Conditions: Leukemia, Myeloid
Keywords: Lenalidomide Revlimid Pediatric Relapsed or Refractory Acute Myeloid Leukemia Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
To determine the activity of lenalidomide in the treatment of pediatric subjects with relapsed/refractory acute myeloid leukemia (AML) (with second or greater relapse or refractory to at least 2 prior induction attempts) measured by morphological complete response defined as either a CR or CRi within the first 4 cycles of treatment.

Detailed description:
This is a multicenter, open-label, single-arm, Phase 2, Simon's Optimal two-stage design study, with an Optional Extension Phase (OEP), that will assess the activity, safety and pharmacokinetics (PK) of lenalidomide in pediatric subjects from 1 to ≤ 18 years of age with second or greater Relapsed or Refractory Acute Myeloid Leukemia (rrAML). A total of 43 evaluable participants (18 participants in Stage 1 and an additional 25 participants in Stage 2) are required for assessment of the primary endpoint. To allow for participants found to be unevaluable for the primary endpoint due to an incorrect diagnosis, not having a disease assessment post screening, or who discontinued prior to receiving lenalidomide, up to 4 additional participants may be enrolled for a maximum of 47 evaluable subjects across approximately 70 sites. Approximately 50% of enrolled participants will be younger than 12 years of age to provide adequate PK data for this age subset.

If during Stage 1, at least 3 of 18 participants achieve a morphologic complete response (either CR or CRi) within the first 4 cycles of study treatment, then the study will proceed to Stage 2; otherwise, the study will be terminated. Similarly, if at the final analysis, at least 8 of 43 evaluable subjects across Stages 1 and 2 achieve a response (CR/CRi) within the first 4 cycles of study treatment, it will be concluded that lenalidomide has sufficient activity in pediatric Acute Myeloid Leukemia (AML) to warrant subsequent study. The optional extension phase (OEP) will allow participants who demonstrate clinical benefit, as assessed by the Investigator at the completion of 12 cycles of lenalidomide therapy, to continue receiving oral lenalidomide until they meet the criteria for study discontinuation. In the OEP, only safety, dosing, concomitant medications/procedures, and second primary malignancies (SPMs) will be monitored.

Arms:
arm 1: Lenalidomide API will administered at a starting dose of 2 mg/kg/day. Lenalidomide will be provided as either a capsule (2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg) or as an oral suspension (10mg/mL).

Interventions: intervention 1: Lenalidomide
Intervention descriptions: intervention 1: Lenalidomide will be administered orally once daily for the first 21 days of every 28-day cycle. The starting dose will be 2 mg/kg/day with a maximum dose of 70 mg/day. Number of cycles: 12, or until evidence of progressive disease. Participants will also be discontinued if unresolved toxicities as described in the protocol occur, or if dose reductions are required and subject does not tolerate minimum dose level of 1mg/kg/day.

Protocol document:
Prot_000.pdf: 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
1
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
TITLE PAGE
A PHASE 2, MULTICENTER, SINGLE-ARM, OPEN-
LABEL STUDY TO EVALUATE THE ACTIVITY,
SAFETY AND PHARMACOKINETICS OF 
LENALIDOMIDE (REVLIMID®) IN PEDIATRIC
SUBJECTS FROM 1 TO ≤ 18 YEARS OF AGE WITH
RELAPSED OR REFRACTORY ACUTE MYELOID
LEUKEMIA
PROTOCOL NUMBER:
CC-5013-AML-002
ORIGINAL DATE FINAL:
28 Apr 2015
AMENDMENT No. 1.0 DATE FINAL:
01 Jun 2016
AMENDMENT No. 2.0 DATE FINAL:
13 Dec 2016
EudraCT NUMBER:
NA
IND NUMBER:
060100
SPONSOR NAME/ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
2
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
MEDICAL MONITOR/EMERGENCY CONTACT INFORMATION
Contact Information:
Name:           
Title:            
Address:     86 Morris Avenue, Summit, NJ 07901
Phone:
    
E-mail:
     
Contact Information:
Name:
Title:
Address:
86 Morris Avenue 
Summit, NJ 07901
Phone:
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls
Back-up 24-Hour Global Emergency Contact Call Center: 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
3
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
4
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, International Conference on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
5
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
6
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
PROTOCOL SUMMARY
Study Title
A Phase 2, Multicenter, Single-arm, Open-label Study to Evaluate the Activity, Safety and 
Pharmacokinetics of Lenalidomide (REVLIMID®) in Pediatric Subjects from 1 to ≤ 18 Years of 
Age with Relapsed or Refractory Acute Myeloid Leukemia.
Indication: Treatment of pediatric subjects (from 1 to ≤ 18 years of age) with second or greater 
relapse or refractory acute myeloid leukemia (rrAML).
Objectives
Primary
!
To determine the activity of lenalidomide in the treatment of pediatric subjects with 
relapsed/refractory acute myeloid leukemia (AML) (with second or greater relapse or 
refractory to at least 2 prior induction attempts) measured by morphological complete 
response defined as either a complete response (CR) or complete remission with 
incomplete blood count recovery (CRi) within the first 4 cycles of treatment.
Secondary
!
To evaluate subject demographics and leukemic blast characteristics and their 
correlation with response to lenalidomide.
!
To further evaluate lenalidomide activity with regards to response assessment 
outcome rates, transplantation rate, duration of response (DoR) and durable response 
rate.
!
To evaluate the safety of lenalidomide including rates of graft-versus-host disease 
(GVHD) flare and reactivation.
!
To determine the pharmacokinetics (PK) of lenalidomide in plasma.
 
 
 
Study Design
This is a multicenter, open-label, single-arm, Phase 2, Simon’s Optimal two-stage design study, 
with an Optional Extension Phase (OEP), that will assess the activity, safety and PK of 
lenalidomide in pediatric subjects from 1 to ≤ 18 years of age with second or greater rrAML. A 
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EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
7
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
total of 43 evaluable subjects (18 subjects in Stage 1 and an additional 25 subjects in Stage 2) are 
required for assessment of the primary endpoint.  To allow for subjects found to be unevaluable
for the primary endpoint due to an incorrect diagnosis, not having a disease assessment post 
screening, or who discontinued prior to receiving lenalidomide, up to 4 additional subjects may 
be enrolled for a maximum of 47 evaluable subjects across approximately 70 sites.  
Approximately 50% of enrolled subjects will be younger than 12 years of age to provide 
adequate PK data for this age subset.
If during Stage 1, at least 3 of 18 subjects achieve a morphologic complete response (either CR 
or CRi) within the first 4 cycles of study treatment, then the study will proceed to Stage 2; 
otherwise, the study will be terminated.  Similarly, if at the final analysis, at least 8 of 43 
evaluable subjects across Stages 1 and 2 achieve a response (CR/CRi) within the first 4 cycles of 
study treatment, it will be concluded that lenalidomide has sufficient activity in pediatric AML to 
warrant subsequent study.
Morphological response will be assessed using the modified AML International Working Group 
(IWG) criteria (Cheson, 2003) (Appendix D).
The Optional Extension Phase will allow subjects who demonstrate clinical benefit, as assessed 
by the Investigator at the completion of 12 cycles of lenalidomide therapy, to continue receiving 
oral lenalidomide until they meet the criteria for study discontinuation.  In the OEP, only safety, 
dosing, concomitant medications/procedures, and second primary malignancies (SPMs) will be 
monitored (Table 2).
An external data monitoring committee (DMC) will evaluate safety and treatment activity data in 
an ongoing, periodic manner to assess benefit-to-risk considerations throughout the study. The 
function of the DMC is to monitor the safety and activity of the study treatment. Once 4 subjects 
having received at least one dose of lenalidomide have completed at least 1 cycle of study 
treatment or discontinued treatment (whichever occurs first), the DMC will evaluate the safety 
data available and provide a recommendation. The DMC will also provide recommendations 
about the continuation of the study from Stage 1 to Stage 2 (continue as planned, continue with 
modifications or stop treatment and/or enrollment) and advise on ways to improve quality.
The study will consist of 3 phases: Screening Phase, Treatment Phase and Follow-up Phase.
The study will be conducted in compliance with International Conference on Harmonisation 
(ICH) Good Clinical Practices (GCPs). 
Screening Phase
The Screening Phase will start from the time of signing the informed consent form 
(ICF)/informed assent form (IAF) and will last no more than 14 days, at which time the 
Treatment Phase will begin (Cycle 1 Day 1).  Subject’s screening procedures are to occur during 
the Screening Phase within 14 days prior to dosing on Cycle 1 Day 1.
As part of the screening procedures, a fresh bone marrow aspirate (BMA) and/or a bone marrow 
biopsy paraffin embedded slide will be collected from all subjects for confirmation of disease.  
The confirmation of disease will be performed locally. 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
8
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
A standard cytogenetic metaphase preparation from the fresh BMA must be prepared for the 
cytogenetic testing/chromosome analysis including karyotype.  The local site will submit the 
reports of the karyotype, fluorescent in situ hybridization (FISH) studies, as well as any available 
data on molecular mutations (FLT3, CEPBa, NPM1, and others including exome sequencing via 
Foundation Medicine or other sources) if performed, to the central reviewer at the 
 
.  If subjects have a FISH detectable marker, the test should be repeated 
until CR/CRi and at relapse.
The BMA slide (and/or bone marrow biopsy paraffin embedded slide) and peripheral blood 
smear from screening must be provided to the central reviewers at 
.  The central review 
 will provide standardized analysis and reporting for all subjects.  The central reviewer’s 
assessment will be used retrospectively to confirm diagnosis.
Creatinine clearance (CLcr) will be measured at screening using Table 4 (see Section 7.2).
Treatment Phase
The lenalidomide dose will be calculated based on body weight.  The starting dose will be 2 
mg/kg/day with a maximum dose of 70 mg/day.  Subjects enrolled in the study will receive 
lenalidomide for the first 21 days of each 28-day treatment cycle for up to a maximum of 12 
cycles of study treatment.  After the completion of 12 cycles of study treatment, subjects who 
demonstrate clinical benefit as per the Investigator may continue to receive lenalidomide in an 
OEP (Appendix L) until they meet the criteria for study discontinuation.
In the event of a specific protocol-defined toxicity, no more than 2 dose reductions will be 
allowed to doses of 1.4 mg/kg/day (not exceeding 50 mg/day) and 1 mg/kg/day (not exceeding 
35 mg/day).  The dose will not be re-escalated once it has been reduced (Table 6).  Subjects who 
do not tolerate the minimum dose level of 1 mg/kg/day (not exceeding 35 mg/day) will be 
discontinued from the study.  For additional details regarding dose reductions and dose capping 
see Section 8.2.1.
During the Treatment Phase, subjects will be assessed for treatment activity based on modified 
IWG AML Response Criteria (Appendix D).  To determine morphologic CR/CRi, BMA/biopsy
and peripheral blood smear must be collected from all subjects at the completion of the 21-day 
treatment period of the predefined treatment Cycles 1, 2, 3 and 4 within 6 days before dosing 
for each subsequent cycle (ie, between Day 22 to Day 27 of that cycle) (Table 2).  If 
morphologic CR/CRi is achieved within the first 2 cycles, BMA/biopsy and peripheral blood 
smear will not be required at the end of Cycle 3.  For all subjects, BMA/biopsy and peripheral 
blood smear must be performed at the completion of Cycle 4, and at the Treatment 
Discontinuation Visit or at the time of suspected relapse (whichever occurs first). For subjects 
who are assessed as having partial response, the BMA/biopsy and peripheral blood smear will be 
repeated at Cycle 8 unless the subject goes to allogeneic hematopoietic stem cell transplantation 
(HSCT), and at the Treatment Discontinuation Visit or at the time of suspected treatment failure 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
9
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
(whichever occurs first). A bone marrow biopsy is required only if a bone marrow aspirate 
cannot be obtained. Subjects demonstrating clinical benefit as per the Investigator at the end of 
Cycle 4 and beyond may continue to receive lenalidomide on study for up to 12 cycles in the 
absence of protocol-defined toxicity or transitioning to allogeneic HSCT.
During the study, repeat of local testing of bone marrow cytogenetics and FISH for any positive 
markers is to be completed whenever a BMA/biopsy is obtained.  However, if the 
cytogenetics/FISH results are ‘normal’ at screening or at any point during the study, cytogenetic 
analysis is not required to be repeated except at the Treatment Discontinuation Visit or at the 
time of bone marrow evaluation for suspected relapse (whichever occurs first).
 
 
 
  
 
In order to establish lenalidomide plasma PK parameters in subjects with rrAML, blood samples 
will be collected at specified time points (Table 3) for up to 24 hours postdose from all enrolled 
subjects during Cycle 1 Day 1 (Appendix H).
  
 
Dose interruptions, delays and modifications may be required to manage adverse events (AEs) 
during study treatment (see Section 8.2.1 for details).  In order to optimally benefit from 
protocol-prescribed therapy, the Investigator should aim to treat subjects for at least 4 cycles
with lenalidomide.  Subjects demonstrating clinical benefit as per the Investigator at the end of 
Cycle 4 and beyond may continue to receive lenalidomide on study up to 12 cycles in the 
absence of protocol-defined toxicity or transitioning to allogeneic HSCT.  Subjects may be 
treated beyond 12 cycles of study treatment in the OEP if they continue to benefit and have not 
undergone HSCT.
Subjects may be discontinued from the treatment at the Investigator’s discretion for any of the 
reasons as detailed in Section 12.  All discontinued subjects, regardless of reason for 
discontinuation, should undergo treatment discontinuation procedures at the time of 
investigational product (IP) discontinuation (Table 2).  The reason for discontinuation will be 
recorded in the electronic case report form (CRF) and in the source document.
Follow-up Phase
Subjects will enter the Follow-up Phase at the time of permanent discontinuation of IP and will 
be followed for up to 5 years from the last subject’s first dose, unless the subject dies, withdraws 
consent or is lost to follow-up. The Follow-up Phase may not be terminated because of new 
anticancer treatment or HSCT.
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EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
10
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
The 28-day Follow-up Visit will occur 28 days after the subject’s last dose of IP.  At this visit, 
subjects will be monitored for the collection of AEs and concomitant medications/procedures 
used to treat the AEs.  Female Children of Childbearing Potential (FCCBP) and Females of 
Childbearing Potential (FCBP) will have a pregnancy test at the 28-day Follow-up Visit (see 
Section 6.8 and Section 7.2).
After the 28-day Follow-up Visit, subjects will be followed up by phone or clinic visit, 
whichever is the institution’s normal standard of care, every 3 months for a maximum of 5 years 
from the last subject’s first dose, regardless of new anticancer treatment or HSCT, for SPMs, 
safety issues (any drug-related SAEs), 
 start of new anticancer 
therapies, and transition to HSCT.
Optional Extension Phase
Upon completion of 12 cycles of lenalidomide therapy per protocol, subjects who are 
demonstrating clinical benefit as assessed by the Investigator and who do not meet any of the 
criteria for treatment discontinuation (see Section 12) may enter the optional extension phase.
Details for the OEP are provided in Appendix L.
Study Population
The study population consists of pediatric subjects with rrAML from 1 to ≤ 18 years of age at the 
time of screening with at least 2 prior induction therapy attempts.  Approximately 50% of 
subjects should be younger than 12 years of age to provide adequate PK data for this age subset.
Length of Study
Enrollment is expected to last approximately 40 months with an accrual rate of 1 to 2 subjects 
per month.  Once 4 subjects having received at least one dose of lenalidomide have completed at 
least 1 cycle of study treatment or discontinued treatment (whichever occurs first), the DMC will 
evaluate the safety data available and provide a recommendation. At the end of Stage 1 and 
following safety and treatment activity data review, the DMC will provide recommendations 
about the continuation of the study from Stage 1 to Stage 2 (continue as planned, continue with 
modifications or stop treatment and/or enrollment) and advise on ways to improve quality.  
Subjects demonstrating clinical benefit as per the Investigator at the end of Cycle 4 and beyond 
may continue to receive lenalidomide on study up to 12 cycles in the absence of protocol-defined 
toxicity or transitioning to allogeneic HSCT. Once lenalidomide has been discontinued, subjects 
will be followed up to 5 years from the last subject’s first dose, unless consent is withdrawn, the 
subject is lost to follow-up or dies.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary 
 analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatment
Lenalidomide will be administered either in capsules containing 2.5 mg, 5 mg, 10 mg, 15 mg, 20 
mg or 25 mg or as an oral suspension (10 mg/mL). The oral suspension is available for use in 
subjects who are unable to swallow the capsules or at the discretion of the investigator.  The 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
11
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
starting dose of lenalidomide will be 2 mg/kg/day with a maximum dose of 70 mg/day. 
Lenalidomide will be administered orally once daily for the first 21 days of every 28-day cycle.  
Daily dosage should be administered using the combinations that yield the least amount of 
capsules.  However, if a subject is unable to swallow big capsules, varying, appropriate strength 
combinations may be considered during medication assignment using the interactive web 
response system (IWRS).  The prescribed dose should be the closest dose that can be given to the 
calculated dose based on the strengths of lenalidomide available.  For dose reductions, the dose 
calculated should be to the nearest whole number.  For a dosing table with guidelines reflecting 
this approach for the lenalidomide capsules, refer to Appendix B.
Refer to Appendix C for dosing guidelines for the lenalidomide oral suspension. 
Overview of Treatment Activity Assessments
The primary endpoint consists of the assessment of the morphologic complete response, defined 
as CR or CRi, within the first 4 cycles of study treatment with lenalidomide.  These responses 
will be determined using the modified IWG AML response criteria (Cheson, 2003) (Appendix 
D).
The morphological complete response rate is defined as the sum of the number of subjects with 
morphological complete response observed during the first 4 cycles of study treatment divided 
by the total number of subjects evaluable for the primary endpoint analysis.
During the Treatment Phase, subjects will be assessed for treatment activity based on IWG AML 
Response Criteria (Appendix D).  To determine morphologic CR/CRi, BMA/biopsy and 
peripheral blood smear must be collected from all subjects at the completion of the 21-day 
treatment period of the predefined treatment Cycles 1, 2, 3 and 4 within 6 days before dosing 
for each subsequent cycle (ie, between Day 22 to Day 27 of that cycle) (Table 2).  If 
morphologic CR/CRi is achieved within the first 2 cycles, BMA/biopsy and peripheral blood 
smear will not be required at the end of Cycle 3.  For all subjects, BMA/biopsy and peripheral 
blood smear must be performed at the completion of Cycle 4, and at the Treatment 
Discontinuation Visit or at the time of suspected relapse (whichever occurs first). For subjects 
who are assessed as having partial response, the BMA/biopsy and peripheral blood smear will be 
repeated at Cycle 8 unless the subject goes to allogeneic HSCT, and at the Treatment 
Discontinuation Visit or at the time of suspected treatment failure (whichever occurs first). A 
bone marrow biopsy is required only if a BMA cannot be obtained. Subjects demonstrating 
clinical benefit as per the Investigator at the end of Cycle 4 and beyond may continue to receive 
lenalidomide on study for up to 12 cycles in the absence of protocol-defined toxicity or 
transitioning to allogeneic HSCT.
During the study, repeat of local testing of bone marrow cytogenetics and FISH for any positive 
markers is to be completed whenever a BMA/biopsy is obtained.  However, if the 
cytogenetics/FISH results are ‘normal’ at screening or at any point during the study, cytogenetic 
analysis is not required to be repeated except at the Treatment Discontinuation Visit or at the 
time of bone marrow evaluation for suspected relapse (whichever occurs first).
In addition, BMA/biopsy will be obtained to confirm CR, CRi, PR, or treatment failure, as 
assessed by the Investigator based on complete blood count [CBC] with white blood cell (WBC) 
differential results (defined in Appendix D).  Morphological response will be assessed based on 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
12
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
peripheral blood count recovery and morphologic assessment of BMAs/biopsies (Table 2). 
Assessments to be collected during the Follow-up Phase will include new anticancer therapies, 
HSCT, SPMs, SAEs, 
Overview of Safety Assessments
Subject safety, including hematology (CBC with differential) and serum blood chemistry 
analyses, physical exams, vital signs, body weight measurement, Lansky/Karnofsky performance
status, AEs, concomitant medications/procedures, urinalysis, echocardiograms, 
electrocardiograms (ECGs), and pregnancy testing for females of childbearing potential/female 
children of childbearing potential (FCBP/FCCBP) will be assessed as outlined in Table 2.  
Peripheral blood and bone marrow aspirate/biopsy may be used to assess IP toxicity.
Adverse events will be reported and recorded in the CRF.  For SAEs, an expedited reporting 
procedure will be used (see Section 11).  The rate of AEs, SAEs, abnormal laboratory AEs and 
vital signs (graded according to the National Cancer Institute [NCI] Common Terminology 
Criteria for Adverse Events [CTCAE] Version 4.03) will be measured while the subject is on 
study treatment.  Following lenalidomide discontinuation, subjects will be assessed at the 28-day 
Follow-up Visit for safety.
Second primary malignancies will be monitored as events of interest and should be included as 
part of the assessment of AEs throughout the course of the study.  Investigators are to report any 
SPM as an SAE regardless of causal relationship to lenalidomide, occurring at any time for the 
duration of the study, from the time of signing the ICF/IAF until all subjects have been followed 
for up to 5 years from the last subject’s first dose, unless consent is withdrawn, the subject is lost 
to follow-up or dies.
Overview of Pharmacokinetic Assessments
Blood samples for PK assessment will be collected from all subjects at specified time points 
(Table 3) for up to 24 hours on Cycle 1 Day 1 (Appendix H).  Key PK parameters of plasma
lenalidomide include apparent clearance and apparent volume of distribution.  Effect of age and 
body size on lenalidomide PK will also be assessed.
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
13
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
 
 
 
 
 
Data Monitoring Committee
An external data monitoring committee (DMC) with multidisciplinary representation will be 
established to evaluate all available data and to ensure the ongoing safety of the subjects both 
currently receiving the study treatment and those still to be enrolled. The DMC will be 
comprised of medical oncologists with experience in treating pediatric subjects with AML and a 
statistician, all of whom are not otherwise involved in the study as Investigators. Following 
available treatment activity and safety data review, the DMC will advise on safety and treatment 
activity considerations and any other issues important to the conduct of the study and will make 
recommendations about the continuing safety of current participants and those yet to be enrolled.  
Once 4 subjects having received at least one dose of lenalidomide have completed at least 1 
cycle of study treatment or discontinued treatment (whichever occurs first), the DMC will 
evaluate the safety data available and provide a recommendation. The DMC will also provide 
recommendations about the continuation of the study from Stage 1 to Stage 2 (continue as 
planned, continue with modifications or stop treatment and/or enrollment) and advise on ways to 
improve quality.  The DMC will meet at least semi-annually after sufficient subject data has been 
collected to review safety data. The DMC responsibilities, authorities, and procedures will be 
documented in the DMC charter, which will be endorsed by the DMC prior to the first data 
review meeting.  Ad hoc DMC meetings may be scheduled if necessary.
Statistical Methods
All statistical analyses will be descriptive.  There will be no formal statistical comparisons due to 
the single-arm study design and the small sample size.  The first 43 subjects enrolled and 
evaluable for the primary endpoint analysis will be used to assess the primary endpoint.
Under Simon’s Optimal two stage design with a 5% significance level and 80% power, assuming 
a lower boundary of interest in the response rate of 10% and an upper boundary of interest in the 
response rate of 25%, a total of 43 evaluable subjects are required for the evaluation of the 
primary endpoint; 18 in Stage 1 and an additional 25 in Stage 2.
If less than 3 of 18 evaluable subjects in Stage 1 achieve a morphologic response (either CR or 
CRi) within a maximum of 4 cycles then the study will terminate, otherwise the study shall 
continue as planned and enrollment of an additional 25 subjects shall continue into Stage 2.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
14
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
If, at the final analysis, less than 8 of 43 evaluable subjects in both Stage 1 and Stage 2 achieve a 
response (either CR or CRi) within a maximum of 4 cycles then it will be concluded that 
lenalidomide, at the dose level tested, does not have sufficient activity in pediatric AML (second 
or greater relapse or refractory).  However, should at least 8 of the 43 evaluable subjects achieve 
a response (either CR or CRi) then it will be concluded that lenalidomide, at the dose level 
tested, demonstrates activity in pediatric subjects with AML (second or greater relapse or 
refractory) to allow further investigation.
Up to 4 additional subjects may be included to account for subjects found to be unevaluable for 
the primary endpoint (eg, incorrect diagnoses, not having a disease assessment post screening, or 
who discontinued prior to receiving lenalidomide therapy).
&(/*(1(35235,(7$5<,1)250$7,21
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
15
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................1
PROTOCOL SUMMARY .............................................................................................6
1.
INTRODUCTION..................................................................................... 23
1.1.
Pediatric Acute Myeloid Leukemia............................................................ 23
1.2.
Treatment of Childhood Acute Myeloid Leukemia .................................... 23
1.3.
REVLIMID® (Lenalidomide) .................................................................... 24
1.3.1.
Lenalidomide Mechanism of Action .......................................................... 24
1.3.2.
Lenalidomide Pharmacokinetics ................................................................ 25
1.3.2.1.
Pharmacokinetics in Pediatric Populations................................................. 25
1.4.
Rationale for Studying Lenalidomide in Relapsed/Refractory Pediatric 
AML ......................................................................................................... 26
1.4.1.
Adult High-Risk MDS and AML Trials..................................................... 26
1.4.2.
Lenalidomide Post-Allogeneic Stem Cell Transplant .................................27
1.4.3.
Pediatric Studies ........................................................................................ 28
1.5.
Summary................................................................................................... 32
2.
STUDY OBJECTIVES.............................................................................. 33
2.1.
Primary Objective...................................................................................... 33
2.2.
Secondary Objectives ................................................................................ 33
3.
STUDY ENDPOINTS............................................................................... 34
3.1.
Primary Endpoint....................................................................................... 34
3.2.
Secondary Endpoints ................................................................................. 34
4.
OVERALL STUDY DESIGN ................................................................... 35
4.1.
Study Design ............................................................................................. 35
4.2.
Study Design Rationale ............................................................................. 40
4.3.
Starting Dose Rationale ............................................................................. 40
4.4.
Study Duration .......................................................................................... 41
4.5.
End of Trial ............................................................................................... 41
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EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
16
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
5.
TABLE OF EVENTS................................................................................ 42
6.
PROCEDURES......................................................................................... 48
6.1.
Screening, Study Entry and Treatment Procedures..................................... 48
6.2.
Administration of Intrathecal Cytarabine ................................................... 48
6.3.
Demographics and Medical History........................................................... 48
6.4.
Prior Medications/Procedures .................................................................... 49
6.5.
Confirmation of Disease Relapse ............................................................... 49
6.6.
Vital Signs.................................................................................................49
6.7.
Physical Examinations............................................................................... 49
6.8.
Pregnancy Testing and Pregnancy Risk and Lenalidomide Counseling ......50
6.9.
Performance Status.................................................................................... 51
6.10.
Echocardiography...................................................................................... 51
6.11.
Electrocardiogram ..................................................................................... 51
6.12.
Height and Weight..................................................................................... 51
6.13.
Chest X-ray ............................................................................................... 51
6.14.
Laboratory Assessments ............................................................................ 51
6.14.1.
Hematology Laboratory Assessments ........................................................ 52
6.14.2.
Chemistry Laboratory Assessments ........................................................... 52
6.14.3.
Urinalysis (dipstick) .................................................................................. 52
6.15.
Concomitant Medications/Procedures........................................................ 52
6.16.
IP Administration ...................................................................................... 53
6.17.
IP Dispensing ............................................................................................ 53
6.18.
IP Accountability....................................................................................... 53
6.19.
Information to be Collected on Screen Failures.......................................... 54
6.20.
Treatment Activity..................................................................................... 54
6.20.1.
Bone Marrow Aspirate or Biopsy and Peripheral Blood............................. 54
6.20.3.
Cytogenetics/FISH..................................................................................... 55
6.20.4.
Modified IWG Response ........................................................................... 55
6.21.
Safety........................................................................................................ 56
6.21.1.
Adverse Events Reporting ......................................................................... 56
6.21.2.
Second Primary Malignancies.................................................................... 56
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
17
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
6.22.
Treatment Discontinuation......................................................................... 57
6.23.
Follow-up Phase ........................................................................................ 57
6.24.
Optional Extension Phase .......................................................................... 57
6.25.
Investigational Product Specific Safety Concerns To Be Monitored or
Assessed.................................................................................................... 57
6.26.
Pharmacokinetic Sample Collection........................................................... 59
6.26.1.
Blood Collection for PK Analysis.............................................................. 59
7.
STUDY POPULATION............................................................................ 62
7.1.
Number of Subjects and Sites .................................................................... 62
7.2.
Inclusion Criteria....................................................................................... 62
7.3.
Exclusion Criteria...................................................................................... 65
7.4.
Inclusion and Exclusion Criteria for OEP .................................................. 66
8.
DESCRIPTION OF STUDY TREATMENTS........................................... 67
8.1.
Description of Investigational Product(s)................................................... 67
8.2.
Treatment Administration and Schedule .................................................... 67
8.2.1.
Dose Reductions/Interruptions................................................................... 69
8.2.2.
Overdose ................................................................................................... 72
8.3.
Method of Treatment Assignment.............................................................. 72
8.4.
Packaging and Labeling............................................................................. 73
8.5.
Investigational Product Accountability and Disposal .................................73
8.6.
Investigational Product Compliance........................................................... 73
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................... 74
9.1.
Permitted Concomitant Medications and Procedures.................................. 74
9.2.
Prohibited Concomitant Medications and Procedures.................................74
10.
STATISTICAL CONSIDERATIONS ....................................................... 75
10.1.
Overview................................................................................................... 75
10.2.
Study Population Definitions ..................................................................... 75
10.3.
Sample Size and Power Considerations...................................................... 75
10.4.
Background and Demographic Characteristics........................................... 76
10.5.
Subject Disposition.................................................................................... 76
10.6.
Efficacy Analysis....................................................................................... 76
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
18
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
10.6.1.
Primary endpoint ....................................................................................... 76
10.6.2.
Secondary endpoints.................................................................................. 77
10.7.
Safety Analysis.......................................................................................... 78
10.7.1.
Toxicity Assessment.................................................................................. 78
10.7.2.
Adverse Events.......................................................................................... 78
10.7.3.
Deaths ....................................................................................................... 78
10.7.4.
Clinical Laboratories ................................................................................. 78
10.7.5.
Vital Signs.................................................................................................78
10.9.
Interim Analysis ........................................................................................ 79
10.9.1.
Stopping Criteria for Acute Graft-Versus-Host Disease ............................. 80
10.9.2.
Statistical Rationale for GVHD Stopping Criteria ...................................... 80
10.10.
Pharmacokinetic Analysis.......................................................................... 80
10.11.
Other Topics.............................................................................................. 80
11.
ADVERSE EVENTS................................................................................. 81
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................... 81
11.2.
Evaluation of Adverse Events.................................................................... 81
11.2.1.
Seriousness................................................................................................ 81
11.2.2.
Severity/Intensity....................................................................................... 83
11.2.3.
Causality ................................................................................................... 84
11.2.4.
Duration .................................................................................................... 84
11.2.5.
Action Taken............................................................................................. 84
11.2.6.
Outcome.................................................................................................... 84
11.3.
Abnormal Laboratory Values..................................................................... 84
11.4.
Pregnancy.................................................................................................. 85
11.4.1.
Female Children of Childbearing Potential and Females of Childbearing 
Potential .................................................................................................... 85
11.4.2.
Male Subjects............................................................................................ 86
11.5.
Reporting of Serious Adverse Events......................................................... 86
11.5.1.
Safety Queries ........................................................................................... 86
11.6.
Expedited Reporting of Adverse Events..................................................... 87
12.
DISCONTINUATIONS ............................................................................ 88
12.1.
Treatment Discontinuation......................................................................... 88
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6
50


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
19
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
12.2.
Study Discontinuation ............................................................................... 88
13.
EMERGENCY PROCEDURES................................................................ 90
13.1.
Emergency Contact.................................................................................... 90
13.2.
Emergency Identification of Investigational Products ................................ 90
14.
REGULATORY CONSIDERATIONS...................................................... 91
14.1.
Good Clinical Practice............................................................................... 91
14.2.
Investigator Responsibilities ...................................................................... 91
14.3.
Subject Information and Informed Consent................................................ 92
14.4.
Confidentiality........................................................................................... 92
14.5.
Protocol Amendments................................................................................ 92
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................... 93
14.7.
Ongoing Information for Institutional Review Board/Ethics Committee ....93
14.8.
Termination of the Study ........................................................................... 93
15.
DATA HANDLING AND RECORDKEEPING........................................ 95
15.1.
Data/Documents........................................................................................ 95
15.2.
Data Management...................................................................................... 95
15.3.
Record Retention....................................................................................... 95
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................... 97
16.1.
Study Monitoring and Source Data Verification......................................... 97
16.2.
Audits and Inspections............................................................................... 97
17.
PUBLICATIONS ...................................................................................... 98
18.
REFERENCES.......................................................................................... 99
19.
APPENDICES......................................................................................... 105
Appendix A:
World Health Organization Classification of Acute Myeloid 
Leukemia................................................................................................. 105
Appendix B:
Lenalidomide Dosing Table – Capsule................................................ 106
Appendix C: 
Lenalidomide Dosing Table – Oral Suspension.................................. 108
Appendix D:
Modified International Working Group AML Response Criteria......... 110
Appendix E:
KARNOFSKY PERFORMANCE STATUS....................................... 112
Appendix F:
LANSKY PERFORMANCE STATUS ............................................... 113
Appendix G:
List of Abbreviations and Definitions of Terms .................................. 114
Appendix H:
Lenalidomide Plasma* 
 PK Sample Handling Instructions... 119
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D:
Appendix
Appendix
ppen
ppen


EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
20
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix I:
Central Pathology Review.................................................................... 121
 
Appendix L:
Optional Extension Phase.................................................................... 130
Appendix M:
Tumor Lysis Syndrome...................................................................... 134
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
21
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
LIST OF TABLES
Table 1:
Predicted Lenalidomide Plasma Exposure in Pediatric Subjects................. 41
Table 2:
Table of Events.......................................................................................... 42
Table 3:
PK Sampling Schedule During Cycle 1 Day 1 ........................................... 60
Table 4:
Creatinine Clearance Estimation using the Schwartz Formula.................... 63
Table 5:
Age-based Cytarabine Dosing.................................................................... 69
Table 6:
Dose Reductions of Lenalidomide ............................................................. 69
&(/*(1(35235,(7$5<,1)250$7,21
50
250
25
1)2


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
22
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
LIST OF FIGURES
Figure 1:
Overall Study Design................................................................................. 39


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
23
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
1.
INTRODUCTION
1.1.
Pediatric Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is the most common acute leukemia in adults.  Acute myeloid 
leukemia comprises approximately one-fifth of pediatric leukemias and is the seventh most 
common pediatric malignancy. The incidence rate is approximately 4 cases per 100,000.  
Approximately 500 children develop AML in the United States (US) per year with an incidence 
of pediatric AML in the US of 5.2 cases/million, peaking at 11 cases/million in children 2 years 
of age, with incidence decreasing until approximately 9 years of age then increasing to 
9 cases/million during adolescence (Rubnitz, 2008; Rudant, 2008; Xie, 2003).  Similar incidence 
rates across age groups for pediatric AML have been observed in Europe (Gatta, 2003; Marcos-
Gragera, 2010). Although 90% of children with AML have no known risk factors, a number of 
predisposing constitutional disorders have been identified in the remaining 10% of children 
(Aplenc, 2000). Leukemia-associated genetic alterations, patterns of epigenetic changes, and 
rates of remission induction differ between pediatric and adult AML; although conventional 
AML therapy is essentially the same for adults and children (Tasian, 2014; Moore, 2013).
Children generally have a relatively higher response rate to induction chemotherapy than adults, 
probably due to their superior ability to tolerate intensive multi-agent therapy, their lower 
prevalence of comorbidities and intensive supportive care remission (Tasian, 2014).
1.2.
Treatment of Childhood Acute Myeloid Leukemia
Treatment of pediatric AML is generally divided into phases that are designed to induce 
remission and consolidate a disease-free post-remission status. Most chemotherapy regimens 
consist of the combination of 2 or 3 drugs, anthracycline and cytarabine, with the frequent 
addition of etoposide or 6-thioguanine. In a typical regimen, 2 intensive initial chemotherapy 
cycles are used to induce remission (Pui, 2004; Rubnitz, 2007) and consolidation therapy 
follows. Allogeneic hematopoietic stem cell transplantation (HSCT) may also be recommended 
for high-risk patients and is the only curative option (Rubnitz, 2007). Cytarabine and 
anthracyclines are gold standard agents for remission induction in patients of all ages. More than 
90% of pediatric AML patients who undergo induction chemotherapy achieve complete 
remission (CR), however, relapse following primary therapy approaches 40%, and the 5-year 
event-free survival (EFS) rate is only approximately 50% (Creutzig, 2001; Stevens, 1998; 
Woods, 2001).
Treatment of children with AML remains unsatisfactory and outcomes are particularly poor for 
refractory and relapsed AML.  Relapsed AML is associated with high morbidity and mortality 
and reinduction attempts are frequently unsuccessful (Tasian, 2014) and patients die of the 
disease or of treatment-related complications (Creutzig, 2012; Kaspers, 2005, Rubnitz, 2008).  
Although some patients with first relapse can achieve second remission (Sander, 2010), most 
patients in second and greater relapse will not achieve subsequent remission despite intensive 
cytotoxic chemotherapy.  Of those patients achieving third remission, outcomes are dismal with 
long-term survivors reported only anecdotally (Gorman, 2010).
To date, treatment options for children with relapse or refractory AML (rrAML) generally 
include intensification of cytotoxic chemotherapy (including anthracyclines and cytarabine), 
HSCT, and supportive care (Shenoy, 2008; Sander 2010; Woods, 2001). Although these 
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ng
ng-t


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
24
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
therapies have led to improved outcomes in primary relapse, there remains little room for further 
treatment intensification in second or greater relapse due to the excess toxicities associated with 
cytotoxic chemotherapy such as infectious complications, end-organ dysfunction, and the high 
probability of bone marrow relapse despite HSCT (Tasian, 2014; Sander, 2010).
1.3.
REVLIMID® (Lenalidomide)
REVLIMID® (lenalidomide) capsules are approved in the US and Canada for the treatment of 
patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic 
syndromes (MDS) associated with a deletion 5q abnormality with or without additional 
cytogenetic abnormalities.  In addition, REVLIMID, in combination with dexamethasone, is 
approved in the US and Canada for the treatment of patients with multiple myeloma (MM) who 
have received at least one prior therapy.  In the US, REVLIMID is also approved for the 
treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or 
progressed after two prior therapies, one of which included bortezomib.  In addition, REVLIMID 
is approved in the US for newly diagnosed MM patients. To date, lenalidomide has been safely 
administered to over 300,000 patients across a wide variety of hematology and oncology 
diseases.  Celgene sponsored and/or Investigator initiated trials (IIT) are currently studying 
lenalidomide in AML, non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), 
solid tumors, and in a number of pediatric oncology diseases.
A lenalidomide formulation for constitution to oral suspension has been developed.  The oral 
suspension is available for use in subjects who are unable to swallow the capsules or at the 
discretion of the investigator. The lenalidomide oral suspension has demonstrated to be 
bioequivalent to the 25 mg capsule for a given dose.  The magnitude of food effect on absorption 
of lenalidomide oral suspension is similar to that on the capsule formulation. The oral suspension
of lenalidomide is not approved by any regulatory agency worldwide for any indication.  
1.3.1.
Lenalidomide Mechanism of Action
Lenalidomide is an immunomodulatory agent with a mechanism of action that includes anti-
neoplastic, anti-angiogenic, pro-erythropoietic, and immunomodulatory properties. Specifically, 
lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells 
(including MM plasma tumor cells, MCL and those with deletions of chromosome 5 [del(5q)] 
MDS in vitro).  Lenalidomide causes a delay in tumor growth in some in vivo nonclinical 
hematopoietic tumor models including MM. Immunodulatory properties of lenalidomide include
activation of T-cell and natural killer (NK) T-cell-mediated immunity and increases the number 
of NK T-cells, inhibits angiogenesis by blocking the migration and adhesion of endothelial cells 
and the formation of microvessels (Lu, 2009), augments fetal hemoglobin production by CD34+ 
hematopoietic stem cells, and inhibits production of pro-inflammatory cytokines (eg, TNF-α and 
IL-6) by monocytes (Corral, 1999; Kotla, 2009). In MDS del(5q), lenalidomide was shown to 
selectively inhibit the abnormal clone by increasing the apoptosis of del(5q) cells (Pellagatti, 
2007; Wei, 2009).
Lenalidomide binds directly to the protein cereblon (CRBN) encoded by the CRBN gene, which 
is part of an E3 ligase complex that includes deoxyribonucleic acid damage-binding protein 1
(DDB1), cullin 4 (CUL4) and regulator of cullins 1 protein (Roc1), and can inhibit the auto-
ubiquitination of CRBN within the complex (Ito, 2010). E3 ubiquitin ligases are responsible for 
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2007; Wei
2007; Wei
enali
enali


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
25
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
the poly-ubiquitination of a variety of substrate proteins, including Ikaros (encoded by the gene 
IKZF1) and Aiolos (encoded by gene IKZF3), targeting them for destruction in the proteasome.
Ikaros and Aiolos are key transcription factors regulating immune cell development and 
homeostasis and degradation of these substrates by lenalidomide results in enhanced production 
of IL-2 and other cytokines known to regulate T-cell function.  Therefore, the lenalidomide-
induced reduction in Ikaros and Aiolos levels represents one possible mechanism of the 
pharmacological effects of lenalidomide, although other mechanisms may also play a role 
(Gandhi, 2014; Krönke, 2014; Lu, 2014). Altered activity of CRBN E3 ligase complexes may 
explain the broad cellular effects observed with lenalidomide treatment. Independent studies 
have confirmed the importance of CRBN in mediating the antiproliferative activity of 
lenalidomide in MM cells (Lopez-Girona, 2012; Zhu, 2011). Also, the importance of CRBN to 
the immunomodulatory activity of lenalidomide was demonstrated in human T-cells, as CRBN 
small interfering ribonucleic acid (siRNA) reduced lenalidomide-mediated increases in IL-2 and 
tumor necrosis factor –alpha (TNF-α) by ~60% (Report DM2528).
The mechanism of action of lenalidomide in AML has not yet been established and there have 
been few mechanistic studies in this indication.  An in vitro evaluation of lenalidomide activity 
in a panel of AML cell lines showed that lenalidomide variably inhibited the viability of AML 
cell lines, and that this inhibitory effect of lenalidomide moderately correlated with cereblon 
expression levels (Report SF-ALM-0012).  In del(5q) AML cells that have evolved from MDS 
patients, lenalidomide induced apoptosis via G2 cell cycle arrest (Wei, 2009).  Lenalidomide 
may exert its effect by modulating cytokine levels in patients with AML as increases in 
interleukin-17 (IL-17) and macrophage colony-stimulating factor (M-CSF) levels were observed 
in responders to lenalidomide (combined with azaciditine treatment) (Pollyea, 2012).  Finally, 
lenalidomide enhances the expression of an N-truncated isoform of C/EBP∀, a transcription 
factor critical for normal myeloid cell differentiation.  This causes an increase in microRNA
(miR)-181a expression leading to strong inhibition of AML tumor growth and augmented
sensitivity of leukemia cells to chemotherapy (Hickey, 2013).  The importance of direct 
tumoricidal effects versus immunomodulatory effects of lenalidomide to anti-leukemic activity 
in patients remains to be elucidated.
1.3.2.
Lenalidomide Pharmacokinetics
1.3.2.1.
Pharmacokinetics in Pediatric Populations
The pharmacokinetics (PK) of lenalidomide have been evaluated in pediatric patients with solid
tumors in two Phase 1 pediatric studies (Berg, 2011; Warren, 2011).  A total of 47 pediatric 
patients were evaluated for PK in the two studies, with ages ranging from 4 to 21 years old.  
Doses studied were 20 to 116 mg/m2/day for children with brain tumors, 15 to 70 mg/m2/day for 
children with solid tumors, and 5 mg/m2/day for children with MDS.  In these pediatric patients, 
plasma lenalidomide exposure (AUC and Cmax) increased approximately proportional to dose.  
The median time to reach the maximum concentration in plasma was approximately 1 to 4 hours 
following the oral administration and the mean terminal half-life (t1/2) of lenalidomide was 2 to 3 
hour in the two studies.  These observations are consistent with those historically observed in 
adult patients with hematological malignancies including AML.
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wing
ur i


EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
26
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
In pediatric patients ≥ 5 years of age, preliminary population PK analysis suggests that body 
weight is positively correlated with lenalidomide clearance and volume of distribution, but age 
has no effect.
The relationship between lenalidomide apparent total clearance (CL/F) and body size (weight or 
body surface area [BSA]) is not available for children younger than 5 years. Because 
gastrointestinal (GI) and renal functions reach the adult level by 1 year of age, oral absorption 
and renal elimination of lenalidomide is not anticipated to be highly age-dependent in patients 1 
to 5 years.  However, effects of the growth-dependent changes in the body size on lenalidomide 
clearance (plasma exposure) and volume distribution is expected in the 1 to < 5 year-old age 
group of pediatric patients.  The impact of growth on plasma lenalidomide exposure has been 
taken into account when considering the weight-based dose for this study.
1.4.
Rationale for Studying Lenalidomide in Relapsed/Refractory 
Pediatric AML
Approximately 5% of children with AML have refractory disease and about one-third to one-half 
of these pediatric patients relapse (Aplenc, 2000).  The prognosis for a child with recurrent or 
progressive AML is generally poor (Webb, 1999; Wells, 2003) and AML at second or greater 
relapse represents an area of high unmet medical need for which novel strategies are needed to 
further improve outcomes. At relapse, pediatric patients are treated with salvage chemotherapy 
followed by allogeneic HSCT.  However, side effects and toxicity still remain a major concern, 
hence the need for new agents (Creutzig, 2012).  Lenalidomide is a novel, oral 
immunomodulatory agent, which has shown clinical activity in Phases 1 and 2 adult MDS and 
AML studies. These Phase 1 and Phase 2 adult studies have evaluated lenalidomide in subjects 
with and without del(5q) (Ades, 2009; Blum, 2010; Fehniger, 2009; Fehniger, 2011; Fenaux, 
2011; List, 2006; Pollyea, 2012; Raza, 2008; Sekeres, 2010; Sekeres, 2011). Not only has 
lenalidomide shown single agent activity and acceptable tolerability at higher doses in adult 
high-risk MDS and AML without del(5q) (Blum, 2010; Fehniger, 2011), lenalidomide has 
established pediatric safety data from 2 completed Phase 1 studies (Berg, 2011; Warren, 2011).
1.4.1.
Adult High-Risk MDS and AML Trials
Overall, lenalidomide monotherapy was relatively well tolerated at doses up to 50 mg/day given 
on Days 1 - 21 of a 28-day treatment cycle, in elderly patients with advanced AML (Blum, 2010; 
Fehniger, 2011).  The observed safety profile was similar to that observed with lenalidomide 
treatment in patients with other hematological malignancies.  No optimal dose or regimen could 
be established or concluded based on the available data.
In a Phase 1 dose-escalation trial in adults with relapsed or refractory leukemia, 31 patients with 
AML were treated with acceptable tolerability, a maximum tolerated dose (MTD) of 50 mg/day 
was established and a dose-limiting toxicity (DLT) of fatigue was observed at 75 mg/day.  Five 
of 31 patients (16%) achieved complete remission and 3 patients of the 5 patients with 
cytogenetic abnormalities achieved cytogenetic CR (none of which was deletion 5q).  Response 
duration ranged from 5.6 to 14 months.  Notably, 2 patients who relapsed following allogeneic 
bone marrow transplantation achieved CR with lenalidomide (Blum, 2010).
A Phase 2 study of high-dose lenalidomide as initial therapy for newly-diagnosed elderly AML 
patients (age > 60 years) evaluated the response to lenalidomide 50 mg daily for two, 28-day 
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cytogene
togen
y
rati


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
27
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
cycles followed by low-dose maintenance therapy (10 mg daily) for up to 12 cycles (Fehniger, 
2011).  Of the 33 patients enrolled, the CR/complete remission with incomplete blood count 
recovery (CRi) rate was 30% (CRi defined as CR with insufficient hematological recovery of 
platelets or neutrophils) and was 53% for the 19 patients completing at least 2 cycles of high-
dose 50 mg lenalidomide.  Median time to CR/CRi was 30 days (range 1 to 72 days) and median 
duration of CR/CRi was 10 months.  The response rate and toxicity profile are favorable 
compared to other low-intensity agents (Fehniger, 2011).
Responses to lenalidomide have been observed in patients with high-risk MDS and AML with 
del(5q). In a Phase 2 study of 47 high-risk MDS patients, most of whom had complex 
cytogenetics, the response rate was 28% with lenalidomide 10 mg/day (Raza, 2008). In the 
Phase 2 Southwest Oncology Group Study (SWOG) S0605 study, 37 elderly AML patients with 
del(5q) were treated with lenalidomide 50 mg daily for 28 days as induction therapy and 10 mg 
daily for 21 days of a 28-day cycle as maintenance. Fourteen patients (38%) completed 
induction therapy and 8 (22%) started maintenance. Five of the 37 total patients (14%) achieved 
a partial or complete response, two with isolated del(5q) and 3 with complex cytogenetics. 
Median relapse-free survival for responders was 5 months (range, 0 to 19 months) (Sekeres, 
2011).
In a Phase 2 IIT by Pollyea and colleagues (Pollyea, 2012), untreated AML patients ineligible for 
conventional chemotherapy received azacitidine 75 mg/m2/day on Days 1 - 7 followed by 
escalating doses of lenalidomide up to 50 mg/day on Days 8 - 28 of 42-day cycles. Treatment 
was continued until progression of disease, unacceptable adverse event (AE) or completion of 12 
cycles. Among 42 evaluable patients, the overall response rate (ORR) was 41%, with 28% of 
patients achieving a complete response (CR/CRi). The median time to CR/CRi was 12 weeks 
(range, 6 to 18 weeks); the median duration of response (CR/CRi/PR) was 28 weeks (range 6 to 
> 104 weeks). Median overall survival (OS) for all patients in the study was 20 weeks (range, 1 
to > 121 weeks) and 69 weeks (range, 10 to > 121 weeks) for patients who responded to therapy. 
Additionally, median overall survival for responders was superior to non-responders (69 versus
15 weeks p < 0.01) (Pollyea, 2012).
In general, AEs encountered with the use of lenalidomide in the treatment of AML and high-risk 
MDS are similar to those observed in patients treated with lenalidomide for other hematological 
malignancies. The most common hematological Grade 3 or higher AEs were neutropenia and 
thrombocytopenia. The most common Grade 3 or higher non-hematological AEs were fever or 
infection, fatigue, and dermatological toxicities including rash (Chen, 2013).
1.4.2.
Lenalidomide Post-Allogeneic Stem Cell Transplant
Two adult studies utilizing lenalidomide as maintenance therapy following allogeneic HSCT in 
MM both reported a high rate of induction of graft versus host disease (GVHD) (Kneppers,
2011; Sockel, 2011). Although this high rate of GVHD was associated with a patient population 
in remission, lenalidomide showed efficacy with tolerable GVHD when studied in relapsed MM
and relapsed AML patients previously treated with allogeneic HSCT (Ades, 2010; Bensinger, 
2012; El-Cheikh, 2012; Ford, 2010; Lioznov, 2010; Montefusco, 2012). Additionally, GVHD 
rash has been reported in relapsed adult AML/MDS and MM patients after achieving CR with 
lenalidomide post allogeneic HSCT (Blum, 2010; Ford, 2010). This observation suggests that 
the immune modulatory effects of lenalidomide activate a graft-versus-leukemia effect and may 
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12;
12;


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
28
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
be particularly beneficial in the control of the disease that has relapsed after allogeneic HSCT. A 
case-matched retrospective analysis comparing lenalidomide after autologous or after allogeneic 
HSCT confirmed this hypothesis by demonstrating a survival advantage in allografted myeloma 
patients (Montefusco, 2012).
The primary objective of this study is to determine the activity of lenalidomide in pediatric 
patients with relapsed/refractory AML (with second or greater relapse or refractory to at least 2 
prior induction attempts). Treatment of an AML recurrence following allogeneic HSCT 
commonly includes a rapid taper of immune-suppression used for prophylaxis and/or treatment 
of acute GVHD. In this setting, mild GVHD is an expected and a desirable toxicity. The use of 
the immune-modulatory drug, lenalidomide, in patients at risk for acute GVHD will be 
challenging but with the potential for benefit to the patient with induction of mild but 
manageable GVHD.  Accordingly, this study will attempt to keep patients with new mild GVHD 
on protocol therapy, while recognizing that Grade 3 or greater acute GVHD will be an 
unacceptable toxicity.  First, patients with active GVHD or requiring immune-suppression 
including steroids for GVHD control are not eligible for enrollment.  Patients with a history of 
Grade 3 or greater GVHD or those on therapeutic dosing of immune suppressive therapy will be 
discussed with the study chair prior to enrollment and require a longer observation time off 
immune-suppression prior to enrollment (4 weeks) compared to those without a history of severe 
GVHD or who are already on tapering dosing of immune suppressive therapy without signs of 
GVHD (2 weeks off immune-suppression) (see Sections 6.25, 7.2 and 8.2.1).  Second, patients 
who develop Grade 3 or greater GVHD, or lower grade GVHD that does not respond to protocol 
prescribed interventions (Section 8.2.1) will be off study treatment.  No dose reduction is 
planned as it is not clear that this toxicity would improve and be altered by dose adjustment.  
Incidence of GVHD will be closely monitored and the study will be closed to post-HSCT 
patients if stopping thresholds for Grade 3 or greater GVHD are crossed (see Section 10.9.1).  
Patients will be monitored for development of chronic GVHD.
1.4.3.
Pediatric Studies
In a Phase 1 study of lenalidomide performed by the 
in 
pediatric patients with relapsed or refractory solid tumors or MDS, 49 subjects were treated with 
dosages up to 70 mg/m2/day for 21 days of a 28-day cycle. Six DLTs were observed, which 
were sporadic and not clearly associated with the dose. These DLTs included Grade 3 
hypercalcemia (15 mg/m2/day), Grade 3 hypophosphatemia (40 mg/m2/day), Grade 3 
hypokalemia (40 mg/m2/day), Grade 4 neutropenia (40 mg/m2/day), Grade 3 somnolence (40 
mg/m2/day), and Grade 3 urticaria (55 mg/m2/day). These DLTs occurred at doses ranging from 
15 mg/m2/day to 55 mg/m2/day. There were no DLTs reported among the 6 patients enrolled at 
70 mg/m2/day and the MTD was not reached (Berg, 2011). At the 25 mg/m2/day dose, 1 patient 
had a cerebrovascular ischemic event of uncertain relationship to lenalidomide.
A second Phase 1 trial of lenalidomide in pediatric patients with recurrent, refractory or 
progressive CNS tumors was performed by the Pediatric Brain Tumor Consortium (Warren, 
2011). In the 44 evaluable patients, treated at doses of 15 to 116 mg/m2/day for 21 days of a 28-
day cycle, the MTD was not reached. A total of 34 patients received more than 1 course of 
therapy, 23 patients received more than 6 courses, and 10 patients received more than 12 courses.
Lenalidomide was well-tolerated in these patients and myelosuppression, a known toxicity in 
adult patients, was the major toxicity observed in this study population. Other common toxicities 
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). 


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
29
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
included fatigue (30%), GI symptoms including nausea (10%), emesis (4%), diarrhea (16%), and 
constipation (8%), as well as rash (14%) and muscle cramping (10%). There was no clear dose 
relationship with these acute toxicities. Of note, 2 patients experienced DLTs. The first patient, 
treated at the 20 mg/m2/day dose level had a presumed myocardial infarction and elevated 
troponin in the setting of multiple risk factors for thromboembolism. A second patient 
experienced a DLT of Grade 4 fatigue at the 68 mg/m2/day dose level. Antitumor activity, 
defined by both objective responses and long-term stable disease, was observed in 2 of 51 
patients, both with low-grade gliomas (Warren, 2011).
Neither of these 2 completed pediatric Phase 1 studies of lenalidomide reached an MTD with one 
stopping at 70 mg/m2/day for 21 days of a 28-day treatment cycle (Berg, 2011), and the other 
stopping at 116 mg/m2/day for 21 days of a 28-day treatment cycle (Warren, 2011). While these 
studies were performed in subjects with solid tumors, they demonstrate that high doses of 
lenalidomide are well-tolerated in children.
Currently, a randomized Phase 2 study (n = 80 planned) of lenalidomide (low dose: 20 
mg/m2/day versus high dose: 115 mg/m2/day) in children with recurrent, refractory, or 
progressive juvenile pilocytic astrocytomas and optic pathway gliomas is ongoing (COG Study 
Number ACNS1022 and clinicaltrials.gov identification number NCT01553149).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
30
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
31
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
32
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
 
 
1.5.
Summary
Treatment of pediatric rrAML remains an unmet medical need due to the low likelihood of 
achieving clinical benefit from existing therapies and limited long-term survival. Thus, given 
lenalidomide’s activity in adults with AML and tolerability in children, a study of lenalidomide 
in pediatric AML subjects with relapsed or refractory disease (with second or greater relapse or 
refractory to at least 2 prior induction attempts) will generate beneficial information in the 
treatment of this subject population.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
33
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the study is:
!
To determine the activity of lenalidomide in the treatment of pediatric subjects with 
relapsed/refractory AML (with second or greater relapse or refractory to at least 2
prior induction attempts) measured by morphological complete response defined as 
either a CR or CRi within the first 4 cycles of treatment.
2.2.
Secondary Objectives
The secondary objectives of the study are:
!
To evaluate subject demographics and leukemic blast characteristics and their 
correlation with response to lenalidomide.
!
To further evaluate lenalidomide activity with regards to response assessment 
outcome rates, transplantation rate, duration of response (DoR) and durable response 
rate.
!
To evaluate the safety of lenalidomide including rates of graft-versus-host disease 
(GVHD) flare and reactivation.
!
To determine the pharmacokinetics (PK) of lenalidomide in plasma.
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
34
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint
!
Morphologic complete response rate (CR or CRi) within the first 4 cycles of 
treatment with lenalidomide.
3.2.
Secondary Endpoints
!
Durable response rate.
!
Duration of response (DoR). 
!
Disease assessment outcomes and overall response rate (ORR).
!
Rate of hematopoietic stem cell transplant (HSCT).
!
Incidence and severity of treatment-emergent adverse events (TEAEs).
!
Rates of acute and chronic graft-versus-host disease (GVHD).
!
Plasma pharmacokinetic (PK) parameters including lenalidomide apparent clearance 
and volume of distribution.
!
Correlation of peripheral white blood cell count, absolute blast count and cytogenetics 
with response to lenalidomide.
 
 
 
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
35
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is a multicenter, open-label, single-arm, Phase 2, Simon’s Optimal two-stage design study, 
with an Optional Extension Phase (OEP), that will assess the activity, safety and PK of 
lenalidomide in pediatric subjects from 1 to ≤ 18 years of age with second or greater rrAML. A 
total of 43 evaluable subjects (18 subjects in Stage 1 and an additional 25 subjects in Stage 2) are 
required for assessment of the primary endpoint.  To allow for subjects found to be unevaluable
for the primary endpoint due to an incorrect diagnosis, not having a disease assessment post 
screening, or who discontinued prior to receiving lenalidomide, up to 4 additional subjects may 
be enrolled for a maximum of 47 evaluable subjects across approximately 70 sites.  
Approximately 50% of enrolled subjects will be younger than 12 years of age to provide 
adequate PK data for this age subset.
If during Stage 1, at least 3 of 18 subjects achieve a morphologic complete response (either CR 
or CRi) within the first 4 cycles of study treatment, then the study will proceed to Stage 2; 
otherwise, the study will be terminated.  Similarly, if at the final analysis, at least 8 of 43 
evaluable subjects across Stages 1 and 2 achieve a response (CR/CRi) within the first 4 cycles of 
study treatment, it will be concluded that lenalidomide has sufficient activity in pediatric AML to 
warrant subsequent study.
Morphological response will be assessed using the modified AML International Working Group 
(IWG) criteria (Cheson, 2003) (Appendix D).
The OEP will allow subjects who demonstrate clinical benefit, as assessed by the Investigator at 
the completion of 12 cycles of lenalidomide therapy, to continue receiving oral lenalidomide 
until they meet the criteria for study discontinuation.  In the OEP, only safety, dosing, 
concomitant medications/procedures, and second primary malignancies (SPMs) will be 
monitored (Table 2).
An external DMC will evaluate safety and treatment activity data in an ongoing and periodic 
manner to assess benefit-to-risk considerations throughout the study. The function of the DMC 
is to monitor the safety and activity of the study treatment. Once 4 subjects having received at 
least one dose of lenalidomide have completed at least 1 cycle of study treatment or discontinued 
treatment (whichever occurs first), the DMC will evaluate the safety data available and provide a 
recommendation. The DMC will also provide recommendations about the continuation of the 
study from Stage 1 to Stage 2 (continue as planned, continue with modifications or stop 
treatment and/or enrollment) and advise on ways to improve quality.  The underlying principles 
for the DMC are ethical and safety aspects for the subjects.  It will be the task of the DMC to 
examine whether the conduct of the study is still ethically justifiable, whether security of the 
subjects is ensured, and whether the process of the study is acceptable.  For this, the DMC has to 
be informed about the adherence to the protocol, the subject accrual, and any observed AE(s).  
The composition and responsibilities of the DMC, including the structure and procedures of its 
meetings, will be outlined in a DMC charter.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
36
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
The study consists of 3 phases: Screening Phase, Treatment Phase and Follow-up Phase.
Screening Phase
The Screening Phase will start from the time of signing the informed consent form 
(ICF)/informed assent form (IAF) and will last no more than 14 days, at which time the 
Treatment Phase will begin (Cycle 1 Day 1).  Subject’s screening procedures are to occur during 
the Screening Phase within 14 days prior to dosing on Cycle 1 Day 1.
As part of the screening procedures, a fresh bone marrow aspirate and/or a bone marrow biopsy 
paraffin embedded slide will be collected from all subjects for confirmation of disease.  The 
confirmation of disease will be performed locally.  
 
 
 
 
 
 
A standard cytogenetic metaphase preparation from the fresh BMA must be prepared for the 
cytogenetic testing/chromosome analysis including karyotype.  The local site will submit the 
reports of the karyotype, FISH studies, as well as any available data on molecular mutations 
(FLT3, CEPBa, NPM1, and others including exome sequencing via Foundation Medicine or 
other sources) if performed, to the central reviewer at 
.  If subjects have a FISH detectable 
marker, the test should be repeated until CR/CRi and at relapse.
The BMA slide (and/or bone marrow biopsy embedded paraffin slide) and peripheral blood 
smear from screening must be provided to the central reviewers at 
.  The central review 
 will provide standardized analysis and reporting for all subjects.  The central reviewer’s 
assessment will be used retrospectively to confirm diagnosis.
Creatinine clearance (CLcr) will be measured at screening using Table 4 (see Section 7.2).
Treatment Phase
The lenalidomide dose will be calculated based on body weight.  The starting dose will be 2 
mg/kg/day with a maximum dose of 70 mg/day.  Subjects enrolled in the study will receive 
lenalidomide for the first 21 days of each 28-day treatment cycle for up to a maximum of 12 
cycles of study treatment.  After the completion of 12 cycles of study treatment, subjects who 
demonstrate clinical benefit as per the Investigator may continue to receive lenalidomide in an 
OEP (Appendix L) until they meet the criteria for study discontinuation.
In the event of a specific protocol-defined toxicity, no more than 2 dose reductions will be 
allowed to doses of 1.4 mg/kg/day (not exceeding 50 mg/day) and 1 mg/kg/day (not exceeding 
35 mg/day).  The dose will not be re-escalated once it has been reduced (Table 6).  Subjects who 
do not tolerate the minimum dose level of 1 mg/kg/day (not exceeding 35 mg/day) will be 
discontinued from the study.  For additional details regarding dose reductions and dose capping 
see Section 8.2.1.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
37
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
During the Treatment Phase, subjects will be assessed for treatment activity based on modified 
IWG AML Response Criteria (Appendix D).  To determine morphologic CR/CRi, BMA/biopsy 
and peripheral blood smear must be collected from all subjects at the completion of the 21-day 
treatment period of the predefined treatment Cycles 1, 2, 3 and 4 within 6 days before dosing 
for each subsequent cycle (ie, between Day 22 to Day 27 of that cycle) (Table 2).  If 
morphologic CR/CRi is achieved within the first 2 cycles, BMA/biopsy and peripheral blood 
smear will not be required at the end of Cycle 3.  For all subjects, BMA/biopsy and peripheral 
blood smear must be performed at the completion of Cycle 4, and at the Treatment 
Discontinuation Visit or at the time of suspected relapse (whichever occurs first).  For subjects 
who are assessed as having partial response, the BMA/biopsy and peripheral blood smear will be 
repeated at Cycle 8 unless the subject goes to allogeneic HSCT, and at the Treatment 
Discontinuation Visit or at the time of suspected treatment failure (whichever occurs first). A
bone marrow biopsy is required only if a bone marrow aspirate cannot be obtained. Subjects 
demonstrating clinical benefit as per the Investigator at the end of Cycle 4 and beyond may
continue to receive lenalidomide on study for up to 12 cycles in the absence of protocol-defined 
toxicity or transitioning to allogeneic HSCT.
During the study, repeat of local testing of bone marrow cytogenetics and FISH for any positive 
markers is to be completed whenever a BMA/biopsy is obtained.  However, if the 
cytogenetics/FISH results are ‘normal’ at screening or at any point during the study, cytogenetic 
analysis is not required to be repeated except at the Treatment Discontinuation Visit or at the 
time of bone marrow evaluation for suspected relapse (whichever occurs first).
 
 
 
 
 
 
 
 
 
In order to establish lenalidomide plasma PK parameters in subjects with rrAML, blood samples 
will be collected at specified time points (Table 3) for up to 24 hours postdose from all enrolled 
subjects during Cycle 1 Day 1 (Instructions for PK sample handling are in Appendix H).
 
Dose interruptions, delays and modifications may be required to manage adverse events (AEs) 
during study treatment (see Section 8.2.1 for details).  In order to optimally benefit from 
protocol-prescribed therapy, the Investigator should aim to treat subjects for at least 4 cycles
with lenalidomide.  Subjects demonstrating clinical benefit as per the Investigator at the end of 
Cycle 4 and beyond may continue to receive lenalidomide on study up to 12 cycles in the 
absence of protocol-defined toxicity or transitioning to allogeneic HSCT.  Subjects may be 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
38
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
treated beyond 12 cycles of study treatment in the OEP if they continue to benefit and have not 
undergone HSCT.
Subjects may be discontinued from the treatment at the Investigator’s discretion for any of the 
reasons as detailed in Section 12.  All discontinued subjects, regardless of reason for 
discontinuation, should undergo treatment discontinuation procedures at the time of 
investigational product (IP) discontinuation (Table 2).  The reason for discontinuation will be 
recorded in the electronic case report form (CRF) and in the source document.
An interim analysis is planned to take place once the first 18 subjects evaluable for the primary 
endpoint have been accrued and completed up to 4 cycles of lenalidomide treatment if they have 
not stopped therapy before 4 cycles.  The interim analysis will assess the number of subjects with 
CR or CRi under lenalidomide treatment.  
Follow-up Phase
Subjects will enter the Follow-up Phase at the time of permanent discontinuation of IP and will 
be followed for up to 5 years from the last subject’s first dose, unless the subject dies, withdraws 
consent or is lost to follow-up.  The Follow-up Phase may not be terminated because of new 
anticancer treatment or HSCT.
The 28-day Follow-up Visit will occur 28 days after the subject’s last dose of IP.  At this visit, 
subjects will be monitored for the collection of AEs and concomitant medications/procedures 
used to treat the AEs.  Female Children of Childbearing Potential (FCCBP) and Females of 
Childbearing Potential (FCBP) will have a pregnancy test at the 28-day Follow-up Visit (see 
Section 6.8 and Section 7.2).
After the 28-day Follow-up Visit, subjects will be followed up by phone or clinic visit, 
whichever is the institution’s normal standard of care, every 3 months for a maximum of 5 years 
from the last subject’s first dose, regardless of new anticancer treatment or HSCT, for SPMs, 
safety issues (any drug-related SAEs), 
 and start of new anticancer 
therapies.
Optional Extension Phase
Upon completion of 12 cycles of lenalidomide therapy per protocol, subjects who are 
demonstrating clinical benefit as assessed by the Investigator and who do not meet any of the 
criteria for treatment discontinuation (see Section 12) may enter the optional extension phase 
(OEP).
Details for the OEP are provided in Appendix L.
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235


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
39
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Figure 1:
Overall Study Design
Screening Phase
Treatment Phase
Follow-up Phase
Day -14 to 0
Up to 5 years from last subject first dose
Adverse Events per protocol
Study Eligibility 
& ICF/IAF 
Signature
Stage 1a: n = 18 subjects
Lenalidomide
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Long Term – SAEs, 
 HSCT and 
anticancer therapies phone call or clinic 
visit
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last subject’s first dose.
5 years after Last Subject first dose
28-day cycle
28 days after last dose
AML = Acute Myeloid Leukemia; HSCT = Hematopoietic Stem Cell Transplant; IAF = Informed Assent Form; ICF = Informed Consent Form;
 
; Max = Maximum; 
; SAE = Serious Adverse Event
a If 3 or more subjects in Stage 1 achieve a morphologic complete response (either complete response or complete response with incomplete blood count 
recovery) within the first 4 cycles, the study will proceed to Stage 2.
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352


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
40
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
4.2.
Study Design Rationale
The main objective of the proposed study is to establish the preliminary activity of lenalidomide
in pediatric subjects with rrAML, specifically looking at the morphologic complete response, 
defined as either CR or CRi, within the first 4 cycles of lenalidomide treatment.
The present study is a Phase 2 study based on Simon’s Optimal two-stage design enabling 
assessment of the overall response rate (ORR) in this subset of pediatric subjects while providing 
the opportunity of early stopping in the event of lack of activity with regards to the ORR being 
observed.
4.3.
Starting Dose Rationale
The proposed initial starting dose for pediatric patients with relapsed or refractory AML aims to 
produce daily plasma AUC close to that observed in adult AML patients treated with 
lenalidomide at 50 mg/day dose.  Data from 2 pediatric Phase 1 studies conducted by 
 and 
the Pediatric Brain Tumor Consortium demonstrate that lenalidomide is well-tolerated at doses 
up to 116 mg/m2/day (Berg, 2011; Warren, 2011).  Pharmacokinetic data from the 
 study 
indicate that the PK parameters in the pediatric subjects (5 to 18 years of age) were generally 
similar to those in adult patients (Berg, 2011).  However, the effect of the growth-dependent 
changes in the body size on lenalidomide clearance (plasma exposure) and volume distribution is 
expected in the 1 to < 5-year-old age group of pediatric patients.  The impact of growth on 
plasma lenalidomide exposure has been taken into account when considering the weight-based 
dose for this study.
Since two Phase 1 pediatric studies have demonstrated that lenalidomide safety profiles in 
pediatric patients are similar to those observed in adult patients (Berg, 2011; Warren, 2011), the 
pediatric AML dose in this proposed study was extrapolated from the adult lenalidomide 
experience in AML trials.  Both the MTD and the active dose of lenalidomide is 50 mg/day in 
adult AML subjects.  Thus, a lenalidomide dose that produces plasma AUC level approximating 
the AUC in adult AML subjects treated with 50 mg/day is considered a reasonable initial starting 
dose for this pediatric study.
By combining available data from pediatric and adult subjects, a population PK model that 
incorporates the impact of body weight on lenalidomide clearance and volume of distribution 
was developed.   Monte Carlo simulations were conducted using the fixed and random effect 
parameters from this population PK model to predict lenalidomide plasma exposure parameters 
at the dose proposed for pediatric subjects.  As summarized in Table 1, the predicted mean 
AUC∞in pediatric subjects > 5 years of age would be close to the target AUC.   Although the 
predicted AUC for subjects 1 to < 5 years old was slightly lower, the predicted Cmax is similar to 
that of adult AML subjects.  Since the activity of lenalidomide was also observed at a lower dose 
of 25 to 35 mg/day in adult AML subjects (Blum, 2010), the lenalidomide exposure at 2 
mg/kg/day is expected to remain within the therapeutic range for the age group of 1 to < 5 years.  
The safety profile of high-dose lenalidomide remains largely unknown for the age group of < 5 
years and a conservative approach (ie, slightly lower AUC) is considered the most acceptable 
approach.
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2


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
41
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Table 1:
Predicted Lenalidomide Plasma Exposure in Pediatric Subjects
Lenalidomide Dose
Study Population
AUC∞(h*ng/mL)
Cmax (ng/mL)
2 mg/kg, not 
exceeding 70 mg/day
Pediatric patients
1 to < 2 years
3029 (25.7)
758 (19.2)
2 to < 3 years
3461 (25.1)
852 (18.6)
3 to < 4 years
3855 (24.9)
944 (18.5)
4-5 years
4420 (32.7)
1069 (26.5)
6-11 years
5871 (30.7)
1343 (23.7)
12-18 years
5988 (26.0)
1222 (21.9)
50 mg/day
AML adults
5509 (37.9)
946 (40.4)
AML = acute myeloid leukemia; AUC∞= area under the plasma concentration-time curve from time zero 
extrapolated to infinity; Cmax  = maximum plasma concentrations.
Data for pediatric population are predicted from the population PK model and expressed as geometric mean 
(geometric CV%); data for AML adults are from literature (Blum, 2010) and expressed as mean (CV%).
4.4.
Study Duration 
Enrollment is expected to last approximately 40 months with an accrual rate of 1 to 2 subjects 
per month.  Once 4 subjects having received at least one dose of lenalidomide have completed at 
least 1 cycle of study treatment or discontinued treatment (whichever occurs first), the DMC will 
evaluate the safety data available and provide a recommendation. At the end of Stage 1 and 
following safety and treatment activity data review, the DMC will provide recommendations 
about the continuation of the study from Stage 1 to Stage 2 (continue as planned, continue with 
modifications or stop treatment and/or enrollment) and advise on ways to improve quality.  
Subjects demonstrating clinical benefit as per the Investigator at the end of Cycle 4 and beyond 
may continue to receive lenalidomide on study up to 12 cycles in the absence of protocol-defined 
toxicity or transitioning to allogeneic HSCT. Once lenalidomide has been discontinued, subjects 
will be followed up to 5 years from the last subject’s first dose, unless consent is withdrawn, the 
subject is lost to follow-up or dies.
4.5.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary 
 analysis, as prespecified in the protocol, 
whichever is the later date.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
42
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
5.
TABLE OF EVENTS
Table 2:
Table of Events
Screening 
Phase
Day -14 
to 0
Treatment Phasea
Follow-up 
Phasea
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle
5-12
OEPβ
Treatment
Discontinuation
28-
day
LT 
F/U
Day
Day
Day
Day
Day
Procedure
1
2
4
8
15
22
1
8
15
22
1
22
1
22
1
22
Study Entry Assessment
Informed consent/assent 
(ICF/IAF)
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Inclusion/Exclusion 
Evaluation
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Medical History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
12-Lead ECGb
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Urinalysisb
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Chest X-rayc
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Prior Treatments and 
Medicationsd
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Lansky/Karnofsky
Performance Status
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
-
-
X
-
-
Echocardiography
X
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
Xe
-
X
-
-
Confirmation of rrAMLf
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Enrollment
-
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
43
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Table 2:
Table of Events (Continued)
Screening 
Phase
Day -14 
to 0
Treatment Phasea
Follow-up 
Phasea
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5-
12
OEPβ
Treatment
Discontinuation
28-
day
LT 
F/U
Day
Day
Day
Day
Day
Procedure
1
2
4
8
15
22
1
8
15
22
1
22
1
22
1
22
Safety Assessment
Adverse Events
After signing ICF/IAF and until 28-day Follow-up Visit
-
Assessment of Second 
Primary Malignancyg
After signing ICF/IAF and for 5 years from last subject, first dose
Physical Examination 
(including Vital Signs)b
X
X
-
-
X
X
X
X
-
X
-
X
-
X
-
X
-
-
X
X
-
Height
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Body Weight
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
-
-
-
-
-
Hematology (including 
Manual Differential with 
Blast count)h
X
X
-
-
X
X
X
X
X
X
X
X
-
X
-
X
-
-
X
X
-
Serum Blood Chemistryh
X
X
X
X
X
X
X
X
X
X
X
X
-
X
-
X
-
-
X
X
-
Serum Pregnancy Testing 
(FCCBP/FCBP)i
X
X
-
-
X
X
X
X
-
-
-
X
-
X
-
X
-
X
X
X
-
Lenalidomide Counselingj
X
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
-
X
X
X
-
Concomitant Medications 
and Proceduresk
After signing ICF/IAF and until 28-day Follow-up Visit
-
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
44
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Table 2:
Table of Events (Continued)
Screening 
Phase
Day -14 
to 0
Treatment Phasea
Follow-up 
Phasea
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5-
12
OEPβ
Treatment
Discontinuation
28-
day
LT 
F/U
Day
Day
Day
Day
Day
Procedure
1
2
4
8
15
22
1
8
15
22
1
22
1
22
1
22
IP Administration and Compliance
IP dispensingl
-
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
-
X
-
-
-
IP accountabilitym
-
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
-
X
X
-
-
Treatment Activity Assessment
Bone Marrow Aspirate
Xn,q
-
-
-
-
-
Xr
-
-
-
Xr
-
Xr
-
Xr
-
Xr,s
-
Xu
-
-
Bone Marrow Biopsyo
Xn,q
-
-
-
-
-
Xr
-
-
-
Xr
-
Xr
-
Xr
-
Xr,s
-
Xu
-
-
Peripheral Blood smear 
(CBC + Cytology) 
Sampling
Xq
-
-
-
-
-
Xr
-
-
-
Xr
-
Xr
-
Xr
-
Xr,s
-
Xu
-
-
IWG Response Assessment
-
-
-
-
-
-
Xr
-
-
-
Xr
-
Xr
-
Xr
-
Xr,s
-
Xu
-
-
Cytogenetic Testing/ 
FISHp,t
X
-
-
-
-
-
X
-
-
-
X
-
X
-
X
-
X
-
Xu
-
-
Follow-up Anticancer
Therapies
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
X
 SAE, HSCT 
Follow-up
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
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0$
0$
0$
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25
25
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X
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-
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( 352


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
45
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Table 2:
Table of Events (Continued)
Screening 
Phase
Day -14 
to 0
Treatment Phasea
Follow-up 
Phasea
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5-
12
OEPβ
Treatment
Discontinuation
28-
day
LT 
F/U
Day
Day
Day
Day
Day
Procedure
1
2
4
8
15
22
1
8
15
22
1
22
1
22
1
22
Other Assessments
PK Sampling (blood)z
-
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Intrathecal (IT) Cytarabineα 
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
OEP Eligibility Criteriaβ
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
AE = adverse event; AML = acute myeloid leukemia; BMA = bone marrow aspirate; CBC = complete blood count; CNS = central nervous system; 
 
; CRF = case report form; CR = complete response; CRi = CR with incomplete blood count recovery; CSF = cerebrospinal fluid; ECG = electrocardiogram; FCBP = 
Female of Childbearing Potential; FCCBP = Female Children of Childbearing Potential; FISH = Fluorescent In Situ Hybridization; F/U = follow-up; HSCT = hematopoietic 
stem cell transplantation; IAF = informed assent form; ICF = informed consent form; IP = investigational product; IT = intrathecal; IWG = International Working Group;
 
; LT = long term; 
; OEP = Optional Extension Phase; 
; PK = pharmacokinetics; rrAML = 
relapsed/refractory acute myeloid leukemia; SAE = serious adverse event; SPM = second primary malignancy.
a
Study visit window is ± 3 days in the Treatment Phase, unless noted otherwise for a particular assessment. Study visit windows should take into account the subject’s 
investigational product supply.  Only enough lenalidomide for 1 cycle of therapy will be dispensed with each cycle of therapy.  In the Follow-up Phase, the study visit window 
is ± 7 days.
b
Additionally, ECG, urinalysis, and physical exam (including vital signs) can be performed at any unscheduled visits (only if clinically indicated).
c
Chest X-ray is not needed if a previous chest X-ray taken within 4 weeks prior to Day 1 of Cycle 1 is available and not clinically significant, otherwise a chest X-ray will be 
performed at screening.
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serious adve
serious adv
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ugh lenalido
physical exam
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previous chest 
revious chest
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0$
0$
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( 3


EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
46
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
d
All prior medications/procedures (including chemotherapy, cytotoxic therapy, radiotherapy and HSCT) related to AML or any malignancy, and received at any point in the 
subject’s history, should be recorded on the CRF at screening, regardless of time.  All other prior medications/procedures used within 14 days of signing the ICF/IAF should 
also be recorded.
e
An echocardiogram will be performed at screening, at the end of Cycles 4 and 12 and at the Treatment Discontinuation Visit.
f
All dates of relapse and/or refractory diagnosis should be recorded (at least 2 required).  Disease relapse (rrAML) will be retrospectively confirmed by a central reviewer at 
screening.
g
Second primary malignancies will be monitored as events of interest and must be reported as SAE’s.  This includes any SPM, regardless of causal relationship to lenalidomide.
h
Hematology and chemistry assessments will be conducted locally. Whenever a hematology sample is collected for a CBC, a peripheral blood smear (Cytology) will be used to 
assess a manual blood count differential including blast count.  Only select analytes will be recorded in the CRF.
i
Female Children of Childbearing Potential is defined as females who have achieved menarche and/or breast development in Tanner stage 2 or greater, and have not undergone 
a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries). Note: Amenorrhea following cancer therapy does not rule 
out childbearing potential.  Female of Childbearing Potential is defined as a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy, has not 
been naturally postmenopausal (amenorrhea following cancer does not rule out childbearing potential) for at least 24 consecutive months.
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for FCCBP/FCBP, including those who commit to complete abstinence.  
FCCBP/FCBP must have 2 negative pregnancy tests (with sensitivity of at least 25 mIU/mL) prior to starting lenalidomide.  The first pregnancy test must be performed within 
10 - 14 days prior to the start of lenalidomide and the second pregnancy test must be performed within 24 hours prior to the start of lenalidomide.  
NOTE: The pregnancy test 10 to 14 days prior to initiation of lenalidomide may be omitted, at the discretion of the investigator, for any FCCBP/FCBP who has high acuity 
disease requiring immediate treatment with lenalidomide. The pregnancy test within 24 hours prior to the first dose of lenalidomide is required to be performed.
FCCBP/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 IP 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 IP discontinuation.  The subject may not receive lenalidomide until the Investigator has 
verified that the result of the pregnancy test performed on Day 1 of every cycle is negative.
j
Subjects (FCCBP/FCBP) must be counseled about pregnancy precautions and risks of fetal exposure at a minimum of every 28 days. They must also be counseled against 
sharing lenalidomide and donating blood, semen or sperm during therapy and within 28 days after Treatment Discontinuation.  Pregnancy counseling and potential risks must 
be conducted on Day 1 of each cycle prior to lenalidomide dispensing.
k
All concomitant over-the-counter/prescription medications/procedures, and intravenous medications taken from signing of the informed consent up to 28 days after the last 
dose of lenalidomide must be recorded on the appropriate CRF.
l
Lenalidomide should be dispensed on Day 1 of each cycle.  Only enough lenalidomide for 1 cycle of therapy will be dispensed with each cycle of therapy.  The first dose of 
lenalidomide should be taken only after all Day 1 procedures have been completed with the exception of the collection of PK sampling.
m
Lenalidomide accountability should be assessed before IP dispensing for each treatment cycle.
n
A fresh bone marrow aspirate (and/or a fresh bone marrow biopsy paraffin embedded slides) will be collected at screening from all subjects for confirmation of 
relapsed/refractory disease.
o
A bone marrow biopsy is required only if a bone marrow aspirate cannot be obtained.
p
A standard cytogenetic metaphase preparation from the fresh BMA must be prepared for the local cytogenetic testing/chromosome analysis including karyotype.  The local site 
will submit the reports of the karyotype, FISH studies, as well as any available data on molecular mutations (FLT3, CEPBa, NPM1, and others including exome sequencing via 
Foundation Medicine or other sources) if performed to the central reviewer for retrospective review at Screening only.  If subjects have a FISH detectable marker, the test 
should be repeated until CR/CRi and at relapse.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
47
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
q
The screening BMA slide (and/or bone marrow biopsy paraffin embedded slide) and peripheral blood smear slide must be provided to the central reviewers at the 
 
  The central review 
 will provide standardized analysis and reporting for all subjects.  The central reviewer’s assessment will be used 
retrospectively to confirm diagnosis. In the case where a study center has an IRB- and Celgene-approved procedural ICF/IAF that allows collection of additional bone marrow 
samples for potential research purposes, the latest pre-study PB and BM aspirate/biopsy may be used for screening study assessments. 
r
BMA/biopsy and peripheral blood smear must be collected at the completion of the 21-day treatment period within 6 days before dosing for the subsequent cycle (ie, 
between Day 22 to Day 27 of that cycle) in Cycles 1, 2, 3 and 4.  If morphologic CR/CRi is achieved within the first 2 cycles, the BMA/biopsy and peripheral blood smear will 
not be required at the end of Cycle 3. These assessments are required for all subjects at the end of Cycle 4, and at the Treatment Discontinuation Visit or at the time of 
suspected relapse (whichever occurs first).  An IWG response assessment will be performed whenever a bone marrow assessment is performed.
s
For subjects who are assessed as having partial response, the BMA/biopsy and peripheral blood smear will be repeated at Cycle 8 unless the subject goes to allogeneic HSCT, 
and at the Treatment Discontinuation Visit or at the time of suspected treatment failure (whichever occurs first).
t
During the study, repeat of bone marrow local cytogenetic/FISH testing is to be completed whenever a bone marrow aspirate/biopsy is obtained.  However, if the 
cytogenetics/FISH results are ‘normal’ at screening or at any point during the study, no further cytogenetic/FISH analysis is required, except at the Treatment Discontinuation 
Visit or at the time of relapse (whichever occurs first).
u
Bone marrow aspirate/biopsy, peripheral blood smear, cytogenetic testing, and an IWG response assessment will be measured at the Treatment Discontinuation Visit or at the 
time of suspected relapse (whichever occurs first). If clinically inappropriate per the treating site, the subject may have bone marrow evaluation omitted if peripheral blast 
results are collected.
 
 
  
 
 
 
 
z
Blood PK sampling time points are specified in Table 3.  
α
As per routine standard of care, intrathecal cytarabine (age-based dosing) will be administered to all subjects within 2 weeks prior to administration of lenalidomide. For 
subjects without CNS involvement, subsequent intrathecal chemotherapy may be administered at the discretion of the treating physician. For subjects with CNS involvement 
at screening, intrathecal cytarabine will be administered twice weekly x 4 doses and until CSF is clear on 2 consecutive evaluations for up to a total of 6 doses. Subsequent 
intrathecal cytarabine may be administered at the discretion of the treating physician. Subjects who have persistent CNS disease despite 6 doses of intrathecal cytarabine will
be off study treatment.
β
See Appendix L - During the OEP, only AEs/SAEs, IP dispensing and accountability, concomitant medications/procedures, and SPMs will be monitored.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
48
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
6.
PROCEDURES
All procedures will be performed as outlined in the table of events (Table 2).
6.1.
Screening, Study Entry and Treatment Procedures
Pediatric subjects from 1 to ≤ 18 years of age with rrAML will be considered for participation in 
this study.  The subject(s) and/or guardian(s) (as appropriate by local law and regulations) will be 
provided with a written ICF or IAF, given the opportunity to ask any questions concerning the 
study and will sign an ICF or IAF prior to participating in any study procedures.
All subjects who sign an ICF/IAF or children of parents and/or guardians who sign the parental 
consent must be screened into the IWRS immediately upon signature.
After giving written informed consent/informed assent, subjects will undergo screening 
assessments to be assessed for study eligibility.  Subjects who do not meet the eligibility criteria 
or who withdraw (for any reason) during the Screening Phase will be considered screen failures 
(sites should log onto the IWRS immediately to screen fail the subject in the system).  Study-
specific medical procedures to confirm eligibility are to be performed after signing ICF/IAF and 
must take place within 14 days prior to Cycle 1 Day 1.
Subjects who fail screening may be rescreened at any time, and as considered appropriate, at the 
Investigator’s discretion.  For subjects who are rescreened, a new ICF/IAF will need to be signed 
and screening procedures will need to be repeated if originally more than 14 days prior to the 
rescreen date.
6.2.
Administration of Intrathecal Cytarabine
Intrathecal cytarabine (age-based dosing) will be administered prior to Cycle 1 in all subjects at 
the time of screening through lumbar puncture.  Intrathecal cytarabine will be given within 2 
weeks prior to administration of lenalidomide:
!
For subjects without CNS involvement, subsequent intrathecal cytarabine may be 
administered at the discretion of the treating physician.
!
For subjects with CNS involvement at screening, intrathecal cytarabine will be 
administered twice weekly x 4 doses and until CSF is clear on 2 consecutive 
evaluations for up to 6 total doses.  
#
Subjects whose CSF was cleared may then receive subsequent intrathecal 
cytarabine doses at the discretion of the treating physician
#
Subjects who have persistent CNS disease despite 6 doses of intrathecal 
cytarabine will be off study treatment.
6.3.
Demographics and Medical History
Demographics including gender, race, ethnicity, and date of birth (DOB) (where allowed by local 
regulations) will be documented at screening only. Race designations should include American 
Indian or Alaska native; Asian; Black or African American; Native Hawaiian or other Pacific 
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6.3.


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
49
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Islander; or White.  For Ethnicity, designations will include Hispanic/Latino or Not 
Hispanic/Latino.
Relevant medical history for the past (up to 5 years) including current disease and the date of 
initial AML diagnosis will be recorded on the respective CRF at screening.
6.4.
Prior Medications/Procedures
All prior medications/procedures (including chemotherapy, cytotoxic therapy, radiotherapy and
HSCT) related to AML or any malignancy, and received at any point in subjects history should 
be recorded on the CRF at screening, regardless of time. All other prior medications/procedures 
used within 14 days of signing the ICF/IAF should also be recorded.
6.5.
Confirmation of Disease Relapse
Disease diagnosis/relapse including morphology will be reviewed locally at screening from all 
subjects and retrospectively confirmed by a central reviewer using bone marrow aspirate slide
(or bone marrow biopsy paraffin embedded slide) and peripheral blood smear slide.  All dates of 
AML relapse or refractory status should be recorded, this should be at least 2 separate 
occurrences per study entry criteria. In the case where a study center has an IRB- and Celgene-
approved procedural ICF/IAF that allows collection of additional bone marrow samples for 
potential research purposes, the latest pre-study PB and BM aspirate/biopsy may be used for 
screening study assessments.
Results from cytogenetics, FISH studies, flow cytometry studies, and molecular studies 
performed locally at initial diagnosis and/or relapse will be reported including FISH for t(16;16), 
t(8;21), MLL (11q23), t(15;17), monosomy 7, del(5q), or any other recurring abnormalities and 
presence or absence of mutations in Fms-like tyrosine kinase 3 (FLT3), or Nucleophosmin 
(NPM1), CCAAT/enhancer-binding protein alpha (CEBP-alpha).  If exome sequencing has been 
performed by the local site (eg, Foundation Heme or other CLIA-approved clinical sequencing 
platform), the results will be reported.
6.6.
Vital Signs
Vital signs (including sitting blood pressure, heart rate, respiration, and temperature) will be 
measured at screening, on Days 1, 8, 15, and 22 of Cycle 1, bi-weekly during Cycle 2, on Day 1 
of every cycle thereafter, at the Treatment Discontinuation Visit, on the 28-day Follow-up Visit, 
and at any unscheduled visits (only if clinically indicated).
6.7.
Physical Examinations
All subjects will have a complete routine physical examination at screening, on Days 1, 8, 15, 
and 22 of Cycle 1, bi-weekly during Cycle 2, and on Day 1 of every cycle thereafter, at the 
Treatment Discontinuation Visit, on the 28-day Follow-up Visit, and at any unscheduled visits 
(only if clinically indicated).
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
50
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
6.8.
Pregnancy Testing and Pregnancy Risk and Lenalidomide 
Counseling
Medically supervised serum pregnancy tests with a sensitivity of at least 25 mIU/mL must be 
conducted in FCCBP/FCBP, including those who commit to complete abstinence. FCCBP
defined as a female who has achieved menarche and/or breast development in Tanner stage 2 or 
greater and has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral 
oophorectomy (the surgical removal of both ovaries). FCBP defined as a sexually mature 
woman who has not undergone a hysterectomy or bilateral oophorectomy and has not been 
naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in 
the preceding 24 consecutive months).  FCCBP/FCBP must have 2 negative pregnancy tests 
(with sensitivity of at least 25 mIU/mL) prior to starting lenalidomide.  The first pregnancy test 
in both FCCBP and FCBP must be performed within 10 – 14 days prior to the start of 
lenalidomide (Screening Phase) and the second pregnancy test must be performed within 24 
hours prior to the start of lenalidomide (Cycle 1 Day 1).  
NOTE: The pregnancy test 10 to 14 days prior to initiation of lenalidomide may be omitted, at 
the discretion of the investigator, for any FCCBP/FCBP who has high acuity disease requiring 
immediate treatment with lenalidomide. The pregnancy test within 24 hours prior to the first 
dose of lenalidomide is required to be performed.
Amenorrhea following cancer therapy does not rule out childbearing potential.
FCCBP/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 Treatment
Discontinuation Visit, and at Day 28 following IP 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 Treatment Discontinuation Visit, and at Days 14 and 28 following IP
discontinuation.
Note: The subject may not receive lenalidomide until the Investigator has verified that the result 
of the pregnancy test performed on Day 1 of every cycle is negative.  See inclusion criteria 
(Section 7.2) for pregnancy testing requirements.
At each visit, the Investigator must confirm with the FCCBP/FCBP that she is continuing to use 
2 reliable methods of birth control if not committing to complete abstinence or plans not to 
commit to complete abstinence.  Counseling about pregnancy precautions and the potential risks 
of fetal exposure to lenalidomide must be conducted at screening, on Day 1 of each cycle prior to 
lenalidomide dispensing and at a minimum of every 28 days, at the Treatment Discontinuation 
Visit, and at the 28-day Follow-up Visit.  If pregnancy or a positive pregnancy test does occur in 
a study subject, lenalidomide must be immediately discontinued.  Pregnancy testing and 
counseling must be performed if a subject misses her period or if her pregnancy test or her 
menstrual bleeding is abnormal.  IP treatment must be discontinued during this evaluation.  
Female children and adult females must agree to abstain from breastfeeding during study 
participation and for at least 28 days after IP discontinuation.  If pregnancy or a positive 
pregnancy test does occur in the partner of a male study subject during study participation, the 
Investigator must be notified immediately.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
51
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Any pregnancies that occur in (FCCBP/FCBP) subjects while the subject is in the Treatment 
Phase, or within 28 days thereafter, are considered immediately reportable events (see Section 
11.4).  Furthermore, FCCBP/FCBP and male subjects that have reached puberty must agree to 
undergo physician-approved reproductive education and discuss the side effects of lenalidomide 
on reproduction with parent(s) and/or guardian(s).  Pregnancy testing is not required for non-
FCCBP subjects, unless deemed necessary by the Investigator.
6.9.
Performance Status
The performance status, depending on age, will be measured using the Karnofsky performance 
status score for subjects ≥ 16 years or Lansky performance status score for subjects < 16 years
(Appendix E and Appendix F, respectively) at screening, on Day 1 of every cycle and at the
Treatment Discontinuation Visit.
6.10.
Echocardiography
An echocardiography will be performed at screening, at the end of Cycles 4 and 12 and at the 
Treatment Discontinuation Visit.  If clinically indicated, echocardiography may be repeated 
during the study at the discretion of the Investigator.
6.11.
Electrocardiogram
An electrocardiogram will be done at screening and at any unscheduled visits (only if clinically 
indicated).
6.12.
Height and Weight
Height will be collected only at screening and on Cycle 1 Day 1. However, weight will be 
collected at screening and Day 1 of every cycle for dose adjustment if weight changes by 10% or 
more during the Treatment Phase.
6.13.
Chest X-ray
A chest X-ray is not needed if a previous chest X-ray taken within 4 weeks prior to Day 1 of 
Cycle 1 is available and not clinically significant, otherwise a chest X-ray will be performed at 
screening.
6.14.
Laboratory Assessments
Laboratory testing will be performed locally at the study sites. It is the responsibility of the 
Investigator to assess the clinical significance of all abnormal values as defined by the reference 
ranges from the laboratory. Requirements for reporting laboratory abnormalities as AEs can be 
found in Section 11.3. Laboratory parameters outside the normal range, which are judged by the 
Investigator to be clinically significant (eg, those which require concomitant therapy or 
procedures, changes in study treatment or further diagnostic measures) will be recorded as AEs
in the CRF.  This does not hold true if the laboratory abnormality in the view of the Investigator
is caused by the underlying disease.  Clinically significant laboratory abnormalities at screening 
may result in a subject being ineligible for the study and should not be captured as an AE.  Any 
abnormal values that persist should be followed at the discretion of the Investigator.  The 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
52
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Investigator should file all copies of the local laboratory reports including faxes with the 
subject’s medical chart.
6.14.1.
Hematology Laboratory Assessments
Hematology testing including red blood cell (RBC) count, hemoglobin, hematocrit, mean 
corpuscular volume (MCV), WBC count and manual differential count (including blasts %, 
immature myeloid, absolute monocyte count, absolute neutrophil count [ANC]), and platelet 
count will be evaluated by the local laboratory at screening, on Days 1, 8, 15, and 22 of Cycles 1 
and 2, on Day 1 of every cycle thereafter, at the Treatment Discontinuation Visit, on the 28-day 
Follow-up Visit, and at unscheduled visits (if clinically indicated).  White blood cell count,
absolute neutrophil count, absolute blast count, and platelet count will be recorded in the CRF, 
all other hematology laboratory values will not be collected on a laboratory CRF; instead, 
laboratory abnormalities that are considered AEs should be reported as AEs on the AE CRF (see 
Section 11).  Whenever a hematology sample is collected for a complete blood count (CBC), a 
peripheral blood smear will be used to assess a manual blood count differential.
6.14.2.
Chemistry Laboratory Assessments
Serum chemistries including sodium, potassium, chloride, bicarbonate, calcium, phosphorus, 
blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase, 
total bilirubin, direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), and lactate dehydrogenase (LDH), and uric acid will be evaluated by the local laboratory 
at screening, on Days 1, 2, 4, 8, 15, and 22 of Cycle 1, on Days 1, 8, 15, and 22 of Cycle 2, on 
Day 1 of every cycle thereafter, at the Treatment Discontinuation Visit, on the 28-day Follow-up 
Visit, and at unscheduled visits (if clinically indicated).  Serum chemistry laboratory values will 
not be collected on a laboratory CRF; instead, laboratory abnormalities that are considered AEs
should be reported on the AE CRF (see Section 11).
6.14.3.
Urinalysis (dipstick)
Urinalysis will include at a minimum specific gravity, pH, glucose, protein, ketones, blood, 
leukocyte esterase and nitrites, and will be performed at screening and at unscheduled visits (if 
clinically indicated).  A microscopic examination (including casts, RBCs, and WBCs) should be 
performed in the event of a positive result for (at a minimum): blood, leukocyte esterase, or 
nitrites.
6.15.
Concomitant Medications/Procedures
All subjects will have concomitant medications and procedures recorded from the time of 
signing the ICF/IAF until the 28-day Follow-up Visit.  A complete list of all medications 
(prescription, over the counter, nutritional, fiber supplements, etc.), dose, dosing regimen, and 
start and stop dates used prior to and during the study will be recorded on the CRF.  Refer to 
Section 9 for a listing of permitted and prohibited concomitant medications.
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EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
53
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
6.16.
IP Administration
Investigational product administration will be accurately recorded including, but not limited to, 
date of administration, dose and any changes in dosage administration (eg, interruption or 
reduction in dosing due to an AE).
Females of child bearing potential (FCBP) should not handle or administer lenalidomide unless 
they are wearing gloves.  All subjects should not extensively handle the lenalidomide capsules or 
oral suspension. The lenalidomide capsules should not be broken, chewed, or opened and should 
be maintained in the packaging until ingestion. Refer to the subject diary and the manual on
preparation, administration, and handling of the lenalidomide oral suspension for specific details.
In investigational studies, lenalidomide will be dispensed through a qualified healthcare 
professional (including but not limited to, nurses, pharmacists and physicians).  These healthcare 
professionals will be trained by Celgene in requirements specific to counseling of 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 for FCBP) and that the subject understands the risks associated with 
lenalidomide.  This step will be documented with a completed Education and Counseling 
Guidance Document 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 will be supplied each time lenalidomide is dispensed.
6.17.
IP Dispensing
Lenalidomide should be dispensed on Day 1 of every cycle including the OEP.  Only enough 
lenalidomide for 1 cycle of therapy will be dispensed with each cycle of therapy.  The first dose 
of lenalidomide will be administered at the study center after the completion of all clinical 
procedures required for Cycle 1 Day 1 with the exception of the collection of PK sampling.  
When multiple capsules are required to make up the accurate daily dosage, detailed instructions 
will be provided to the subject to ensure accurate dosages are taken (Appendix B).
Refer to Appendix C for dosing guidelines for the lenalidomide oral suspension.
Detailed instructions on preparation, administration, and handling of the lenalidomide oral 
suspension will be provided in a separate manual. 
6.18.
IP Accountability
All IP that is dispensed during the course of the study will be reconciled and accounted for by the 
Investigator (or designee).  Applicable information such as lot number, date dispensed, numbers 
of capsules or vials dispensed, date returned, the number of capsules returned, or number of vials
returned should be collected as well as information provided by the subject or the caregiver (eg, 
subject dosing diary). IP accountability should be completed on Cycle 1 Day 1, at the end of
every treatment cycle (eg, on Day 1 of Cycle 2, Day 1 of Cycle 3), at the end of every cycle in 
the OEP if treatment continues beyond 12 cycles, and at the Treatment Discontinuation Visit.
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EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
54
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
6.19.
Information to be Collected on Screen Failures
The informed consent date, demographics, reason subject did not qualify for the study and the 
Investigator’s signature will be collected for all subjects determined to be screen failures. If the 
reason for the screen failure is an AE, the AE and concomitant medications used to treat the AE
will be recorded on the CRF and captured in the subject’s source documents from the date of 
signing informed consent to the day the subject is confirmed to be a screen failure.  Relevant 
information will also be recorded on the Screening Log.
6.20.
Treatment Activity
The primary endpoint consists of the assessment of the morphologic complete response rate
within the first 4 cycles of study treatment with lenalidomide.  Morphological complete response 
is defined as CR or CRi.  These response criteria will be determined using the revised AML IWG 
criteria (Cheson, 2003) (Appendix D).
6.20.1.
Bone Marrow Aspirate or Biopsy and Peripheral Blood
To determine morphologic CR/CRi, BMA/biopsy and peripheral blood smear must be collected 
from all subjects at screening and at the completion of the 21-day treatment period of the 
predefined treatment Cycles 1, 2, 3 and 4 within 6 days before dosing for each subsequent 
cycle (ie, between Day 22 to Day 27 of that cycle) (Table 2).  If morphologic CR/CRi is 
achieved within the first 2 cycles, BMA/biopsy and peripheral blood smear will not be required 
at the end of Cycle 3.  For all subjects, BMA/biopsy and peripheral blood smear must be 
performed at the completion of Cycle 4, and at the Treatment Discontinuation Visit or at the time 
of suspected relapse (whichever occurs first).  For subjects who are assessed as having partial 
response, the BMA/biopsy and peripheral blood smear will be repeated at Cycle 8 unless the 
subject goes to allogeneic HSCT, and at the Treatment Discontinuation Visit or at the time of 
suspected treatment failure (whichever occurs first).   A bone marrow biopsy is required only if 
a bone marrow aspirate cannot be obtained. Subjects demonstrating clinical benefit as per the 
Investigator at the end of Cycle 4 and beyond may continue to receive lenalidomide on study for 
up to 12 cycles in the absence of protocol-defined toxicity or transitioning to allogeneic HSCT.
In the case where a study center has an IRB- and Celgene-approved procedural ICF/IAF that 
allows collection of additional bone marrow samples for potential research purposes, the latest 
pre-study PB and BM aspirate/biopsy may be used for screening study assessments.
The screening BMA slide (and/or bone marrow biopsy paraffin embedded slide) and peripheral 
blood smear slide must be provided to the central reviewers at 
.  The central review 
 
will provide standardized analysis and reporting for all subjects.  The central reviewer’s 
assessment will be used retrospectively to confirm diagnosis.
 
In addition, BMA/biopsy will be obtained to confirm CR, CRi, partial remission (PR), or 
treatment failure, as assessed by the Investigator based on complete blood count [CBC] with 
white blood cell (WBC) differential results (defined in Appendix D).  Morphological response 
will be assessed based on peripheral blood count recovery and morphologic assessment of 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
55
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
BMAs/biopsies (Table 2). Assessments to be collected during the Follow-up Phase will include 
new anticancer therapies, HSCT, SPMs, SAEs, 
.
For screening assessments, instructions for submission of pathology data (flow cytometry, 
reports of cytogenetics and FISH) to 
, central reviewer, are provided in Appendix I.
 
 
 
 
6.20.3.
Cytogenetics/FISH
A bone marrow aspirate sample for cytogenetics testing/chromosome analysis/FISH testing for 
prior positive markers will be obtained to analyze karyotype at screening and whenever a 
BMA/biopsy is obtained at the completion of the 21-day treatment period of treatment cycles 
within 6 days before dosing for each subsequent cycle (ie, between Day 22 to Day 27 of that 
cycle), and at the Treatment Discontinuation Visit or at the time of suspected relapse (whichever 
occurs first).
During the study, a repeat of local testing of bone marrow cytogenetics and FISH for any 
positive markers is to be completed whenever a BMA/biopsy is obtained.  However, if the 
cytogenetics/FISH results are ‘normal’ at screening or at any point during the study, cytogenetic 
analysis is not required to be repeated except at the Treatment Discontinuation Visit or at the 
time of bone marrow evaluation for suspected relapse (whichever occurs first).
For the screening assessment, the cytogenetic files must be provided to the central reviewers at 
.  The central review 
will provide standardized analysis and reporting for all 
subjects. Instructions for submission of cytogenetics files to 
, central reviewer, are 
provided in Appendix I.
6.20.4.
Modified IWG Response
Modified International Working Group response (Appendix D) criteria will be used to assess
activity at the completion of predefined treatment Cycles 1, 2, 3 and 4 and at the Treatment 
Discontinuation Visit or at the time of suspected relapse (whichever occurs first).  An IWG 
response assessment will be performed whenever a bone marrow assessment is performed in 
order to confirm CR or CRi, PR, or treatment failure. For subjects who are assessed as having 
partial response, the IWG response will be repeated at Cycle 8 unless the subject goes to 
allogeneic HSCT, and at the Treatment Discontinuation Visit or at the time of suspected 
treatment failure (whichever occurs first).
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
56
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
6.21.
Safety
Safety assessments will consist of evaluating AEs, SAEs and concomitant medications/therapies 
used to treat them.  Safety assessments may include monitoring of any or all of the following 
parameters: subject’s clinical symptoms, physical examination findings, laboratory assessment of 
hematology and serum chemistry parameters, vital signs, performance status, ECG, 
echocardiogram, urinalysis, or pregnancy testing for FCCBP/FCBP, pathological, radiological or 
surgical findings, or other appropriate tests and procedures.
6.21.1.
Adverse Events Reporting
All AEs will be recorded by the Investigator from the time the informed consent/assent signing 
until 28 days after the last dose of lenalidomide, as well as those SAEs made known to the 
Investigator at any time thereafter that are suspected of being related to lenalidomide.  Adverse 
events, including second malignancies and cardiovascular events, will be monitored and reported 
throughout the reporting period as AEs/SAEs as applicable. Adverse events and SAEs will be 
recorded on the AE page of the CRF and in the subject’s source documents.  All SAEs must be 
reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by 
facsimile, or other appropriate method, using the SAE Report Form, or approved equivalent 
form.  For additional details see Section 11.
6.21.2.
Second Primary Malignancies
Second primary malignancies (SPMs) will be monitored as events of interest and should be 
included as part of the assessment of AEs throughout the course of the study. Investigators are to
report any SPM as SAEs regardless of causal relationship to lenalidomide, occurring at any time 
for the duration of the study, from the time of signing the ICF/IAF until all subjects have been 
followed for up to 5 years from the last subject’s first dose, unless consent is withdrawn, the 
subject is lost to follow-up or dies. Events of SPM are to be reported using the SAE report form 
and must be considered an “Important Medical Event” even if no other serious criteria apply; 
these events must also be documented in the appropriate page(s) of the CRF and subject’s source 
documents.  Documentation on the diagnosis of the SPM must be provided at the time of 
reporting as a SAE (eg, any confirmatory histology or cytology results, X-rays, computed 
tomography [CT] scans, etc.).
Information about common side effects already known about lenalidomide will be included in 
the subject informed consent form and should be discussed with the subject as needed during the 
study. This information can also be found in the Investigator’s Brochure (IB) or will be 
communicated between IB updates in the form of Investigator notifications.
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EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
57
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
6.22.
Treatment Discontinuation
All discontinued subjects, regardless of reason for discontinuation, should undergo treatment 
discontinuation procedures at the time of IP discontinuation. The treatment discontinuation 
procedures include physical examination, vital signs, echocardiogram, performance status, 
hematology, serum blood chemistry, pregnancy testing for FCCBP/FCBP, lenalidomide 
counseling, collections of AEs, concomitant medications and procedures, IP administration 
recording, and IP accountability. Bone marrow aspirate/biopsy, peripheral blood smear, 
cytogenetic testing, and IWG response assessment will be measured. If clinically inappropriate 
per the treating site, the subject may have bone marrow evaluation omitted if peripheral blast 
results are collected. The reason for discontinuation will also be documented in the CRF and in 
the source document.
6.23.
Follow-up Phase
Subjects will enter the Follow-up Phase at the time of permanent discontinuation of IP and will 
be followed for up to 5 years from the last subject’s first dose, unless the subject dies, withdraws 
consent or is lost to follow-up. The Follow-up Phase may not be terminated because of new 
anticancer treatment or HSCT.
A 28-day Follow-up Visit will occur 28 days after the subject’s last dose of IP.  At this visit, 
subjects will be monitored for the collection of AEs and concomitant medications/procedures 
used to treat the AEs, physical examination (including vital signs), hematology, serum blood 
chemistry, lenalidomide counseling, SPMs, and anticancer therapies.  Female Children of 
Childbearing Potential and FCBP will have a pregnancy test at the 28-day Follow-up Visit (see 
Section 6.8 and Section 7.2).
After the 28-day Follow-up Visit, subjects will be followed-up long term by phone or clinic visit, 
whichever is the institution’s normal standard of care, every 3 months for a maximum of 5 years 
from the last subject’s first dose, regardless of new anticancer treatment or HSCT, for SPMs, 
safety issues (any drug-related SAEs),
start of new 
anticancer therapies, and transition to HSCT.
6.24.
Optional Extension Phase
Upon completion of 12 cycles of lenalidomide therapy per protocol, subjects who are 
demonstrating clinical benefit as assessed by the Investigator and who do not meet any of the 
criteria for treatment discontinuation (see Section 12) may enter the optional extension phase 
(OEP).  Details for OEP are provided in Appendix L.
6.25.
Investigational Product Specific Safety Concerns To Be Monitored or
Assessed
Embryo-Fetal Exposure and PregnancyWarning: Lenalidomide is a chemical analog of 
thalidomide structurally related to thalidomide. Thalidomide is a known human teratogen that 
causes severe life-threatening birth defects. Lenalidomide induced malformations in monkeys 
similar to those described with thalidomide. If lenalidomide is taken during pregnancy, a 
teratogenic effect of lenalidomide in humans cannot be ruled out.
Sexually mature subjects will 
be required to adhere to the Celgene approved pregnancy prevention program. Additionally, all
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523


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
58
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
subjects and/or parents/guardians will be required to have an understanding that lenalidomide
could have a potential teratogenic risk. All FCCBP/FCBP and male subjects will be counseled 
about pregnancy precautions and risks of fetal exposure according to the REVLIMID REMS 
(Risk Evaluation and Mitigation Strategies) program (Lenalidomide IB).
Adverse Events of Specific Concern: Adverse events of specific concerns associated with the 
administration of lenalidomide observed in adults in marketed indications include:
!
Hematologic toxicity: Lenalidomide is associated with significant neutropenia and 
thrombocytopenia. Subjects may require dose interruption and/or dose reduction.
!
Deep vein thrombosis and pulmonary embolism: Physicians and subjects should be 
observant for signs and symptoms of thromboembolism. Subjects with a history of
non-catheter associated thromboembolic events or with a known genetic 
predisposition to thrombophilia (ie, Factor V Leiden mutation) will receive 
prophylactic anticoagulation with low-molecular-weight heparin (LMWH), or other 
appropriate medication. All other subjects enrolled on study will be considered for 
prophylactic antithrombotic treatment in accordance with local treatment practices, 
current treatment guidelines, treating physician discretion, and a careful risk-benefit 
assessment.  Should prophylactic anticoagulation be instituted, the platelet count will 
be maintained greater than 50,000 with platelets transfusions as needed. If the 
platelet count cannot be maintained > 50,000 with transfusions, the Investigator
should interrupt anticoagulation.
!
Allergic reactions: Allergic reactions associated with lenalidomide include 
hypersensitivity, angioedema, Stevens-Johnson syndrome, and toxic epidermal 
necrolysis (TEN). In some cases, these allergic reactions may be fatal. Lenalidomide
will be discontinued if any such reactions are suspected.  Lenalidomide will not be 
resumed following discontinuation for these reactions.
!
Hepatotoxicity: Hepatic failure, include fatal cases, has occurred in patients treated 
with lenalidomide in combination with dexamethasone.  The mechanism of drug-
induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline 
liver enzymes, and concomitant medications may be risk factors.  Monitor liver 
enzymes periodically.  Stop lenalidomide upon elevation of significantly elevated 
liver enzymes.  After return to baseline values, treatment at a lower dose may be 
considered.
!
Lenalidomide capsules contain lactose. The risk-benefit of lenalidomide treatment 
will be evaluated in subjects with lactose intolerance.
!
Tumor lysis syndrome (TLS): Fatal instances of TLS have been reported during 
treatment with lenalidomide. Subjects at risk for TLS (ie, those with high tumor 
burden) will be closely monitored for development of TLS with the initiation of 
lenalidomide.
!
Tumor flare reaction (TFR): Serious tumor flare reactions have occurred during 
investigational use of lenalidomide for CLL and lymphoma.  Although TFR has not 
been reported in adult AML, patients at risk of TLS (ie, those with high tumor 
burden) will be closely monitored for development of TFR.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
59
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
!
Increased mortality due to cardiac events: Serious and fatal cardiac adverse reactions 
were observed in patients with CLL.  Please refer to the REVLIMID US prescribing 
information (REVLIMID USPI) for further information.  Appropriate monitoring
measures for cardiac toxicity are implemented in the protocol.
!
Second primary malignancy (SPM): Higher incidences of SPM were observed in 
controlled trials of patients with MM receiving lenalidomide. All subjects will be 
followed for SPM for 5 years from the last subject’s first dose of IP, until withdrawal 
of consent, lost to follow-up or death.
!
Graft-versus-host disease (GVHD): GVHD was observed in adult IIT trials 
investigating lenalidomide as maintenance therapy in patients following allogeneic 
HSCT in remission (Kneppers, 2011; Sockel, 2011), and in relapsed MM and 
relapsed AML patients previously treated with allogeneic HSCT who responded to 
lenalidomide (Ades, 2010; Bensinger, 2012; El-Cheikh, 2012; Ford, 2010; Lioznov,
2010; Montefusco, 2012).
Additionally, GVHD rash has been reported in relapsed 
adult AML/MDS and MM patients after achieving CR with lenalidomide post
allogeneic stem cell transplantation HSCT (Blum, 2010; Ford, 2010). Subjects in this 
study will be closely monitored for GVHD and specific GVHD stopping criteria have 
been developed. For additional details see Section 8.2.1.
6.26.
Pharmacokinetic Sample Collection
6.26.1.
Blood Collection for PK Analysis
Collection of blood samples for PK assessments in plasma will be performed in all subjects.  On 
Cycle 1 Day 1, the subjects will receive the dose of lenalidomide in the morning at the study 
center.  Subjects will undergo PK sampling of blood at scheduled time points (Table 3) for 24 
hours postdose.  The actual date and time for dosing and blood sampling should be recorded in 
CRF.
As food may affect the absorption of lenalidomide, subjects will be asked to fast at least 2 hours 
prior to dosing and 2 hours after dosing of lenalidomide on Day 1 in order to reduce variability in 
PK results.  Approximately 1 mL of blood will be drawn for each PK sample.  Specific details 
regarding the collection, handling, processing, storage, and shipment of PK samples (blood) can 
be found in Appendix H.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
60
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Table 3:
PK Sampling Schedule During Cycle 1 Day 1
Collection time after 
lenalidomide administrationa
Collection window
Weight ≤ 20 kgb
Weight > 20 kgc
0.5 hour
± 10  min
-
x
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x
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± 10  min
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± 10  min
x
x
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± 10  min
-
x
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± 10  min
x
x
24 hours*
± 2 hours
x
x
PK = pharmacokinetic.
* The 24 hour blood sample must be taken prior to the lenalidomide administration on Day 2.
a The blood draw volume is 1 mL per sample.
b Only 5 PK blood samples will be taken from subjects with weight ≤ 20 kg at the specified time points.
c Seven PK blood samples will be taken from subjects with weight > 20 kg.
Subjects should return to the clinic on Day 2 for the 24-hour postdose PK sample, which should 
be taken prior to lenalidomide administration.  However, at the discretion of the Investigator and 
for convenience of the subject, the subject can be hospitalized overnight at the clinic from Day 1 
to Day 2 of Cycle 1 to facilitate collection of the 24-hour postdose sample.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
61
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
62
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
The study will enroll pediatric subjects from 1 to ≤ 18 years of age at the time of screening with 
rrAML with at least 2 prior induction therapy attempts.  A total of up to 43 evaluable subjects 
(18 in Stage 1 and an additional 25 in Stage 2) are required for assessment of the primary 
endpoint.  To allow for subjects found to be unevaluable for the primary endpoint due to an 
incorrect diagnosis, not having a disease assessment post screening, or who discontinued prior to 
receiving lenalidomide, up to 4 additional subjects may be enrolled for a maximum of 47 
evaluable subjects across approximately 70 sites.  Approximately 50% of enrolled subjects will 
be younger than 12 years of age to provide adequate PK data for this age subset.  The study will 
be conducted initially in North America (United States of America and Canada) and may be 
expanded globally.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Male or female is 1 to ≤ 18 years of age at the time of signing the ICF/IAF.
2. Subject (when applicable, parental/legal representative) must understand and voluntarily 
provide permission to the ICF/IAF prior to conducting any study-related 
assessments/procedures.
3. Subject has rrAML after at least 2 prior induction attempts:
!
Bone marrow aspirate or biopsy must have ≥ 5% blasts by morphology and/or flow 
cytometry.
!
Each block of chemotherapy (ie, ADE, MA) is a separate reinduction attempt.
!
Donor lymphocyte infusion (DLI) is considered a reinduction attempt.
4. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
5. Subject has a Karnofsky score of ≥ 50% (subjects ≥16 years of age) or a Lansky score ≥ 
50% (subjects < 16 years of age).
6. Subject has a resting left ventricular ejection fraction (LVEF) of ≥40% obtained by 
echocardiography.
7. Subject has recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to first dose. All prior treatment-related toxicities 
must have resolved to ≤ Grade 2 prior to enrollment.
8. Regarding radiation therapy, time elapsed prior to first dose of lenalidomide:
!
2 weeks for local palliative radiation therapy (XRT).
!
8 weeks if prior craniospinal chemoradiation therapy (CRT) or if ≥ 50% radiation of 
pelvis.
!
6 weeks if other bone marrow radiation has been administered.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
63
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
9. Graft-versus-host disease criteria:
!
Subject must be at least 2 months (from first dose of lenalidomide) from stem cell 
infusion.
!
Subject must have no evidence of active acute or chronic GVHD (Grade 0) for 4 
weeks prior to the first dose of lenalidomide.
o
If the subject has a history of maximum Grade 1 or 2 GVHD that was treated 
with systemic steroid (≥ 0.5 mg/kg/day prednisone equivalents) or other non-
steroid systemic IST, the subject must be off all IST for at least 2 weeks, and 
must have ceased treatment doses of steroids for GVHD (≥ 0.5 mg/kg/day 
prednisone equivalents) for at least 4 weeks.  
o
If the subject has a history of Grade 3 or greater GVHD, the subject must be 
off all systemic IST for 4 weeks. 
o
Topical therapy is permitted and does not imply the subject has active acute or 
chronic GVHD.
!
Physiologic dosing of hydrocortisone is permitted.
10. At least 4 weeks (from first dose) elapsed from donor lymphocyte infusion (DLI) without 
conditioning.
11. Subject has adequate renal function, which is defined as:
!
Creatinine clearance calculated (Table 4) using the Schwartz formula, (Schwartz, 
1976) or radioisotope glomerular filtration rate (GFR) > 70 mL/min/1.73 m2.
Table 4:
Creatinine Clearance Estimation using the Schwartz Formula
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
1 month to < 6 months
0.4
0.4
6 months to < 1 year
0.5
0.5
1 to < 2 years
0.6
0.6
2  to < 6 years
0.8
0.8
6 to < 10 years
1.0
1.0
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
The threshold creatinine values in this table were derived from the Schwartz formula for estimating glomerular 
filtration rate (GFR) (Schwartz, 1976) utilizing child length and stature data published by the Center for Disease 
Control (CDC).
12. Subject has adequate liver function, which is defined as:
!
Total bilirubin is ≤ 2 mg/dL unless the increase in bilirubin is attributable to Gilbert’s 
Syndrome
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12.2. S


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
64
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
!
AST is ≤ 3.0 x upper normal limit (ULN) for age. For the purpose of this study, the 
ULN for AST is 50 U/L. 
!
ALT is ≤3.0 x upper normal limit (ULN) for age. For the purpose of this study, the 
ULN for ALT is 45 U/L. 
13. Female Children of Childbearing Potential, Female of Childbearing Potential and male 
subjects that have reached puberty must agree to undergo physician-approved 
reproductive education and discuss the side effects of the study therapy on reproduction 
with parent(s) and/or guardian(s).
14. All subjects and/or parents/guardians must have an understanding that lenalidomide could 
have a potential teratogenic risk.  Female Children of Childbearing Potential, defined as 
females who have achieved menarche and/or breast development in Tanner Stage 2 or 
greater and have not undergone a hysterectomy or bilateral oophorectomy and FCBP 
defined as a sexually mature woman who has not undergone a hysterectomy or bilateral 
oophorectomy and has not been naturally postmenopausal for at least 24 consecutive 
months (ie, has had menses at any time in the preceding 24 consecutive months) must 
meet the following conditions below (Note: Amenorrhea following cancer therapy does 
not rule out childbearing potential):
!
Medically supervised serum pregnancy tests with a sensitivity of at least 25 mIU/mL 
must be conducted in FCCBP/FCBP, including those who commit to complete 
abstinence*.  FCCBP/FCBP must have two pregnancy tests (with a minimum 
sensitivity of 25 mIU/mL) prior to starting treatment with lenalidomide.  The first 
pregnancy test must be performed within 10 – 14 days prior to the start of 
lenalidomide treatment and the second pregnancy test must be performed within 24 
hours prior to starting treatment with lenalidomide. 
NOTE: The pregnancy test 10 to 14 days prior to initiation of lenalidomide may be 
omitted, at the discretion of the investigator, for any FCCBP/FCBP who has high 
acuity disease requiring immediate treatment with lenalidomide. The pregnancy test 
within 24 hours prior to the first dose of lenalidomide is required to be performed.
The subject may not receive IP until the Investigator has verified that the results of 
these pregnancy tests performed on Cycle 1 Day 1 are negative.  FCCBP/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 
Treatment Discontinuation Visit, and at Day 28 following IP 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 Treatment Discontinuation 
Visit, and at Days 14 and 28 following IP discontinuation.
!
Female subjects must, as appropriate to age and at the discretion of the study 
Investigator, either commit to true abstinence* from heterosexual contact (which 
must be reviewed on a monthly basis) and/or agree to the use of two reliable forms of 
approved and effective contraceptive methods simultaneously.  The two methods of 
reliable contraception must include one highly effective method and one additional 
effective (barrier) method (oral, injectable, or implantable hormonal contraceptive; 
tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or 
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Fe
F


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
65
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
vasectomized partner) without interruption, 28 days prior to starting lenalidomide
treatment, throughout the entire duration of study treatment including dose 
interruptions and 28 days after the end of study treatment.
!
All male and female subjects must follow all requirements defined in the Pregnancy 
Prevention Program.
15. Male subjects, as appropriate to age and the discretion of the study physician:
!
Must practice true abstinence* or agree to use a condom during sexual contact with a 
pregnant female or a female of childbearing potential while participating in the study, 
during dose interruptions and for at least 28 days following lenalidomide 
discontinuation, even if he has undergone a successful vasectomy or practices 
complete abstinence.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has Down syndrome.
2. Subject has French-American-British classification (FAB) type M3 leukemia (acute 
promyelocytic leukemia) or identification of t(15;17).
3. Subject has isolated CNS involvement or extramedullary relapse. (Subjects with 
combined CNS/marrow relapse may be enrolled).
4. Subject has had prior treatment with cytotoxic chemotherapy within 2 weeks of the first 
dose of lenalidomide with the exception of hydroxyurea (allowed prior to the first dose of 
lenalidomide and through Day 14 of Cycle 1) and intrathecal (IT) cytarabine will be 
administered within 2 weeks prior to administration of lenalidomide.
5. Subject has had prior treatment with biologic antineoplastic agents less than 7 days 
before the first dose of lenalidomide. For agents that have known AEs occurring beyond
7 days after administration (ie, monoclonal antibodies), this period must be extended 
beyond the time during which acute AEs are known to occur.
6. Subject has had prior treatment with lenalidomide.
7. Subject is pregnant or lactating.
8. Subject has an uncontrolled systemic fungal, bacterial, or viral infection (defined as 
ongoing signs/symptoms related to the infection without improvement despite 
appropriate antibiotics, antiviral therapy, and/or other treatment).
9. Subject has known Human Immunodeficiency Virus (HIV) positivity (subjects who are 
receiving antiretroviral therapy for HIV disease).
10. Subject has a prior history of malignancies other than AML unless the subject has been 
free of the disease for ≥ 5 years from first dose of lenalidomide.
11. The presence of any of the following will exclude a subject from enrollment:
!
Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study.
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Su


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
66
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
!
Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study.
!
Subject has any condition that confounds the ability to interpret data from the study.
12. Subject has cardiac disorders (Common Terminology Criteria for Adverse Events 
[CTCAE] version 4.03 Grade 3 or 4).
13. Subject has a history of well-documented prior veno-occlusive disease (VOD).
14. Subject has any other organ dysfunction (CTCAE version 4.03 Grade 4) that will 
interfere with the administration of the therapy according to this protocol.
7.4.
Inclusion and Exclusion Criteria for OEP
Refer to Appendix L – Optional Extension Phase.
Note: *True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception].
&(/*(1(35235,(7$5<,1)250$7,21
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
67
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Product(s)
Investigational product will be provided as capsule formulation and as active pharmaceutical 
ingredient (API) in vials for constitution to oral suspension. 
Celgene Corporation will supply lenalidomide 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg 
capsules as hard gelatin capsules for oral administration. The 2.5 mg dose is contained in a size 
4 hard gelatin capsule.  The 5 mg dose is contained in a size 2 hard gelatin capsule.  The 10 mg, 
15 mg, 20 mg and 25 mg doses are contained in a size 0 hard gelatin capsule.  Lenalidomide 
capsules should be swallowed whole and should not be broken, chewed or opened. Each dosage 
will be provided in 21 count bottles.
Celgene Corporation will supply lenalidomide API in individual sealed vials for constitution to 
oral suspension.  Each vial contains 80 mg of lenalidomide with no inactive ingredients. The 
lenalidomide powder in each vial is constituted with 8 ml of suspending agent
 to 
create a lenalidomide suspension with a final concentration of 10 mg/ml. This suspension is 
intended for oral administration only.  
Females of child bearing potential (FCBP) should not handle or administer lenalidomide unless 
they are wearing gloves.  All subjects should not extensively handle the lenalidomide capsules 
or oral suspension. The lenalidomide capsules should not be broken, chewed, or opened and 
should be maintained in the packaging until ingestion. Refer to the subject diary and the manual 
on preparation, administration, and handling of the lenalidomide oral suspension for specific 
details.
If a subject is receiving lenalidomide oral suspension, a home healthcare company can be 
available to assist with the preparation and administration of the oral suspension at the subject’s
home. The home trial support agent that may visit the subject’s home would be a licensed nurse.
Refer to the manual on preparation, administration, and handling of the lenalidomide oral 
suspension for specific details.
In investigational studies, lenalidomide will be dispensed through a qualified healthcare 
professional (including but not limited to nurses, pharmacists and physicians). These healthcare 
professionals will be trained by Celgene in requirements specific to counseling of 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 for FCBP) and that the subject understands the risks associated with 
lenalidomide.  This step will be documented with a completed Education and Counseling 
Guidance Document 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 will be supplied each time lenalidomide is dispensed.
8.2.
Treatment Administration and Schedule
Lenalidomide will be administered either in capsules containing 2.5 mg, 5 mg, 10 mg, 15 mg, 20 
mg or 25 mg or as an oral suspension (10 mg/mL). The oral suspension is available for use in 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
68
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
subjects who are unable to swallow the capsules or at the discretion of the investigator. The 
starting dose of lenalidomide will be 2 mg/kg/day with a maximum dose of 70 mg/day. 
Lenalidomide will be administered orally once daily for the first 21 days of every 28-day cycle.  
Daily dosage should be administered using the combinations that yield the least amount of 
capsules.  However, if a subject is unable to swallow big capsules, varying, appropriate strength 
combinations may be considered during medication assignment using the IWRS.  The prescribed 
dose should be the closest dose that can be given to the calculated dose based on the strengths of 
lenalidomide available. If the calculated dose falls between two integers, the dose calculated 
should be rounded up or down to the nearest whole number. The actual dose to be administered 
can be determined after rounding the calculated dose. For dose reductions, the dose calculated 
should be to the nearest whole number.  For a dosing table with guidelines reflecting this 
approach for the lenalidomide capsules, refer to Appendix B.
Refer to Appendix C for dosing guidelines for the lenalidomide oral suspension. 
After completion of 12 cycles of study treatment, if deemed necessary or useful by the 
Investigator and with approval of the Sponsor, subjects who demonstrate clinical benefit as per 
the Investigator from lenalidomide may continue to receive oral lenalidomide (either capsules or 
oral suspension) in an OEP until they meet the criteria for study discontinuation (see Section 12).
Dose interruptions/reductions will be permitted for episodes of myelosuppression, non-
hematologic toxicities, and AEs.  For additional details see Section 8.2.1.
In the event of specific protocol-defined toxicity, no more than 2 dose reductions will be allowed 
to doses of 1.4 mg/kg/day (not exceeding 50 mg/day) and 1 mg/kg/day (not exceeding 
35 mg/day) during the study.  The dose will not be re-escalated once it has been reduced
(Table 6).  Subjects who do not tolerate the minimum dose level of 1 mg/kg/day (not exceeding 
35 mg/day) will be discontinued from the study.
As per routine standard of care, intrathecal cytarabine (age-based dosing) will be administered 
prior to Cycle 1 in all subjects at the time of screening through lumbar puncture (Table 5).  
Intrathecal cytarabine will be administered within 2 weeks prior to administration of 
lenalidomide:
!
For subjects without CNS involvement, subsequent intrathecal cytarabine may be 
administered at the discretion of the treating physician.
!
For subjects with CNS involvement at screening, intrathecal cytarabine will be 
administered twice weekly x 4 doses and until CSF is clear on 2 consecutive 
evaluations for up to 6 total doses. 
#
Subjects whose CSF was cleared may receive subsequent intrathecal cytarabine 
doses at the discretion of the treating physician.
#
Subjects who have persistent CNS disease despite 6 doses of intrathecal 
cytarabine will be off study treatment.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
69
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Table 5:
Age-based Cytarabine Dosing
Age (years)
Dose
0 – 0.99
20 mg
1 – 1.99
30 mg
2 – 2.99
50 mg
≥ 3
70 mg
8.2.1.
Dose Reductions/Interruptions
Dose reduction guidelines are as follows:
!
Two dose reductions will be allowed (Table 6) in the event of specific protocol-
defined toxicity.  If treatment is interrupted for toxicity as described below, 
lenalidomide will be resumed at dose level -1 once the toxicity has resolved to <
Grade 1.  If toxicity recurs, lenalidomide will be interrupted and upon resolution, the 
subject will resume at dose level -2.
!
The dose will not be re-escalated if the lower dose is tolerated.
!
Subjects who do not tolerate 1 mg/kg/day (dose level -2) will discontinue 
lenalidomide administration.
Table 6:
Dose Reductions of Lenalidomide
Dose Level
Dose
Starting dose
2.0 mg/kg/day
(maximum dose of 70 mg/day for subjects ≥ 35 kg)
Dose Level -1
1.4 mg/kg/day
(not exceeding 50 mg/day for subjects initially dosed at 70 mg/day)
Dose Level -2
1.0 mg/kg/day
(not exceeding 35 mg/day for subjects initially dosed at 70 mg/day)
Definition of Toxicity Requiring Treatment Interruption and/or Dose De-escalation
Lenalidomide dosing will be interrupted for any of the following toxicities at least possibly 
attributed to lenalidomide:
!
Any Grade 4 non-hematological toxicity with the specific exclusion of fever or 
infection.
!
Any Grade 3 non-hematological toxicity with the specific exclusion of:
#
Grade 3 nausea and vomiting controlled by antiemetics.
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!


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
70
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
#
Grade 3 fever or infection.
#
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia 
responsive to oral supplementation.
#
Grade 3 TLS: With close monitoring per the 
 TLS monitoring guidelines
(Appendix M Tumor Lysis Syndrome), lenalidomide dose may be continued 
uninterrupted provided continued treatment does not pose a safety concern in the 
presence of TLS event.  If interrupted, lenalidomide treatment may be restarted at
the same dose level after TLS is under control at the discretion of the Investigator.
NOTE:  For purposes of grading AST and ALT adverse events in this study, the ULN for AST 
is 50 U/L and the ULN for ALT is 45 U/L.
Lenalidomide will be held for any subject experiencing hemorrhagic or bullous skin rash until a 
specific evaluation to exclude toxic epidermal necrolysis and/or Stevens-Johnson syndrome has 
been performed.  Any subject with evidence of TEN or Stevens-Johnson syndrome will not be 
retreated with lenalidomide.
Grade 3 ALT/AST values that return to levels that meet initial eligibility criteria within 7 days of 
IP interruption do not require a dose reduction. These subjects may resume treatment at the 
original dose level.  If the toxicity recurs, then dose de-escalation is indicated.
Day 1 of Cycle 2 and beyond may be delayed up to 14 days from the end of the prior cycle in 
order for subjects to recover from toxicity.  If a study interruption has lasted for more than 14 
days, the Investigator should contact the Medical Monitor to discuss whether the subject should 
be continued on the study.
Special Instructions for Myelosuppression:
Due to the underlying marrow infiltrating malignancy, myelosuppression is universal and 
expected in patients with AML. Therefore, myelosuppression (anemia, neutropenia, and 
thrombocytopenia) will not require dose reduction or interruption except in the case of 
neutropenia or thrombocytopenia due to prolonged bone marrow aplasia at the end of a treatment 
cycle in subjects who have achieved remission.
!
For subjects who have achieved remission:
!
Prolonged bone marrow aplasia is defined as lack of peripheral blood count 
recovery to ANC ≥ 500/mm3 and platelets ≥ 50,000/mL without transfusion 
for 7 days in the absence of leukemia (bone marrow biopsy demonstrate 
hypocellularity without evidence of leukemia) at Day 43 of a cycle (ie, failure 
to start the next cycle within 14 days).
!
The lenalidomide dose will be interrupted and the start of the next cycle will 
be delayed until count recovery.
!
Prolonged delay (ie, failure to start the next cycle within 14 days) for subjects 
in remission will require dose de-escalation.
!
If the peripheral blood counts recover within 14 days, the subject will proceed 
to the next cycle without dose reduction.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
71
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
!
If the peripheral blood counts do not recover within 14 days, repeat bone 
marrow evaluation including bone marrow biopsy every 7-14 days to assess 
cellularity and to evaluate for relapse/persistent leukemia.
!
For subjects who have not achieved remission:
#
In general, subjects who have not achieved remission and have evidence of 
residual leukemia will proceed to the next cycle as scheduled regardless of count 
recovery. 
!
For subjects with residual leukemia:
!
If residual leukemia is demonstrated and the subject previously had achieved 
CR/CRi, the subject will be discontinued from the study.
o
If residual leukemia is demonstrated, which is stable from prior assessments 
(ie, subject with previous PR/treatment failure), the subject will proceed to the 
next cycle of lenalidomide as scheduled without delay and without regard to 
peripheral blood counts. Lenalidomide dose will NOT be decreased.
Special Instructions for Management of Graft Versus Host Disease (GVHD):
Post-HSCT subjects will be monitored closely for development of GVHD of the skin, liver, 
or gut, see Appendix K for grading criteria.
!
Subjects with Grade 1 or 2 GVHD (any site, biopsy proven or probable, ie, requires 
systemic steroid treatment) will be managed at the discretion of the local bone 
marrow transplant (BMT) physician and lenalidomide will be held.
#
If the acute GVHD resolves within 14 days and the subject is being treated with 
no more than topical therapies and/or up to 0.5 mg/kg/day corticosteroids 
(prednisone equivalents), lenalidomide will be restarted at the same prior dose.
#
After 14 days, subjects requiring more than 0.5 mg/kg/day corticosteroids or other 
systemic therapy (ie, not including topical therapies) to manage the acute GVHD 
will be discontinued from the study.
!
Subjects with Grade 3 or 4 GVHD (any site, suspected or biopsy proven) will have 
lenalidomide discontinued permanently and will be managed at the discretion of the 
local HSCT physician.  These subjects will be discontinued from the study.
Guidelines for Renal Insufficiency
!
Lenalidomide is primarily excreted unchanged by the kidney; therefore, study 
treatment will be held for subjects who experience CLcr < 70 mL/min (confirmed by 
repeat creatinine measurement within 3 days).  If CLcr returns to levels that meet 
initial eligibility criteria (> 70 mL/min) within 7 days of IP interruption, the subject 
may resume treatment at a full dose.  However, if the subject improves within 14 
days, a dose reduction by 1 dose level of study treatment will be considered at the 
discretion of the Investigator, and after careful consideration of the subject’s renal 
impairment etiology and the subject’s tolerability to lenalidomide.  If toxicity does 
not resolve to eligibility by 14 days of dose interruption, then the subject will be off 
study treatment.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
72
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Dose Discontinuation:
!
Subjects experiencing a thromboembolic event unrelated to a central line will be 
discontinued from lenalidomide treatment.
!
As described above, under dose interruption, any subject with evidence of TEN or 
Stevens-Johnson syndrome will not be retreated with lenalidomide.
!
Subjects who do not tolerate 1 mg/kg/day will discontinue lenalidomide treatment.
!
Subjects with non-hematologic toxicities that do not resolve to less than or equal to 
Grade 1 or baseline levels within 14 days will be off study treatment.
!
Subjects with prolonged renal impairment (CLcr < 70 mL/min) lasting more than 14 
days will be off study treatment.
!
Subjects who do not demonstrate clinical benefit as per the Investigator at the end of 
Cycle 4 and beyond will be discontinued from lenalidomide treatment.
8.2.2.
Overdose
Overdose, as defined for this protocol, refers to lenalidomide dosing.  On a per dose basis, an 
overdose is defined as the following amount over the protocol-specified dose of lenalidomide 
assigned to a given subject, regardless of any associated AEs or sequelae.
!
>10% over the protocol-specified dose.
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol-required schedule or frequency.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the CRF.  See Section 11 for the 
reporting of AEs associated with overdose.
8.3.
Method of Treatment Assignment
All subjects will be enrolled into the study using an IWRS.  The Investigator or designated site 
staff will be assigned password protected, coded identification numbers that give them 
authorization to log into the IWRS.  At screening, the Investigator or designated staff will log 
into the IWRS and provide the requested identifying information for the subject. The IWRS will 
then confirm the assignment of a 2-part unique subject number. The first part is the center 
number and the second part is one of a series of numbers allocated to subjects at that center.  
Once assigned to a subject, the subject number will not be reused.  If the subject is not enrolled 
into the study the IWRS must be notified.
Prior to enrolling a subject, written ICF/IAF must be obtained, all screening evaluations must be 
completed, and eligibility criteria must be verified by the Sponsor.  Once these actions have been 
completed, the Investigator or designated staff will log into the IWRS and confirm that the 
subject fulfills all the inclusion and exclusion criteria.  The IWRS will assign an enrollment 
number to the subject which will be used to identify the subject in the study.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
73
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
8.4.
Packaging and Labeling
The label(s) for IP will include Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable.  Additional information may be included on the label as applicable per local 
regulations.
8.5.
Investigational Product Accountability and Disposal
Accountability for lenalidomide administered during the course of the study is the responsibility 
of the Investigator (or designee).
Investigational clinical supplies must be received by a designated person at the study site and 
kept in a temperature-controlled location.  Lenalidomide should be stored according to the 
storage conditions described on the packaging label and in a locked, safe area to prevent 
unauthorized access.
The Investigator (or designee) is responsible for taking an inventory of each shipment of 
lenalidomide received, and comparing it with the accompanying lenalidomide accountability 
form.  The Investigator (or designee) will verify the accuracy of the information on the form, 
sign and date it, retain a copy in the study file, and return a copy to Celgene.
The investigational site must maintain accurate records demonstrating dates and amounts of 
lenalidomide received, to whom it was administered (subject-by-subject accounting), and 
accounts of any lenalidomide accidentally or deliberately destroyed or returned.  Accurate 
recording of all lenalidomide administration will be made in the appropriate section of the 
subject’s CRF and source documents.
Unless otherwise notified, all lenalidomide both used and unused must be saved for IP
accountability.  After IP accountability has been completed by the monitor, Celgene (or 
designee) will review with the Investigator and relevant site personnel the process for 
lenalidomide return, disposal, and/or destruction including responsibilities for the site versus
Celgene (or designee).
8.6.
Investigational Product Compliance
All IP used by subjects will be documented by study site personnel and accurate recording of all 
lenalidomide used will be made in the appropriate section of the subject’s CRF and source 
documents.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
74
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
9.
CONCOMITANT MEDICATIONS AND PROCEDURES
9.1.
Permitted Concomitant Medications and Procedures
All supportive care is permitted, including but not limited to:
!
Platelet transfusions
!
Intravenous immunoglobulin
!
RBC transfusions
!
G-CSF per American Society of Clinical Oncology (ASCO) guidelines
!
Leukapheresis
!
Exchange transfusions
!
Hemodialysis
!
Hydration
!
Allopurinol
!
Sodium bicarbonate (NaHCO3)
!
Dexamethasone ophthalmic solution or isotears
!
Pyridoxine
!
Antiemetics
!
Chlorhexidine solution
!
Pain medications
!
Antibiotics
!
Anti-herpetics
!
Anti-fungals
!
Hydroxyurea is permitted prior to start of lenalidomide (Cycle 1 Day 1) and through 
Day 14 of Cycle 1 if needed to control leukocytosis. Administration will be at the 
discretion of the investigator.
9.2.
Prohibited Concomitant Medications and Procedures
!
Other chemotherapy or IP than what is specified in the protocol
!
Live vaccines
!
Biological therapies
!
Other investigational agents
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
75
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
10.
STATISTICAL CONSIDERATIONS
10.1.
Overview
All statistical analyses will be descriptive. There will be no formal statistical comparisons due to 
the study being single-armed and due to a low sample size.
Secondary endpoints can only be analyzed and reported based on subjects who have had at least
6 months from study enrollment. The final analysis will be conducted once the last remaining 
subject in the Follow-up Phase has completed up to 5 years from the last subject’s first dose.
10.2.
Study Population Definitions
Response Rate population
The response rate (RR) population shall consist of all subjects classified as evaluable for the 
primary endpoint, ie, all subjects fulfilling the eligibility criteria, having received at least one 
dose of the lenalidomide and having at least one disease assessment post enrollment or having 
treatment failure before an assessment can be conducted.  The RR population shall be applied to 
the analysis of the primary endpoint.
Intention to treat population
The intention to treat (ITT) population shall consist of all enrolled subjects regardless of whether 
they received lenalidomide.  The ITT population shall be applied to all treatment activity-based 
primary and secondary endpoints.
Safety population
The safety population consists of all subjects receiving at least one dose of lenalidomide and 
shall be applied to all safety based endpoints.
Pharmacokinetic population
The PK population consists of all subjects receiving at least one dose of lenalidomide and having 
at least one measurable lenalidomide concentration.
10.3.
Sample Size and Power Considerations
Under Simon’s Optimal two stage design with a 5% significance level and 80% power, assuming 
a lower boundary of interest in the response rate of 10% and an upper boundary of interest in the 
response rate of 25%, a total of 43 evaluable subjects are required for the evaluation of the 
primary endpoint; 18 in Stage 1 and an additional 25 in Stage 2.
If less than 3 of 18 evaluable subjects in Stage 1 achieve a morphologic response (either CR or 
CRi) within a maximum of 4 cycles then the study will terminate, otherwise the study shall 
continue as planned and enrollment of an additional 25 subjects shall continue into Stage 2.
If, at the final analysis, less than 8 of 43 evaluable subjects in both Stage 1 and 2 achieve a 
response (either CR or CRi) within a maximum of 4 cycles then it will be concluded that 
lenalidomide, at the dose level tested, does not have sufficient activity in pediatric AML (second 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
76
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
or greater relapse or refractory). However, should at least 8 of the 43 evaluable subjects achieve 
a response (either CR or CRi) then it will be concluded that lenalidomide, at the dose level 
tested, demonstrates activity in pediatric subjects with AML (second or greater relapse or 
refractory) to allow further investigation.  Up to 4 additional subjects may be included to account 
for subjects found to be unevaluable for the primary endpoint (eg, incorrect diagnoses, not 
having a disease assessment post screening, or who discontinued prior to receiving lenalidomide 
therapy).  The first 43 subjects enrolled and evaluable for the primary endpoint analysis will be 
used to assess the primary endpoint.
10.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations.  Medical history data will be summarized using frequency tabulations by system 
organ class and preferred term.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both Treatment 
and Follow-up Phases. A summary of subjects enrolled by site will be provided.  Protocol 
deviations will be summarized using frequency tabulations.
10.6.
Efficacy Analysis
10.6.1.
Primary endpoint
Morphologic complete response rate (CR or CRi) rate within 4 investigational product 
cycles
The primary endpoint is the morphological complete response rate within a maximum of 4 cycles 
of treatment. Morphological complete response is defined as CR or CRi. These response criteria
will be assessed according to the revised AML IWG Criteria (Cheson, 2003).
The morphological complete response rate is defined as the total number of subjects with 
morphological complete response observed within the first 4 cycles of study therapy (regardless 
of whether the CR/CRi is observed at the end of Cycle 1, 2, 3 or 4) over the total number of 
subjects evaluable for this endpoint (maximum likelihood estimator). The CR/CRi does not need 
to be present at the end of Cycle 4 if observed before this time for the subject to be considered as 
having achieved a complete response with regards to the primary endpoint. The corresponding 
Clopper Pearson 95% confidence interval will be calculated for the response rate. The primary 
analysis of this endpoint will be based upon the ITT population and the Response Rate 
population. Decision making with regard to continuation to Stage 2 and at the end of Stage 2 will 
be based on responses within the Response Rate population.
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
77
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
10.6.2.
Secondary endpoints
Overall Response Rate
Overall response rate defined as the proportion of subjects with CR, CRi or PR among all 
subjects evaluable for ORR assessment. The ORR rate at the end of Cycles 1, 2, 3, 4, 8 and 12
will be categorized, and the rate will be calculated by dividing the number of subjects completing 
each given cycle of interest. The corresponding Clopper Pearson 95% confidence interval will 
be calculated for the response rate at the end of each pre-specified cycle.
Disease Assessment Outcome
Disease assessment outcome at the end of Cycles 1, 2, 3, 4, 8 and 12 of lenalidomide
administered shall be categorized according to the Cheson criteria (Cheson, 2003). The response
rate for each of the best response criteria will be calculated as the total number of subjects in a 
given category at each time point over the number of subjects completing each corresponding 
cycle. The corresponding Clopper Pearson 95% confidence interval will be calculated per 
response category at the end of each pre-specified cycle.
Durable Response Rate
Durable response rate is defined as the proportion of subjects achieving a bone marrow 
confirmed CR/CRi lasting at least 3 months or until transplantation if earlier among all subjects 
evaluable for the durable response rate assessment.  The corresponding Clopper Pearson 95% 
confidence interval will be calculated for the durable response rate.
Duration of Response
Duration of response is defined as the time from date of the first observed response (CR, CRi or 
PR) until morphologic relapse, molecular/cytogenetic relapse, or death only for subjects 
achieving a response. Subjects alive and leukemia-free at the time of the statistical analysis will 
be censored at the time of their last disease assessment.  The median DoR time along with the 
corresponding 95% confidence interval based on Greenwood’s standard error will be calculated 
using Kaplan-Meier methods.  The proportion of subjects remaining without a DoR event at 6, 
12 and 24 months will also be presented. Should the number of subjects considered for inclusion 
in DoR analysis fall below a third of the total sample size, the DoR shall be analyzed 
descriptively due to the low number of subjects available for analysis. Duration of response shall 
be analyzed both allowing for censoring of subjects at time of HSCT and without censoring of 
subjects at the time of HSCT.
Transplantation Rate
The proportion of subjects undergoing a transplant of any kind during the conduct of this study 
will be calculated over the total number of subjects enrolled into this study. The corresponding 
Clopper Pearson 95% confidence interval for the proportion of transplantations shall be 
calculated. Proportions shall also be calculated based on whether the transplantation is first, 
second, or subsequent transplants.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
78
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Subject/blast Characteristics Correlating With Response
Laboratory results obtained at diagnosis and relapse (peripheral WBC and blast count, bone 
marrow blast percentage, cytogenetics, molecular alterations, etc.) will be evaluated in 
association with response parameters by means of Pearson’s rank correlation.
10.7.
Safety Analysis
10.7.1.
Toxicity Assessment
Toxicity will be monitored real-time through study chair notification and end of course reports.  
Descriptive statistics will be used to summarize the proportion of subjects experiencing any and 
Grade 3 or higher non-hematologic toxicities, summarize length of hospitalization time, and to 
estimate count recovery.  This study will utilize the CTCAE version 4.03 of the NCI for toxicity 
grading.
10.7.2.
Adverse Events
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) (updated version).  The severity of AEs will be graded according to the NCI-CTCAE 
(version 4.03, June 2010).
Treatment-emergent adverse events are defined as any AE occurring or worsening on or after the 
first treatment of the study medication and within 28 days after the last dose.  All TEAEs, AEs
leading to study medication discontinuation, AEs leading to dose reduction/interruption, AEs
related to the lenalidomide, SAEs and AE leading to death will be summarized by cycle and 28-
day period after last cycle as well as by subject (worse recorded grade) per event type (organ 
class and preferred tern) and grade.  A summary of AEs with NCI-CTCAE Grade 3 or higher, as 
well as the most frequent preferred terms will also be provided by grade and term.
10.7.3.
Deaths
Deaths during study treatment (defined as deaths, which occur starting from the first dose and 
within 28 days after the last dose of study medication) and during the Follow-up Phase shall be 
summarized by frequency of occurrence and corresponding percentage by cause of death per 
period (during Treatment or Follow-up Phases) as well as overall.
10.7.4.
Clinical Laboratories
Clinical laboratory adverse events will be graded according to NCI-CTCAE (version 4.03, June 
2010) for applicable tests.  Baseline grade and worst grade during study treatment for selected 
laboratory results will be summarized.  Shift from baseline to the worst grade observed during 
the study treatment for selected laboratory results will also be provided.
10.7.5.
Vital Signs
For vital signs, shift from baseline to worst during the treatment in below, within, and above the 
normal ranges will be displayed in cross-tabulations.  Summary statistics (N, mean, standard 
deviation, median, minimum, and maximum) of observed and change from baseline values will 
be presented.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
79
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.9.
Interim Analysis
Once 4 subjects having received at least one dose of lenalidomide have completed at least 1 
cycle of study treatment or discontinued treatment (whichever occurs first), the DMC will 
evaluate the safety data available and provide a recommendation. 
An interim analysis is planned to take place once the first 18 subjects evaluable for the primary 
endpoint have been accrued and completed up to 4 cycles of lenalidomide treatment if they have 
not stopped therapy before 4 cycles. The interim analysis will assess the number of subjects with 
CR or CRi under lenalidomide treatment. If fewer than 3 of 18 subjects achieve a response then 
the study will be closed; otherwise the study shall continue as planned and enrollment shall 
continue into Stage 2.
At the end of Stage 1 and following safety and treatment activity data review, the DMC will 
provide recommendations about the continuation of the study from Stage 1 to Stage 2 (continue 
as planned, continue with modifications or stop treatment and/or enrollment) and advise on ways 
to improve quality.  A DMC shall meet at least semi-annually after sufficient subject data has 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
80
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
been collected to review safety and treatment activity data. This close monitoring for safety of 
the IP will ensure a low exposure rate of the IP to subjects by ensuring the boundary of 
considered acceptable toxicity is not crossed.
10.9.1.
Stopping Criteria for Acute Graft-Versus-Host Disease
Subjects who are post-allogeneic HSCT will be monitored closely for the development of acute 
graft-versus-host disease (GVHD). While Grade 1 to 2 GVHD will be tolerated, if 40% or more 
of subjects develop Grade 3 or higher GVHD, lenalidomide at this dose will be deemed 
intolerable for subjects who are post-HSCT.
10.9.2.
Statistical Rationale for GVHD Stopping Criteria
The GVHD stopping rule is designed so that the trial will stop rarely when the true GVHD rate is 
10% and frequently when the true GVHD rate is 40% (H0: p = 0.10, H1: p = 0.40, and alpha =
0.10, power is 90%). In this case, if 4 or more post-HSCT subjects in the first 15 develop Grade 
3 or 4 GVHD, the stopping rule threshold would be crossed and further post-HSCT subjects 
would not be enrolled.
10.10.
Pharmacokinetic Analysis
Approximately 50% of subjects should be younger than 12 years of age to provide adequate PK 
data for this age subset.  Lenalidomide concentration data from this study will be combined with 
the concentration data from other pediatric studies and literature data to perform a population 
pharmacokinetic analysis.  Main pharmacokinetic parameters in plasma to be estimated include 
AUC, Cmax, apparent clearance, and apparent volume of distribution. Effect of age and body size 
on lenalidomide PK will be assessed. Other relevant covariates for the main PK parameters may 
be identified.  The between-subject variability for PK parameters will be estimated.  If data 
allow, main PK parameters (clearance and volume of distribution) will be summarized by age as 
appropriate (eg, 1 to < 6, 6 to < 12, and 12 to < 18 years).
Non-compartmental PK parameters in plasma may also be estimated using intensive 
lenalidomide concentration data collected from this study.  
 
 
 
 
10.11.
Other Topics
Not Applicable.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
81
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria below), regardless of etiology. Any worsening 
(ie, any clinically significant adverse change in the frequency or intensity of a pre-existing 
condition) should be considered an AE.  A diagnosis or syndrome should be recorded on the AE 
page of the CRF rather than the individual signs or symptoms of the diagnosis or syndrome.
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE.  An overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF.  For the definition of overdose see Section 8.2.2.  Any sequelae
of an accidental or intentional overdose of an investigational product should be reported as an 
AE on the AE CRF. If the sequelae of an overdose is an SAE, then the sequelae must be 
reported on an SAE report form and on the AE CRF. The overdose resulting in the SAE should 
be identified as the cause of the event on the SAE report form and CRF but should not be 
reported as an SAE itself.
In the event of overdose or exaggerated response, the subject should be monitored as appropriate 
and should receive supportive measures as necessary. There is no known specific antidote for a 
lenalidomide overdose. Actual treatment should depend on the severity of the clinical situation 
and the judgment and experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters: the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or other 
appropriate tests and procedures.
All AEs will be recorded by the Investigator from the time the subject signs ICF/IAF until 28 
days after the last dose of IP, as well as those SAEs made known to the Investigator at any time 
thereafter that are suspected of being related to IP.  Adverse events and SAEs will be recorded on 
the AE page of the CRF and in the subject’s source documents.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.
11.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to:
11.2.1.
Seriousness
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
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SAE is
E is


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
82
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
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 
SAEs regardless of causal relationship to IP.  This includes any SPM, regardless of causal 
relationship to IP, occurring at any time for the duration of the study, from the time of signing 
the ICF/IAF up to 5 years from the date of the last subject’s first dose unless withdrawal of 
consent, lost to follow-up or death. Events of SPM are to be reported using the SAE report form 
and must be considered an “Important Medical Event” even if no other serious criteria apply; 
these events must also be documented in the appropriate page(s) of the CRF and subject’s source 
documents.  Documentation on the diagnosis of the second primary malignancy must be 
provided at the time of reporting as an SAE (eg, any confirmatory histology or cytology results, 
X-rays, CT scans, etc.).
Events not considered to be SAEs are hospitalizations for:
!
a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE.
!
routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.
!
hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
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or 
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ge(s) of the
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nd primary
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onfirmatory
izatio
zations
n fo
fo
ol therapy a
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transfusion 
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SAE.
AE
!
h


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
83
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
!
an elective treatment of or an elective procedure for a pre-existing condition,
unrelated to the studied indication, that has not worsened from baseline.
!
emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE report form
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
11.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/intensity of the event.
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of NCI CTCAE, version 4.03;
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_4003);
AEs that are not defined in the NCI CTCAE should be evaluated for severity/intensity according 
to the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required.
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required.
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible.
!
Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable.
!
Grade 5 = Death – the event results in death.
In addition, for purposes of grading AST and ALT adverse events in this study, the ULN for 
AST is 50 U/L and the ULN for ALT is 45 U/L. 
The term “severe’ is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.
Seriousness, not severity, serves as a guide for defining regulatory obligations.
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ousness, 
ousness, 


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
84
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
11.2.3.
Causality 
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
11.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or dose reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event.
11.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, death (due to 
the SAE).
11.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/interruption of IP dose, or any other therapeutic 
intervention; or
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n taken with
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red
reatments w
eatments w
eport the o
eport the o
e not resolv
 not resolv
ed until rec
d until rec
Abno
Abno
n abnormal
n abnormal
!


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
85
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
!
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as an SAE.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF. If possible, the laboratory 
abnormality should be recorded as a medical term and not simply as an abnormal laboratory 
result (eg, record thrombocytopenia rather than decreased platelets).
11.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.
The exposure of any pregnant female (eg, caregiver, pharmacist, study coordinator or monitor) to 
lenalidomide is also an immediately reportable event.
11.4.1.
Female Children of Childbearing Potential and Females of Childbearing 
Potential
Pregnancies and suspected pregnancies (including elevated beta-human chorionic gonadotropin 
(β-hCG) or positive pregnancy test in a female of childbearing potential regardless of disease 
state) occurring while the subject is on IP, or within 28 days of the subject’s last dose of IP, are 
considered immediately reportable events.
IP must be discontinued immediately and the subject will be instructed to return any unused 
portion of the IP to the Investigator. The pregnancy, suspected pregnancy, or positive pregnancy 
test must be reported to Celgene Drug Safety by email, phone, or facsimile, or other appropriate 
method, using the Initial Pregnancy Report Form, or approved equivalent form.
The female should be referred to an obstetrician-gynecologist, preferably one experienced in 
reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Follow-up Pregnancy Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE. If the abnormal outcome meets any 
of the seriousness criteria, it must be reported as an SAE to Celgene Drug Safety immediately by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
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childbearin
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eona
ausalit
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
86
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
11.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP 
should notify the Investigator, and the pregnant female partner should be advised to call her 
healthcare provider immediately. The IP may need to be discontinued in the male subject, but 
may be resumed later at the discretion of the Investigator and Medical Monitor.
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form.  This instruction pertains to initial SAE reports as well as any follow-up reports.
Second primary malignancies will be monitored as events of interest and must be reported as 
SAEs regardless of causal relationship to IP.  This includes any SPM, regardless of causal 
relationship to IP, occurring at any time for the duration of the study, from the time of signing 
the ICF/IAF up to 5 years from the date of the last subject’s first dose unless withdrawal of 
consent, lost to follow-up or death. Events of SPM are to be reported using the SAE report form 
and must be considered an “Important Medical Event” even if no other serious criteria apply; 
these events must also be documented in the appropriate page(s) of the CRF and subject’s source 
documents.  Documentation on the diagnosis of the second primary malignancy must be 
provided at the time of reporting as an SAE (eg, any confirmatory histology or cytology results, 
X-rays, CT scans, etc.).
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent/assent to at least 28 days after the last dose of 
IP), and those made known to the Investigator at anytime thereafter that are suspected of being 
related to IP.  Serious adverse events occurring prior to treatment (after signing the ICF/IAF) will 
be captured.
The SAE report should provide a detailed description of the SAE and include summaries of 
hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data will be detailed in a subsequent 
SAE report form, or approved equivalent form, and sent to Celgene Drug Safety.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than 5 business days.  
Urgent queries (eg, missing causality assessment) may be handled by phone.
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1.5.1.
er


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
87
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to lenalidomide based on the IB.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
Events of disease progression for the disease under study (including death due to disease 
progression that are considered to be fatal) will be assessed as expected adverse events and will 
not be reported as expedited safety reports to regulatory authorities.
Celgene or its authorized representative shall notify the Investigator of the following 
information:
!
Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR).
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC (see Section 15.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form/Completion Guidelines or to the Pregnancy Report Form/Completion Guidelines.
other studi
other stud
gnificant ri
gnificant r
nicicity
ty
i
or ca
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is/her IRB/
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subjects.
ubjec
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15.3 fo
f
n, please r
, please r
regnancy
regnancy R


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
88
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
12.
DISCONTINUATIONS
12.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product:
!
Adverse Event
!
Withdrawal by parent/guardian(s)/subject
!
Death
!
Lost to follow-up
!
Pregnancy
!
Non-compliance with IP
!
Physician decision
!
Protocol violation 
!
Other
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.  
12.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
!
Adverse Event
!
Withdrawal by parent/guardian(s)/subject
!
Death
!
Lost to follow-up
!
Other 
The reason for study discontinuation should be recorded in the CRF and in the source 
documents.
All subjects who are withdrawn from the study should complete all protocol-required evaluations 
scheduled for treatment discontinuation at the time of withdrawal.
ed in the
ed in the C
remains the
remains th
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!
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the
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he reason 
docum
documen
su


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
89
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Since the follow-up of subjects who discontinue prematurely is of particular importance, every 
attempt should be made to collect all survival information and AML treatment/therapy, unless 
the subject has specifically withdrawn consent from further follow-up.  The Investigator must 
make every effort to obtain minimal information regarding the subject’s survival status before 
determining the subject is lost to follow-up.
To allow for subjects found to be unevaluable for the primary endpoint due to an incorrect 
diagnosis, not having a disease assessment post screening, or who discontinued prior to receiving 
lenalidomide, up to 4 additional subjects may be enrolled for a maximum of 47 evaluable 
subjects across approximately 70 sites.
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
90
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor (or designee) by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor (or designee) cannot 
be reached, please contact the global Emergency Call Center by telephone at the number listed 
on the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor (or designee) for 
emergency calls.
13.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
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the pack


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
91
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
14.
REGULATORY CONSIDERATIONS
14.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by GCP, as described in International Conference on Harmonisation 
(ICH) Guideline E6 and in accordance with the general ethical principles outlined in the 
Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should 
maintain a list of Sub-investigators and other appropriately qualified persons to whom he or she 
has delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF)/informed assent form (IAF) and are screened for entry into the study.  Subjects who 
fail screening must have the reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg,
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the
information provided by Celgene on public registry websites) is considered Celgene confidential
information. Only information that is previously disclosed by Celgene on a public registry
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical
Trial Agreement. Celgene protocol, amendment and IB information is not to be made publicly
available (for example on the Investigator’s or their institution’s website) without express written
approval from Celgene. Information proposed for posting on the Investigator’s or their
institution’s website must be submitted to Celgene for review and approval, providing at least 5
business days for review.
At the time results of this study are made available to the public, Celgene will provide
Investigators with a summary of the results that is written for the lay person. The Investigator is
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
92
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
14.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent/pediatric assent of the subject and/or the subject’s 
legal representative(s) prior to any study-related procedures.
Documentation that informed consent/pediatric assent occurred prior to the study subject’s entry 
into the study and of the informed consent process should be recorded in the study subject’s 
source documents including the date.  The original informed consent form/informed assent form
and/or the informed consent of the subject’s legal representative(s) signed and dated by the study 
subject, the subject’s legal representative(s) and by the person consenting the study subject prior 
to the study subject’s entry into the study, must be maintained in the Investigator’s study files 
and a copy given to the study subject/legal representative(s).
In the case where a study center has an IRB- and Celgene-approved procedural ICF/IAF that 
allows collection of additional bone marrow samples for potential research purposes, the latest 
pre-study PB and BM aspirate/biopsy may be used for screening study assessments. 
In addition, if a protocol is amended and it impacts on the content of the informed 
consent/informed assent, the informed consent/informed assent form must be revised.  Study 
subjects and/or legal representative(s) of study subject’s participating in the study when the 
amended protocol is implemented must be reconsented with the revised version of the informed 
consent/informed assent form. The revised informed consent/informed assent form and/or the 
informed consent of the subject’s legal representative(s) signed and dated by the study subject, 
the subject’s legal representative(s) and by the person consenting the study subject prior to the 
study subject’s entry into the study, must be maintained in the Investigator’s study files and a 
copy given to the study subject and/or legal representative(s).
14.4.
Confidentiality
Celgene affirms the subject’s right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene’s representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent form/informed assent form, it is the responsibility of the 
Investigator to obtain such permission in writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator’s name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/EC approval but will be submitted to the IRB/EC for 
information purposes.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
93
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent form/informed assent form, 
and any other appropriate documents will be submitted to the IRB/EC with a cover letter or a 
form listing the documents submitted, their dates of issue, and the site (or region or area of 
jurisdiction, as applicable) for which approval is sought. If applicable, the documents will also 
be submitted to the authorities in accordance with local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements.  Amendments must be evaluated to 
determine whether formal approval must be sought and whether the informed consent/assent 
document should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.
14.7.
Ongoing Information for Institutional Review Board/Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible;
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
14.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc.).
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
94
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
In addition, the Investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;
!
Falsification of records;
!
Failure to adhere to the study protocol.
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
95
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
15.
DATA HANDLING AND RECORDKEEPING 
15.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; X-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
15.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene SOPs. This 
data will be electronically verified through use of programmed edit checks specified by the 
clinical team.  Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary.  Resolutions to these issues will be reflected in the 
database.  An audit trail within the system will track all changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:
!
Signed ICFs/IAFs for all subjects;
!
Subject identification code list, screening log (if applicable), and enrollment log;
!
Record of all communications between the Investigator and the IRB/EC;
!
Composition of the IRB/EC;
!
Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);
!
List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.);
!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
96
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented.
All study documents should be made available if required by relevant health authorities.
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
&(/*(1(35235,(7$5<,1)250$7,21
of 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
97
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigator’s Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, CRFs, procedures for obtaining informed 
consent/assent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring 
will include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  At each monitoring visit, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative for accuracy, adherence 
to the protocol and Good Clinical Practice.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents/assents, adherence to 
inclusion/exclusion criteria and documentation of SAEs and their proper recording be verified.  
Additional monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs [or appropriate SOP] to evaluate compliance with 
Good Clinical Practice guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives.  The Investigator should make every effort to be available 
for the audits and/or inspections.  If the Investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene immediately.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
98
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
17.
PUBLICATIONS
As described in Section 14.2, all protocol- and amendment-related information, with the
exception of the information provided by Celgene on public registry websites, is considered
Celgene confidential information and is not to be used in any publications. Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review
and approval, and should not be utilized in a publication without express written approval from
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to
results from all Phase 3 clinical studies, and any other study results of significant medical
importance. This also includes results relating to investigational medicines whose development
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes. Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.  
Eligibility for external authorship, as well as selection of first authorship, will be based on
several considerations, including, but not limited to, contribution to protocol development, study
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
99
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
18.
REFERENCES
 
 
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after allogeneic stem cell transplant for multiple myeloma [abstract].  54th ASH Annual Meeting 
and Exposition, Atlanta, GA, 8-11 Dec, 2012;Abstract 3064.
Berg SL, Cairo MS, Russell H, Ayello J, Ingle AM, Lau H, et al. Safety, pharmacokinetics, and 
immunomodulatory effects of lenalidomide in children and adolescents with relapsed/refractory 
solid tumors or myelodysplastic syndrome: a Children’s Oncology Group Phase 1 Consortium 
report. J Clin Oncol 2011;29(3):316-323.
Blum W, Klisovic RB, Becker H, Xang X, Rozewski DM, Phelps MA, et al. Dose escalation of 
lenalidomide in relapsed or refractory acute leukemias. J Clin Oncol. 2010;28(33):4919-4925.
 
Chen Y, Borthakur G. Lenalidomide as a novel treatment of acute myeloid leukemia. Expert 
Opin Investig Drugs 2013;22(3):389-397.
Cheson B, Bennett J, Kopecky K, Buchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in 
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Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, et al. Differential cytokine 
modulation and T cell activation by two distinct classes of thalidomide analogues that are potent 
inhibitors of TNF-α. J Immunol 1999;163(1):380-386.
&
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-792
W, Pollock R
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e Inter
ia, Treatme
ia, Treatm
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
100
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Creutzig U, van den Heuvel-Eibrink MM, Gibson B, Dworzak MN, Adachi S, de Bont E, et al. 
Diagnosis and management of acute myeloid leukemia in children and adolescents: 
recommendations from an international expert panel. Blood 2012;120(16):3187-3205.
Creutzig U, Ritter J, Zimmermann M, Reinhardt D, Hermann J, Berthold F, et al. Improved 
treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with 
high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-
Frankfurt-Munster 93. J Clin Oncol 2001;19(10):2705-2713.
 
 
El-Cheikh J, Crocchiolo R, Furst S, Ladaique P, Castagna L, Faucher C, et al. Lenalidomide plus 
donor-lymphocytes infusion after allogeneic stem-cell transplantation with reduced-intensity 
conditioning in patients with high-risk multiple myeloma. Exp Hematol 2012;40:521-527.
Fehniger TA, Byrd JC, Marcucci G, Abboud CN, Kefauver C, Payton JE, et al. Single-agent 
lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated 
trisomy 13. Blood 2009;113(5):1002-5100.
Fehniger TA, Uy GL, Trinkaus K, Nelson AD, Demland J, Abboud CN, et al. A phase 2 study of 
high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia. Blood 
2011;117(6):1828-1833.
Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittleman M, et al. A 
randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients 
with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 
2011;118(14):3765-3776.
Ford CD, Asch J, Konopa K, Petersen FB. CR with lenalidomide in del(5)(q13q33) AML 
relapsing after allogeneic hematopoietic SCT. Bone Marrow Transpl 2010;45(2):403-404.
Gandhi A, Kang J, Havens CG, Conklin T, Ning Y, Wu L, et al. Immunomodulatory agents 
lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
101
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
102
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
103
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
104
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
105
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
19.
APPENDICES
Appendix A:
World Health Organization Classification of Acute Myeloid 
Leukemia
World Health Organization Classification
Acute Myeloid Leukemia (AML) with recurrent genetic abnormalities:
!
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
!
AML with inv(16)(p13;q22) or t(16;16)(p13;q22); CBFB-MYH11
!
Acute promyelocytic leukemia with t(15;17)(q22;q11-12); PML-RARα
!
AML with t(9;11)(p22;q23); MLLT3-MLL
!
AML with t(6;9)(p23;q34); DEK-NUP214
!
AML with inv(q21;q26.2) or t(q21;q26.2); RPN1-EVI1
!
AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
!
Provisional entity: AML with mutated NPM1
!
Provisional entity: AML with mutated CEBPA
AML with myelodysplasia-related changes
Therapy-related myeloid neoplasm
AML not otherwise categorized:
!
AML with minimal differentiation
!
AML without maturation
!
AML with maturation
!
Acute promyelocystuc leukemia
!
Acute myelomonocytic leukemia
!
Acute monoblastic and monocytic leukemia
!
Acute erythroid leukemia
!
Acute megakaryoblastic leukemia.
!
Acute basophilic leukemia.
!
Acute panmyelosis with myelofibrosis.
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
Blastic plasmacytoid dendritic cell neoplasm
Source:  National Cancer Institute, 2014.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
106
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix B:
Lenalidomide Dosing Table – Capsule 
Lenalidomide* Dosing Table – Capsule 
Calculated Dose
(mg/day)**
Actual Dose 
Administered 
(mg/day)
Number of Capsule Strength
2.5 mg
5 mg
10 mg
15 mg
20 mg
25 mg
15
15
1
16
15
1
17
17.5
1
1
18
17.5
1
1
19
20
1
20
20
1
21
20
1
22
20
1
23
22.5
1
1
24
25
1
25
25
1
26
25
1
27
25
1
28
27.5
1
1
29
30
1
1
30
30
1
1
31
30
1
1
32
30
1
1
33
35
1
1
34
35
1
1
35
35
1
1
36
35
1
1
37
35
1
1
38
40
2
39
40
2
40
40
2
41
40
2
42
40
2
43
45
1
1
44
45
1
1
45
45
1
1
46
45
1
1
47
45
1
1
48
50
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EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
107
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Lenalidomide* Dosing Table – Capsule 
Calculated Dose
(mg/day)**
Actual Dose 
Administered 
(mg/day)
Number of Capsule Strength
2.5 mg
5 mg
10 mg
15 mg
20 mg
25 mg
50
50
2
51
50
2
52
50
2
53
52.5
1
2
54
55
1
2
55
55
1
2
56
55
1
2
57
60
3
58
60
3
59
60
3
60
60
3
61
60
3
62
60
3
63
65
1
2
64
65
1
2
65
65
1
2
66
65
1
2
67
65
1
2
68
70
1
2
69
70
1
2
70
70
1
2
* Using CC-5013 strengths: 2.5 mg (Size 4), 5 mg (Size 2), 10 mg (Size 0), 15 mg (Size 0), 20 mg (Size 0) and 25
mg (Size 0).
** If the calculated dose falls between two integers, the dose calculated should be rounded up or down to the nearest 
whole number. The actual dose to be administered can be determined after rounding the calculated dose.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
108
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix C: Lenalidomide Dosing Table – Oral Suspension
Calculated Dose
(mg/day)
Actual Dose Administered 
(mg/day)
Volume Administered 
(mL)
15
16
1.6
16
16
1.6
17
18
1.8
18
18
1.8
19
20
2
20
20
2
21
22
2.2
22
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2.2
23
24
2.4
24
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2.4
25
26
2.6
26
26
2.6
27
28
2.8
28
28
2.8
29
30
3
30
30
3
31
32
3.2
32
32
3.2
33
34
3.4
34
34
3.4
35
36
3.6
36
36
3.6
37
38
3.8
38
38
3.8
39
40
4
40
40
4
41
42
4.2
42
42
4.2
43
44
4.4
44
44
4.4
45
46
4.6
46
46
4.6
47
48
4.8
48
48
4.8
49
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
109
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Calculated Dose
(mg/day)
Actual Dose Administered 
(mg/day)
Volume Administered 
(mL)
51
52
5.2
52
52
5.2
53
54
5.4
54
54
5.4
55
56
5.6
56
56
5.6
57
58
5.8
58
58
5.8
59
60
6
60
60
6
61
62
6.2
62
62
6.2
63
64
6.4
64
64
6.4
65
66
6.6
66
66
6.6
67
68
6.8
68
68
6.8
69
70
7
70
70
7
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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Confidential and Proprietary
110
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix D:
Modified International Working Group AML Response 
Criteria
Hematologic Response According to IWG Criteria for AML
Category
Definition
Morphologic Complete
Remission (CR)
The following conditions should be met:
!
Absolute neutrophil count (ANC) ≥1000/μL and platelets 
≥100,000/μL without transfusions and/or exogenous 
growth factor support (ie, no transfusion or exogenous 
growth factor within 7 days of assessment).
!
Bone marrow with < 5% blasts and evidence of trilineage 
hematopoiesis.
!
No evidence of extramedullary disease.
Morphologic Complete
Remission With Incomplete
Blood Count Recovery
(CRi)
!
ANC < 1000/μL.
!
Platelets < 100,000/μL or > 100,000/μL without platelet 
recovery (requiring transfusion within 7 days of 
assessment).
!
Bone marrow with < 5% blasts and evidence of trilineage 
hematopoiesis.
!
No evidence of extramedullary disease.
Partial Remission (PR)a
!
ANC ≥1000/μL and platelets ≥100,000/μL without 
transfusions and/or exogenous growth factor support (ie, 
no transfusion or exogenous growth factor within 7 days 
of assessment).
!
Bone marrow with 5% to 25% blasts and at least a 50% 
decrease in bone marrow blast percent from baseline.
!
No evidence of extramedullary disease.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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Confidential and Proprietary
111
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Hematologic Response According to IWG Criteria for AML
Category
Definition
Treatment Failure
Resistant Disease:
Patient survives ≥7 days post-therapy and failed to achieve CR, 
CRi, or PR with persistent AML in blood or bone marrow.
Aplasia:
Patient survives ≥ 7 days post-therapy; death while cytopenic, 
with aplastic bone marrow.
Indeterminate cause:
!
Patients who die < 7 days post-therapy.
!
Patients who die > 7 days post-therapy with no peripheral 
blood blasts, but no bone marrow examination.
!
Patients who do not complete the first course of therapy.
Morphologic relapse after CR or CRi:
!
the reappearance of > 5% blasts in the peripheral blood, or
!
a single finding of > 15% blasts in the bone marrow.
All of the above occurrences should be attributed to relapse
following CR or CRi and not attributable to another cause (eg,
bone marrow regeneration after consolidation therapy).
Molecular or cytogenetic relapse:
Reappearance of molecular or cytogenetic abnormality.
a
If the pretreatment bone marrow blast percentage was 50% to 100%, the percentage of blasts must decrease to a value
between 5% and 25%; if the pretreatment blast percentage was 20% to less than 49%, they must decrease by at least half to a 
value of more than 5%.
Source:  Cheson, 2003.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
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CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix E:
KARNOFSKY PERFORMANCE STATUS
Numeric Score Representing the Functional Capabilities of a Person 16 Years and Older 
(≥16 years) According to the Karnofsky Scale
Score
Description
100
Normal; no complaints; no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of disease.
80
Normal activity with effort; some signs or symptoms of disease.
70
Cares for self; unable to carry on normal activity or to do active work.
60
Requires occasional assistance, but is able to care for most of his needs.
50
Requires considerable assistance and frequent medical care.
40
Disabled; requires special care and assistance.
30
Severely disabled; hospitalization is indicated although death not imminent.
20
Very sick; hospitalization necessary; active support treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead.
Source:  Karnofsky, 1948.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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Confidential and Proprietary
113
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix F:
LANSKY PERFORMANCE STATUS
Numeric Score Representing Performance Status of a Subject 0-15 Years of Age (<16 
years) According to the Lansky Scale
Score
Description
100
Fully active, normal.
90
Minor restrictions in physically strenuous activity.
80
Active, but tires more quickly.
70
Both greater restriction of, and less time spent in, active play.
60
Up and around, but minimal active play; keeps busy with quieter activities.
50
Gets dressed, but lies around much of the day; no active play; able to participate 
in all quiet play and activities.
40
Mostly in bed; participates in quiet activities.
30
In bed; needs assistance even for quiet play.
20
Often sleeping; play entirely limited to very passive activities.
10
No play; does not get out of bed.
0
Unresponsive.
Source: Lansky, 1987.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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Confidential and Proprietary
114
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix G:
List of Abbreviations and Definitions of Terms
ABC
Activated B Cell
ADE
Daunorubicin, Cytarabine, Etoposide
AE
Adverse Event
ALL
Acute Lymphoblastic Leukemia
ALT (SGPT)
Alanine Transaminase (Serum Glutamate Pyruvic Transaminase)
AML
Acute Myeloid Leukemia
AMP
Adenosine Monophosphate
ANC
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
AST (SGOT)
Aspartate Transaminase (Serum Glutamate Oxaloacetic Transaminase)
AUC
Area Under the Concentration-Time Curve
β-hCG
Beta-Human Chorionic Gonadotropin
BMA
Bone Marrow Aspirate
BMT
Bone Marrow Transplant
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CEBP-alpha
CCAAT/Enhancer-binding Protein alpha
CBC
Complete Blood Count
CDC
Center for Disease Control
CLcr
Creatinine Clearance
CL/F
Apparent Total Clearance
CLL
Chronic Lymphocytic Leukemia
Cmax
The Maximum Concentration
CML
Chronic Myeloid Leukemia
CN-AML
Cytogenetically Normal Acute Myeloid Leukemia
CNS
Central Nervous System
CR
Complete Remission
CRBN
Cereblon
CRF
Case Report Form
CRi
CR with Incomplete Blood Count Recovery
CRO
Clinical Research Organization
CRT
Chemoradiation Therapy
CSF
Cerebrospinal Fluid
CT 
Computed Tomography
(
Comp
Comp
(
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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CTCAE
Common Terminology Criteria For Adverse Events
CUL4
Cullin 4
DDB1
DNA Damage-binding Protein 1
DLBCL
Diffuse Large B Cell Lymphoma
DLI
Donor Lymphocyte Infusion
DLT
Dose Limiting Toxicities
DMC
Data Monitoring Committee
DOB
Date of Birth
EC
Ethics Committee
ECG
Electrocardiogram
EFS
Event-free Survival
EGTA
Ethylene Glycol Tetraacetic Acid
EMA
European Medicines Agency
FAB
French-American-British Classification
FCBP
Female of Childbearing Potential 
FCCBP
Female Children of Childbearing Potential 
FDA
Food and Drug Administration
FISH
Fluorescent In Situ Hybridization
FLT3
Fms-like tyrosine kinase 3
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony Stimulating Factor
GFR
Glomerular Filtration Rate
GPR68
G protein-Coupled Receptor 68
GI
Gastrointestinal
GVHD
Graft Versus Host Disease
HIV
Human Immunodeficiency Virus
HSCT
Hematopoietic Stem Cell Transplant
IAF
Informed Assent Form
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
ICU
Intensive Care Unit
IIT
Investigator Initiated Trial
IL
Interleukin
IFN
Interferon
&
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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Confidential and Proprietary
116
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
IP
Investigational Product
IRB
Institutional Review Board
IRF4
Interferon Factor 4
IST
Immune Suppressive Therapy
IT
Intrathecal
ITT
Intention to Treat 
IV
Intravenous
IWG
International Working Group
IWRS
Interactive Web Response System
JAK
Janus Kinase
LDH
Lactate Dehydrogenase
LMWH
Low-Molecular-Weight Heparin
MA
Mitoxantrone, Cytarabine
MCL
Mantle Cell Lymphoma
M-CSF
Macrophage Colony-Stimulating Factor
MCV
Mean Corpuscular Volume
MDF
Multidimensional Flow Cytometry 
MDS
Myelodysplastic Syndromes
MDSL
MDS Patient-derived Cell Line
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
Microribonuleic Acid
MLL
Mixed Lineage Leukemia
MM
Multiple Myeloma
MRD
Minimal Residual Disease
mRNA
Messenger Ribonucleic Acid
MTD
Maximum Tolerated Dose
MYD88
Myeloid Differentiation Primary Response Gene (88)
NaHCO3
Sodium Bicarbonate
NCI
National Cancer Institute
NF-κB
Nuclear Factor kappa-Light-Chain-Enhancer of Activated B Cells
NHL
Non-Hodgkin’s Lymphoma
NK
Natural Killer (T-Cell)
NPM1
Nucleophosmin
OEP
Optional Extension Phase
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
117
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ORR
Overall Response Rate
PK
Pharmacokinetics
PR
Partial Response
RBC
Red Blood Cell (Count)
Roc 1
Regulator of Cullins 1 Protein
RR
Response Rate
rrAML
Relapsed or Refractory Acute Myeloid Leukemia
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
sCr
Serum Creatinine
SCT
Stem Cell Transplantation
SD
Stable Disease
shRNAs
Small Hairpin RNA or Short Hairpin RNA
siRNA
Small Interfering Ribonucleic Acid
SOP
Standard Operating Procedures
SPID
Surgical Pathology Identification Number
SPM
Second Primary Malignancy
SUSARs
Suspected Unexpected Serious Adverse Reactions
SWOG
Southwest Oncology Group 
TEAE
Treatment-emergent Adverse Event
tmax
Time of Maximum Exposure
TEN
Toxic Epidermal Necrolysis
TFR
Tumor Flare Reaction
TLS
Tumor Lysis Syndrome
TNF
Tumor Necrosis Factor
TPN
Total Parenteral Nutrition
TTP
Thrombotic Thrombocytopenic Purpura
t1/2
Half-life
ULN
Upper Limit of Normal
UMVUE
Uniformly Minimum Variance Unbiased Estimator 
US
United States
USPI
United States Prescribing Information
VOD
Veno-occlusive Disease
WBC
White Blood Cell (Count)
&
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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Confidential and Proprietary
118
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
WHO
World Health Organization
XRT
Palliative Radiation Therapy
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
119
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix H:
Lenalidomide Plasma*
 PK Sample Handling 
Instructions
Preparation of Collection Tubes and Storage Vials
All labels will be provided by central lab.  The labels will contain the following information:
!
Protocol No.: CC-5013-AML-002
!
Subject ID number: (To be added by site)
!
Treatment: Lenalidomide
!
Nominal Time: eg, 1 hour after dosing
!
Sample Type: Plasma, 
 
All blood, plasma 
 collection tubes and storage vials should be labeled and chilled on 
wet ice prior to sample collection and processing.
Lenalidomide Plasma PK Sample Handling
1. Blood Sample Collection
!
Fill an ice bucket with a sufficient amount of ice to pre-chill all collection tubes 
before blood draw.
!
Collect approximately 1 mL of whole blood into a pre-chilled K2 EDTA tube.
!
Accurately record the time of blood collection.
!
Gently invert the tube 3 to 5 times and immerse it into ice bath immediately to 
prevent possible compound degradation at room temperature.
2. Blood Sample Processing to Obtain Plasma
!
Within 30 minutes of collection, the blood sample must be centrifuged at 1,500 g 
(about 3,000 rpm) for 10 minutes at 4°C to obtain plasma.
!
Transfer approximately 0.25 mL of plasma into each of the pre-labeled, pre-chilled, 
polypropylene storage tubes (ie, primary and back up).  Keep storage tubes on ice 
before they are ready to be transferred into a freezer.
!
Within 60 minutes of blood collection, transfer plasma samples in storage vials into 
a –70oC freezer, where they will remain stored until shipping.
!
Immediately record the time of sample entry into the freezer.
 
 
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are ready t
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60 minute
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mediate
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&(
&


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
120
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
Plasma 
 PK Sample Shipment  
All PK sample label information on the storage tubes have to be checked against the 
requisition form and then the samples must be shipped from the sites on dry ice to the 
central lab.
A copy of the completed specimen manifest must accompany the shipment, and must list the 
following information at minimum:
!
Sponsor name: Celgene Corp
!
Celgene Study Number: CC-5013-AML-002
!
Subject ID Numbers
!
Collection date (ie, dd mmm yyyy)
!
Nominal collection time (ie,1 hour, post dose)
!
Sample types (eg, plasma, 
)
The central lab will then ship the samples to
 for sample analysis.
*Only 5 PK blood samples will be taken from subjects with weight ≤ 20 kg at the specified time points and seven PK blood 
samples will be taken from subjects with weight > 20 kg.
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235
3


EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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Appendix I:
Central Pathology Review
For this study, acute myeloid leukemia will be classified according to the WHO criteria.  Submit 
slides, all pertinent institutional reports and the CC-5013-AML-002 pathology transmittal form 
to the bio-pathology center as described below. These samples should be submitted within 7 
days of the procedure.
REQUIRED STUDIES FOR ALL SUBJECTS AT BASELINE
1. A completed pathology report, bone marrow aspirate/biopsy report, and flow cytometry 
report.
2. One (1) peripheral blood smear (Wright-Giemsa stained).
3. A concurrent complete blood count including white blood cell differential (manual or 
automated).
4. One (1) representative bone marrow aspirate smear (Wright-Giemsa stained).
5. One (1) H&E stained slide from bone marrow clot section and/or one (1) stained slide 
from core biopsy.
6. Four (4) unstained slides from aspirate smears.
7. Four (4) unstained slides from clot section and/or core biopsy (preferably on charged 
slides).
8. Cytogenetic report, FISH studies and molecular testing (FLT3, CEPBA, NPM1, exome 
sequencing (if performed)).
RECOMMENDED ADDITIONAL MATERIALS:
1. Additional aspirate smears (stained and/or unstained).
2. Cytochemical stains (myeloperoxidase, non-specific esterase, PAS).
3. Immunohistochemical stains (ex.CD34, CD74, CD117, myeloperoxidase).
4. Tissue blocks.
CENTRAL PATHOLOGY REVIEW MATERIALS WILL BE RETAINED BY 
 
AND WILL NOT BE RETURNED UNLESS OTHERWISE INDICATED ABOVE.
Instructions for Labeling Slides
Bone Marrow Slides (aspirate smears, core biopsy, and clot section) - Please label bone marrow 
slides with the subject’s 7-digit study ID number and the surgical pathology identification 
(SPID) number (eg, specific specimen number) from the matching bone marrow report.
Peripheral Blood Slides (Smears) - If there is a procedure or report number on the institutional 
laboratory report, please label the peripheral blood slides with the subject’s 7-digit study ID 
Number and the report (or procedure) number from the institutional report. If there is not a 
number on the report, then please label the slide with the date the blood was drawn and the 
subject’s 7-digit study ID Number.
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umbe
umbe


EDMS Doc. Number:
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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Ship materials by regular mail or using your institution’s courier account to the Biopathology 
Center:
ATTN: Celgene CC-5013-AML-002 Study
Phone: 
**Be sure to include the room number. Packages received without the room number may be 
returned to the sender.
&(/*(1(35235,(7$5<,1)250$7,21
mber may b
mber may b


EDMS Doc. Number: 
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Protocol CC-5013-AML-002
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CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
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Protocol CC-5013-AML-002
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124
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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125
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
250$7,21
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EDMS Doc. Number: 
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Protocol CC-5013-AML-002
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126
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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127
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
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128
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
129
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
130
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix L:
Optional Extension Phase
Subject Eligibility
At the Investigator’s discretion and with approval of the Sponsor, subjects meeting all of the 
following eligibility criteria are eligible to enter the Optional Extension Phase:
!
Subjects have received oral lenalidomide for 12 cycles and are continuing to have 
response or demonstrating clinical benefit from therapy as assessed by the Investigator
without unacceptable toxicities.
!
Subjects who have signed the informed consent for the extension phase.
!
Subjects who do not meet any of the criteria for treatment discontinuation (see Section 
12).
!
All subjects must be counseled about pregnancy precautions and risks of fetal exposure 
prior to the start of lenalidomide and during IP treatment and 28 days after last dose of IP.  
They must also be counseled against sharing IP and donating blood during and within 28 
days of discontinuing IP.
!
For FCCBP/FCBP subjects, the pregnancy tests are negative when performed within 10-
14 days and within 24 hours prior to the start of lenalidomide.
Subjects will start the extension study at the time of the next regularly scheduled dosing cycle.
Dosage for First Treatment Cycle
The dose and schedule for the first treatment cycle should be administered at the identical dose 
as the final treatment phase cycle.  If a dose reduction was required in the last cycle of the 
treatment phase, the first treatment phase cycle should be administered at the identical (reduced) 
dose/or schedule.  Capsules of same strengths used in the treatment phase will be utilized in the 
OEP.  The oral suspension will be available for use in subjects who are unable to swallow the 
capsules or at the discretion of the investigator in the OEP. 
Study Duration of the OEP
Subjects may continue to receive oral lenalidomide in the OEP until they meet the criteria for 
study discontinuation (Section 12).
Subsequent Treatment Cycles
Cycles should be repeated every 28 days.  Subjects should be monitored for AEs, SPMs, 
pregnancy testing for FCCBP and FCBP, concomitant medications/procedures collection, IP 
dispensing (for each 28-day cycle), and IP accountability.
Oral lenalidomide Dispensing and Administration in the OEP
Subjects will be dispensed only one cycle of oral lenalidomide at a time (typically within an 
approximate 28-day period).  All subjects should not extensively handle the lenalidomide 
capsules or oral suspension. The lenalidomide capsules should not be broken, chewed, or opened 
and should be maintained in the packaging until ingestion. Subjects will be instructed to inspect 
each capsule and only take capsules that are totally intact.  Subjects should be instructed to return 
any capsule that is not totally intact to the study clinic.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
131
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Detailed instructions on preparation, administration, and handling of the lenalidomide oral 
suspension will be provided in a separate manual.
The dose and schedule for the first dose of treatment cycle in the OEP should be administered at 
the same dose and schedule as the final treatment cycle (Cycle 12).  If a dose modification was 
required in the last cycle of the treatment phase, the first extension cycle should be administered 
at the identical (modified) dose and/or schedule.  For dose modifications refer to Section 8.2.1.
Management of Toxicity and Dose Modifications
The subject’s dose of lenalidomide should be calculated on the first day of each dosing cycle
based on weight.  If a subject’s body weight changes by more than 10% compared with baseline 
body weight, or compared with a previous body weight value that required a dose adjustment, 
then the dose of IP should be recalculated.  The dose of lenalidomide during a treatment cycle in 
the OEP should not be altered.
Hematological and non-hematological toxicity will be graded using Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  In all cases, the reason for dose 
modification must be recorded in the subject’s medical record.  If the subject discontinues the 
protocol-prescribed therapy because of an AE, this event must be reported in accordance with the 
procedures outlined in Section 11.
Prior and Concomitant Medications and Therapy in the OEP
Refer to Section 9 for permitted and prohibited concomitant therapies.
Adverse Event Reporting
Adverse events should be reported and managed as per Section 11.
Second primary malignancies (SPMs) will be monitored as events of interest and should be 
included as part of the assessment of AEs throughout the course of the study.  Investigators are to 
report any SPM as SAEs regardless of causal relationship to lenalidomide, occurring at any time 
for the duration of the study, from the time of signing the ICF/IAF until all subjects have been 
followed for up to 5 years from the last subject’s first dose, unless consent is withdrawn, the 
subject is lost to follow-up or dies.  Events of SPM are to be reported using the SAE report form 
and must be considered an “Important Medical Event” even if no other serious criteria apply; 
these events must also be documented in the appropriate page(s) of the CRF and subject’s source 
documents.  Documentation on the diagnosis of the SPM must be provided at the time of 
reporting as a SAE (eg, any confirmatory histology or cytology results, X-rays, computed 
tomography [CT] scans, etc.).
Concomitant Medications
All concomitant medications that are necessary for the subject’s welfare and are unlikely to 
interfere with lenalidomide may be given at the Investigator’s discretion during the extension 
study.  However, treatment with any other investigational medication is not permitted.
Investigational Product Accountability and Disposal
The investigational site must maintain accurate records demonstrating dates and amounts of 
lenalidomide received, to whom it was administered (subject-by-subject accounting), and 
accounts of any lenalidomide accidentally or deliberately destroyed or returned.  Accurate 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
132
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
recording of all lenalidomide administration will be made in the appropriate section of the 
subject’s CRF and source documents.
Unless otherwise notified, all lenalidomide both used and unused must be saved for IP 
accountability.  After IP accountability has been completed by the monitor, Celgene (or 
designee) will review with the Investigator and relevant site personnel the process for 
lenalidomide return, disposal, and/or destruction including responsibilities for the site versus 
Celgene (or designee).
Investigation Product Compliance
Administration of all IPs will be accurately recorded including dispensing, dosing and any 
changes in dosage administration such as interruption or reduction in dosing due to an adverse 
event.
Females of child bearing potential (FCBP) should not handle or administer lenalidomide unless 
they are wearing gloves.  All subjects should not extensively handle lenalidomide capsules or 
oral suspension. All subjects should not break, chew, or open lenalidomide capsules and should 
maintain storage of capsules in the packaging until ingestion. Refer to the subject diary and the
manual on preparation, administration, and handling of the lenalidomide oral suspension for 
specific details.
In investigational studies, lenalidomide will be dispensed through a qualified healthcare 
professional (including but not limited to, nurses, pharmacists and physicians). These healthcare 
professionals will be trained by Celgene in requirements specific to counseling of 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 for FCBP) and that the subject understands the risks associated with 
lenalidomide.  This step will be documented with a completed Education and Counseling 
Guidance Document 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 will be supplied each time lenalidomide is dispensed.
Recommended Monitoring of Subjects
1. Complete blood count with WBC differential and platelet count as needed.
2. Additional tests or more frequent monitoring are at the Investigator’s discretion based on 
the subject’s clinical status.
Investigator’s Responsibility
3. Complete Extension Phase Case Report Form pages.
4. Report serious adverse events (including second primary malignancies) and other 
immediately reportable events, as required by the protocol (see Section 11).  A completed 
SAE form must be faxed to Celgene Drug Safety within 24 hours of the Investigator’s 
knowledge of the event, as detailed in the Serious Adverse Event Report Form 
Completion Guidelines.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
133
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
5. Document all adverse events (serious and non-serious) on the adverse event log page of 
the Extension Phase Case Report Form, as detailed by the protocol (see Section 11).
6. Report to the Sponsor drug accountability.
7. Report to the Sponsor and complete the case report form page for extension phase 
termination when the subject completes, discontinues, or terminates treatment.
8. The subject must stop the treatment if any of the following occur:
a.
Additional investigational treatment is started;
b. Subject is no longer receiving clinical benefit, as per Investigator discretion;
c.
Subject withdraws consent;
d. A CTCAE toxicity Grade 3 or 4 that represents a worsening from baseline (prior to 
the first dose) persists for more than 21 days, despite the temporary interruption of the 
regimen;
e.
A positive pregnancy test in a FCCBP/FCBP, at any time; or
f.
At the specific request of the Sponsor or its authorized representative.
9. The Investigator must be available for periodic monitoring visits and allow the Sponsor
access to all medical records.
10. The Investigator will maintain source documents on the subject for all case report form 
data points, which include the following:
a.
Informed consent/assent;
b. Adverse events;
c.
Dosing information (date of administration, dose);
d. Termination date and reason.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
134
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
Appendix M: Tumor Lysis Syndrome
Subjects at greatest risk are those with bulky disease or high tumor burdens with malignancies 
exquisitely sensitive to chemotherapy; WBC > 100,000/mL, lymphadenopathy, 
hepatosplenomegaly, elevated LDH, and large primary masses of the abdomen, thorax, or 
mediastinum. Diseases most commonly associated with TLS include Acute Lymphoblastic 
Leukemia (ALL), T-cell Leukemia/Lymphoma and Non-Hodgkin’s Lymphoma (eg, Burkitt’s 
lymphoma), although it can occur in tumors such as neuroblastoma where the bone marrow is 
completely replaced by tumor. The risk for serious acute TLS is usually restricted to the first 72 
hours after initiation of therapy; however, it may spontaneously occur prior to treatment.
TLS is characterized by severe hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, 
and acute renal failure. Suggested initial studies to be obtained prior to initiating therapy include 
CBC, prothrombin and activated partial thromboplastin times, fibrinogen, D-dimer, and serum 
electrolytes (including creatinine, BUN, uric acid, phosphorous, and calcium). Imaging 
pretreatment may include an abdominal ultrasound to assess renal parenchymal infiltration, as 
occasionally there may also be an obstructive element due to tumor pressure, and a chest X-ray 
including lateral to assess for mediastinal mass and tumor burden. Continued monitoring of 
these studies should be carried out at suitable intervals until abnormalities have resolved or the 
risk has abated.
Prevention and Monitoring
1. Maintain strict attention to subject’s fluid balance (input and output).
2. Hydration with 2400 - 3000 mL/m2/day of IV fluid (D5 ¼ or D5 ½) NS (no potassium) + 
NaHCO3 25 - 100 mEq/L. Adjust bicarbonate to maintain urine pH 6.5 - 7.5 and not in 
excess of 8.5 for subjects taking allopurinol. No potassium should be administered until 
tumor lysis is controlled. Alkalinization is not recommended when treating with uricase 
or rasburicase.
3. Begin allopurinol prior to chemotherapy. Allopurinol should be infused in a separate IV 
line from the chemotherapy. Continue until peripheral blasts and extramedullary disease 
are reduced.
Dose: Daily doses > 300mg should be administered in divided doses.
Children < 10 years:
!
IV: 200 mg/m2/day in 1 - 3 divided doses; maximum dose: 600 mg/day.
!
PO: 10 mg/kg/day in 2 - 3 divided doses or 200 - 300 mg/m2/day in 2 - 3 divided 
doses.
Maximum dose: 800 mg/day.
Children > 10 years and adults:
!
IV: 200 - 400 mg/m2/day in 1 - 3 divided doses; maximum dose: 600 mg/day.
!
PO: 600 - 800 mg/day in 2 - 3 divided doses.
4. In some situations it may be appropriate to use rasburicase (recombinant urate oxidase) as 
initial therapy, such as in subjects who are at a significant risk of TLS due to disease or 
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
135
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
subject-related risk factors or those who are demonstrating signs of evolving TLS. 
Subjects who present with renal insufficiency (serum creatinine [sCr] > 0.7 mg/dL in 
children or > 1.3 mg/dL in adults), either preexisting or due to new disease, and subjects 
with hyperuricemia at presentation are also good candidates for upfront rasburicase. 
Dosing for rasburicase is 0.15 - 0.2 mg/kg/dose IV over 30 minutes daily until uric acid 
levels have normalized and subject is clinically stable; typically 1 to 3 days. Sodium 
bicarbonate is not required when using rasburicase. Rasburicase is contraindicated in 
subjects with glucose-6-phosphate dehydrogenase (G-6PD) deficiency.
5. Check subject’s urine for specific gravity and hematuria after every void.
6. Assess subject’s weight twice daily.
7. Assess the subject’s vital signs frequently, at a minimum every 4 hours and observe 
subject for irregular pulse and decrease in blood pressure.
8. Monitor the subject’s laboratory values (ie, electrolytes, calcium, uric acid, creatinine, 
and phosphate) at least every 8 hours.
9. Hyperkalemia (> 6.0 mEq/L) leads to ventricular arrhythmias and possibly death.
a. Assess for symptoms of cardiac arrhythmias by using a cardiac monitor if clinically 
indicated.
b. Calcium administration is the fastest means of reversing the cardiac effects of 
hyperkalemia. Onset of action is within minutes but the duration is only one-half hour. 
Consider slow infusions and in a separate line from the sodium bicarbonate.
c. Sodium bicarbonate as well as insulin and glucose administration will move excess 
potassium into the cell; administer sodium bicarbonate at 1 - 2 mEq/kg IV or administer 
continuous glucose infusion at 0.5 g/kg/hour with insulin 0.1 unit/kg/hour.
10. Maintain urine output >100 mL/m2/hour administering mannitol 0.5 g/kg or furosemide 1
- 2 mg/kg by IV as needed.
11. If urine output declines, an ultrasound study of the kidney may be useful to rule out 
tumor infiltration or obstructive uropathy.
12. Perform a minimum of 1 daily physical exam for signs of dyspnea, rales, wheezing, 
cardiac arrhythmias, edema, ascites, neuromuscular changes, and gastrointestinal 
complaints.
13. Minimize exogenous potassium and phosphorous intake.
14. Avoid IV contrast and nephrotoxic medications when possible.
15. Medical management of hypocalcemia, hyperphosphatemia, hypercalcemia, and/or renal 
failure should be undertaken aggressively and in consultation with nephrology and the
intensive care unit (ICU).
16. Monitor calcium-phosphorus product; if > 60 discontinue alkalinization.
Additional Procedures:
1. More aggressive hydration, leukapheresis, or exchange transfusion may be considered for 
elevated WBC (> 100,000 to 200,000) and multiple metabolic abnormalities.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
136
CC-5013-AML-002 Amendment 2.0 Final: 13 Dec 2016
2. Dopamine 3 mcg/kg/minute may aid in increasing renal blood flow.
3. Hemofiltration or dialysis may be warranted.
Dialysis indications when above fail:
a.
QRS interval widening with serum potassium > 6 mEq despite kayexalate and rising 
creatinine with urine output < 60 mL/m2/hour.
b. Serum uric acid > 10 mg/dL with rising creatinine and urine output < 60 mL/m2/hour.
c.
Serum creatinine > 10 mg/dL.
d. Serum phosphorus > 10 mg/dL or rapidly rising despite aluminum hydroxide with 
rising creatinine and urine output < 60 mL/m2/hour.
e.
Volume overload.
f.
Symptomatic hypocalcemia with hyperphosphatemia.
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EDMS Doc. Number: 
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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EDMS Doc. Number: 
Lenalidomide (CC-5013)
Summary of Changes CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
3
CC-5013-AML-002 Amendment #2 Final: 13 Dec 2016
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Removed progressive disease as part of the response criteria to avoid confusion with 
the overlapping definition of treatment failure. Progressive disease adds no utility in 
addition to treatment failure in the criteria. Language was updated throughout the 
document to align with the modified response criteria, including the use of the term 
‘relapse’ and the deletion of ‘resistant disease’ (Protocol Summary, Table 2, Sections
4.1, 4.4, 6.20.1, 6.20.3, 6.20.4, 8.2, 8.2.1, 10.2, 10.6.2, 10.8, 12.1, Appendix D and 
G).
!
Clarified that if clinically inappropriate per the treatment site, a subject may have the 
bone marrow evaluation omitted at treatment discontinuation if peripheral blast 
results are collected (Table 2 and 6.22). 
!
Clarified that subjects demonstrating clinical benefit as per the Investigator at the end 
of Cycle 4 and beyond may continue to receive lenalidomide on study for up to 12 
cycles in the absence of protocol-defined toxicity, or transitioning to allogeneic 
HSCT (Protocol Summary, Sections 4.1, 4.4, 6.20.1). Clarified that subjects who do 
not demonstrate clinical benefit as per the Investigator at the end of Cycle 4 and 
beyond will be discontinued from lenalidomide treatment (Section 8.2.1).
!
Updated the ALT/AST inclusion criteria by providing a specific upper limit of normal 
(ULN), as well as updated ULN for ALT/AST when considering dose 
reduction/interruption and AE grading (Sections 7.2, 8.2.1, 11.2.2). 
!
 
The amendment also includes typographical and formatting corrections, and several other minor 
clarifications and corrections, including:
!
The brand name of REVLIMID was capitalized throughout the document to maintain 
consistency (Protocol Summary, Sections 6.25 and 18). 
!
Updated the word ‘relapse’ to ‘relapsed’ throughout the document (Section 1.4.2 and 
Table 2)
!
Added ‘(with second or greater relapse or refractory to at least 2 prior induction 
attempts)’ as part of the primary objective to align with Section 2 (Section 1.4.2).
!
Amended wording from ‘summaries’ to ‘summarized’ under Molecular and Cellular 
Measurements (Section 10.8). 
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
3
CC-5013-AML-002 Amendment #1 Final: 01 Jun 2016
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
The Medical Monitor/Emergency Contact Information section was updated. 
!
Duration of response was added as a secondary endpoint 
 
 (Protocol Summary, Sections 2.2, 3.2, 10.6.2). 
!
Updated the number of study sites from 75 to 70 to better reflect the number of sites 
involved with the study (Protocol Summary, Sections 4.1, 7.1, 12.2).
!
Provided clarification language to state the DMC will evaluate available safety data 
and provide a recommendation once 4 subjects having received at least one dose of 
lenalidomide have completed at least 1 cycle of study treatment or discontinued 
treatment (whichever occurs first) (Protocol Summary, Sections 4.1, 4.4, 10.9). 
!
Amended the word ‘banked’ to ‘stored’ in regard to the central biorepository samples 
in order to clarify how samples will be handled (Protocol Summary, Sections 4.1, 5, 
6.27).
!
Language was added to introduce the lenalidomide oral suspension (in addition to 
capsule formulation). The development of the oral suspension and implementation in 
the study is a key binding element of the pediatric Written Request for lenalidomide. 
The oral suspension is available for use in subjects who are unable to swallow the 
capsule formulation or at the discretion of the investigator (Protocol Summary, 
Sections 1.3, 8.1, 8.2, 19). 
!
Amended language to state the pregnancy test 10 to 14 days prior to initiation of 
lenalidomide may be omitted, at the discretion of the investigator, for any 
FCCBP/FCBP who has high acuity disease requiring immediate treatment with 
lenalidomide. This change was made to recognize that potential subjects identified for 
enrollment into the study may have high acuity AML disease and may necessitate 
immediate treatment with lenalidomide. The pregnancy test within 24 hours prior to 
the first dose of lenalidomide is still required to be performed (Sections 5, 6.8, 7.2).
!
Added language to allow use of pre-study PB and BM aspirate/biopsy results for 
screening study assessments in the case where a study center has an IRB- and 
Celgene-approved procedural ICF/IAF that allows collection of additional bone 
marrow samples for potential research purposes. This update was made to recognize 
that performing additional PB and BM assessments at screening may not be feasible 
for certain subjects (Sections 5, 6.5, 6.20.1, 14.3).
!
Added absolute neutrophil count and platelet count as hematology laboratory 
assessments that will be recorded in the CRF. These two assessments are part of the 
response assessment and must be recorded in the CRF (Section 6.14.1).
!
Language was added to specify handling requirements for the lenalidomide capsules 
and to reference a new manual on preparation, administration, and handling of the 
lenalidomide oral suspension (Sections 6.16, 6.17, 8.1, 8.2, 19). 
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Lenalidomide (CC-5013)
Summary of Changes CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
4
CC-5013-AML-002 Amendment #1 Final: 01 Jun 2016
!
Language was added to reference the new Appendix C, which contains the dosing 
guidelines for the lenalidomide oral suspension (Sections 6.17, 8.2). 
!
IP accountability language was updated to reflect requirements to document the 
number of lenalidomide vials dispensed, the date dispensed, the date returned, and the 
number of vials returned (Section 6.18). 
!
Removed the inclusion criterion stating that a subject must be able to swallow intact 
oral capsules.  This inclusion criterion was updated since the lenalidomide oral 
suspension will be available for subjects unable to swallow an intact capsule (Section 
7.2). 
!
Provided clarification language for the graft-versus-host-disease inclusion criteria 
(Section 7.2). 
!
Amended protocol to allow for use of hydroxyurea prior to the first dose of 
lenalidomide and through Day 14 of Cycle 1. Hydroxyurea is now permitted per 
protocol  to control leukocytosis (Sections 7.3, 9.1). 
!
Added language regarding the home healthcare company that can assist with the 
preparation and administration of the lenalidomide oral suspension (Section 8.1). 
!
Corrected the administrative error involving the age range for cytarabine dosing from 
‘3-2.99’ to ‘2-2.99’ (Section 8.2 Table 5). 
!
Amended the “Dose Reductions/Interruptions” section in the protocol in order to 
provide more concise and clear dosing guidelines (Section 8.2.1)
!
Updated Appendix B lenalidomide dosing table to specify that the table specifically 
refers to the capsule formulation (Section 19). 
!
Added a new Appendix C lenalidomide dosing table specifically for the oral 
suspension (Section 19). References to subsequent appendices were updated 
throughout the document.
!
Removed 
-specific references, including 
 registration number, from 
Appendix I Central Pathology Review in order to clarify which steps are involved for 
the central pathology review (Section 19).
!
Updated the shipping address for the biopathology center in Appendix I based on new 
information provided by
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 2, MULTICENTER, SINGLE-ARM, OPEN-LABEL STUDY TO EVALUATE 
THE ACTIVITY, SAFETY AND PHARMACOKINETICS OF LENALIDOMIDE 
(REVLIMID®) IN PEDIATRIC SUBJECTS FROM 1 TO ≤18 YEARS OF AGE WITH 
RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA
STUDY DRUG:
LENALIDOMIDE (REVLIMID®)
PROTOCOL NUMBER:
CC-5013-AML-002
DATE FINAL:
02 Jan 2018
Prepared by:
on behalf of
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations. Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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The inform
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................7
1.
LIST OF ABBREVIATIONS...................................................................................8
2.
INTRODUCTION..................................................................................................11
3.
STUDY OBJECTIVES...........................................................................................12
3.1.
Primary Objective...................................................................................................12
3.2.
Secondary Objectives .............................................................................................12
4.
INVESTIGATIONAL PLAN .................................................................................13
4.1.
Overall Study Design and Plan ...............................................................................13
4.2.
Study Endpoints .....................................................................................................16
4.2.1.
Primary Endpoint....................................................................................................16
4.2.2.
Secondary Endpoints ..............................................................................................16
4.3.
Stratification , Randomization, and Blinding...........................................................17
4.4.
Sample Size Determination.....................................................................................17
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................18
5.1.
Reporting Conventions ...........................................................................................18
5.2.
Calculation of Treatment Start Dates, Cycles, and Treatment End dates..................19
5.3.
Study Population Definitions ..................................................................................19
5.3.1.
Informed Consent/Assent Population......................................................................19
5.3.2.
Response Rate Population.......................................................................................19
5.3.3.
Intention-to-Treat Population..................................................................................20
5.3.4.
Safety population....................................................................................................20
5.3.5.
Pharmacokinetic Population....................................................................................20
6.
SUBJECT DISPOSITION......................................................................................21
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................23
8.
BACKGROUND AND DEMOGRAPHIC CHARACTERISTICS .........................24
8.1.1.
Demographics.........................................................................................................24
8.1.2.
Baseline Characteristics..........................................................................................24
8.1.3.
Medical History......................................................................................................25
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
3
8.1.4.
Prior and Concomitant Medications/Procedures......................................................25
9.
STUDY TREATMENT AND EXTENT OF EXPOSURE......................................27
9.1.
Treatment Duration.................................................................................................27
9.2.
Cumulative Dose ....................................................................................................27
9.3.
Dose Exposure........................................................................................................28
9.4.
Average Weekly Dose ............................................................................................28
9.5.
Dose Intensity.........................................................................................................28
9.6.
Relative Dose Intensity...........................................................................................28
9.7.
Exposure and Dose Reduction/Interruption.............................................................28
9.8.
Overdose ................................................................................................................30
10.
EFFICACY ANALYSIS ........................................................................................31
10.1.
Analysis of Primary Efficacy Endpoint...................................................................31
10.2.
Analysis of Secondary Efficacy Endpoints..............................................................32
10.2.1.
Time to Response ...................................................................................................32
10.2.2.
Overall Response Rate............................................................................................32
10.2.3.
Disease Assessment Outcome.................................................................................32
10.2.4.
Durable Response Rate...........................................................................................33
10.2.5.
Transplantation Rate...............................................................................................33
10.2.6.
Subject/blast Characteristics Correlating with Response .........................................33
11.
SAFETY ANALYSES ...........................................................................................36
11.1.
Adverse Events.......................................................................................................36
11.1.1.
Overview of TEAEs ...............................................................................................36
11.1.2.
TEAEs by System Organ Class and Preferred Term................................................37
11.1.3.
Adverse Events of Special Interest..........................................................................38
11.2.
Deaths ....................................................................................................................39
11.3.
Second Primary Malignancy...................................................................................39
11.4.
Clinical Laboratory Evaluations..............................................................................40
11.4.1.
Hematology............................................................................................................40
11.4.2.
Chemistry Laboratory Assessments ........................................................................41
11.4.3.
Urinalysis (dipstick) ...............................................................................................41
11.5.
Vital Signs..............................................................................................................41
11.6.
Rates of acute and chronic graft-versus-host disease (GVHD).................................42
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
4
11.7.
Karnofsky or Lansky Performance Status Score......................................................43
11.8.
Other Safety Assessments.......................................................................................43
13.
PHARMACOKINETIC (PK)
ANALYSES...........................................................................................................46
13.1.
Pharmacokinetics....................................................................................................46
13.1.1.
Handling of Pharmacokinetic Data..........................................................................46
13.1.2.
Pharmacokinetic Parameters...................................................................................46
13.1.3.
Presentation of Pharmacokinetic Results.................................................................47
13.1.4.
Population Pharmacokinetic Analysis .....................................................................48
14.
INTERIM ANALYSIS...........................................................................................49
15.
PRIMARY AND END OF STUDY FINAL ANALYSES ......................................50
16.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................51
17.
REFERENCES.......................................................................................................52
18.
APPENDICES........................................................................................................53
18.1.
Modified International Working Group AML Response Criteria.............................53
18.2.
Pharmacokinetic Sample Collection........................................................................55
18.2.1.
Blood Collection for PK Analysis...........................................................................55
18.3.
Handling of Dates...................................................................................................56
18.3.1.
Calculation Using Dates .........................................................................................56
18.4.
Date Imputation Guideline......................................................................................57
18.4.1.
Impute Missing Dates for Adverse Events/ Prior or Concomitant 
Medications............................................................................................................57
18.4.2.
Medical History......................................................................................................59
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
5
18.5.
Reference Ranges from Literature 
60
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
6
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................8
Table 2:
Dose Reductions of Lenalidomide ..........................................................................29
Table 3
Normal Ranges of Vital Sign Measurements...........................................................41
Table 4:
Hematologic Response According to IWG Criteria for AML..................................53
Table 5:
PK Sampling Schedule During Cycle 1 Day 1 ........................................................55
Table 6
Laboratory Reference Ranges from Literature 
.......................60
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
7
SIGNATURE PAGE
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
8
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation
Meaning
AE
Adverse Event
Ae
Cumulative Amount of Drug Excreted
ALT
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
AST 
Aspartate Aminotransferase 
ATC
Anatomical Therapeutic Chemical
AUC 
Area Under the Curve
BMA
Bone Marrow Aspirate
BSA
Body Surface Area
CI
Confidence Interval
CLcr
Creatinine Clearance
CLR
Renal Clearance
CL/F
Apparent Total Clearance
Cmax
Observed Maximum Concentration
CR
Complete Remission
CRi
Complete Remission with Incomplete blood count recovery
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DAO
Disease Assessment Outcome
DMC
Data Monitoring Committee
eCRF
Electronic Case Report Form
EWOG
European Working Group
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
9
Abbreviation
Meaning
fe
Cumulative Percentage of the Administered Dose Excreted
GCP
Good Clinical Practices
GVHD
Graft-Versus-Host Disease
HSCT
Hematopoietic Stem Cell Transplantation
IAF
Informed Assent Form
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IP
Investigational Product
ITT
Intention to Treat
IWG
International Working Group
LDH
Lactate Dehydrogenase
Max
Maximum
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
NCI
National Cancer Institute 
OEP
Optional Extension Phase
PK 
Pharmacokinetic
PP
Per-Protocol
PR
Partial Remission
PT
Preferred Term
Q1
First Quartile
Q3
Third Quartile
RBC
Red Blood Cells
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
10
Abbreviation
Meaning
rrAML
Relapse or Refractory Acute Myeloid Leukemia
RR
Response Rate
Rsq
Regression Coefficient for Calculation of !z
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SQRT 
Square Root
StdDev
Standard Deviation
SOC
System Organ Class
SPM 
Second Primary Malignancy
TEAE
Treatment Emergent Adverse Event
TFR
Tumor Flare Reaction
TL
Topline 
TLS
Tumor Lysis Syndrome
Tmax
Time at which Maximum Concentration is Observed
t½
Terminal Phase Half-life
TTR
Time to Response
Vz/F
Apparent Volume of Distribution
WBC
White Blood Cells
WHO 
World Health Organization 
λz
Terminal Phase Rate Constant
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Phase Rate 


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
11
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-5013-AML-002 titled “A phase 2, multicenter, single-arm, open-label study to 
evaluate the activity, safety and pharmacokinetics of lenalidomide (Revlimid®) in pediatric 
subjects from 1 to ≤18 years of age with relapsed or refractory acute myeloid leukemia”, dated
13 Dec 2016. This SAP contains definitions of analysis populations, derived variables and 
statistical methods for the analyses of efficacy, safety, pharmacokinetic 
 
.
These analyses include the interim analysis, the primary final analysis and the end of study final 
analysis at the close of study. 
The purpose of the SAP is to ensure the credibility of the study findings by pre-specifying the 
statistical approaches to the analysis of study data prior to database lock and any data analysis for 
the interim/primary final analysis/end of study final analyses. This SAP is developed after the 
finalization of the protocol and will be finalized and signed at a minimum 6 weeks prior to the 
clinical database lock. All statistical analyses detailed in this SAP will be conducted using SAS® 
Version 9.1 or higher. The clinical cutoff date will be determined based on the completion of 
stage 1 for the interim analysis (enrollment of 18 subjects) and on completion of stage 2 
(enrollment of 43 subjects) for the primary final analysis of the primary endpoint (morphologic 
complete response rate within the first four cycles of lenalidomide) and other endpoints defined 
in the protocol. All subjects will be observed until the end of the treatment and will continue to 
be followed for second primary malignancies (SPM), safety issues (any drug-related SAEs), 
), start of new anticancer 
therapies, and transition to hematopoietic stem cell transplantation (HSCT) for up to 5 years after 
the last subject first dose of lenalidomide, regardless of new anticancer treatment or HSCT.
The following analyses will be performed:
∀
Periodic reports (at least semi-annually) will be provided to an external data monitoring 
committee (DMC). The first DMC meeting will be held after 4 subjects have completed 
at least 1 cycle of study treatment, if having not stopped therapy earlier due to a safety 
issue, in order to evaluate safety and provide a recommendation.
∀
An interim analysis will be conducted once 18 evaluable subjects will have completed 
their Cycle 4 assessments, or will have met discontinuation criteria, whichever occurs 
first.
∀
Primary final analysis will be conducted when all on treatment subjects will have 
completed their Cycle 4 assessments or will have met discontinuation criteria, whichever 
occurs first.
∀
End of study final analysis will be performed once all subjects will have discontinued the 
follow-up period (up to 5 years after the last subject first dose of lenalidomide).
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
12
3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective of the study is to determine the activity of lenalidomide in the treatment of 
pediatric subjects with relapsed or refractory acute myeloid leukemia (rrAML) (with second or 
greater relapse or refractory to at least 2 prior induction attempts) measured by morphological 
complete response defined as either a CR (Complete Remission) or CRi (Complete Remission 
with Incomplete blood count recovery) within the first 4 cycles of treatment.
3.2.
Secondary Objectives
The secondary objectives of the study are:
∀
To evaluate subject demographics and leukemic blast characteristics and their
correlation with response to lenalidomide.
∀
To further evaluate lenalidomide activity with regards to response assessment
outcome rates, transplantation rate and durable response rate.
∀
To evaluate the safety of lenalidomide including rates of graft-versus-host disease 
(GVHD) flare and reactivation.
∀
To determine the pharmacokinetics (PK) of lenalidomide in plasma.
 
 
 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
13
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a multicenter, open-label, single-arm, Phase 2, Simon's Optimal two-stage design study, 
with an Optional Extension Phase (OEP), that will assess the activity, safety and PK of 
lenalidomide in pediatric subjects from 1 to ≤18 years of age with second or greater rrAML. A 
total of 43 evaluable subjects (18 subjects in Stage 1 and an additional 25 subjects in Stage 2) are 
required for assessment of the primary endpoint. To allow for subjects found to be unevaluable 
for the primary endpoint due to an incorrect diagnosis, not having a disease assessment post 
screening, or who discontinued prior to receiving lenalidomide, up to 4 additional subjects may 
be enrolled for a maximum of 47 evaluable subjects across approximately 75 sites. 
Approximately 50% of enrolled subjects will be younger than 12 years of age to provide 
adequate PK data for this age subset.
If during Stage 1, at least 3 of 18 subjects achieve a morphologic complete response (either CR 
or CRi) within the first 4 cycles of study treatment, then the study will proceed to Stage 2; 
otherwise, the study will be terminated. Similarly, if at the primary final analysis, at least 8 of 43 
evaluable subjects across Stages 1 and 2 achieve a response (CR/CRi) within the first 4 cycles of 
study treatment, it will be concluded that lenalidomide has sufficient activity in pediatric acute 
myeloid leukemia (AML) to warrant subsequent study.
Morphological response will be assessed using the modified AML International Working Group 
(IWG) criteria (Cheson, 2003) (section 18.1 ). 
The OEP will allow subjects who demonstrate clinical benefit, as assessed by the Investigator at 
the completion of 12 cycles of lenalidomide therapy, to continue receiving oral lenalidomide 
until they meet the criteria for study discontinuation. In the OEP, only safety, dosing, 
concomitant medications/procedures, and SPMs will be monitored.
An external independent data monitoring committee (DMC) will evaluate safety and treatment 
efficacy data in an ongoing, periodic manner to assess benefit-to-risk considerations throughout 
the study. The function of the DMC is to monitor the safety and activity of the study treatment. 
After 4 subjects have completed at least 1 cycle of study treatment, the DMC will evaluate the 
safety data and provide a recommendation. The DMC will also provide recommendations about 
the continuation of the study from Stage 1 to Stage 2 (continue as planned, continue with 
modifications or stop treatment and/or enrollment) and advise on ways to improve quality. The 
DMC responsibilities, authorities, and procedures will be documented in the DMC charter, 
which will be endorsed by the DMC prior to the first data review meeting.
The study will consist of 3 phases: Screening Phase, Treatment Phase and Follow-up Phase.
The study will be conducted in compliance with International Conference on Harmonisation 
(ICH) Good Clinical Practices (GCPs).
Screening Phase
The Screening Phase will start from the time of signing the informed consent form 
(ICF)/informed assent form (IAF) and will last no more than 14 days, at which time the 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
14
Treatment Phase will begin (Cycle 1 Day 1). Subject's screening procedures are to occur during 
the Screening Phase within 14 days prior to dosing on Cycle 1 Day 1.
Treatment Phase
The lenalidomide dose will be calculated based on body weight. The starting dose will be 2 
mg/kg/day with a maximum dose of 70 mg/day. Subjects enrolled in the study will receive 
lenalidomide for the first 21 days of each 28-day treatment cycle for up to a maximum of 12 
cycles of study treatment. After the completion of 12 cycles of study treatment, subjects who 
demonstrate clinical benefit (CR/CRi/PR) or resistant disease as per the Investigator may 
continue to receive lenalidomide in an OEP until they meet the criteria for study discontinuation.
In the event of a specific protocol-defined toxicity, no more than 2 dose reductions will be 
allowed to doses of 1.4 mg/kg/day (not exceeding 50 mg/day) and 1 mg/kg/day (not exceeding 
35 mg/day). The dose will not be re-escalated once it has been reduced. Subjects who do not 
tolerate the minimum dose level of 1 mg/kg/day (not exceeding 35 mg/day) will be discontinued 
from the study. 
Follow-up Phase
Subjects will enter the Follow-up Phase at the time of permanent discontinuation of the 
investigational product (IP) and will be followed for up to 5 years from the last subject's first 
dose, unless the subject dies, withdraws consent or is lost to follow-up. The Follow-up Phase 
may not be terminated because of new anticancer treatment or HSCT.
The 28-day Follow-up Visit will occur 28 days after the subject's last dose of IP. At this visit, 
subjects will be monitored for the collection of AEs and concomitant medications/procedures 
used to treat the AEs. Female Children of Childbearing Potential (FCCBP) and Females of 
Childbearing Potential (FCBP) will have a pregnancy test at the 28-day Follow-up Visit.
After the 28-day Follow-up Visit, subjects will be followed up by phone or clinic visit, 
whichever is the institution's normal standard of care, every 3 months for a maximum of 5 years 
from the last subject's first dose, regardless of new anticancer treatment or HSCT, for SPMs, 
safety issues (any drug-related SAEs), 
 start of new anticancer 
therapies, and transition to HSCT.
Optional Extension Phase
Upon completion of 12 cycles of lenalidomide therapy per protocol, subjects who are 
demonstrating clinical benefit as assessed by the Investigator and who do not meet any of the 
criteria for treatment discontinuation may enter the OEP.
The study schematic is presented in Figure 1.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
15
Figure 1:
Overall Study Design
Screening Phase
Treatment Phase
Follow-up Phase
Day -14 to 0
Up to 5 years from last subject first dose
Adverse Events per protocol
Study Eligibility 
& ICF/IAF 
Signature
Stage 1a: n = 18 subjects
Lenalidomide
days 1-21
(max. 12 cycles)
Stage 2: n = 25 subjects
Lenalidomide
days 1-21
(max. 12 cycles)
Long Term – SAEs, 
 
, HSCT and 
anticancer therapies phone call or clinic 
visit
∀Every 3 months until 5 years from the 
last subject’s first dose.
5 years after Last Subject first dose
28-day cycle
28 days after last dose
AML = Acute Myeloid Leukemia; HSCT = Hematopoietic Stem Cell Transplant; IAF = Informed Assent Form; ICF = Informed Consent Form; 
 
 Max = Maximum; 
; SAE = Serious Adverse Event
a If 3 or more subjects in Stage 1 achieve a morphologic complete response (either complete response or complete response with incomplete blood count 
recovery) within the first 4 cycles, the study will proceed to Stage 2.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
16
4.2.
Study Endpoints
4.2.1.
Primary Endpoint
The primary endpoint is the morphologic complete response rate (CR or CRi) within the first 4 
cycles of treatment with lenalidomide based on the modified IWG AML response criteria 
(Cheson, 2003, see Section 18.1).
4.2.2.
Secondary Endpoints
The secondary endpoints of the study are the following:
∀
Time to response.
∀
Durable response rate based on the revised AML IWG Criteria (Cheson, 2003, see 
Section 18.1).
∀
Disease assessment outcomes and overall response rate (ORR).
∀
Rate of hematopoietic stem cell transplant (HSCT).
∀
Incidence and severity of treatment-emergent adverse events (TEAEs).
∀
Rates of acute and chronic graft-versus-host disease (GVHD).
∀
Plasma pharmacokinetic (PK) parameters including lenalidomide apparent clearance 
and volume of distribution.
∀
Correlation of peripheral white blood cell count, absolute blast count and cytogenetics 
with response to lenalidomide.
 
 
 
 
 
 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
17
4.3.
Stratification , Randomization, and Blinding
This is a single arm study with no randomization, blinding, or stratification planned in the study 
design.
4.4.
Sample Size Determination
Under Simon’s Optimal two stage design with a 5% significance level and 80% power, assuming 
a lower boundary of interest in the response rate of 10% and an upper boundary of interest in the 
response rate of 25%, a total of 43 evaluable subjects are required for the evaluation of the 
primary endpoint; 18 in Stage 1 and an additional 25 in Stage 2.
If less than 3 of 18 evaluable subjects in Stage 1 achieve a morphologic response (either CR or 
CRi) within a maximum of 4 cycles then the study will terminate, otherwise the study shall 
continue as planned and enrollment of an additional 25 subjects shall continue into Stage 2.
If, at the primary final analysis, less than 8 of 43 evaluable subjects in both Stage 1 and 2 achieve 
a response (either CR or CRi) within a maximum of 4 cycles then it will be concluded that 
lenalidomide, at the dose level tested, does not have sufficient activity in pediatric AML (second 
or greater relapse or refractory).  However, should at least 8 of the 43 evaluable subjects achieve 
a response (either CR or CRi) then it will be concluded that lenalidomide, at the dose level 
tested, demonstrates activity in pediatric subjects with AML (second or greater relapse or 
refractory) to allow further investigation.  Up to 4 additional subjects may be included to account 
for subjects found to be unevaluable for the primary endpoint (eg, incorrect diagnoses, not
having a disease assessment post screening, or who discontinued prior to receiving lenalidomide 
therapy).  The first 43 subjects enrolled and evaluable for the primary final analysis will be used 
to assess the primary endpoint.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
18
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
The summary tables, listings, and any supportive SAS output will include the explanatory 
“headers” that indicate, at a minimum:
∀
protocol number
∀
data cutoff date
∀
company name (Celgene Corporation)
∀
page number (Page x of x)
The Summary tables, listings, and any supportive SAS output will include the explanatory 
“footers” that indicate, at a minimum:
∀
program source (ie, SAS program name, including the path, run date)
∀
data extraction date 
∀
data source (ie, list of datasets used for the display)
The purpose of the data extraction date is to link the output to the database, either active or 
archived, that is write-protected for replication and future reference.  The program run date is the 
output date which will appear on each output page and will indicate the date the output was 
generated by the analysis program.  Individual source listings will display all the relative values 
supporting corresponding table(s) and figure(s).
In addition, the following reporting conventions will be implemented:
∀
Data from all study centers will be combined for analysis;
∀
Confidence intervals (CIs) will be presented as 2-sided 95% CIs unless otherwise 
specified;
∀
Summary statistics will consist of the number and percentage of subjects in each 
category for discrete variables, and the sample size, mean, median, standard deviation 
(StdDev), first quartile (Q1), third quartile (Q3), minimum (Min), and maximum
(Max) for continuous variables;
∀
All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal 
places than the measured value;
∀
All percentages will be rounded to one decimal place. The number and percentage of 
responses will be presented in the form xx (xx.x), where the percentage is in the 
parentheses.  In the case the numerator is equal to the denominator, the percentage 
should be presented as (100) instead of (100.0);
∀
All listings will be sorted for presentation in order of study center, subject, and date 
of procedure or event;
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
19
∀
All analysis and summary tables will have the analysis population sample size (ie, 
number of subjects) wherever applicable;
∀
Baseline is defined as the latest value collected on or before the date when the first 
dose of study treatment is administered.  If multiple values are present for the same 
date, the mean of these values will be used as the baseline, with the exception of lab 
data where the value with the worst Common Terminology Criteria for Adverse 
Events (CTCAE) grade will be set as baseline.  For subjects who were not treated, the 
baseline value will be defined as the latest value collected on or prior Day 1 of the 
Cycle 1 visit if available.
5.2.
Calculation of Treatment Start Dates, Cycles, and Treatment End 
dates
Treatment will commence on Day 1 and planned cycle lengths are 28 days. Day 1 of treatment is 
defined as the first day of study drug. Day 1 of a cycle is defined as day 1 of study drug for the 
given cycle as recorded on the eCRF.
Cycle end dates are defined as the day before Day 1 of the following cycle. The treatment end 
date, and the end date of the last cycle, will be calculated as follows:
∀
For subjects who discontinue prior to the clinical cutoff date, treatment end date is the 
date of treatment discontinuation from the treatment disposition page in the eCRF;
∀
For subjects who are still on treatment at the time of study closure or clinical cutoff, 
the last date of planned cycle (27 days after first dose of the last cycle) will be used as 
the treatment end date.
The cycle number for each date of interest, e.g. Adverse Event (AE) start date, will be calculated 
based on the cycle window set by their start and end dates. 
The following rules will be implemented for cycle calculations for Treatment-Emergent AEs 
(TEAEs):
∀
TEAEs present on or after Day 1 Cycle i but before Day 1 of the subsequent Cycle 
belong to Cycle i;
∀
All TEAEs which occur after Day 1 of the last cycle will be included only in the last 
cycle.
5.3.
Study Population Definitions
5.3.1.
Informed Consent/Assent Population 
Informed consent/assent population will consist of all subjects with signed informed 
consent/assent. 
5.3.2.
Response Rate Population
The response rate (RR) population shall consist of all subjects classified as evaluable for the 
primary endpoint, ie, all subjects fulfilling the eligibility criteria, having received at least one 
dose of the lenalidomide and having at least one disease IWG  response assessment post 
End 
nd 
1 of
1 of treatm
treatm
tudy
tudy drug 
drug 
y
ycle.
cle. The tr
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toff date, tr
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5.3.2.
5.3.2.


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
20
enrollment or having treatment failure (as assessed in the “Disposition - Treatment” eCRF page) 
before an assessment can be conducted.  The RR population shall be applied to the analysis of 
the primary endpoint.
5.3.3.
Intention-to-Treat Population
The intention to treat (ITT) population shall consist of all enrolled subjects regardless of whether 
they received lenalidomide.  The ITT population will be used for the analysis of all efficacy-
based endpoints and for listings if not otherwise specified.
5.3.4.
Safety population
The safety population consists of all subjects receiving at least one dose of lenalidomide and 
shall be applied to all safety based endpoints.
5.3.5.
Pharmacokinetic Population
The PK population consists of all subjects receiving at least one dose of lenalidomide and having 
at least one measurable lenalidomide concentration. The PK population shall be used for analysis 
of PK data. 
 
 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
21
6.
SUBJECT DISPOSITION
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency counts and percent for each
phase of the study. 
Subjects completing the Screening Phase and reasons for screen failures, as collected in the 
eCRF page “Disposition - Screening” will be presented for all screened subjects (defined as 
subjects having a signed ICF/IAF) using the following categories:
∀
Completed
∀
Screen failure
∀
Death
∀
Adverse Event
∀
Withdrawal by subject
∀
Lost to follow-up
∀
Withdrawal by parent/guardian
∀
Other
∀
Missing
Completed subjects and reasons for treatment discontinuation during the fixed Treatment Phase 
as recorded in the “Disposition - Treatment” eCRF page will be summarized for intention to treat 
subjects with the following categories:
∀
Completed
∀
Death
∀
Adverse event
∀
Withdrawal by subject
∀
Lost to follow-up
∀
Withdrawal by parent/guardian
∀
Pregnancy
∀
Non-compliance with study drug
∀
Physician decision
∀
Protocol violation
∀
Other
∀
Missing
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∀
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∀


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
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Subjects completing the study OEP/Follow-up Phase and reasons for not completing it will be 
collected on the eCRF (“Disposition - Treatment OEP” or “Disposition - Follow-up” pages) and 
will be summarized for all intention to treat subjects with the following categories in two 
separate tables:
∀
Completed
∀
Death
∀
Adverse event*
∀
Withdrawal by subject
∀
Lost to follow-up
∀
Withdrawal by parent/guardian
∀
Pregnancy*
∀
Non-compliance with study drug*
∀
Physician decision*
∀
Protocol violation*
∀
Other
∀
Missing
*Not applicable to the Follow-up Phase.
Table for the OEP phase will report disposition only for subjects who will have entered the OEP 
treatment period.
Analysis population allocation will be tabulated and listed.  A summary of subjects enrolled by 
site will be provided.
Listings will be provided about patient disposition for all periods after the treatment start (first 12 
cycles, optional extension phase, follow-up), for subjects who failed eligibility criteria and for 
subjects with previous participation to the study screening. 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
23
7.
PROTOCOL DEVIATIONS/VIOLATIONS
The protocol deviations/violations will be identified and assessed by the clinical monitor of the 
sponsor or designee following company standard operational procedure: these possible 
deviations and violations are entered into the clinical trial management system by the clinical 
monitor and are reviewed by the sponsor for confirmation/correction. This adjudicated file will 
be used for analysis.
The protocol violations will be summarized for the ITT population using frequency tabulations. 
Moreover frequencies will be provided for number of subject with one, two or more than two 
protocol violations.
A listing of subjects with protocol violations/deviations in the ITT population will be provided. 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
24
8.
BACKGROUND AND DEMOGRAPHIC CHARACTERISTICS 
The demographics and baseline characteristics will be summarized in the ITT population.  
Individual subject listings will be provided to support the summary tables.
8.1.1.
Demographics
The following demographics will be summarized descriptively:
∀
Age (years)
∀
Sex
∀
Race
∀
Ethnicity
∀
Reproductive Status
∀
Weight (kg)
∀
Height (cm)
For age, also frequency counts and percentages for the following categories will be presented: ≤ 
2, 3-6, 7-12, 13-16, 17-18 years. Years reached are to be used for categorization.
During calculation of age, when day of birth is missing (e.g. for regulatory authority directions) 
impute first day of the month, as requested in Section 18.3.1. Both ages, computed and collected 
in the eCRF, will be summarized.
Listing will be provided for demographic characteristic. Within listings, age will be displayed in 
years and months as computed following directions given in Section 18.3.1 while within tables 
summary statistics for age in years will be used.
8.1.2.
Baseline Characteristics
The following baseline clinical characteristics will be summarized descriptively:
∀
Lansky and Karnofsky performance score (for subjects ≤ 16 and > 16 years of age, 
respectively)
∀
Baseline electrocardiogram (ECG)
∀
Vital Signs (with respiratory rate)
∀
White blood cell count
∀
Absolute blasts
∀
Absolute neutrophils
∀
Platelets
∀
Peripheral blood smear blasts
∀
Bone marrow differential
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Lenalidomide
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Celgene Corporation
Confidential and Proprietary
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8.1.3.
Medical History
All medical history, up to 5 years before ICF/IAF signature, will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA®).  The version of the MedDRA will be 
indicated in the footnote of relevant tables based on the current version used in the clinical data.
A summary of medical and surgical history will be presented by MedDRA system (Version 18.0 
or higher) and system organ class (SOC) and preferred term (PT). A similar summary will be 
generated for the currently active abnormalities only, by SOC and PT.  Listing will be provided 
for the ITT population.
Prior cancer history will also be summarized and listed as collected in the “Prior Cancer History
Question”, “Prior Cancer History” and “Prior Cancer History II” pages of eCRF.
8.1.4.
Prior and Concomitant Medications/Procedures
Medications reported on the eCRF will be coded to therapeutic drug classes and generic drug 
names using Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health 
Organization (WHO) drug dictionary (WHO-DDE March 2015 will be the initial version used, 
with subsequent eventual updates). Medications/procedures will be recorded from the time of the 
signing of informed consent/assent (medications within 14 days) until 28 days after the last dose 
of the IP. All prior medications/procedures related to AML or any malignancy, and received at 
any point in subjects history should be recorded on the CRF at screening, regardless of time. 
Medications initiated prior to the start of study treatment and continued after the start of study 
treatment will be counted as both prior and concomitant medications. In the occurrence of partial 
dates, refer to Appendix 18.4 where the date imputation guideline is located. 
A summary showing the number and percentage of subjects who took prior/concomitant 
medications will be presented by WHO therapeutic drug class and generic drug name. 
Therapeutic drug class and generic drug name will be listed in alphabetical order. A separate 
summary showing the number and percentage of subjects who underwent prior/concomitant 
procedures will be presented by MedDRA SOC and PT. SOC and PT will be listed in 
alphabetical order. Prior medication/procedure summaries will be presented for the ITT 
population while concomitant medication/procedure summaries will be presented for safety 
population.
A complete list of all prior and concomitant medications (prescription, over the counter, 
nutritional, fiber supplements, etc.), indication/diagnosis, dose, dosing regimen (frequency, 
route), and start and stop dates used prior to and during the study will be reported. A separate 
complete list of all prior and concomitant procedures, indication and date of procedure or surgery 
will be reported.
8.1.4.1.
Prior Medications/Procedures
Prior medications and procedures are defined as medications and procedures starting before the 
start of the study treatment and either ending before the start of the study treatment or continuing 
after study treatment start. A summary showing the number and percentage of subjects who took 
prior medications will be presented for the ITT population. 
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Lenalidomide
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Celgene Corporation
Confidential and Proprietary
26
Prior medications collected on the “Prior/Concomitant Medication” eCRF page and prior 
procedures collected on the “Prior/Concomitant procedures” eCRF page will be summarized.
Medications/procedures collected on the “Prior Radiation Therapies”, “Prior Cancer Surgeries 
for this Disease”, “Prior Hormonal Anti-Cancer Therapies for this Disease”, “Prior Systemic 
Anti-Cancer Therapies”, “Procedures for Prior Cancers Not Under Study”, and “Radiation 
Treatment For Prior Cancers Not Under Study” eCRF pages will be summarized for the safety 
population and listed for the ITT population.
8.1.4.2.
Concomitant Medications/Procedures
Concomitant medications and procedures are defined as medications and procedures either 
initiated before the first dose of study drug and continuing during the study treatment, or initiated 
between first date of first dose of study drug and 28 days from the date of last dose of study 
medication.
Concomitant medications collected on the “Prior/Concomitant Medication” eCRF pages and 
concomitant procedures collected on the “Prior/Concomitant procedures” eCRF page will be 
summarized for the safety population.
A separate listing will be provided for data collected in the “Intrathecal Cytarabine” eCRF page
and “Stem cell transplant” eCRF page for the ITT population.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
27
9.
STUDY TREATMENT AND EXTENT OF EXPOSURE
All study treatment and extent of exposure summaries will be provided based on the RR and 
safety populations. Descriptive statistics will be provided for treatment duration, average weekly 
dose, number of cycles, cumulative dose, dose intensity, relative dose intensity, treatment 
exposure and dose reductions / interruptions. Study drug record will be presented in a listing for 
the safety population.
The fixed Treatment Period and OEP treatment period will be considered together as a unique 
period for exposure analysis. In addition, summary statistics for treatment duration and dose 
information will be provided only for subjects that enter the OEP treatment phase and is limited 
to the OEP period.
9.1.
Treatment Duration
Treatment Duration (weeks) is defined as: 
[(date of end of treatment) – (date of first treatment) + 1]/7
Date of first treatment is defined as the date of the first non-zero dose of lenalidomide 
administered for each phase, fixed phase and OEP phase.
Date of end of treatment is defined as follows:
∀
For subjects who completed 12 (or more if the subject entered the OEP of treatment) 
full cycles of lenalidomide, the end of lenalidomide is defined as Day 28 of last 
completed cycle 12.
∀
For subjects not considered in the previous point and for subjects who prematurely 
discontinued lenalidomide before day 21 of the cycle, the end of lenalidomide is the 
date either the investigator or subject decided to prematurely discontinue 
lenalidomide, which is referred to as “Date of Completion/Discontinuation” recorded 
on the eCRF page called “Disposition - Treatment” (or “Disposition - Treatment 
OEP” if the subject entered the OEP of treatment).
Descriptive statistics will be provided for treatment duration (n, Mean, StdDev, Median, Q1, Q3, 
Min, Max), total number of cycles completed (frequency count); if a subject has completed the 
21 treatment days, the cycle will be considered completed. In addition, summary statistics will be 
provided only for subjects that enter the OEP treatment phase and limited to the OEP period.
9.2.
Cumulative Dose 
Cumulative dose of lenalidomide will be computed as the sum of all doses administered, defined 
as the values entered on the actual dose assigned field on the dosing eCRF, taken across the 
treatment period (including OEP). Cumulative dose will be in mg/kg for all subjects.
Descriptive statistics will be presented for cumulative dose for subjects in the RR and safety 
population.  Tabulations will be presented as dose information, by cycle and overall separately.  
In addition, for the OEP overall (ie all OEP cycles together) period, summary statistics will be 
provided for subjects that will enter the OEP treatment phase.
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limited 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
28
9.3.
Dose Exposure
Dose exposure in weeks is defined as the total number of actual days on drug during the 
treatment period divided by 7. Descriptive statistics will be presented for dose exposure for 
subjects in the RR and safety population.  Tabulations will be presented as dose information, by 
cycle and overall separately. In addition, for the OEP overall period, summary statistics will be 
provided for subjects that will enter the OEP treatment phase.
9.4.
Average Weekly Dose
Average weekly dose will be calculated as the cumulative dose in mg/kg divided by dose 
exposure in weeks. Descriptive statistics will be presented for average weekly dose for subjects 
in the RR and safety population. Tabulations will be presented as dose information, by cycle and 
overall separately. In addition, for the OEP overall period, summary statistics will be provided 
for subjects that will enter the OEP treatment phase.
9.5.
Dose Intensity
Dose intensity during the treatment is defined as the cumulative dose in mg/kg divided by the 
treatment duration in weeks.
Dose intensities will be calculated as follows: Dose intensity (mg/kg/weeks) = [cumulative dose 
for lenalidomide in mg/kg]/[treatment duration in weeks].
Dose intensity will be presented as dose information, by cycle and overall separately, for the 
treatment period of the study for the response rate and safety populations.  In addition, for the 
OEP overall period, summary statistics will be provided for subjects that will enter the OEP 
treatment phase.
9.6.
Relative Dose Intensity
Relative dose intensity is the dose intensity divided by the protocol specified weekly dose (both 
expressed as mg/m2/week), expressed as a percentage:
Relative dose intensity (%) = (dose intensity / protocol weekly dose) * 100% 
where protocol weekly dose (the planned dose intensity) is the mean of the expected 
weekly doses (14 mg/kg/week) of all cycles of treatment initiated by the subject.
Relative dose intensity of lenalidomide will be categorized into <70%, ≥70% to < 80%, and ≥80
to <90% and ≥90%, and frequency counts will be provided together with summary statistics for 
the RR and safety population and will be tabulated together with overall dose information. In 
addition, summary statistics will be provided only for subjects that enter the OEP treatment 
phase and limited to the OEP period.
9.7.
Exposure and Dose Reduction/Interruption
Dose reduction/interruption due to AE and other reasons will be summarized.  A dose reduction 
is defined as any non-zero reduced dose of lenalidomide with AE or any other reason recorded 
on the eCRF page “Study Drug Record”.  Dose interruption is defined as any zero dose of 
lenalidomide with AE or any other reason recorded on the eCRF.
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mg/kg
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Dose redu
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
29
If an interruption happens at the start of a cycle and causes the cycle to be delayed, it is also 
called a dose delay. A maximum delay of 2 weeks in the start of cycle will be allowed. For 
example subjects treated with lenalidomide at Cycle 1 should start the second cycle of treatment 
no later than 42 days after cycle Day 1 of Cycle 1. Dose delays will be considered together with 
dose interruptions. 
Dose Interruption Criteria:
∀
Lenalidomide will be held for any subject experiencing hemorrhagic or bullous skin 
rash until a specific evaluation to exclude toxic epidermal necrolysis and/or Stevens-
Johnson syndrome has been performed.  Any subject with evidence of toxic 
epidermal necrolysis or Stevens-Johnson syndrome will not be retreated with 
lenalidomide.
∀
Guidelines for GVHD as reported in the protocol section 8.2.1 in “Special 
Instructions for Management of Graft Versus Host Disease (GVHD)” paragraph.
Dose Reduction:
∀
Two dose reductions will be allowed (Table 2) in the event of specific protocol-
defined toxicity.  If treatment is interrupted for toxicity as described below, 
lenalidomide will be resumed at dose level -1 once the toxicity has resolved to <
Grade 1.  If toxicity recurs, lenalidomide will be interrupted and upon resolution, the 
subject will resume at dose level -2.
∀
The dose will not be re-escalated if the lower dose is tolerated.
∀
Subjects who do not tolerate 1 mg/kg/day (dose level -2) will discontinue 
lenalidomide administration.
Table 2:
Dose Reductions of Lenalidomide
Dose Level
Dose
Starting dose
2.0 mg/kg/day
(maximum dose of 70 mg/day for subjects ≥ 35 kg)
Dose Level -1
1.4 mg/kg/day
(not exceeding 50 mg/day for subjects initially dosed at 70 mg/day)
Dose Level -2
1.0 mg/kg/day
(not exceeding 35 mg/day for subjects initially dosed at 70 mg/day)
The total number of cycles received and the overall number of dose reductions/interruptions for 
lenalidomide will be presented. The overall number and percentage of subjects who have at least 
one dose reduction/interruption for lenalidomide will be provided for each reason.  Time to first 
dose reduction/interruption due to any reason will be descriptively provided.  Time to first dose 
reduction/interruption due to AE will also be descriptively provided. Computation of similar 
summary statistics and frequency counts will be repeated by cycle and presented in a separated 
table.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
30
The cycle when the dose reduction/interruption due to AE for lenalidomide, defined as the cycle
number during which the dose of lenalidomide was reduced/interrupted due to AE, will be 
summarized as frequencies within the 4 categories: 1, 2, 3, and >3 cycle.
9.8.
Overdose
Overdose, as defined in the protocol, refers to lenalidomide dosing.  On a per dose basis, an 
overdose is defined as the following amount over the protocol-specified dose of lenalidomide 
assigned to a given subject, regardless of any associated AEs or sequelae: >10% over the 
protocol-specified dose.
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol-required schedule or frequency.
Complete data about any overdose, regardless of whether the overdose was accidental or 
intentional, will be collected on the eCRF page “Investigational Drug Overdose” and will be 
presented in a listing.
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and will b
and will b


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
31
10.
EFFICACY ANALYSIS
Efficacy analyses for the primary endpoints will be performed on the RR and ITT population. 
Secondary efficacy endpoints will be analyzed for the ITT population.
Data listings will be provided for all endpoints, including bone marrow sample collection and 
assessment. Moreover bone marrow assessment performed at screening for diagnosis 
confirmation will also be listed. 
10.1.
Analysis of Primary Efficacy Endpoint
The primary endpoint is the morphological complete response rate within a maximum of 4 cycles 
of treatment.  Morphological complete response is defined as CR or CRi as assessed locally and 
reported in the ”Modified IWG Response Assessment” eCRF page.  These response criteria will 
be assessed according to the revised AML IWG Criteria (Cheson, 2003, see Section 18.1).
The morphological complete response rate is defined as the total number of subjects with 
morphological complete response observed within the first 4 cycles of study therapy (regardless 
of whether the CR/CRi is observed at the end of Cycle 1, 2, 3 or 4) over the total number of 
subjects evaluable for this endpoint. The CR/CRi does not need to be present at the end of Cycle 
4 if observed before this time for the subject to be considered as having achieved a complete 
response with regards to the primary endpoint.  Responses occurring after a treatment failure 
assessment outcome will not be considered.  The corresponding Clopper Pearson 95% 
confidence interval will be calculated for the response rate. 
The primary analysis of this endpoint will be based upon the ITT population and the RR 
population.
 
 
 
Data as collected in the “Modified IWG Response Assessment” eCRF page will be listed.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
32
10.2.
Analysis of Secondary Efficacy Endpoints
Secondary efficacy endpoints will be analyzed and reported based on subjects in the ITT 
population, if not otherwise specified. All secondary efficacy endpoints will be analyzed at the 
time when the primary endpoint is due for analysis.
10.2.1.
Time to Response
Time to response (TTR) is defined as the time from treatment start until a documented disease 
response (either CR, CRi or PR). Subjects not observed with a response will not be included in 
the analysis. Summary statistics (n, mean, StdDev, median, Q1, Q3, min, max) will be provided 
for time to response.
10.2.2.
Overall Response Rate
Overall response rate defined as the proportion of subjects with best response (CR, CRi or PR)
among all subjects in the ITT population (i.e. subject will be considered as having a response if 
they achieve at least PR). Subject achieving less than PR (i.e. ‘treatment failure’) or having no
assessment will be considered as a non-responder. If a subject is missing some assessments, their
best response from available assessments will be selected as the response. Responses occurring 
after a treatment failure will not be considered. All assessments collected while a subject is under 
study treatment (incorporating, wherever applicable, the 28 day rule, i.e. last dose plus 28 days)
will be considered.
The ORR formula will be the following
ORR = (number of CR, CRi or PR from start to the end of period under analysis) / (number 
of subjects within the ITT population).
The ORR rate at the end of Cycles 1, 2, 3, 4, 8 and 12 will be categorized, and the rate will be 
calculated for each cycle dividing the number of subjects with response in the cycle by the 
number of subjects entering the cycle.  The formula will be the following
ORR cyclei  = (number of CR, CRi or PR form start of Cycle i to the end of Cycle i) / 
(number of subjects entering Cycle i within the ITT population). 
Proportions will be presented as percentages with frequency counts together with the Clopper-
Pearson 95% CI, at the end of each pre-specified cycle.
10.2.3.
Disease Assessment Outcome
Disease assessment outcome (DAO) at the end of Cycles 1, 2, 3, 4, 8 and 12 of lenalidomide 
administration shall be categorized according to the Cheson criteria (Cheson, 2003, see Section
18.1) into the following categories: CR, CRi, PR, Treatment Failure (Resistant Disease, Aplasia, 
Indeterminate Cause, Relapse after CR or CRi, Molecular or Cytogenetic relapse), Missing/not 
done. Responses occurring after a treatment failure will not be considered. The DAO rate for 
each of the response criteria will be calculated as the total number of subjects in a given response 
category at each time point over the number of subjects entering each corresponding cycle. The 
formula will be the following:
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
33
DAO category cyclei = (number of subjects with DAO category from start of Cycle i Day 1 
to the end of Cycle i) / (number of subjects entering Cycle i within the ITT 
population)*100. 
Proportions will be presented as percentages with frequency counts together with the Clopper-
Pearson 95% CI, per response category at the end of each pre-specified cycle.
10.2.4.
Durable Response Rate
Durable response rate is defined as the proportion of subjects achieving a bone marrow 
confirmed CR/CRi, as collected in the Modified IWG Response Assessment page of the eCRF, 
lasting at least 3 months (from time complete response observed until treatment failure or worse) 
or until transplantation if earlier among all subjects eligible for durable response rate analysis (all 
ITT population subjects that achieve at least a CR or CRi, provided the CR/CRi is confirmed in a 
bone marrow sample).
A durable response is a response, either CR or CRi, maintained for at least three cycles (or 84 
days) from the first time a response is observed, either CR or CRi whichever occurs first. 
Durable response occurs when the responses assessed thereafter the first observed CR/CRi are
either CR or CRi until at least 84 days after the first observed CR/CRi. If the subject undergoes a 
transplant before 84 days, the subject will be considered as having achieved a durable response. 
A CR or CRi observed after a PR or treatment failure will not be considered. If a subject has a 
PR or treatment failure directly following a missed assessment(s) then consider only up to the 
last completed assessment prior to the missed assessment(s). Should only one assessment be 
missing (i.e. no consecutive missing assessment) and the next available assessment directly 
following the missing assessment shows the subject to still have either a CR or CRi then the CR 
or CRi can still be considered. Any completed disease assessment following 2 or more 
consecutively missed disease assessments will not be considered.
Proportions will be presented as percentages with frequency counts together with the Clopper-
Pearson 95% CI.
10.2.5.
Transplantation Rate
The proportion of subjects undergoing a HSCT after treatment start during the conduct of this 
study will be calculated over the total number of subjects in the ITT population.  Proportions 
shall also be calculated based on whether the transplantation is the first, second, or subsequent 
transplants post PI administration.
Proportions will be presented as percentages with frequency counts together with the 
corresponding Clopper-Pearson 95% CI. Collected data will be also listed.
10.2.6.
Subject/blast Characteristics Correlating with Response
Laboratory results obtained at baseline/screening [peripheral white blood cell (WBC) and blast 
count, bone marrow blast percentage, cytogenetics, molecular alterations, etc.] will be evaluated 
in association with response parameters by means of correlation. Response will be categorized in 
two levels (response and non-response), as done for the primary efficacy endpoint analysis and 
for ORR analysis.
The following parameters will be analyzed:
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
34
∀
Hematology 
o
WBC count
o
Absolute blasts
o
Absolute neutrophils
o
Platelets
∀
Peripheral blood smear blasts
∀
Bone Marrow differential
∀
Cytogenetics (Karyotype Description)
o
t(8;21)
o
inv(16)
o
Normal
o
+8
o
t (9;11)
o
complex (>/= 3 abnormalities)
o
-5
o
-7
o
5q-
o
7q-
o
11q 23 abnormalities 
o
inv (3)
o
t (3;3) 
o
t (6;9)
o
Other
∀
Cytogenetics (Gene mutations)
o
FLT3-ITD
o
FLT3-TKD
o
NPM
o
CEBPA
o
MLL
o
WT
o
NRAS
o
None
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cs (
cs (Gene m
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FLT3
FLT3-I-ITD
TD
o
FLT3
FLT
o
N
o


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
35
Point-biserial correlation coefficient will be computed for continuous parameters, while rank 
point-biserial correlation coefficient will be computed for parameters expressed as ordinal 
categories (e.g. megakaryocytes and cellularity). Phi coefficient will be computed for parameters 
expressed as nominal dichotomous categories.
Summary statistics and listings will be provided for cytogenetics.
&(/*(1(35235,(7$5<,1)250$7,21


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
36
11.
SAFETY ANALYSES
The purpose of this section is to describe the safety analyses for the treatment period of the study 
(after signing ICF/IAF and until the 28-day safety follow-up visit). For subjects who will enter 
the OEP, AEs will be reported for the two treatment periods, the fixed and the OEP period, the 
latter including the 28-day safety follow-up visit.
Drug-related SAEs will be collected and reported for the whole period of the study, i.e. including 
the 5 year follow-up period.
Listing for safety analyses will be provided for safety population if not otherwise specified.
11.1.
Adverse Events
Adverse Events will be coded according to MedDRA dictionary version18.0 or higher. The 
severity of AEs will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) (version 4.03, May 2009), except for tumor flare 
reaction, which is defined using CTCAE version 3.
All AEs will be recorded by the Investigator from the time the subject signs the ICF/IAF until 28 
days after the last dose of lenalidomide and those SAEs made known to the Investigator at any 
time thereafter that are suspected of being related to lenalidomide.
In the occurrence of partial dates, refer to Appendix 18.4 where date the imputation guideline is 
located.
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on 
or after the first treatment of the IP and within 28 days after the last dose administration date. All 
TEAEs, AEs leading to IP discontinuation, AEs leading to dose reduction/ interruption, AEs 
related to lenalidomide, and SAEs and AEs leading to death will be summarized by cycle up to a 
28-day period after last cycle (see section 5.2), as well as by subject worst recorded grade per 
event type, SOC, PT and grade. A summary of AEs with NCI CTCAE v 4.0 Grade 3 or higher
(except for tumor flare reaction, which is defined using CTCAE version 3), as well as the most 
frequent PTs, will also be provided by grade and PT. If a subject experiences the same AE more 
than once with different severity grade, then the event with the highest grade will be tabulated in 
“by grade” tables. If a subject experiences multiple AEs under the same PT/SOC, then the 
subject will be counted only once for that PT/SOC. In addition, AEs with a missing intensity will 
be presented in the summary table as an intensity category of “Missing”.
11.1.1.
Overview of TEAEs
The number and percentage of subjects experiencing TEAEs will be summarized in the 
following categories:
∀
All TEAE 
∀
All TEAE related to lenalidomide;
∀
NCI CTC grade 3/4 TEAE;
∀
Treatment related NCI CTC grade 3/4 TEAE;
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∀
A


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
37
∀
NCI CTC grade 5 TEAE;
∀
Serious TEAE;
∀
Treatment-related serious TEAE;
∀
Serious TEAE leading to dose discontinuation;
∀
TEAE leading to dose discontinuation;
∀
TEAE leading to dose reduction;
∀
TEAE leading to dose interruption; 
∀
TEAE leading to death.
11.1.2.
TEAEs by System Organ Class and Preferred Term
The incidence of TEAEs will be summarized by MedDRA SOC and PT. The intensity of AEs 
will be graded 1 to 5 according to the NCI CTCAE. 
Tables summarizing the incidence of TEAEs will be generated for each of the following:
∀
All TEAEs;
∀
All TEAEs with CTCAE grades 3 or 4;
∀
All TEAE by CTCAE grade; 
∀
TEAEs reported as treatment-related; 
∀
Treatment-related CTCAE grade 3 or 4 TEAEs;
∀
Treatment-related CTCAE grade 3 or 4 TEAEs by CTCAE grade;
∀
CTCAE grade 5 TEAEs;
∀
Serious TEAE;
∀
TEAEs leading to death
∀
Treatment-related serious TEAEs;
∀
Serious TEAEs leading to discontinuation of lenalidomide
∀
TEAEs leading to discontinuation of  lenalidomide
∀
TEAEs leading to dose reduction;
∀
TEAEs leading to dose interruption;
∀
TEAEs by cycle; 
∀
TEAEs with CTCAE grade 3 or 4 by cycle;
∀
Non-treatment emergent AEs.
Frequency distributions for shift from baseline to the maximum CTCAE grade during treatment 
period will be presented for all grades and focusing on grade 3 or 4.
ntensit
ensity y of
of
of the fo
of the follo
llo
TEAEs;
TEAEs;
or 4 TEAE
or 4 TEA
th
d serious TE
serious T
Es leading 
leadi
eading to d
eading to
Es
Es leading
leading
TEAEs
TEAEs lea
lea
∀
TEAEs
TEAE
∀
TE
TE
∀
equ


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
38
System organ classes are sorted by descending order of frequency of SOC, and by descending 
order of frequency of PT within SOC, according to the overall column. In tables where the two 
treatment periods and the overall period are reported, the sorting order will be defined on the 
basis of frequencies found in the overall column.
For all tables showing results by cycle, OEP and 12th cycle will be considered as a unique cycle 
labelled “Cycle 12 and higher”.
Listing of AE, SAE, SAE of special interest and AE leading to treatment discontinuation will be 
provided in separated displays.
11.1.3.
Adverse Events of Special Interest
Selected TEAEs/ serious AEs (SAEs) of interest, including second malignancies and 
cardiovascular events, as determined by the mechanism of action, known class effects, or TEAEs 
observed to date will be summarized. Standardized MedDRA queries (SMQs) will be used in the 
search strategy for some of the selected AEs of special interest related to study drug, intending to 
aid in case identification. The groupings of selected AEs, described by one phrase or topic term 
will be determined by clinicians based on SMQ or relevant search terms and provided to 
statistician, prior to database lock.
Analysis of AEs of special interest will be presented with tabulations for: summary of TEAEs of 
interest by category, TEAEs of interest, NCI-CTCAE grade 3 or 4 TEAEs of interest, TEAEs of 
interest related to study medication, NCI-CTCAE grade 3 or 4 TEAEs of interest related to study 
medication, serious TEAEs of interest, serious TEAEs of interest related to study medication,
serious TEAEs of interest and TEAEs of interest leading to study medication discontinuation, 
TEAEs of interest by CTCAE maximum grade 1 or 2 and 3 or 4 and TEAEs of interest by 
CTCAE maximum grade. The following AE of interest categories and preferred terms include 
but are not limited to:
∀
Thrombocytopenia and bleeding
∀
Neutropenia and infection 
∀
Venous thromboembolism 
∀
Cutaneous reactions 
∀
Hypersensitivity and angioedema 
∀
Diarrhoea and constipation 
∀
Peripheral neuropathy 
∀
Cardiac failure and cardiac arrhythmia 
∀
Renal failure 
∀
Ischaemic heart disease (previously myocardial infarction) 
∀
Interstitial lung disease (interstitial pneumonitis) 
∀
Liver function laboratory abnormalities 
∀
Second primary malignancies (SPMs) 
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cts, or TEA
ts, or TEA
ill be used 
ill be used
y dr
dr
y
ug, inte
ug, inte
phrase or 
phrase or 
s and provi
 and provi
ioions fo
for:r: s
or 4 TEAE
or 4 TEAE
or 4 TEAE
or 4 TEAE
f interest
f interest r
ding to stud
ding to stud
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2 and 3
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interest ca
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∀
Rena
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∀
I


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
39
∀
Tumor lysis syndrome (TLS)
∀
Tumor flare reaction (TFR)
∀
Graft versus host disease (GVHD)
Frequency distributions for shift from baseline to the maximum CTCAE grade during treatment 
period will be presented for all grades and focusing on grade 3 or 4.
All AEs of special Interest will be identified by appropriate MedDRA preferred term.
11.2.
Deaths
Deaths during treatment (defined as deaths from the day of first dosing to 28 days after the last 
dose of study medication) and during the follow-up will be summarized by frequency of 
occurrence and corresponding percentage by cause of death per period (during treatment or 
follow-up) as well as overall. Listings of all deaths will be provided. 
11.3.
Second Primary Malignancy 
Second primary malignancies are any occurring regardless of relationship to study drug during 
the conduct of the study including up to 5 years after last subject first dose date.
Events of SPMs will be tabulated for the following categories:
∀
All SPMs (invasive and non-invasive SPMs)
∀
All invasive SPMs (hematologic and solid tumor SPMs)
∀
All hematologic SPMs (AML, myelodysplastic syndromes (MDS), MDS to AML (for 
MDS events that transform to AML), B-cell malignancies, and other hematologic 
cancers)
∀
All solid tumor SPMs
∀
All non-invasive SPMs (non-melanoma skin cancers)
For each of the above SPM categories, SPMs will be further tabulated using the MedDRA 
preferred term.  Each subject is counted only once within each SPM category as well as within 
each preferred term.
Additionally, the number and percentage of subjects with SPMs who died and those who did not 
die will be tabulated by SPM category.
It should be noted that these analyses with regard to SPMs are based on the number of subjects
with at least one SPM and not the total number of SPMs.
For each SPM category, time to onset will be calculated as time (in months) from the start of the 
study treatment to the onset of the SPM for each affected subject. For the subjects with more 
than one new malignancy within an SPM category, the onset of the earliest SPM will be used. 
Time to onset will be summarized descriptively for each SPM category [mean, median, Standard 
Deviation (StdDev), first quartile (Q1), third quartile (Q3), minimum (Min), and maximum
(Max)].
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Deviat


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
40
A scatter plot to graphically display the time to onset of hematologic and solid tumor SPMs for 
each SPM by dose level will be provided.
For each SPM category, the incidence rate per 100 person-years will be calculated as:  (the 
number of subjects with any SPM in the SPM category/total person-years)*100.  Total person-
years are defined as the total time from the date of first treatment to the first onset date of the 
specified SPM for subjects with the specified SPM plus the total time from the date of first 
treatment to the date of the last follow-up or death for subjects without the specified SPM.  
Incidence rates per 100 person-years and the 95% confidence intervals will be calculated for 
each treatment arm and SPM category. Confidence interval at 95% level for the incidence rate 
per 100 person-years is calculated as follows: incidence rate*exp{+/-1.96*n^(-1/2)}.
Listings for “Second Primary Malignancies” and for “Second Primary Malignancies Procedures 
for Cancers Not Under Study” will be produced by Celgene.
11.4.
Clinical Laboratory Evaluations
Clinical laboratory values from the local laboratories will be graded according to NCI CTCAE 
version 4.03 for applicable tests using computerized programs. Frequency distributions for shift 
from baseline to the worst grade during treatment period will be presented.
Local lab results will be converted to standard units by a 
 programmer using standard 
conversion factors and then each standardized result will be compared to literature reference 
ranges according to the age of the subject in order to compute the abnormality flags. Laboratory 
normal ranges from literature were provided by the Sponsor and can be found in Section 18.5.
Listings of clinical laboratory data from local laboratory with abnormal flags (H=High, L=Low) 
will be provided by subject and by parameter.
Both original and standardized results will be listed.
11.4.1.
Hematology
Hematology testing including red blood cell (RBC) count, hemoglobin, hematocrit, mean 
corpuscular volume (MCV), WBC count and manual differential count (including blasts %, 
immature myeloid, absolute monocyte count, absolute neutrophil count (ANC)), and platelet 
count will be evaluated by the local laboratory at screening, on Days 1, 8, 15, and 22 of Cycles 1 
and 2, on Day 1 of every cycle thereafter, at the Treatment Discontinuation Visit, on the 28-day 
Follow-up Visit, and at unscheduled visits.  
White blood cell count, absolute blasts, absolute neutrophils and platelets will be recorded in the 
eCRF and results for all other hematology laboratory assay will not be collected on the eCRF 
but, instead, laboratory abnormalities that are considered AEs will be reported as AEs on the AE 
eCRF page.
The number and percentage of subjects with each NCI CTCAE grade will be presented for the 
parameters where grade will be assigned using computerized programs. A shift table 
representing the shift from the baseline grade to the worst grade (i.e. any time after first dose of 
study drug) will be provided for the safety population.
All collected hematology parameters will be presented in a listing for the ITT population. 
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ocedures 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
41
11.4.2.
Chemistry Laboratory Assessments
Serum chemistries including sodium, potassium, chloride, bicarbonate, calcium, phosphorus, 
blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase, 
total bilirubin, direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), and lactate dehydrogenase (LDH), and uric acid will be evaluated by the local laboratory 
at screening, on Days 1, 2, 4, 8, 15, and 22 of Cycle 1, on Days 1, 8, 15, and 22 of Cycle 2, on 
Day 1 of every cycle thereafter, at the Treatment Discontinuation Visit, on the 28-day Follow-up 
Visit, and at unscheduled visits.  Serum chemistry laboratory values will not be collected on a 
laboratory eCRF; instead, laboratory abnormalities that are considered AEs should be reported 
on the AE eCRF page. No descriptive analysis of the chemistry laboratory results will thus be 
provided.
11.4.3.
Urinalysis (dipstick)
No report will be provided for urinalysis.
11.5.
Vital Signs
Vital signs (including sitting blood pressure, heart rate, respiration, and temperature) will be 
measured at screening, on Days 1, 8, 15, and 22 of Cycle 1, bi-weekly during Cycle 2, on Day 1 
of every cycle thereafter, at the Treatment Discontinuation Visit, on the 28-day Follow-up Visit.
At unscheduled visits vital signs will be measured. Height will be collected only at screening and 
on Cycle 1 Day 1.  However, weight will be collected at screening and Day 1 of every cycle for 
dose adjustment.
Baseline is defined as the latest value collected on or before the date when the first dose of study 
treatment is administered.  If multiple values are present for the same date, the mean of these 
values will be used as the baseline.
Summary statistics (n, mean, median, StdDev, Q1, Q3, Min, and (Max) of observed and change 
from baseline values will be presented.
Shift from baseline to worst value during the treatment (most extreme post-baseline value, where 
most extreme includes low and high category) will be displayed in cross–tabulations. For each 
vital sign parameter, the baseline grade and the worst grade post-baseline will be determined for 
each subject classified in below, within, and above the normal ranges. This table may include 
subjects with both normal and missing results for the vital sign, provided no abnormal (low or 
high) results will be reported. Low and high categories will be presented separately. In Table 3
normal ranges are reported.
Table 3
Normal Ranges of Vital Sign Measurements
Test 
Age group1
Normal Range 
(Unit)
Diastolic Blood Pressure (DBP) 
<2
[34,66] (mmHg)
2-5
[34,74] (mmHg)
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will be colle
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or before
e present f
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, Q1,
d.
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d high cate
d high cate
seline grad
seline gr
below, w
below
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are reported
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(/
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
42
Test 
Age group1
Normal Range 
(Unit)
6-8
[35,80] (mmHg)
9-13
[37,87] (mmHg)
14-16
[40,91] (mmHg)
≥17
[40,89] (mmHg)
Systolic Blood Pressure (SBP) 
<2
[58,112] (mmHg)
2-5
[60,125] (mmHg)
6-8
[65,131] (mmHg)
9-13
[68,141] (mmHg)
14-16
[76,153] (mmHg)
≥17
[70,139] (mmHg)
Pulse Rate
1-2
[95, 178] (bpm)
3-7
[62, 124] (bpm)
8-15
[48, 110] (bpm)
≥16
[60, 100] (bpm)
Temperature 
All
[35, 38] (°C)
[95, 100.4.] (F)
Respiratory Rate
1-3
[24,50] (BPM)
4-6
[22,34] (BPM)
7-12
[18,30] (BPM)
13-21
[12,16] (BPM)
1- Years reached at the time of the assessment.
Listings will be provided for all vital sign parameters for the ITT population.
11.6.
Rates of acute and chronic graft-versus-host disease (GVHD)
Graft-versus-host disease (GVHD) will be summarized as collected in the “Adverse Events” 
eCRF page with the following preferred terms: “Acute graft versus host disease”, “Chronic graft 
versus host disease” and “Overlap syndrome”. 
The incidence of GVHD TEAEs will be summarized by maximum CTCAE grade (1 or 2, higher 
than 2) within type of GVHD (overall, overlap, acute, chronic and overlap + acute GVHD).
Safety population subjects that had previous transplant (as collected in the “Stem Cell 
Transplants” eCRF page) will be selected for these summary tables and their total number will 
be used as denominator for the computation of incidence rates.
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62
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
43
GVHD data as collected in the “GVHD” eCRF page will also be listed.
11.7.
Karnofsky or Lansky Performance Status Score
Performance status will be measured using either the Karnofsky or Lansky performance status 
score (Karnofsky performance status score for subjects ≥ 16 years of age or Lansky performance 
status score for subjects < 16 years of age) at screening, on Day 1 of each cycle and at the 
Treatment Discontinuation Visit. For performance status scores, shift from baseline to worst 
value and best score during the treatment period will be displayed for the whole treatment period 
and by cycle. Subjects changing age category during the study, ie, having both performance 
status results, will be included into the summary statistics computation. 
Performance status scores will also be presented in a listing for the ITT population.
11.8.
Other Safety Assessments
Data collected for other safety assessments including pregnancy status, chest x-ray, 
electrocardiogram and echocardiography will be listed.
Summary of pregnancy status will be provided for females of childbearing potential.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
44
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
45
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
46
13.
PHARMACOKINETIC (PK)
 
ANALYSES
13.1.
Pharmacokinetics
13.1.1.
Handling of Pharmacokinetic Data
Concentrations that are below the limit of quantitation (BLQ) prior to the first dose will be 
assigned a numerical value of zero.  Post-treatment concentrations that are BLQ will be treated 
as missing.  Concentrations assigned a value of missing will be omitted from the descriptive 
statistics.  A concentration value of zero will be excluded from the computation of the geometric 
mean (geometric CV%). Geometric CV(%) is calculated as follows: CV (%)=100× 
SQRT(exp(V)-1), where V denotes the variance of the log-transformed values.
If any subjects are found to be noncompliant with respect to dosing, have incomplete data, or 
encounter other circumstances that would affect the evaluation of pharmacokinetics, a decision 
will be made on a case-by-case basis as to their inclusion in the PK analysis.  Data excluded 
from pharmacokinetic analysis will be included in the data listings, but not in the summaries.
In tables and listings for the derived PK data, there should be four decimal places for numerical 
values below 1, three decimal places for numeric values below 10 but above 1, and two decimal 
places for numeric values above 10.  However, the listings of raw data should not have more or 
fewer decimal places than the actual data.
13.1.2.
Pharmacokinetic Parameters
Pharmacokinetic parameters of lenalidomide will be calculated from concentration-time profiles 
using non-compartmental methods, though compartmental analysis may be employed if 
appropriate. Pharmacokinetic parameters will include, but not be limited to:  
∀
Cmax:  observed maximum plasma concentration
∀
Tmax:  observed time to maximum plasma concentration
∀
AUCt:  area under the plasma concentration-time curve from time zero to the last 
quantifiable timepoint, calculated by the linear trapezoidal rule
∀
AUC24:  area under the plasma concentration-time curve from time zero to 24 hours 
postdose calculated by the linear trapezoidal rule
∀
AUC∞:  area under the plasma concentration-time curve from time zero to infinity, 
calculated by the linear trapezoidal rule and extrapolated to infinity will be calculated 
according to the following equation:  
AUC∞= AUCt + (Ct/λz), where Ct is the last quantifiable concentration.
∀
λz:  terminal phase rate constant, determined by linear regression of the terminal 
points of the log-linear plasma concentration-time curve. Visual assessment may be 
used to identify the terminal linear phase of the log concentration-time profile.  A 
minimum of 3 data points will be used for the calculation.  The ʎz will not be 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
47
estimated if the terminal phase of the log-concentration-time profile does not exhibit a 
linear decline phase, or if the regression coefficient (Rsq) is less than 0.8
∀
t½: terminal phase half-life, calculated as t½ = [0.693/λz]
∀
CL/F: apparent total clearance when dosed orally, calculated as [Dose/AUC∞]
∀
Vz/F: apparent volume of distribution when dosed orally, calculated as: Vz = [CL/λz]
 
 
 
 
 
 
 
 
 
 
  
The following plasma PK parameters will be calculated for diagnostic purposes summarized and 
listed,.
∀
!z lower: lower limit of time (h) included in the calculation of !z
∀
!z upper: upper limit of time (h) included in the calculation of !z
∀
!z N: number of data points used in the calculation of !z
∀
Rsq: regression coefficient for calculation of !z
∀
AUC %extrap: percentage of AUC∞due to extrapolation from the time for the last 
quantifiable concentration to infinity, calculated as (AUC∞-AUCt)/AUC∞*100
The PK parameters shown above will be calculated from samples collected on Day 1 as 
described in section 18.2.1. Additional parameters may also be calculated. Actual blood draw 
times relative to dosing will be used for all plasma PK parameters computations.
Only subjects included in the PK population shall be considered for PK analysis. 
13.1.3.
Presentation of Pharmacokinetic Results
Listings of PK blood sample collection times, derived sampling time deviations, drug 
concentrations, and PK parameters will be provided by subject in the PK population. 
Plasma 
 concentrations for lenalidomide will be summarized by nominal time points or 
collection intervals, including sample size (N), mean, StdDev, % coefficient of variation (CV%), 
geometric mean, geometric CV%, minimum, median, and maximum.  Mean (±StdDev) and 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
48
individual plot of lenalidomide plasma concentrations versus time will be presented in both 
linear scale and semi-logarithmic scale. 
 
PK parameters will be summarized descriptively (N, mean, StdDev, CV%, geometric mean, 
geometric CV%, minimum, median, and maximum) by age class (1 to < 6, 6 to < 12 and >=12 
years) and overall.
 
 
 
13.1.4.
Population Pharmacokinetic Analysis 
Lenalidomide concentration data from this study will be combined with the concentration data 
from other pediatric studies and literature data to perform a population pharmacokinetic analysis.  
Main pharmacokinetic parameters in plasma to be estimated include AUC, Cmax, apparent 
clearance, and apparent volume of distribution. Effect of age and body size on lenalidomide PK 
will be assessed. Other relevant covariates for the main PK parameters may be identified.  The 
between-subject variability for PK parameters will be estimated.  If data allow, main PK 
parameters (clearance and volume of distribution) will be summarized by age as appropriate (eg, 
1 to < 6, 6 to < 12, and >=12 years).
This analysis is not within the scope of this SAP and report, as it will be documented in a 
separate report.
 
 
 
 
 
 
 
 
 
 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
49
14.
INTERIM ANALYSIS
Periodic reports (at least semi-annually) will be provided to an external data monitoring 
committee (DMC). The first DMC meeting will be held after 4 subjects have completed at least 1 
cycle of study treatment, if having not stopped therapy earlier due to a safety issue, in order to 
evaluate safety and provide a recommendation.
An interim analysis is planned to take place, at the end of Stage 1, once the first 18 subjects 
evaluable for the primary endpoint have been accrued and completed up to 4 cycles of 
lenalidomide treatment if they have not stopped therapy before 4 cycles, ie, the RR population.  
The interim analysis will assess the number of subjects with CR or CRi under lenalidomide 
treatment. If fewer than 3 of 18 subjects achieve a response then the study will be closed; 
otherwise the study shall continue as planned and enrollment shall continue into Stage 2.
At the interim analysis, only a subset of the summary outputs detailed in this SAP will be 
produced. No figures and listings will be provided, with the exception of AE listings. These 
summaries will include: analysis populations, subject disposition, demography and baseline 
characteristics, concomitant medications and procedures, morphological complete response rate 
within the first four cycles of treatment, overall response rate, summary of disease assessment 
outcome, summaries on exposure to lenalidomide, TEAE, TEAE with CTCAE grades 3 or 4, 
TEAE with CTCAE grade 3 or 4 related to lenalidomide, TEAE with CTCAE grade 5, cause of 
death during treatment period and cause of death after 28 days of end of treatment.
Should the study stop after Stage 1 then the primary final analysis will take place.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
50
15.
PRIMARY AND END OF STUDY FINAL ANALYSES
All tables, listings and figures detailed in this SAP will be provided for the primary final analysis 
that will be conducted when all on treatment subjects will have completed their Cycle 4 Day 28 
assessments or will have met discontinuation criteria, whichever occurs first.
For the end of study final analysis, all outputs will be rerun once all subjects will have 
discontinued the follow-up period (up to 5 years after the last subject first dose of lenalidomide).


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
51
16.
Changes to the Statistical Analyses Section of the Protocol
Denominator of the ORR rate will be defined as the number of subjects starting the cycle of 
interest instead of the number of subjects completing the cycle of interest as stated in the 
protocol.
Correlation will be computed between response and laboratory results obtained at baseline, 
instead of correlation between response and laboratory results at diagnosis and relapse as stated 
in the protocol.
The IWG response criteria in this study was brought in line with the actual criteria, ie. 
‘Progressive Disease’ was replaced with ‘Treatment Failure’. 
Time to response endpoint was added as a secondary endpoint.
 
During the course of the study, due to a low (1 or fewer) number of subjects reporting certain 
measurements or to redundant presentation, it was determined that the analyses listed below 
would not be conducted:
∀
Summaries of prior cancer history, prior procedures/surgeries, procedures for prior 
cancers not under study and radiation treatment for prior cancers not under study.
∀
  
∀
Correlation between response with baseline/screening peripheral white blood cell count, 
absolute blast count, cytogenetics,
∀
Summary of durable response rate.
∀
AE summary tables for (treatment-emergent adverse events leading to death, SAEs
related to lenalidomide, SAEs leading to discontinuation, Grade ¾ TEAEs by maximum 
intensity. 
∀
Summary for AE of special interest related to lenalidomide, SAEs of special interest 
related to lenalidomide or leading to discontinuation of lenalidomide. AEs of special 
interest by maximum intensity.  
∀
Second primary malignancy related tables, listings and figures.
∀
∀
Population PK analysis.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
52
17.
REFERENCES
Cheson B, Bennett J, Kopecky K, Buchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in 
Acute Myeloid Leukemia. J Clin Oncol 2003;21(24):4642-4649.
 
 
 
&(/*(1(35235,(7$5<,1)250$7,21
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
53
18.
APPENDICES
18.1.
Modified International Working Group AML Response Criteria
Hematologic Response According to IWG Criteria for AML is reported in table Table 4.
Table 4:
Hematologic Response According to IWG Criteria for AML
Category 
Definition
Morphologic Complete Remission (CR)
The following conditions should be met:
∀
Absolute neutrophil count (ANC) > 
1000/uL and platelets > 100,000/uL 
without transfusions and/or exogenous 
growth factor support (ie, no transfusion 
or exogenous growth factor within 7 days 
of assessment).
∀
Bone marrow with < 5% blasts and 
evidence of trilineage hematopoiesis.
∀
No evidence of extramedullary disease.
Morphologic Complete Remission With 
Incomplete Blood Count Recovery (CRi)
∀
ANC < 1000/uL.
∀
Platelets < 100,000/uL or > 100,000/uL 
without platelet recovery (requiring 
transfusion within 7 days of assessment). 
∀
Bone marrow with < 5% blasts and 
evidence of trilineage hematopoiesis.
∀
No evidence of extramedullary disease.
Partial Remission (PR)a
∀
ANC > 1000/uL and platelets > 
100,000/uL without transfusions and/or 
exogenous growth factor support (ie, no 
transfusion or exogenous growth factor 
within 7 days of assessment).
∀
Bone marrow with 5% to 25% blasts and 
at least a 50% decrease in bone marrow 
blast percent from baseline.
∀
No evidence of extramedullary disease.
Treatment Failure
Resistant Disease:
Patient survives ≥ 7 days post-therapy 
and failed to achieve CR, CRi, or PR but 
are stable with persistent AML in blood 
or bone marrow.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
54
Category 
Definition
Aplasia:
Patient survives ≥ 7 days post-therapy; 
death while cytopenic, with aplastic bone 
marrow.
Indeterminate cause:
∀
Patients who die < 7 days post-therapy.
∀
Patients who die > 7 days post-therapy 
with no peripheral blood blasts, but no 
bone marrow examination.
∀
Patients who do not complete the first 
course of therapy.
Morphologic relapse after CR or CRi:
∀
the reappearance of > 5% blasts in the 
peripheral blood, or 
∀
a single finding of > 15% blasts in the 
bone marrow.  
All of the above occurrences should be 
attributed to relapse following CR or CRi 
and not attributable to another cause (eg, 
bone marrow regeneration after 
consolidation therapy).
Molecular or cytogenetic relapse:
Reappearance of molecular or 
cytogenetic abnormality.
a
If the pretreatment bone marrow blast percentage was 50% to 100%, the percentage of blasts must decrease to a value
between 5% and 25%; if the pretreatment blast percentage was 20% to less than 49%, they must decrease by at least half to a 
value of more than 5%.
Source:  Cheson, 2003.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
55
18.2.
Pharmacokinetic Sample Collection
18.2.1.
Blood Collection for PK Analysis
Collection of blood samples for PK assessments in plasma will be performed in all subjects.  On 
Cycle 1 Day 1, the subjects will receive the dose of lenalidomide in the morning at the study 
center.  Subjects will undergo PK sampling of blood at scheduled time points (Table 5) for 24 
hours post-dose.  The actual date and time for dosing and blood sampling should be recorded in 
the eCRF.
Table 5:
PK Sampling Schedule During Cycle 1 Day 1
Collection time after 
lenalidomide administrationa
Collection window
Weight ≤ 20 kgb
Weight > 20 kgc
0.5 hour
± 10  min
-
x
1 hour
± 10  min
x
x
2 hours
± 10  min
x
x
4 hours
± 10  min
x
x
6 hours
± 10  min
-
x
8 hours
± 10  min
x
x
24 hours*
± 2 hours
x
x
PK = pharmacokinetic.
* The 24 hour blood sample must be taken prior to the lenalidomide administration on Day 2.
a The blood draw volume is 1 mL per sample.
b Only 5 PK blood samples will be taken from subjects with weight ≤ 20 kg at the specified time points.
c Seven PK blood samples will be taken from subjects with weight > 20 kg.
 
 
 
 
 
 
 
 
 
 
 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
56
18.3.
Handling of Dates
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. date format in SAS). Dates in the clinical database are 
classified into the categories of procedure dates, log dates, milestone dates, outcome dates, and 
special dates.
∀
Procedure Dates are the dates on which given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, tumor 
scans, etc. They should be present whenever data for a protocol-specified procedure 
are present and should only be missing when a procedure are marked as NOT DONE 
in the database. Procedure dates will not be imputed.
∀
Log Dates are dates recorded in eCRF data logs. Specifically, they are the start and 
end dates for adverse events and concomitant medications/procedures. They should 
not be missing unless an event or medication is marked as ongoing in the database. In 
listings, log dates will be shown as recorded without imputation.
∀
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc. They should not be 
missing if the milestone occurs for a subject. They will not be imputed.
∀
Outcome Dates are dates corresponding to study endpoints such as survival, 
treatment failure, etc. In most cases they are derived either from a milestone (eg, the 
survival date is derived from the death date), or a procedure date (eg, the treatment 
failure date is derived from the date of the tumor scan that was used to determine 
treatment failure). They may be subject to endpoint-specific censoring rules if the 
outcome did not occur, but are not otherwise subject to imputation.
∀
Special Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules. 
∀
Last Contact Dates for the survival analysis are the maximum date collected in the 
database. If the imputed date used for response date or AE date, the last contact dates 
should be the latest date of those imputed date and maximum date in the database.
Dates recorded in comment fields will not be imputed or reported in any specific format. 
18.3.1.
Calculation Using Dates
Calculations using dates (e.g. subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions:  
∀
Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study drug plus 1 day. The 
generalized calculation algorithm for relative day is the following:  
#
If TARGET DATE >= DSTART then STUDY DAY = (TARGET DATE –
DSTART) + 1; 
#
Else use STUDY DAY = TARGET DATE – DSTART.
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
57
Note that Study Day 1 is the first day of treatment of study drug. Negative study days 
are reflective of observations obtained during the baseline/screening period. Note:  
Partial dates for the first study drug are not imputed in general. All effort should be 
made to avoid incomplete study drug start dates. 
∀
Age (expressed in days) is calculated:  AGE = CONSENT DATE – DATE of BIRTH 
+ 1. In practice, age will be transformed to years by dividing the difference by 365.25 
days, then truncating.
#
Preference is for using calculated age from clinical database. When not available, 
calculated age from eCRF or IVRS may be used
#
Partial birth date: impute missing day as 1st of the month; set missing age for 
missing month; set missing age for missing year
∀
Age in listings will be displayed in years and months and will be calculated as 
follows:
#
first, the age in months will be calculated as: 
Integer part of [age expressed in days / 30.4375]
#
then, the resulting number will be divided by 12 in order to express age in years 
and months: 
integer part of [(age in months / 12)] years and [remainder of (age in months / 
12)] months
∀
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS /7
∀
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS /30.4375
18.4.
Date Imputation Guideline
18.4.1.
Impute Missing Dates for Adverse Events/ Prior or Concomitant Medications 
Incomplete Start Date
∀
If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date. 
Missing day and month
∀
If the year is the same as the year of the first dosing date, then the day and month of 
the first dosing date will be assigned to the missing fields.
∀
If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields.
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∀
IfIf


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
58
∀
If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields.
Missing day only 
∀
If the month and year are the same as the year and month of first dosing date, then the 
first doing date will be assigned to the missing day.
∀
If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same but the month of partial 
date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day.
∀
If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day.
Missing day, month, and year
∀
No imputation is needed, the corresponding AE will be included as TEAE if end date 
of AE is after the first dose date or the end date is also missing. 
Incomplete Stop Date
∀
If the imputed stop date is before the start date, then the imputed stop date will be 
equal to the start date.
Missing day and month
∀
If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 
∀
If the year of study drug start and stop are different, and the year of the incomplete 
stop date is the same as the year of the first dosing date, then December 31 will be 
assigned to the missing fields.
∀
If the year of the incomplete stop date is prior to the year of the last dosing date but 
is the same as the year of the first dosing date, then the first dosing date will be 
assigned to the missing date. 
∀
If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1 will be assigned to the missing fields.
Missing day only 
∀
If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day. 
∀
If either the year of the partial date is not equal to the year of the last dosing date or 
the years of the partial date and the last dosing date are the same but the month of 
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Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
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59
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day. 
18.4.1.1.
Adverse Events
Partially missing AE start dates will be imputed in the derived dataset for AEs, but partially 
missing AE end dates will not be imputed in the same dataset. If the AE end date is complete 
with no missing year, month, or day, and the partially missing start date imputed by the rules 
below is after the AE end date, then the start date will be imputed by the AE end date.
18.4.1.2.
Prior/Concomitant Medications/Procedures
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the derived dataset for 
prior/concomitant medications/procedures. For prior/concomitant medications, if the stop date is 
complete with no missing year, month, or day, and the partially missing start date imputed by the 
rule below is after the stop date, then the start date will be imputed by the stop date.
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date.
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date.
18.4.2.
Medical History
Partially missing medical history start dates will be imputed in the derived dataset for medical 
history. The 16th of the month will be used to impute a partially missing start date that has only 
the day missing, and July 1st will be used to impute a partially missing start date that has both the 
month and day missing.
&(/*(1(35235,(7$5<,1)250$7,21
g start 
start 
he stop dat
he stop da
ate imputed
e impute
op date.
p date.
l be impute
be impute
imputed b
imputed
mputed in 
mputed in 
ute a partia
ute a parti
pute a part
pute a part


Lenalidomide
Statistical Analysis Plan. Protocol CC-5013-AML-002
Celgene Corporation
Confidential and Proprietary
60
18.5.
Reference Ranges from Literature 
Table 6
Laboratory Reference Ranges from Literature 
TEST NAME
Gender
(F,M or Both)
AGE
For non-specific age range 
enter 0-99
RANGE
UNITS
LOW (>/=)
HIGH (<)
LOW
HIGH
White blood cell count (WBC) (B)
Both
1–6yrs
5.0–14.5
103/μL
7–12yrs
5.0–14.5
13–18yrs
4.5–13.5
≥19yrs
4.5–11.0
Absolute Neutrophil Count  (ANC) (B)
Both
1–6yrs
1.5–8.0
103/μL
7–12yrs
1.5–8.0
13–18yrs
1.8–8.0
≥19yrs
1.8–7.7
Platelet count (B) 
Both
0-99
150,000–450,000
μL
&(/*(1(35235,(7$5<,1)250$7,21
ary
ry
)250
250
RANGE
50
,1)2
1)2
W
)2
,1
5<
$5
7$
7$
7$
7$
rs
(7
12yrs
12yrs
5,(
13–
13–18yrs
8yr
35
≥19
≥1
23
52
35