lack of progression.
For subjects who do not develop progressive disease at the time of analysis, if the response from 
the last visit was ‘not evaluable’, the most prior visit date with complete evaluation indicating no 
progressive disease will be used as the censor date.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
82
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Event-free Survival (EFS)
Event free survival (EFS) is the interval between the start of treatment to the first sign of disease 
progression, or treatment for relapse, or death (whichever occurs first)
Time-to-Progression (TTP)
TTP is defined as the time from randomization to the first documented progression.  For subjects 
who do not progress during the study, TTP will be censored at the last adequate response 
assessment showing evidence of no disease progression. TTP is the same as PFS when there is 
no death.
Overall Survival (OS)
OS 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 have withdrawn consent or were lost to follow-up before death was 
documented.
The analysis of OS will include survival information for all randomized subjects.  Subjects who 
discontinued from 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 may
be performed in which these subjects will be censored at the date of the first dose date of the 
anti-cancer therapy.
15.4.
Regression Analyses 
In addition we plan to perform both classical and Bayesian regression analyses in which 
predictors such as the stratification factors, treatment and possibly the treatment-by-stratification 
factor are included as covariates. Under the Bayesian framework these models will also be used 
to estimate posterior predictive probabilities for comparing the various treatments.
15.5.
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 
regimens. Medical history data will be summarized using frequency tabulations for each 
treatment arm separately and pooled over both arms. Individual patient 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.
15.6.
Study Drug
Dosage statistics (mean, median, mode, standard deviation and final dose, dose at each 
evaluation) will be provided for each treatment arm.  Time to the first dose reduction and reasons 
for dose reduction will be summarized for each treatment arm.  Reasons for discontinuation will 
be summarized.
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('06'RF1XPEHU
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Protocol CC-5013-CLL-009
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Confidential and Proprietary
83
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
15.7.
Concomitant Therapy
All concomitant treatment usage documented during the study period will be summarized in 
frequency tabulations for each treatment group separately.  The Anatomical Therapeutical 
Chemical (ATC) coding scheme of the World Health Organization (WHO) will be used to group 
medications into relevant categories for these tabulations.
15.8.
Safety Evaluation
All subjects who receive at least one dose of study drug 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.
AE frequency will be tabulated by body system, MedDRA preferred term for each treatment 
regimen during the Treatment Phase as well as for the Follow-up Phase when appropriate. In the 
by-patient 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.  In the case that the AEs or 
event frequencies are judged to be clinically important, an exact test may be used to analyze the 
difference between the treatment groups.
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, and 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.
15.9.
Interim Analyses
Adverse events will be summarized and assessed by the DMC first when at least 18 subjects 
have finished one treatment cycle. Then toxicity and progression will be assessed subsequently at 
13-week intervals. 
 
 
 
 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
84
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
 
The interim analyses will be performed by a third party statistician not affiliated with Celgene. 
15.10.
Sample Size and Power Considerations
The sample size will be approximately 105 subjects, 35 per arm, barring early stopping.  The 
original accrual rate was assumed to increase with time such that approximately 9-12 subjects 
will accrue in the first 3 months and a total of 41 to 55 subjects will accrue by 6 months with the 
remainder accruing by 60 weeks. Therefore, in addition to monitoring toxicity and progression, 
the accrual rate will be monitored.
 
15.11.
Other Topics
15.11.1.
Pharmacokinetics Analysis:
If the data are sufficient, noncompartmental PK parameters, such as Tmax, Cmax, AUC, CL/F, and 
t1/2, will be estimated.  Descriptive statistics will be provided for plasma concentrations and PK 
parameters.  Lenalidomide concentration data obtained from all visits may be used to develop the 
population PK model.  The relationship between pharmacokinetics and response (biomarkers or 
clinical outcomes as appropriate) will be explored.  Detailed methodology will be outlined in a 
separate PK data analysis plan and the results will be presented in a stand-alone PK report.
15.11.2.
Exploratory Analysis 
 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
85
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
16.
QUALITY CONTROL AND QUALITY ASSURANCE
16.1.
Monitoring 
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  Before the study is initiated at a site visit or at an investigator meeting, all aspects of 
the study are reviewed with the investigator(s) and the staff.  Prior to enrolling subjects into the 
study, a Celgene representative will review the protocol, eCRFs, 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, eCRFs, 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.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRF 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 eCRFs or via source data clarification forms 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.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  From time to time, representatives of this unit will conduct audits of 
clinical research activities in accordance with Celgene 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, eCRFs and applicable supporting records of subject participation for audits 
and inspections by IRB/IECs, regulatory authorities (e.g. FDA, EMA) and company authorized 
representatives.  The Investigator(s) should make every effort to be available for the audits 
and/or inspections.  If the Investigator(s) is contacted by any regulatory authority regarding an 
inspection, he/she should contact Celgene immediately.
16.3.
Investigator(s) Responsibilities
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice and in the 
US Code of Federal Regulations.  Celgene or a representative will contact and select all principal 
investigators or co-investigators who in turn will select their staff.  The investigator must give 
the monitor access to relevant records to confirm the above.  
The Investigator(s) is responsible for keeping a record of all 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 on the 
Screening Log provided by Celgene.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
86
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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 eCRFs supplied by Celgene.  The data on the 
eCRF 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 (e.g., medical records, office charts, hospital charts, and study related 
charts) for source data verification.  The eCRFs 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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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
87
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
17.
REGULATORY CONSIDERATIONS
17.1.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki (see Appendix 21.2).  The review of this protocol by the 
IRB/IEC and the performance of all aspects of the study, including the methods used for 
obtaining informed consent, must also be in accordance with principles enunciated in the 
declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 
50 Protection of Human Subjects and Part 56 Institutional Review Boards.  Before implementing 
this study, the protocol, the proposed informed consent form(s) 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.
17.2.
Protocol Amendments
Any amendment to this protocol that seems appropriate, as the study progresses (e.g. affects 
safety or efficacy) will be agreed upon between the coordinating and/or principal investigator(s) 
and the Celgene study physician.  Amendments will be submitted to the IRB/IEC for written 
approval before the implementation of the amended version.  The written signed approval from 
the IRB/IEC should refer specifically to the investigator(s) and to the protocol number and title 
and mention any amendment numbers that are applicable. Amendments that are administrative in 
nature do not require IRB/IEC approval but will be submitted to the IRB/IEC for information 
purposes.
17.3.
Informed Consent
The Investigator(s) must obtain informed consent of a subject or his/her designee prior to any 
study related procedures as per Good Clinical Practices (GCP) as set forth in 21 CFR Parts 50 
and 56 and ICH guidelines.
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Documentation that informed consent occurred prior to any study specified screening procedures 
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.  
17.4.
Subject Confidentiality
Celgene affirms the subject’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 
subject’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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Lenalidomide (CC-5013)
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Celgene Corporation
Confidential and Proprietary
89
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
18.
DATA HANDLING AND RECORDKEEPING
18.1.
Data/Documents
The investigator(s) must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is, copies of eCRFs and source documents, 
original documents, data, and records (e.g., hospital records; clinical and office charts; laboratory 
notes; memoranda; subject’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; subject files) and records kept at the pharmacy, at the laboratories, and at medico-technical 
departments involved in the clinical study are complete, accurate, and filed and retained.
18.2.
Data Management
Data will be entered into the clinical database per the guidelines established for the study.  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 staff.  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 appropriate SOP(s) for the study.
18.3.
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, monitor 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 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 (i.e., 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 pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
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Lenalidomide (CC-5013)
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Celgene Corporation
Confidential and Proprietary
90
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
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CC-5013-CLL-009 Amendment 6 Final 15Apr2015
19.
PREMATURE DISCONTINUATION OF THE STUDY
19.1.
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
19.2.
Study as a Whole
Celgene reserves the right to terminate this clinical study at any time for reasonable medical or 
administrative reasons.
Any possible premature discontinuation would have to be documented adequately with reasons 
being stated, and information would be issued according to local requirements (e.g., IRB/EC, 
regulatory authorities, etc.).
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20.
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Bartlett JB, Dredge K, Dalgleish A.  The evolution of thalidomide and its IMiD derivatives as 
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Bekele BN, Ji Y., Shen Y, Thall P.F. Monitoring late-onset toxicity in phase I trials using
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Bekele BN, Thall PF. Dose-finding based on multiple toxicities in a soft tissue sarcoma trial. 
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Bekele N, Ji Y.  Adaptive randomization for multi-arm comparative clinical trials based on joint 
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leukemia derived from a multivariate survival analysis.  Cancer.  1981; 48:198-204.
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Chanan-Khan A, Miller KC, DiMiceli L, et al. Results of Phase II study of Lenalidomide (L) 
{Revlimid®} in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood. 
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Chanan-Khan A, Miller KC, Musail L, et al. Clinical Efficacy of Lenalidomide in Patients With 
Relapsed or Refractory Chronic Lymphocytic Leukemia:  Results of a Phase II Study. J 
ClinOncol. 2006a;22(34): 5343-5349.
Chanan-Khan A, Musial L, Miller KC, et al.  Low-dose Prednisone Decreases the Severity but 
Not the Frequency of Lenalidomide Associated Tumor Flare Reaction (TFR) in Chronic 
Lymphocytic Leukemia (CLL) Patients. Blood.  2006b; Abstract 4987.
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arker expre
arker expre
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assificat
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Cancer.  
zed phase 2
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Cancer 
opiridol ad
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Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
93
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Chanan-Khan A, Miller KC, Whitworth A, et al.  Clinical activity of lenalidomide in relapsed or 
refractory chronic lymphocytic leukemia (CLL) patients:  updated results of a phase II clinical 
trial.  Leukemia and Lymphoma.  2007; 48(suppl 1):S166.
Chen C, Harminder P, Xu W, et al. A Phase II Study of Lenalidomide in Previously Untreated, 
Symptomatic Chronic Lymphocytic Leukemia (CLL). Blood (ASH Annual Meeting Abstracts),
2008; 112: 44
Cockcroft DW, Gault MH.  Prediction of creatinine clearance from serum creatinine.  Nephron 
1976; 16: 31-41.  
Corral LG, Haslett PAJ, Muller GW, et al. Differential cytokine modulation and T- cell 
activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-α. 
Journal of Immunology 1999; 163(1):380-6.
Corral LG, Muller GW, Moreira AL, Chen Y, Wu M, Stirling D, Kaplan G. Selection of novel 
analogs of thalidomide with enhanced tumor necrosis factor α inhibitory activity. Molecular 
Medicine 1996; 2(4): 506-15.
Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent chronic lymphocytic 
leukemia. French Co-operative Group on Chronic Lymphocytic Leukemia. New England 
Journal of Medicine 1998; 338 (21):1506.
Eichhorst B, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine 
alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006; 
107(3): 885-891.
Ferrajoli A, Lee BN, Schlette E, et al. Lenalidomide induces complete and partial responses in 
patients with relapsed and treatment-refractory chronic lymphocytic leukemia (CLL). Blood.  
2008; 111(11):5291-5297
Ferrajoli A, Keating M, Wierda W, et al.  Lenalidomide is active in patients with relapsed / 
refractory chronic lymphocytic leukemia (CLL) carrying unfavorable chromosomal 
abnormalities.  Blood.  2007;110(11).
Fiegl M, Falkner A, Hopfinger G, et al. Routine Clinical Use of Alemtuzumab in Patients with 
Heavily Pretreated B-Cell Chronic Lymphocytic Leukemia. Cancer. 2006; 107(10):2408-2416.
Galustian C, Labarthe MC, Bartlett BJ, Thalidomide-derived immunomodulatory drugs as 
therapeutic agents. Expert Opin. Biol. Ther. 2004;4(12): 1963-1970.
Ghai P, Circosta P, Scielzo C, et al.  In:  Caligaris-Cappio F, Dalla-Favera R, eds.  Chronic 
Lymphocytic Leukemia. Germany:  Springer-Verlag Berlin Heidelberg; 2005:135-145.
Hallek M, Cheson B, Catovsky D et al.  Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia:  a report from the International Workshop on Chronic Lymphocytic 
Leukemia (iwCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 
Guidelines; Blood; January 23, 2008; 111:5446-5456.
Hayashi T, Hideshima T, Akiyama M, Podar K, Yasui H, Raje N, Kumar S, Chauhan D, Treon 
SP, Richardson P, Anderson KC. Molecular mechanisms whereby immunomodulatory drugs 
activate natural killer cells: Clinical application. British Journal of Haematology 2005; 
128(2):192-203.
f TNF
TNF-α.α.
lect
ectioion of n
n o
vit
vity.y. Molec
ol
chroni
chronic lym
c lym
ukemia.
ukemia. N
cyclophosp
cyclophosp
nic lymphoc
c lymph
de induces
de induce
y chroni
chronic ly
c ly
l. .  Lenalido
Lenalid
emia (CLL)
mia (CL
11).
11).
er G, et al. 
er G, et al. 
Chronic Ly
hronic L
MC, Bartle
MC, Bartl
Expert Opi
Expert Opi
a P, Scielz
a P, Scie
c Leukemia
c Leukemi
M, Cheson 
M, Cheson
hocy
hocytiti
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e
eukemia (iw
ukemia (iw
Gui
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('06'RF1XPEHU
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Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
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CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, et al. Immunomodulatory drug CC-5013 or CC-
4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse 
lymphoma model. Clinical Cancer Research 2005; 11(16): 5984-92.
Hillmen P, Skotnicki A, Robak T, et al. Alemtuzumab Compared with Chlorambucil as First-
Line Therapy for Chronic Lymphocytic Leukemia. Journal of Clinical Oncology. 
2007;25(35):5616-5623.
Hoffbrand AV, Panayiotidis P, Reittie J, Ganeshaguru K Autocrine and paracrine growth loops
in chronic lymphocytic leukemia.  Semin Hematol. 1993;30(4):306-17.  PMID: 7505482 
[PubMed - indexed for MEDLINE].
Keating M, Flinn I, Jain V et al.  Therapeutic role of alemtuzumab (Campath-1H) in patients 
who failed fludarabine:  results of a large international study.  Blood 2002;19 (10):3554-3561.
Lapalombella R, Yu B, Triantafillou G, Liu Q, et al. Lenalidomide down-regulates the CD20 
antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on 
primary chronic lymphocytic leukemia cells. Blood. 2008; 112(13):5180-9.
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lymphoma.org/attachments/National/br_1215783647.pdf; The Leukemia and Lymphoma 
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1995; 6:219-235.
O’Brien SM, Kantarjian HM, Cortes J, et al.  Results of the Fludarabine and Cyclophosphamide 
combination Regimen in Chronic Lymphocytic Leukemia.  J ClinOncol.  2001;19(5): 1414-
1420.
Osterborg A, Dyer M, Bunjes D, et al. Phase II Multicenter Study of Human CD52 Antibody in 
Previously Treated Chronic Lymphocytic Leukemia. Journal of Clinical Oncology. 1997; 15(4): 
1567-1574.
Rai KR.  A critical analysis of staging in CLL.  In:  Gale RP, Rai KR, eds. Chronic Lymphocytic 
Leukemia:  Recent Progress and Future Directions.  New York:  Alan R. Liss.; 1987:253-264.
Rai K, Peterson BL, Applebaum FR, et al. Fludarabine compared with chlorambucil as primary 
therapy for chronic lymphocytic leukemia. N Engl J Med. 2000; 343 (24):1750-1757.
Ramsay AG, Johnson AJ, Lee AM, Gorgün et a.  Chronic lymphocytic leukemia T cells show 
impaired immunological synapse formation that can be reversed with an immunomodulating 
drug. Journal of Clinical Investigation 2008;118(7):2427-37.
Smith TJ, Khatcheressian J, Lyman GH, et al..  2006 update of recommendations for the use of 
white blood cell growth factors: an evidence-based clinical practice guideline. Journal Clinical 
Oncology 2006;24(19):3187-205.
Tam C, O’Brien S, Lerner S, et al., The natural history of fludarabine-refractory chronic 
lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy.  
Leukemia & Lymphoma. 2007; 48(10):  1931 – 1939.
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('06'RF1XPEHU
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Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
95
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Thomas D, O’Brien S, Kantarjian H et al.  Outcome in 203 patients (pts) with relapsed or 
refractory B-cell chronic lymphocytic leukemia (CLL) with salvage therapy (RX):  retreatment 
with fludarabine (FLU).  ASH 1998; Abstract 419.
Tohnya TM, Sylvia SW, Dahut WL, et al. A Phase I Study of Oral CC-5013 (Lenalidomide, 
Revlimid™), a Thalidomide Derivative, in Patients with Refractory Metastatic Cancer. Clinical 
Prostate Cancer. 2004; 2(4): 241-243.
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Wendtner C, Mahadevan D, Stilgenbauer S, et al.  Final Results of the Phase I Study of 
Lenalidomide In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL-001 
Study). Blood (ASH Annual Meeting Abstracts), 2010; Abstract 1376.
Wierda W, O’Brien S, Wen S, et al. Chemoimmunotherapy With Fludarabine, 
Cyclophosphamide, and Rituximab for Relapsed and Refractory Chronic Lymphocytic 
Leukemia. J ClinOncol. 2005;23(18): 4070-4078.
Wu L, Adams M, Carter T, et al. Lenalidomide enhances natural killer cell and monocyte-
mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. 
Clinical Cancer Research 2008;14(14):4650-7.
Yang H, Rosove MH, Figlin RA.  Tumor lysis syndrome occurring after the administration of 
rituximab in lymphoproliferative disorders:  high-grade non-Hodgkin’s lymphoma and chronic 
lymphocytic leukemia.  American journal of hematology. 1999 Dec;62(4):247-50.
CLL
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Celgene Corporation
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21.
APPENDICES
21.1.
Adverse Event
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence occurring at 
any dose that may appear or worsen in a 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 the signing of informed 
consent 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 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 signing of informed consent to the 
treatment discontinuation visit.  All AEs that lead to study discontinuation should be followed 
until resolution or stabilization. For subjects who discontinue study treatment but continue to be 
followed every 28 days until PD or new CLL therapy, AEs will be reported until 30 days post 
last dose of study drug or until study discontinuation, whichever occurs last.  SAEs will be 
reported from time informed consent form is signed to 30 days post last dose of study drug.  
SAEs will be reported at any time post last dose of study drug if it is considered related to study 
drug.  AEs will be recorded on the AE page of the eCRF 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 eCRF. If the abnormality was not a part 
of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE.
Serious adverse event
A serious adverse event (SAE) is any AE which:
!
Results in death
!
Is life-threatening (i.e., in the opinion of the Investigator(s) the 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)
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
97
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
!
Is a congenital anomaly/birth defect
!
Constitutes an important medical event
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events.  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 80% of the subjects have progressed or died
or up to five years after the last subject was randomized, whichever occurs later.  Events of 
second primary malignancy are to be reported using the SAE report form and must be considered 
an “Important Medical Event” even if no other serious criteria apply; these events must also be 
documented in the appropriate page(s) of the CRF and subject's source documents.  
Documentation of the diagnosis of the second primary malignancy must be provided at the time 
of reporting as a serious adverse event (e.g., any confirmatory histology or cytology results).   
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 eCRF 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 of hematological toxicities and TLS.  Hematological toxicities will be graded as 
specified in the iwCLL guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia (Hallek, 2008) (Appendix 21.4).  TLS will be graded as specified by the Cairo-Bishop 
grading system (Appendix 21.3).  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
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
98
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Grade 5 = Death
Classification of Relationship/Causality of adverse events (SAE/AE) to study drug
The Investigator(s) must determine the relationship between the administration of study drug and 
the occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
The temporal relationship of the adverse event to study drug 
administration makes a causal relationship unlikely or 
remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the 
observed event
Suspected:
The temporal relationship of the adverse event to study drug 
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions 
do not provide a sufficient explanation for the observed event.
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 an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE pages of the eCRF.  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 last dose of study drug, 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 80% of the subjects have progressed or died
or up to five years after the last subject was randomized, whichever occurs later.  Events of 
second primary malignancy are to be reported using the SAE report form and must be considered 
an “Important Medical Event” even if no other serious criteria apply; these events must also be 
documented in the appropriate page(s) of the CRF and subject's source documents.  
Documentation of the diagnosis of the second primary malignancy must be provided at the time 
of reporting as a serious adverse event (e.g., any confirmatory histology or cytology results).   
The SAE must be reported immediately (i.e., within 24 hours of the Investigators’ knowledge of 
the event) to the Celgene Safety Monitor by telephone and facsimile.  A phone call is to be made 
to the Safety Monitor and an initial written report (prepared by the Investigator(s) using the SAE 
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
99
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Report Form provided by Celgene) is to be faxed to the Safety Monitor (see below for contact 
information).
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 30 days of the subject’s last dose of study drug, 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 phone and 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 the Celgene Safety Monitor 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 an SAE (i.e., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly [including that in an aborted 
fetus]), the Investigator(s) should follow the procedures for reporting SAEs (i.e., report the event 
to the Celgene Safety Monitor by telephone and 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 the Celgene Safety 
Monitor by telephone and 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.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
100
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to lenalidomide based on the Investigator Brochure.
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 studies on medicinal products for human use (ENTR/CT3) and also in accordance with 
country-specific requirements.
Celgene shall notify the Investigator of the following information:
Any AE associated with the use of study drug in this study or in other studies that is both serious 
and unexpected, i.e., suspected unexpected serious adverse reaction (SUSAR). Note that such 
cases from blinded studies will be unblinded for reporting purposes.
Any finding from tests in laboratory animals 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.
Celgene safety contact information
For Local Drug Safety Affiliate Office contact information, please refer to the Serious Adverse 
Event Report Form / Completion Guidelines or to the Pregnancy Report Form / Completion 
Guidelines.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
101
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.2.
Declaration of Helsinki
The Declaration of Helsinki can be found at: http://www.wma.net/e/policy/b3.htm
&(/*(1(35235,(7$5<,1)250$7,21


('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
102
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.3.
Cairo-Bishop Definition and Grading of Tumor Lysis Syndrome 
(Cairo, 2004)
Cairo-Bishop Definition of Laboratory Tumor Lysis Syndrome (LTLS)
Uric Acid
≥ 476 μmol/l (≥ 8.0 mg/dl) or 25% increase from baseline
Potassium
≥ 6.0 mmol/l (≥ 6.0 mEq/l) or 25% increase from baseline
Phosphorous
≥1.45 mmol/l  (≥ 4.5 mg/dl) or 25 % increase from baseline
Calcium
≤ 1.75 mmol/l (≤ 7.0 mg/dl) or 25% decrease from baseline
Laboratory tumor lysis syndrome (LTLS) is defined as either a 25% change or level above or below normal, as 
defined above, for any two or more serum values of uric acid, potassium, phosphate, and calcium within 3 days 
before or 7 days after the initiation of chemotherapy.  This assessment assumes that a patient has or will receive 
adequate hydration (± alkalinization) and a hypouricaemic agent(s).
Cairo-Bishop Definition of Clinical TLS
The presence of laboratory TLS and one or more of the following criteria:
1.
Creatinine:  ≥ 1.5 ULN (age > 12 years or age adjusted)
2.
Cardiac arrhythmia / sudden death
3.
Seizure*
ULN, Upper limit of normal
*Not directly attributable to a therapeutic agent
Cairo-Bishop Grading System for TLS
Grade
LTLS
Creatinine
Cardiac Arrythmia
Seizure
0
-
≤ 1.5 x ULN
None
None
1
+
1.5 x ULN
Intervention not 
indicated
None
2
+
> 1.5 – 3.0 x ULN
Non-urgent medical 
intervention indicated
One brief generalized seizure; seizure(s) 
well controlled or infrequent; focal motor 
seizures not interfering with ADL
3
+
> 3.0 – 6.0 x ULN
Symptomatic and 
incompletely controlled 
medically or controlled 
with device
Seizure in which consciousness is altered; 
poorly controlled seizure disorder; 
breakthrough generalized seizures despite 
medical intervention
4
+
> 6.0 x ULN
Life-Threatening
Seizures of any kind that are prolonged, 
repetitive, or difficult to control
5
+
Death*
Death*
Death*
LTLS, laboratory tumor lysis syndrome; ULN, upper limit of normal; ADL, activities of daily living
*Probably or definitely attributable to clinical TLS
5
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
103
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.4.
Grading of Hematological Toxicity (Hallek, 2008)
Gradea
Decrease in Plateletsb or Hbc (nadir) 
From Pretreatment value (%)
Absolute neutrophil count/μLd (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
a.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.
b.
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 (e.g., 20,000/μL) was present pretreatment, in which case the patient is not evaluable for toxicity 
referable to platelet counts.
c.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.
d.
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.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
104
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.5.
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, e.g., light housework, 
office work.
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair
5
Dead
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
105
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.6.
Clinical Staging of CLL Patients
21.6.1.
Rai staging system (modified) (Rai, 1987)
Low-risk disease
Lymphocytosis with leukemia cells in the blood and/or marrow 
(lymphoid cells > 30%)
Intermediate risk disease
Lymphocytosis, enlarged nodes in any site, and splenomegaly 
and/or hepatomegaly (lymph nodes being palpable or not)
High risk disease
Disease-related anemia (as defined by hemoglobin level less 
than 11 g/dl or thrombocytopenia (as defined by platelet count 
of less than 100 x 109 / L)
21.6.2.
Binet staging system (Binet, 1981)
Staging is based on the number of involved areas, as defined by the presence of enlarged lymph 
nodes of > 1 cm in diameter or organomegaly, and on whether there is anemia or 
thrombocytopenia.
Area of involvement considered for staging:
1. Head and neck, including the Waldeyer ring (this counts as one area, even if more than 
one group of nodes is enlarged)
2. Axillae (involvement of both axillae counts as one area)
3. Groins, including superficial femorals (involvement of both groins counts as one area)
4. Palpable spleen 
5. Palpable liver (clinically enlarged)
Stage A
Hemoglobin ≥ 10 g/dL and platelets ≥ 100 x 109/L and up to two of the 
above areas involved
Stage B
Hemoglobin ≥ 10 g/dL and platelets ≥ 100 x 109/L and organomegaly 
greater than that defined for stage A (i.e. three or more areas of nodal or 
organ enlargement)
Stage C
Hemoglobin < 10 g/dL and/or platelet count < 100 x 109/L, irrespective of 
organomegaly
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
106
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.7.
FACT-Leu Questionnaire
50$7,21


('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
107
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
50$7,21


('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
108
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
&(/*(1(35235,(7$5<,1)250$7,21


('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
109
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.8.
EQ-5D Health Questionnaire
Health Questionnaire
(English version for the UK)
(validated for use in Eire)
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UK)
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
110
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
111
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.9.
Pregnancy Prevention Risk Minimization Plans
21.9.1.
Lenalidomide Pregnancy Prevention Risk Management Plan
21.9.1.1.
Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials 
Section 21.9.1 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 21.9.1.2); 
2. Lenalidomide Education and Counseling Guidance Document (Section 21.9.1.3); 
3. Lenalidomide Information Sheet (Section 21.9.1.4).
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable 
Birth Control Methods document (Section 21.9.1.2) 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 21.9.1.3) 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 21.9.1.4) 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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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
112
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.9.1.2.
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 (i.e., 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 (i.e., 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 21.9.1.2).
!
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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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
113
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the 
following are met (i.e., 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 (i.e., 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 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 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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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
114
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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 10-14 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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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
115
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
116
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.9.1.3.
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 (i.e., 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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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
117
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
!
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:
! Intrauterine device (IUD)
! Hormonal (birth control pills, injections, implants)
! Tubal ligation
! Partner’s vasectomy
#
Additional effective methods:
! Male condom
! Diaphragm
! 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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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
118
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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 risk 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 risk 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 lenalidomide 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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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
119
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
21.9.1.4.
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 contract 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
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
120
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
! Do not breastfeed while taking lenalidomide
! 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 child bearing 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 who 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  
o
Male patients should not donate sperm or semen while taking study 
drug and for 28 days after stopping study drug.
o
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.
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('06'RF1XPEHU
Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
121
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
122
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
123
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
124
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
 
 
 
 
 
 
 
  
 
 
  
 
 
 
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
125
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Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
126
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Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
127
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
128
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
129
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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Lenalidomide (CC-5013)
Protocol CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
130
CC-5013-CLL-009 Amendment 6 Final 15Apr2015
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
3
CC-5013-CLL-009 Amendment 6 Final 15 Apr 2015
1.
JUSTIFICATION FOR AMENDMENT
The CC-5013-CLL-009 protocol has been ongoing since 2009.  The intent of the protocol 
amendment is to facilitate the ongoing conduct for the patients that remain on study drug.
The key change in this protocol amendment is to change the study drug packaging from blister 
cards with matching placebo capsules to bottles.  This will reduce the number of capsules
patients are required to take each day.
The amendment further clarifies that patients currently on study drug may remain on study drug, 
beyond the 80% event milestone, until final completion of the study at which time they may 
transition to non-study lenalidomide.  The transition will be at the discretion of the site primary 
investigator and any local regulations.
Significant changes included in this protocol amendment #6 are summarized below:
!
IVRS will be discontinued for this protocol.  Sites will order study drug when needed 
through Celgene investigational drug dispensing program.  This will permit sites to order 
study drug only when needed rather than maintain a stock of study drug for the IVRS to 
allocate.  The change is possible at this time since few patients remain on study drug and 
the study drug is no longer blinded.  
!
Removed the 1.25-mg dose level and applied corresponding changes in the Dose 
Reduction Steps for Lenalidomide (Table 6) as no patients utilize this dose level.
!
As all subjects are beyond the risk for TLS, Celgene will no longer provide allopurinol 
supply for site outside of North America.
!
Remove lymph node biopsy and fine needle aspirate assessments as no patients consented 
for these additional tests.
!
Remove additional PK sample collection.  PK samples were drawn at study day 1 and at 
dose escalation.  Since the last patient randomized was 2012, further dose escalations are 
not anticipated and hence no further PK samples.  This will permit the final analysis and 
reporting of this exploratory endpoint at this time.
!
Remove the requirement to submit blood samples (hematology, chemistry, thyroid 
hormone, 
 MRD), urine (urinalysis) and bone marrow 
(biopsy and aspirate) samples to central lab for analysis.  Local labs will continue to be 
collected in this protocol.  The purpose of this change is to simplify the protocol 
procedures in effort to reduce the workload for the site personnel.
!
  Tumor flare 
events are anticipated at the start of study drug administration.  Since the last patient 
randomized was 2012, additional events of tumor flare are not anticipated.  The purpose 
of this change is to simplify the protocol procedures in effort to reduce the workload for 
the site personnel.
!
Remove the text for blinding and emergency unblinding activities as the protocol is 
unblinded.
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-CLL-009
Celgene Corporation
Confidential and Proprietary
4
CC-5013-CLL-009 Amendment 6 Final 15 Apr 2015
!
Change of Medical Monitor
!
Changes for grammar and topographical errors
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-CLL-009
          Celgene Corporation
Confidential and Proprietary                                            3       CC-5013-CLL-009 Amendment 5.0 Final 9Nov2011
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Increased the sample size and required that following the enrollment of 90 
subjects, participation in the PK sub-study will be mandatory.  
At least 6 subjects per treatment arm are needed to provide evaluable PK data.  At the 
time of this amendment, a sufficient number of patients have not been enrolled into the 
PK sub-study.  The protocol sample size will be increased to collect additional PK 
subject samples.  Enrollment will be extended to only those subjects who agree to 
participate in the PK sub-study. 
!
Clarify that the second primary malignancy assessment should be completed during 
the progression free survival follow up phase and the survival phase
Clarified that the assessment for second primary malignancy should be completed during 
the 28-day follow up visits for all patients that discontinue the treatment phase for 
reasons other than progression of disease or withdraw of consent.  
Additionally, the assessment for second primary malignancy should be completed for all 
subjects in the survival phase regardless of the reason for study discontinuation.  These 
assessments were already included in Amendment 4 (but not specified in each sentence 
that mentioned the respective follow up).  
!
Clarify the schedule for the baseline bone marrow biopsy and aspirate 
The bone marrow biopsy and aspirate may be completed either during the screening 
phase or may be completed once the patient has been confirmed as eligible and entered 
into the study.  The bone marrow biopsy and aspirate procedures are an invasive 
procedure.  The results are not specifically part of the inclusion exclusion criteria.  This 
change is being implemented to avoid unnecessary sampling for a subject who may 
eventually fail screening and not enter the study.  
!
Expanded exclusion criteria surrounding history of prior malignancies from 2
years to 5 years.
Recent multivariate analyses conducted by Celgene have demonstrated that patients with 
a history of prior invasive malignancies are at risk for developing another malignancy 
during lenalidomide-containing therapy.  As a result, various Health Authorities have 
requested that Celgene amend protocols to exclude patients who have a history of 
malignancies within the 5 years prior to starting the trial.  
!
Update study contact information
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-CLL-009
          Celgene Corporation
Confidential and Proprietary                                            4       CC-5013-CLL-009 Amendment 5.0 Final 9Nov2011
Contact information was updated to reflect the new Clinical Research Physician and 
Study Manager.
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