Conditions: Central Nervous System Neoplasms Medulloblastoma
Keywords: Pediatric Brain Tumor Central Nervous System Neoplasms Glioma High-grade glioma HGG Ependymoma Medulloblastoma DIPG Diffuse intrinsic pontine gliomaProgressive RecurrentPomalidomide PomalystImnovid CC-4047 Children
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 53
Healthy volunteers: no

Brief summary:
This study will assess the efficacy, safety and tolerability of pomalidomide in children and young adults aged 1 to \< 21 years with recurrent or progressive primary brain tumors in one of four primary brain tumor types: high-grade glioma (HGG), medulloblastoma, ependymoma and diffuse intrinsic pontine glioma (DIPG).

Detailed description:
The study will consist of 4 parallel groups of participants, one for each of the following primary brain tumor types: high-grade glioma, medulloblastoma, ependymoma and DIPG. A Simon's Optimal two-stage study design will be applied to each group and enrollment will occur as follows:

* Stage 1: Nine participants will be enrolled in each brain tumor type group
* Stage 2: If during Stage 1, ≥ 2 participants achieves either an objective response (either complete response or partial response) within the first 6 cycles of treatment (or within the first 3 cycles for DIPG participants), or a long-term stable disease, an additional 11 participants shall be enrolled; otherwise no additional participants will be enrolled into that group.
* If a total of 5 or more participants across all 20 participants in a given group (Stage 1 and 2) evaluable for the primary endpoint are observed as having either an objective response (either complete response or partial response) within the first 6 cycles of treatment (or within the first 3 cycles for DIPG participants) or a long-term stable disease, pomalidomide will be considered effective in that disease indication.

Once treatment has been discontinued, participants will be followed up for up to 5 years from enrollment of the last participant.

Participants who withdraw from either stage for reasons other than disease progression prior to completing Cycle 1 of study treatment will be replaced.

Arms:
arm 1: Pomalidomide will administered at a starting dose of 2.6 m2/day. Pomalidomide will be provided as either a capsule (0.5 mg, 1 mg, 2 mg, 3 mg or 4 mg) or as an oral suspension (2 mg/mL).

Interventions: intervention 1: Pomalidomide intervention 2: Pomalidomide
Intervention descriptions: intervention 1: : Subjects will be administered pomalidomide on Days 1 to 21, followed by a 7-day rest period, of each 28-day treatment cycle and will continue treatment for up to 24 cycles or until disease progression, withdrawal of consent/assent or unresolved toxicities as described in the protocol. intervention 2: Pomalidomide will be provided as gelatin capsules and as an oral suspension. The starting dose will be 2.6 mg/m²/day, administered on Days 1 to 21, followed by a 7-day rest period, of each 28-day treatment cycle.

Protocol document:
Prot_000.pdf: 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
1
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
TITLE PAGE
A PHASE 2 CLINICAL STUDY OF POMALIDOMIDE
(CC-4047) MONOTHERAPY FOR CHILDREN AND 
YOUNG ADULTS WITH RECURRENT OR
PROGRESSIVE PRIMARY BRAIN TUMORS
PROTOCOL NUMBER:
CC-4047-BRN-001
ORIGINAL DATE FINAL:
20 December 2016
AMENDMENT No. 1 DATE FINAL:
16 June 2017
AMENDMENT No. 2 DATE FINAL:
18 August 2017
AMENDMENT No. 3 DATE FINAL:
20 December 2017 
EudraCT NUMBER:
2016-002903-25
IND NUMBER:
123692
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:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
2
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information (Clinical Research Physician/Medical Monitor):
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:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
3
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic 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:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
4
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
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 Council on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
5
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
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:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
6
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
PROTOCOL SUMMARY
Study Title
A Phase 2 clinical study of pomalidomide (CC-4047) monotherapy for children and young adults 
with recurrent or progressive primary brain tumors.
Indication
Treatment of children and young adults aged 1 to < 21 years with recurrent or progressive 
primary brain tumors in one of four primary brain tumor types: high-grade glioma, 
medulloblastoma, ependymoma and diffuse intrinsic pontine glioma (DIPG).  
Objectives
Primary:
!
To identify potential tumor type(s) for further development by establishing the 
preliminary efficacy of pomalidomide in children and young adults with recurrent or 
progressive primary brain tumors within four distinct tumor types.
Secondary:
!
To evaluate the safety of pomalidomide within the study populations. 
!
To estimate the long-term efficacy of pomalidomide treatment.
Exploratory:
!
To assess the pharmacokinetics (PK) of pomalidomide in children and young adults 
with recurrent or progressive primary brain tumors.
Study Design
This is a Phase 2, multicenter, open-label, parallel-group study that will assess the efficacy, 
safety and tolerability of pomalidomide in children and young adults aged 1 to < 21 years with 
recurrent or progressive brain tumors after at least one prior standard therapy.
The study will consist of 4 parallel strata, one for each of the following primary brain tumor 
types: high-grade glioma, medulloblastoma, ependymoma and DIPG. A Simon’s Optimal two-
stage study design will be applied to each stratum and enrollment will occur as follows:
!
Stage 1: Nine subjects will be enrolled.
!
Stage 2: If during Stage 1, ≥ 2 subjects achieve either an objective response (OR; 
either complete response [CR] or partial response [PR]) within the first 6 cycles of 
treatment (within 3 cycles for DIPG) or a long-term SD (SD maintained for ≥ 6 
cycles [> 3 cycles for DIPG]), an additional 11 subjects shall be enrolled; otherwise 
no additional subjects will be enrolled into that stratum.
!
If a total of 5 or more subjects across all 20 subjects in a given stratum (Stage 1 and 
2) evaluable for the primary endpoint are observed as having either an OR (either CR 
or PR) within the first 6 cycles of treatment (within 3 cycles for DIPG) or a long-term 
SD, pomalidomide will be considered effective in that disease indication.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
7
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Subjects who withdraw from either stage for reasons other than PD prior to completing Cycle 1 
of study treatment will be replaced.  Subjects completing at least one cycle of study therapy but 
not having a post-baseline disease assessment will be considered a non-responder.
An independent Data Monitoring Committee (DMC) will monitor the study conduct.  Details of 
the DMC structure, composition, and roles/responsibilities will be outlined within a DMC charter
described in Section 9.9.2.
The study will be conducted in compliance with International Council on Harmonisation (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practices (GCPs) and applicable regulatory requirements.
Study Population
Male or female children and young adults aged 1 to < 21 years with recurrent or progressive 
primary brain tumors after at least one prior standard therapy, in 1 of 4 primary brain tumor 
types: high-grade glioma, medulloblastoma, ependymoma and DIPG will be enrolled.  Up to 80
subjects (36 subjects in Stage 1 and 44 subjects in Stage 2) will be included should all strata 
enroll the maximum number of subjects and assuming no subjects are replaced.  Approximately 
80% of subjects across all strata will be < 17 years of age. 
Length of Study
The study will have the following sequential periods for all subjects: Screening Period, 
Treatment Period and Follow-up Period. The Screening Period will start from the time of 
obtaining informed consent/assent and will last no more than 28 days, at which time the 
Treatment Period will begin (Cycle 1 Day 1, first day of actual study drug administration).  Each 
subject will receive treatment for up to 24 cycles.  Once treatment has been discontinued, 
subjects will enter the Follow-up Period which will continue for up to 5 years from the 
enrollment of the last subject, unless consent/assent is withdrawn, the subject is lost to follow-up, 
or death.
The Stage 1 portion of the study is expected to last up to approximately 18 months prior to 
reaching the decision point. The Stage 2 portion of the study is expected to last up to 
approximately 27 months should all strata enroll the maximum number of subjects and assuming 
no subjects are replaced.  
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 and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
Pomalidomide will be provided by Celgene in 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg gelatin 
capsules and as an oral suspension.  Subjects will be administered pomalidomide on Days 1 to 
21, followed by a 7-day rest period, of each 28-day treatment cycle and will continue treatment 
for up to 24 cycles or until documented PD, withdrawal of consent/assent, treatment becomes 
intolerable or death. The starting dose will be 2.6 mg/m2/day which has been determined as the 
maximum tolerated dose (MTD) in the Phase 1 trial conducted by the Pediatric Brain Tumor 
Consortium (PBTC-043).
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
8
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Overview of Key Efficacy Assessments
Response evaluations will be based on MRI results obtained at each site and will be assessed 
locally and by an independent central reviewer. Corticosteroid use and clinical assessments (ie, 
neurologic status) will also be considered when determining overall response.  The local 
Investigator’s assessment will be used for subject eligibility and treatment decisions.  Efficacy 
based endpoints incorporating tumor assessments (primary and secondary) will be based on the 
independent central assessment.  
Tumor assessments will be conducted by standard MRI with and without contrast (ie,
gadolinium) using three MRI sequences (T1-weighted pre- and post-contrast, 
T2-weighted, fluid-attenuated inversion recovery [FLAIR]).  Overall radiographic objective 
response will be assessed utilizing the sequence(s) best representative of tumor in the opinion of 
the neuroradiologist.  Subjects who do not meet the criteria for an objective response or disease 
progression by the end of Cycle 6 (end of Cycle 3 for DIPG subjects) will be considered as 
having long-term SD.
Overview of Key Safety Assessments
Subject safety, including hematology (complete blood count with differential), serum blood 
chemistry analyses, physical examinations, vital signs, body weight measurement, 
Lansky/Karnofsky performance status, symptom review for adverse events (AEs), and pregnancy 
testing for females of childbearing potential/female children of childbearing potential 
(FCBP/FCCBP) will be assessed.
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 from the time of 
signing the informed consent form (ICF)/ informed assent form (IAF) until the end of the Long-
term Follow-up Period.  Investigators are to report any SPM as a serious adverse event (SAE)
regardless of causal relationship to study treatment.
Overview of Pharmacokinetics Assessments
Pharmacokinetics evaluations will include the following parameters:
!
PK endpoints as assessed by population pharmacokinetic analysis.
!
Clinically relevant intrinsic/extrinsic covariates of pomalidomide exposure from 
population PK analysis.
Statistical Methods
This study consists of 4 independent strata for each distinct disease indications (high-grade 
glioma, medulloblastoma, ependymoma and DIPG).  The primary endpoint, objective response 
and long-term stable disease rate (ORSDR), is defined as the total number of subjects achieving 
either an OR (CR or PR) within the first 6 cycles of treatment (within 3 cycles for DIPG) or a 
long-term SD (SD maintained for ≥ 6 cycles [> 3 cycles for DIPG]) over the total number of 
subjects evaluable for analysis.  An evaluable subject is defined as completing at least one cycle 
of study therapy or stopping earlier due to a PD. Subjects completing at least one cycle of study 
therapy but not having a disease assessment (post baseline) will be considered a non-responder.  
Under Simon’s Optimal two-stage design with a 5% significance level and 90% power, assuming 
a lower boundary of interest in the response rate of 10% and an upper boundary of interest in the 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
9
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
response rate of 40%, a total of 20 subjects evaluable for the primary endpoint are required per 
stratum; 9 per stratum (36 total) in Stage 1 and an additional 11 per stratum (44 total) in Stage 2.
All efficacy based endpoints will be presented by stratum.
&&,
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
10
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................17
1.1.
Disease Background ...............................................................................................17
1.1.1.
Pediatric Brain Tumors...........................................................................................17
1.1.2.
Current Treatment for Pediatric Brain Tumors........................................................18
1.2.
Pomalyst® (Pomalidomide) Background.................................................................19
1.2.1.
Pomalidomide Mechanism of Action......................................................................20
1.2.2.
Pharmacokinetics and Pharmacodynamics of Pomalidomide...................................21
1.2.2.1.
Pharmacokinetics in Adults ....................................................................................21
1.2.2.2.
Pharmacokinetics in Pediatric Populations..............................................................22
1.2.3.
Adult Clinical Trials of Pomalidomide....................................................................23
1.2.4.
Pediatric Clinical Trials of Pomalidomide...............................................................23
1.3.
Rationale ................................................................................................................24
1.3.1.
Study Rationale and Purpose ..................................................................................24
1.3.2.
Rationale for the Study Design ...............................................................................26
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................27
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................28
3.
OVERALL STUDY DESIGN ................................................................................30
3.1.
Study Design ..........................................................................................................30
3.2.
Study Duration for Subjects....................................................................................34
3.3.
End of Trial ............................................................................................................34
4.
STUDY POPULATION.........................................................................................35
4.1.
Number of Subjects ................................................................................................35
4.2.
Inclusion Criteria....................................................................................................35
4.3.
Exclusion Criteria...................................................................................................38
5.
TABLE OF EVENTS.............................................................................................41
6.
PROCEDURES......................................................................................................45
6.1.
Screening Period.....................................................................................................45
6.1.1.
Information to be Collected on Screen Failures.......................................................46
6.1.2.
Demographics.........................................................................................................46
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.1.
.1.


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Pomalyst® (Pomalidomide)
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6.1.3.
Complete Medical History......................................................................................47
6.1.4.
Prior Disease History and Therapies .......................................................................47
6.1.5.
Enrollment..............................................................................................................47
6.2.
Treatment Period ....................................................................................................47
6.2.1.
End of Treatment....................................................................................................48
6.3.
Follow-up Period....................................................................................................49
6.3.1.
Safety Follow-up ....................................................................................................49
6.3.2.
Second Primary Malignancy Follow-up Period.......................................................50
6.3.3.
Long-term Follow-up..............................................................................................50
6.4.
Assessment Types ..................................................................................................50
6.4.1.
Efficacy Assessments .............................................................................................50
6.4.1.1.
Selection of Target and Non-Target Lesions ...........................................................51
6.4.1.2.
Methodology to Determine Tumor Measurement....................................................52
6.4.1.3.
Tumor Response Criteria for Target Lesions...........................................................54
6.4.1.4.
Tumor Response Criteria for Non-Target Lesions...................................................55
6.4.1.5.
Clinical Status (Neurologic Symptoms/Examination) .............................................55
6.4.1.6.
Corticosteroid Administration.................................................................................55
6.4.1.7.
Overall Response Assessment.................................................................................55
6.4.1.8.
Independent Central Response Review ...................................................................55
6.4.2.
Safety and Tolerability Assessments.......................................................................56
6.4.2.1.
Physical Examinations (Including Vital Signs) .......................................................56
6.4.2.2.
Height.....................................................................................................................57
6.4.2.3.
Weight....................................................................................................................57
6.4.2.4.
Body Surface Area Calculation...............................................................................57
6.4.2.5.
Lansky/Karnofsky Performance Status ...................................................................57
6.4.2.6.
Laboratory Evaluations...........................................................................................57
6.4.2.7.
Pulse Oximetry (Oxygen Saturation).......................................................................58
6.4.2.8.
Neurological Assessment........................................................................................58
6.4.2.9.
Pregnancy Testing and Pregnancy Risk Counseling................................................58
6.4.2.10.
Assessment of Second Primary Malignancy............................................................59
6.5.
Pharmacokinetics – Optional ..................................................................................60
7.
DESCRIPTION OF STUDY TREATMENTS........................................................61
7.1.
Description of Investigational Product ....................................................................61
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6.4.2.10
.4.2.1


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Pomalyst® (Pomalidomide)
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7.2.
Treatment Administration and Schedule .................................................................61
7.2.1.
Criteria for Starting Subsequent Treatment Cycles..................................................63
7.2.2.
Dose Reductions, Interruptions and Discontinuation Criteria for Toxicities.............63
7.2.2.1.
Dose Modifications.................................................................................................64
7.2.3.
Overdose ................................................................................................................65
7.3.
Method of Treatment Assignment...........................................................................66
7.3.1.
Subject Numbering.................................................................................................66
7.4.
Packaging and Labeling..........................................................................................66
7.5.
Investigational Product Accountability and Disposal ..............................................66
7.6.
Investigational Product Compliance........................................................................67
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................68
8.1.
Permitted Concomitant Medications and Procedures...............................................68
8.1.1.
Anti-emetics ...........................................................................................................68
8.1.2.
Corticosteroids........................................................................................................68
8.1.3.
Colony Stimulating Growth Factors........................................................................68
8.1.4.
Anticonvulsants......................................................................................................69
8.1.5.
Neurosurgical or Other Surgical Procedure.............................................................69
8.1.6.
Alternative Supplements.........................................................................................69
8.1.7.
Antibiotics Associated with Febrile Neutropenia ....................................................69
8.2.
Prohibited Concomitant Medications and Procedures..............................................69
8.2.1.
Radiotherapy ..........................................................................................................69
8.2.2.
Deep Venous Thrombosis Prophylaxis....................................................................69
8.2.3.
Anti-coagulation Medications.................................................................................70
8.2.4.
Moderate to Strong CYP1A2 Inhibitors..................................................................70
8.3.
Required Concomitant Medications and Procedures................................................70
9.
STATISTICAL CONSIDERATIONS ....................................................................71
9.1.
Overview................................................................................................................71
9.2.
Study Population Definitions ..................................................................................71
9.3.
Sample Size and Power Considerations...................................................................71
9.4.
Background and Demographic Characteristics........................................................72
9.5.
Subject Disposition.................................................................................................72
9.6.
Efficacy Analysis....................................................................................................72
9.7.
Safety Analysis.......................................................................................................74
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9.4.
.4.


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
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Confidential and Proprietary
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9.8.
Interim Analysis .....................................................................................................74
9.9.
Other Topics...........................................................................................................75
9.9.1.
Pharmacokinetic Analysis.......................................................................................75
9.9.2.
Data Monitoring Committee ...................................................................................75
9.9.3.
Steering Committee ................................................................................................75
10.
ADVERSE EVENTS..............................................................................................76
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................76
10.2.
Evaluation of Adverse Events.................................................................................76
10.2.1.
Seriousness.............................................................................................................76
10.2.2.
Severity/Intensity....................................................................................................78
10.2.3.
Causality ................................................................................................................78
10.2.4.
Duration .................................................................................................................79
10.2.5.
Action Taken..........................................................................................................79
10.2.6.
Outcome.................................................................................................................79
10.3.
Abnormal Laboratory Values..................................................................................79
10.4.
Pregnancy...............................................................................................................79
10.4.1.
Females of Childbearing Potential: .........................................................................80
10.4.2.
Male Subjects.........................................................................................................80
10.5.
Reporting of Serious Adverse Events......................................................................80
10.5.1.
Safety Queries ........................................................................................................81
10.6.
Expedited Reporting of Adverse Events..................................................................81
11.
DISCONTINUATIONS .........................................................................................83
11.1.
Treatment Discontinuation......................................................................................83
11.2.
Study Discontinuation ............................................................................................83
12.
EMERGENCY PROCEDURES.............................................................................85
12.1.
Emergency Contact.................................................................................................85
12.2.
Emergency Identification of Investigational Products .............................................85
13.
REGULATORY CONSIDERATIONS...................................................................86
13.1.
Good Clinical Practice............................................................................................86
13.2.
Investigator Responsibilities ...................................................................................86
13.3.
Subject Information and Informed Consent/Assent .................................................87
13.4.
Confidentiality........................................................................................................87
13.5.
Protocol Amendments.............................................................................................87
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13.2.
3.2.


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
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13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................87
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................88
13.8.
Termination of the Study ........................................................................................88
14.
DATA HANDLING AND RECORDKEEPING.....................................................90
14.1.
Data/Documents.....................................................................................................90
14.2.
Data Management...................................................................................................90
14.3.
Record Retention....................................................................................................90
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................92
15.1.
Study Monitoring and Source Data Verification......................................................92
15.2.
Audits and Inspections............................................................................................92
16.
PUBLICATIONS ...................................................................................................93
17.
REFERENCES.......................................................................................................94
18.
APPENDICES........................................................................................................98
Appendix A: Table of Abbreviations.........................................................................................98
Appendix B:  Tumor Response Categories for Target and Non-target Lesions.........................102
Appendix C:  Overall Response Assessment ...........................................................................103
Appendix D:  Performance Status............................................................................................104
Appendix E:  Plasma PK Sample Handling Instruction............................................................105
Appendix F:  Pomalidomide Dosing........................................................................................107
&&,
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Instruction
..............
.............


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................28
Table 2:
Study Endpoints .....................................................................................................29
Table 3:
Serum Creatinine by Age and Gender.....................................................................36
Table 4:
Table of Events.......................................................................................................41
Table 5:
Local Clinical Laboratory Parameters Collection Plan ............................................58
Table 6:
Pharmacokinetic Sampling Time Points..................................................................60
Table 7:
Dose Reductions of Pomalidomide .........................................................................64
Table 8:
Dose Modification Criteria .....................................................................................64
Table 9:
Abbreviations and Specialist Terms........................................................................98
Table 10:
Overall Response Assessment...............................................................................103
Table 11:
Performance Status...............................................................................................104
Table 12:
Pomalidomide Capsule Dosing Tables..................................................................107
Table 13:
Pomalidomide Dosing Table – Oral Suspension....................................................109
&&,
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58
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
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Confidential and Proprietary
16
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
LIST OF FIGURES
Figure 1:
Simon’s Optimal Two-Stage Parallel Design ..........................................................32
Figure 2:
Overall Study Design..............................................................................................33
Figure 3:
Guidelines for Measurement of Tumor Size............................................................54
&&,
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
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CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
1.
INTRODUCTION 
1.1.
Disease Background
1.1.1.
Pediatric Brain Tumors
Central nervous system (CNS) tumors (including brain and spinal cord) are the most common 
solid tumors among children and account for up to 25% of all childhood cancer cases 
(Fleming, 2012).  Although overall survival (OS) is estimated to be over 70% at 5 years for the 
less aggressive tumor types such as pilocytic astrocytoma (PA), medulloblastoma and low-grade 
gliomas, these rates drop to below 50% for children with aggressive variants such as high-grade 
gliomas and diffuse intrinsic pontine glioma (DIPG) (Kohler, 2011).  Outcomes for children with 
recurrent/progressive disease are much lower and once a child with a malignant brain tumor has 
suffered a recurrence, survival outcomes diminish considerably (Dolecek, 2012; Fangusaro, 
2009). In the United States, approximately 2500 children are diagnosed annually with brain 
tumors (Gajjar, 2013).  Brain tumors occur most commonly in the first decade of life.
Pediatric brain tumors vary greatly in histology, and there is a great deal of heterogeneity even 
among specific diagnoses (Fangusaro, 2009).  The most common brain tumors fall under the 
broad category of glioma and account for 53% of tumors in children ages 0 to 14 years and 
37% in adolescents ages 15 to 19 years (Dolecek, 2012).  Other common pediatric CNS tumors 
include medulloblastomas and ependymomas.
Gliomas are primary brain tumors of glial origin with different cell lineages.  Some of the more 
common tumors of this class found in children include fibrillary astrocytomas, PA, 
ependymomas, glioblastoma multiforme, and pleomorphic xanthochromic astrocytomas.  
Gliomas are classified by the World Health Organization (WHO) into I to IV grades (Kleihues, 
2002).  Most (80%) of these tumors in children are low grade (grade I and II) including the most 
frequently occurring pilocytic astrocytoma (WHO grade I) and diffuse astrocytoma (WHO grade 
II) and approximately 20% are WHO grade III or IV (high-grade gliomas) (Grondin, 2009; Sie, 
2014).  Survival rates for patients with low grade glioma are reported to be in excess of 90% for 
OS and 60% to 85% for progression-free survival (PFS) (Heath, 2012).  
High-grade gliomas are a heterogeneous group of tumors that can originate from any location in 
the CNS, but are primarily in the supratentorial brain or in the brainstem. High-grade gliomas 
account for 3% to 7% of primary brain tumors in children and include anaplastic astrocytomas 
(WHO grade III), anaplastic pleomorphic xanthochromic astrocytomas (WHO grade III) and 
glioblastomas (WHO grade IV) with glioblastoma multiforme (GBM) being the most aggressive 
type (Cage, 2012; Kleihues, 2002; Sie, 2014). High-grade gliomas are particularly difficult to 
treat due to their infiltrative nature and resistance to radiotherapy and current chemotherapy 
regimens.  Diffuse intrinsic brain stem gliomas which are mainly grade III or IV astrocytomas 
have the worst prognosis with a median OS of approximately 9 to 12 months, and most patients 
die from the disease within 2 years (Sie, 2014).  They account for 60% to 75% of brainstem 
tumors and are the major cause of mortality in children with brain tumors occurring between the 
ages of 5 to 10 years with short time to the onset of symptoms (Walker, 1999).  A review of 
Pediatric Brain Tumor Consortium (PBTC) trials that have included patients with DIPG show a 
median PFS of 4.5 months from diagnosis. DIPG are generally diagnosed by magnetic resonance 
imaging (MRI) in the context of a typical clinical presentation (Rao, 2008). Patients with these 
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types of tumors (high-grade gliomas and DIPG) generally succumb to their disease and the 5-
year survival rate remains < 10 to 30% (Johnson, 2012; Gajjar, 2013).
Medulloblastomas, one of the embryonal brain tumor types, are primary brain tumors that occur 
in the cerebellum of children and young adults.  Medulloblastomas are the most common 
malignant brain tumor in pediatrics and the second most common pediatric brain tumor overall, 
representing approximately 20% of all pediatric CNS tumors (Fangusaro, 2009).  This tumor has 
the propensity to disseminate along the cerebrospinal fluid (CSF) pathway, and approximately 
30% of patients have metastatic disease at diagnosis (Gerber, 2014).  Medulloblastomas can be 
stratified into four distinct histological subtypes that together with age at diagnosis and the 
metastatic status of the disease, categorize patients into risk groups, which could be used to 
predict the survival outcome (Ajeawung, 2013).  These groups include classical 
medulloblastoma, large cell/anaplastic medulloblastoma, nodular desmoplastic medulloblastoma, 
and medulloblastoma with extensive nodularity.  Large-cell/anaplastic medulloblastomas are 
associated with poor prognosis especially in patients less than 3 years of age, while the nodular 
desmoplastic and medulloblastoma with extensive nodularity, are associated with a better 
prognosis (Ajeawung, 2013; Heath, 2012).  The 5-year survival ranges from 60% (high-risk) to 
> 80% (standard-risk) (Gajjar, 2013).  More recently, medulloblastomas have been molecularly 
subclassified and further updated risk stratifications defined.
Ependymomas, though relatively rare, are the third most common pediatric brain tumor and 
represent approximately 8% to 10% of all CNS tumors seen in children.  Ependymomas are 
histologically classified into myxopapillary ependymoma (WHO grade I), grade II ependymoma 
(cellular, papillary, clear cell, tanycytic) and anaplastic ependymoma (WHO grade III), although 
there does not appear to be a correlation between grade and clinical outcome (Sie, 2014).  As 
with medulloblastomas, molecular subclassifications of ependymoma have recently been 
defined. Sixty-five percent of patients with ependymoma are cured after surgery and radiation 
therapy depending on the degree of resection and histopathology of the tumor (Gajjar, 2013). 
Surgical resection remains to be a crucial factor in determining long-term disease control and 
survival.  The 5-year survival ranges from 67 to 80% (completely resected tumor) to 22 to 47% 
(incompletely resected tumor) (Merchant, 2002). 
1.1.2.
Current Treatment for Pediatric Brain Tumors
The treatment approach for pediatric brain tumors in general includes surgical resection, 
radiotherapy, and chemotherapy.  Over the last decades, significant advances in surgery, 
radiation therapy and chemotherapy have led to better treatment outcomes with around two 
thirds of patients being long-term survivors (Grondin, 2009; Hummel, 2013; Cage 2012; Gerber, 
2014); however, some tumor types remain a challenge. 
Surgical resection, with the aim of achieving a gross total resection (GTR), defined as > 90% 
resection, is usually the initial treatment approach.  Surgical resection has shown to be one of the 
most important prognostic factors, irrespective of age, location, or histology. Surgery alone is 
curative for some completely resected tumors; however, GTR is not always achievable due to 
tumor location or involvement of critical structures (Grondin, 2009; Hummel, 2013).  Therefore, 
depending on tumor location, GTR must be balanced against the development of disabling 
neurologic deficits (Grondin, 2009; Hummel, 2013).  
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
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Confidential and Proprietary
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Radiation therapy is a standard adjuvant to surgical resection in children older than 3 years, and 
has been shown to reduce the risk of recurrence.  However, treatment-related toxicity often has a 
major impact on long-term quality of survival particularly in younger children and those with 
neurofibromatosis type-1.  Radiation is often associated with an increase in long-term 
morbidities including intellectual impairment, impaired growth, endocrine abnormalities, 
vascular injury and second malignancies.  Because the impact of these factors (especially 
intellectual impairment) is particularly severe in very young children, irradiation is usually 
delayed or avoided in younger children (Grondin, 2009; Hummel, 2013; Heath, 2012; Cage 
2012).  
Many children have disease recurrence or progression, require multiple sequential therapies, and 
suffer significant treatment-related toxicities. Novel approaches, including noncytotoxic 
therapies and targeted therapies, offer the potential for improved outcomes in these patients. 
Most recently, a number of immune modulating therapies have been explored in both pediatric 
and adult malignancies, including CNS tumors (Grothey, 2012; Gururangan, 2012; Gururangan 
2010). The immunomodulatory compounds (IMiDs®) are a group of drugs with structural 
characteristics similar to thalidomide. These agents, which also include lenalidomide and 
pomalidomide, have multiple pharmacologic properties and potential antitumor effects including 
antiangiogenesis, immune-modulation, anti-inflammatory properties and cytotoxic activity. The 
complete and exact antitumor mechanisms of action are unclear and may be multipronged and 
disease-dependent (Li, 2010).  The immunomodulatory compounds have shown significant 
efficacy in patients with multiple myeloma (MM) and myelodysplastic syndrome (MDS), and 
their activity against hematologic and non-hematologic malignancies, autoimmune diseases, and 
fibrotic disorders are being evaluated due to their tolerability, multiple mechanisms of action and 
efficacy data in a variety of tumor models and patients.
1.2.
Pomalyst® (Pomalidomide) Background
Pomalidomide (CC-4047) (Pomalyst) is the third member of a series of drugs known as 
immunomodulatory compounds, which also include thalidomide and lenalidomide. 
Pomalidomide was granted accelerated approval by the Food and Drug Administration (FDA) on 
08 Feb 2013, for the treatment of adult patients with MM who have received at least two prior 
therapies including lenalidomide and bortezomib and have demonstrated disease progression on 
or within 60 days of completion of the last therapy.  A new marketing authorization application 
(MAA) for pomalidomide, later changed to Imnovid, was also approved in the European Union 
(EU) on 05 Aug 2013 in combination with low-dose dexamethasone for the treatment of adult 
patients with relapsed and refractory MM who have received at least 2 prior treatment regimens, 
including both lenalidomide and bortezomib, and have demonstrated disease progression on the 
last therapy. Imnovid was first launched in the EU in September 2013. Imnovid has also been 
approved with the same indication in Iceland and Norway.  As of 07 Aug 2017, pomalidomide is 
approved in 65 countries worldwide: 28 countries in the EU, 3 countries in the European 
Economic Area (EEA) outside of the EU, and 34 countries outside of the EEA.
A pomalidomide formulation for constitution to oral suspension has been developed for use in 
clinical trials.  The oral suspension is available for use in subjects who are unable to swallow the 
capsules or at the discretion of the Investigator. The oral suspension of pomalidomide is not 
approved by any regulatory agency worldwide for any indication.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
20
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile of 
pomalidomide.
1.2.1.
Pomalidomide Mechanism of Action
Pomalidomide has several potential antitumor mechanisms.  Its exact antitumor mechanism may 
be disease-specific, although this is not entirely clear.  Pomalidomide has in vitro and in vivo 
antiproliferative and antineoplastic activity against hematologic B cell malignancies such as MM 
and non-Hodgkin’s lymphoma (NHL).  Pomalidomide is directly tumoricidal for MM cells and it 
also has immunomodulatory activity with direct effects on T and natural killer (NK)-mediated 
immunity.  Pomalidomide’s pleiotropic activities in a range of cell types including MM cells and 
immune effector cells suggests the existence of multiple molecular targets and downstream 
modulation of multiple molecular pathways.  The possibility exists that a common molecular 
mediator present in various cell types that is proximal to the downstream modulation of multiple 
signaling pathways is involved in the inhibition of proliferation and induction of apoptosis in 
tumor cells and in the activation of immune effector cells.  One such molecular target is cereblon 
(encoded by the CRBN gene), a protein that forms a ubiquitin E3 ligase complex with DNA 
damage-binding protein 1 (DDB1), cullin 4 (CUL4) and protein Roc1.  Pomalidomide binding to 
cereblon induces the polyubiquitination of two substrate proteins – Ikaros (encoded by the gene 
IKZF1) and Aiolos (encoded by the gene IKZF3) (Gandhi, 2014; Kronke, 2014; Lu, 2014), 
which are key transcription factors regulating immune cell development and homeostasis (John, 
2011).  This pomalidomide-induced ubiquitination targets these substrates for destruction by the 
proteasome resulting in enhanced production of interleukin (IL-2) and other cytokines known to 
regulate T cell function (Gandhi, 2014; Kronke, 2014; Lu, 2014).  In activated human T cells in 
which cereblon was transiently decreased, IL-2 and tumor necrosis factor-alpha (TNF-α) 
induction by pomalidomide was markedly reduced.  Since IL-2 and TNF-α are important for 
tumor surveillance by activated T cells, these results indicate that some of the 
immunomodulatory effects of pomalidomide are mediated via initial binding to cereblon.  
Therefore, the pomalidomide-induced reduction in Ikaros and Aiolos levels represents one 
possible mechanism for the pharmacological effects of pomalidomide, although other 
mechanisms may also play a role.  
The activity of pomalidomide is cell type- and context-dependent (Bartlett, 2004; Davies, 2001; 
Dredge, 2002; Escoubet-Lozach, 2009; Teo, 2005; Xu, 2009).  Activities include effects on the 
cell cycle such as G0/G1 arrest associated with the upregulation of the cyclin-dependent kinase 
(CDK) inhibitor p21WAF-1(Escoubet-Lozach, 2009), downregulation of the expression of 
interferon regulatory factor 4 (IRF4) in MM cell lines (Li, 2011), and modulation of Rho 
guanosine-5'-triphosphate binding and hydrolyzing enzymes, which are critical for actin 
hyperpolymerization and immune synapse formation (Xu, 2009).
It has become clear that inflammation plays an important role in the pathogenesis of many 
diseases, including cancer.  Pomalidomide has numerous anti-inflammatory effects, including 
enhancing T cell and NK cell-mediated immunity and inhibition of pro-inflammatory cytokine 
production (eg, TNF-α and IL-6) by peripheral blood mononuclear cells. Pomalidomide 
augments T helper cell type 1 (Th1) (cell-mediated), and inhibits Th2 (humoral-mediated) T cell 
responses.  Pomalidomide enhances T cell proliferation and production of the Th1 cytokines IL-2 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
21
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
and interferon-gamma (IFN-γ) by freshly isolated human peripheral T cells in vitro (Reddy, 
2008; Corral, 1999). 
Pomalidomide also inhibits angiogenesis by blocking the migration and adhesion of endothelial 
cells.  Angiogenesis plays an important role in the growth and progression of hematopoietic and 
solid tumors and depends on proper activation, proliferation, adhesion, migration, and maturation 
of endothelial cells in order to form functional vessels.  In vitro, pomalidomide inhibited 
umbilical cord microvessel formation as well as the vascular endothelial growth factor (VEGF)-
induced endothelial cord formation (Payvandi, 2005; Lu, 2009).  Furthermore, pomalidomide
inhibited endothelial cell invasion (through fibronectin-coated membranes) toward VEGF, basic 
fibroblast growth factor (β-FGF), transforming growth factor alpha (TGF-α), and TNF-α, 
suggesting that the pomalidomide antiangiogenic activity is in part due to inhibition of 
endothelial cell migration (Dredge, 2002).
1.2.2.
Pharmacokinetics and Pharmacodynamics of Pomalidomide
1.2.2.1.
Pharmacokinetics in Adults
Pomalidomide has been evaluated with respect to its absorption, distribution, metabolism and 
elimination characteristics.  Pomalidomide was absorbed in healthy subjects under fasting
conditions at single, orally administered doses of 0.5 mg to 50 mg with a maximum plasma 
concentration (Cmax) at a median time to maximum plasma concentration (Tmax) of approximately
3 hours postdose at clinically relevant doses.  The systemic exposure of single dose 
pomalidomide as determined from the area under the plasma concentration-time curve (AUC0-tz
and AUC0-∞) increased in an approximately dose-proportional manner, whereas Cmax increased in 
a proportional manner over 0.5 mg to 2 mg and in a less than dose proportional manner over the
1 mg to 50 mg dose range.  Exploratory analysis suggests absorption rate decreases at doses 
greater than 10 mg.  Multiple dose exposure over the 0.5 mg to 2 mg dose range was 
approximately dose proportional, with pomalidomide reaching steady-state by Day 3.
Pomalidomide was evaluated for potential food effect interaction as a capsule formulation that 
was used during development but not commercialized.  The effect of food, such as a high-fat
meal, was evaluated with that formulation in a single dose study in healthy subjects according to 
the appropriate FDA Guidance “Guidance for Industry Food-Effect Bioavailability and Fed 
Bioequivalence Studies” December 2002. The median Tmaxobserved in the fed state was 
approximately 3 hours later than that observed in the fasted state.  Exposure to pomalidomide 
was slightly decreased with food.  The mean ratio estimates for Cmaxand AUC0-twere 75.6% and 
91.5% in the fed state relative to the fasted state, respectively.  The mean plasma terminal 
elimination half-life (t1/2)of pomalidomide was not affected by food administration.  In 
summary, a high-fat meal decreased the rate of absorption but had minimal effect on overall 
extent of absorption; therefore, pomalidomide can be administered without regard to food intake.
The distribution of pomalidomide to brain has been characterized in mice and rats.  An oral 
administration of pomalidomide to mice and rats resulted in pomalidomide brain to plasma/blood 
ratios ranging from 0.39 to 0.49, indicating adequate pomalidomide distribution into the brain 
(Report AP1505/AP1506).  The distribution of pomalidomide has been characterized in humans 
with a mean volume of distribution (Vd/F) (coefficient of variation %) of pomalidomide in 
healthy subjects after a single dose ranging from 74 L (20%) to 138 L (30%) across a dose range 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
22
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
of 1 mg to 10 mg daily.  Pomalidomide distributes into semen, with a geometric mean 
concentration of 16.4 ng/mL at 4 hours postdose after 4 daily doses of 2 mg. This value was 
approximately 67% of pomalidomide plasma concentration observed at the same time point on 
Day 5 (ie, 24.5 ng/mL).  In vitro data indicate that pomalidomide protein binding in human 
plasma was low to moderate (15.8% for R-enantiomer, 42.2% for S-enantiomer) and the binding 
was concentration independent.
The metabolism of pomalidomide has been evaluated both preclinically and in healthy human 
subjects.  In vitro, pomalidomide (up to 30 μM) did not inhibit cytochrome P450 (CYP) 1A2, 
2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5 activities in human liver microsomes.  
Treatment of cultured human hepatocytes with up to 3 μM pomalidomide twice daily for 3 
consecutive days had little inductive effect on the enzymatic activities of CYP1A2, CYP2B6, 
CYP2C9, CYP2C19 and CYP3A4/5.  In transporter-expressing cells, pomalidomide had little to 
no inhibitory effects on P-glycoprotein, breast cancer resistant protein, organic anion transporter 
(OAT)1, OAT3, OATP1B1, OATP1B3 or organic cation transporter (OCT)2.  When evaluated 
in the human absorption, distribution, metabolism, and excretion study, eight metabolites were
detected in plasma, each at exposures < 10% of the plasma pomalidomide.  The metabolites 
observed were formed primarily via hydroxylation with subsequent glucuronidation or 
hydrolysis of the parent compound.  CYP-dependent metabolites accounted for approximately
43% of the excreted radioactivity, while non-CYP-dependent hydrolytic metabolites accounted
for 25%, and excretion of unchanged pomalidomide accounted for 10%.
The elimination of pomalidomide occurs predominantly through renal excretion (~73% of the 
administered dose), with < 3% of the administered dose excreted in urine as unchanged 
pomalidomide across all dose levels.
Pomalidomide has been evaluated for potential drug interaction effects in healthy subjects. 
Pomalidomide is partly metabolized by CYP1A2 and CYP3A4/5 and is also a substrate for 
P- glycoprotein. In CC-4047-CP-008 study, co-administration of pomalidomide with the strong 
CYP3A4/5 and P-glycoprotein inhibitor “ketoconazole”, or the strong CYP3A4/5 inducer 
“carbamazepine”, had no clinically relevant effect on exposure to pomalidomide. Co-
administration of a strong CYP1A2 inhibitor (fluvoxamine) with pomalidomide in the presence 
of a strong CYP3A4 inhibitor (ketoconazole) approximately doubled the mean exposure to 
pomalidomide compared to pomalidomide with ketoconazole alone.  In this study, co-
administration with moderate to strong CYP1A2 inhibitors (eg, ciprofloxacin, enoxacin, 
fluvoxamine, etc) are not permitted due to the potential drug interactions with pomalidomide.  
Subjects taking a known moderate to strong CYP1A2 inhibitor are excluded.  
1.2.2.2.
Pharmacokinetics in Pediatric Populations
A Phase 1, dose escalation trial of pomalidomide in pediatric subjects with recurrent, refractory 
or progressive CNS tumors performed within the PBTC (PBTC-043) is currently ongoing.  To 
date, pharmacokinetic (PK) data have been collected from 17 pediatric subjects.  In general, 
pomalidomide exposures for both AUC and Cmax appeared to increase in a dose dependent 
manner from 1.9 mg/m2 to 3.4 mg/m2. Mild to moderate between-subject variability was 
observed for both AUC and Cmax in pediatric subjects.  Preliminary PK data analyses suggest that 
the clearances (CL/F) in pediatric subjects correlate with body surface area, body weight, and 
age.  
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
23
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
1.2.3.
Adult Clinical Trials of Pomalidomide
Pomalidomide has been studied in adult hematologic malignancies and solid tumors as part of 
Celgene-sponsored and Investigator initiated trials (IITs).  The majority of the current safety and 
efficacy profile has been generated on studies in the approved indication, relapsed and/or 
refractory MM.  As of 07 Feb 2016, approximately 41,000 patients are estimated to have 
received 1 or more doses of pomalidomide ranging from 0.5 mg to 50 mg in clinical studies and 
the commercial setting.
Pomalidomide was well tolerated in Phase 1 studies in healthy volunteers at doses of up to 
50 mg. All AEs were considered by the Investigators to be mild or moderate in severity and 
there was no discernible trend in type of AE.  Overall, the healthy subject studies did not result in 
any new safety signals.
Pomalidomide was generally well tolerated in solid tumor studies, including studies in small cell 
lung cancer, castration-resistant prostate cancer, soft tissue sarcomas, pancreatic cancer and 
advanced solid tumors, with no significant safety findings (Amato, 2011; Ellis, 2013).
The most frequently occurring treatment emergent adverse events (TEAEs) across clinical 
studies (in hematologic and solid tumors) were fatigue, anemia, and neutropenia, except for 
study in patients with myelofibrosis (MF), where the most frequently reported TEAE in 
pomalidomide-treated subjects was peripheral edema.  Other less frequently occurring TEAEs 
observed in the majority of studies were constipation, nausea and dyspnea.  The most frequently 
occurring Grade 3 or 4 TEAEs across studies were neutropenia, thrombocytopenia, and anemia.  
As shown in a Phase 1 study (Richardson, 2013), the incidence of Grade 3 or 4 neutropenia in 
subjects with relapsed and refractory MM appeared to have a relationship to the dose of 
pomalidomide.  In this study, Grade 4 neutropenia was managed by dose reductions and/or 
interruptions and growth factor support (granulocyte colony-stimulating factor [G-CSF]
treatment).
Across most of the completed studies of efficacy and safety, serious adverse events (SAEs) were 
reported by approximately 40% to 70% of subjects. Infections, particularly pneumonia, were the 
most frequently reported SAE in subjects across studies
Overall pomalidomide was tolerated at doses of up to 50 mg in a Phase 1 single-dose study, well 
tolerated when orally administered at doses of 1 mg and 2 mg daily in subjects with prostate 
cancer, up to 2 mg daily, 5 mg every other day, or 4 mg/day for 21 of 28 days in a multiple-dose 
study in subjects with relapsed or refractory MM, and at 0.5 mg daily in subjects with MF. Data 
from the ongoing studies are consistent with the completed studies and demonstrate that 
pomalidomide has an acceptable safety profile in the intended subject populations studied to 
date.
1.2.4.
Pediatric Clinical Trials of Pomalidomide
In the Phase 1 dose escalation trial of pomalidomide monotherapy in children with recurrent, 
progressive or refractory CNS tumors (PBTC-043), subjects were treated at doses levels of 
1.9, 2.6 and 3.4 mg/m2/day on Days 1 through 21 of a 28-day cycle.  The maximum tolerated 
dose (MTD) of 2.6 mg/m2/day was reached with 3 subjects experiencing a total of 4 dose 
limiting toxicities (DLTs) at the 3.4 mg/m2/day dose level. These DLTs included Grade 4 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
24
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
absolute neutrophil count (ANC) decrease ≥ 5 days during treatment rest period, Grade 3 
diarrhea, Grade 3 platelet count decrease and Grade 3 lung infection.  
The main toxicity (most commonly reported Grade 3/4 AE) associated with pomalidomide 
treatment was myelosuppression (decreased neutrophils, platelets, lymphocytes and anemia).  
Myelosuppression is a known adverse effect of pomalidomide treatment and can be managed 
effectively with supportive care.  Myelosuppression was also the main toxicity observed in the 
Phase 1 studies of lenalidomide in children with CNS tumors (Warren, 2011; Berg, 2011).  The 
majority of cases observed during the PTBC-043 study resolved without sequelae. 
Per protocol, expansion cohorts were initiated with further enrollment at the MTD stratified 
based on age (< 12 years vs. ≥12 years) and steroid use (not on steroids [or on physiologic doses 
alone] vs. those taking therapeutic doses of steroids).  No excessive toxicities or unexpected 
safety concerns have further been identified.  One subject in the expansion cohort experienced a 
DLT of Grade 4 platelet count decrease; however, per protocol, the criteria for modifying the 
already identified MTD was not reached. This study is currently ongoing. 
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
Although the prognosis for pediatric patients with brain tumors has improved over the last few 
decades with diverse intensive therapeutic modalities such as neurosurgery, chemotherapy and 
radiation, many brain tumors remain difficult to treat and are associated with a poor prognosis.  
Overall, brain tumors are still the leading cause of cancer morbidity and mortality among 
children.  Therefore, alternative therapeutic strategies are desperately needed and pomalidomide 
is considered to be well suited to treat pediatric brain tumors given its multi-modal mechanism of 
action and seeming ability to cross the blood-brain barrier.
Pomalidomide can cross the blood-brain barrier
Central nervous system tumors may have a specialized immunobiology that allows evasion of 
immune clearance and promotion of tumor growth, and the tissue milieu within which a CNS 
tumor grows may be especially important in supporting this immunobiology.  This immunology 
of the CNS excludes or attenuates effective immune responses in malignancies, which may 
contribute to resistance to standard radiation and chemotherapy.  The presence of the blood-brain 
barrier limits the CNS penetration of many chemotherapeutic agents and although it does not 
block lymphocytes or myeloid cells from migrating to sites of inflammation or tumor growth, 
these components of the immune system are ineffective in producing an immune response thus 
maintaining the “immune privilege” status of the CNS (Johnson, 2012).  Pomalidomide has been 
shown to have moderate CNS penetration in murine models of CNS lymphoma with significant 
therapeutic activity and a major impact on the CNS tumor microenvironment (Li, 2013).  
Approximately 39% of systemically administered pomalidomide penetrated the CNS.  These 
data indicate that pomalidomide may be suitable for treatment of primary CNS tumors and brain 
metastases.  Consistent with this, there are clinical reports in adults demonstrating 
pomalidomide’s effectiveness against myeloma meningitis and CNS myelomatosis, again 
suggesting adequate CNS penetration and efficacy within the CNS (Gertz, 2013; Mussetti, 
2013).  
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
25
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Pomalidomide has anti-angiogenic properties
Angiogenesis plays a role in tumor growth and metastases in CNS tumors (Sie, 2014).  Pediatric 
brain tumors have previously been shown to possess significant neovascularization and can 
produce potent angiogenic factors (Ozer, 2004; Sie, 2014).  Many of the common histologies 
among pediatric brain tumors, such as embryonal tumors (medulloblastoma, atypical teratoid 
rhabdoid tumor [ATRT], low grade-gliomas, and high-grade gliomas exhibit significant 
angiogenic activity.  Similar to other tumors, pediatric brain tumors secrete cytokines with 
varying angiogenic properties, such as acidic and basic fibroblastic growth factor (α, β-FGF), 
angiogenin, TNF-α, and VEGF, which assist in cell proliferation, metastases and survival.  
Alternatively, tumor cells can release angiogenic peptides through the production of proteases 
and the subsequent breakdown of the extracellular matrix where some cytokines are stored (ie, β-
FGF).  Angiogenesis can also be induced indirectly through the recruitment of inflammatory 
cells (particularly macrophages) and their subsequent release of angiogenic cytokines (ie, TNF-α, 
β-FGF) (Jain, 2007).  Pomalidomide has demonstrated antiangiogenic activity (Section 1.2.1), 
which makes it an ideal candidate for treating pediatric brain tumors.
Lenalidomide (related agent) is well tolerated in children with brain and solid tumors 
A pediatric Phase 1 study of lenalidomide was performed within the Children’s Oncology Group 
(COG) in subjects with relapsed or refractory solid tumors or MDS (ADVL0319) (Berg, 2011).  
The primary objectives were to determine the MTD or the recommended Phase 2 dose (RP2D)
for children with refractory solid tumors and describe the toxicities in this population.  Forty-
nine subjects treated at doses up to 70 mg/m2/day x 21 days followed by a 7-day rest were 
evaluated.  Although 6 episodes of DLTs were observed, the DLTs were sporadic and not clearly 
associated with dose.  These DLTs included Grade 3 hypercalcemia, Grade 3 hypophosphatemia, 
Grade 3 hypokalemia, Grade 4 neutropenia, Grade 3 somnolence, and Grade 3 urticaria 
occurring at doses ranging from 15 mg/m2 to 55 mg/m2.  The MTD was not reached.  No 
objective responses were observed; however, there was evidence of immunomodulatory activity 
of lenalidomide with a significant increase in serum IL-2, IL-15, granulocyte-macrophage 
colony-stimulating factor, NK cells, NK cytotoxicity, and lymphokine activated killer 
cytotoxicity, and a significant decrease in CD4+/CD25+ regulatory T cells.
A Phase 1 trial of lenalidomide in pediatric subjects with recurrent, refractory or progressive 
CNS tumors was performed within the PBTC (PBTC-018) (Warren, 2011).  Fifty-one subjects 
were enrolled; 44 subjects were evaluable for toxicity and response.  Subjects were treated at 
doses levels of 15, 20, 25, 32, 40, 52, 68, 88, 101 and 116 mg/m2/day for Days 1 through 21 of a 
28-day cycle.  A MTD was not reached and lenalidomide was relatively well tolerated.  Two 
DLTs were reported with an unclear association with lenalidomide.  One subject treated at the 
20 mg/m2/day dose level experienced a cardiac DLT with a presumed myocardial infarct and 
elevated troponin; however, this subject was subsequently found to have had multiple risk factors 
for thromboembolism.  One subject at a dose level 68 mg/m2/day had dose-limiting fatigue 
associated with concurrent disease progression.  Twenty-three subjects representing all dose 
levels received 6 or more cycles of treatment and 9 subjects have received 12 or more cycles. 
In the PBTC-018 study (Warren, 2011), myelosuppression was the primary toxicity and occurred 
sporadically.  No subject had Grade 4 myelosuppression during Cycle 1.  Myelosuppression for 
subjects treated for ≥ 6 cycles was also sporadic and not clearly associated with dose although 
data at the higher dose levels (≥ 68 mg/m2/day) showed a possible trend toward more frequent 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
26
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
episodes of Grades 3 and 4 myelosuppression.  Other common toxicities included fatigue (30%), 
gastrointestinal symptoms including nausea (10%), emesis (4%), diarrhea (16%), and 
constipation (8%), as well as rash (14%) and muscle cramping (10%).  In this study, it was 
unclear if responses were dose-related.  Objective responses (two partial responses) were 
reported; one in a subject diagnosed with PA treated with 88 mg/m2/day for 18 cycles and 
another subject diagnosed with optic pathway glioma treated with 116 mg/m2/day for 11 cycles. 
Long-term stable disease (SD; SD sustained for ≥6 cycles), particularly in patients with low 
grade glioma, was observed in 52% of patients.  Of note, the 12-month PFS rate for patients with 
low grade glioma was 67%.  Results from PK analysis show that the lenalidomide AUC and Cmax
increased with dosage over the range studied.  The median lenalidomide plasma t1/2 and apparent 
oral clearance were 2.5 hours (range, 0.9 to 4.2 hours) and 11.4 L/h/m2 (range, 5.1 to 33.9 
L/h/m2), respectively. 
Based on the apparent activity profile of lenalidomide in children with low-grade gliomas 
enrolled in the pediatric Phase 1 study (PBTC-018), a Phase 2 trial (ACNS1022) of lenalidomide 
monotherapy in PA and optic pathway gliomas was initiated. This study compares low dose 
(20 mg/m2/day) with high dose (115 mg/m2/day) lenalidomide.  A planned interim analysis for 
futility and efficacy, evaluating both objective responses and PFS, was performed after the first 
20 subjects were enrolled in each arm.  Both arms met the criteria for continued accrual and this 
study is currently ongoing.  
Pomalidomide is a more potent antiproliferative and immunomodulating agent than 
lenalidomide
Although there is overlap between pomalidomide and lenalidomide in terms of pharmacologic 
effects, there are data suggesting that they may also have different targets.  Notably, 
pomalidomide has demonstrated activity in lenalidomide-resistant cell lines and in adult patients 
with MM refractory to lenalidomide treatment, suggesting unique targets and properties between 
these two agents (Li, 2010; Lopez-Girona, 2012; Cooney, 2012; Schey, 2011; Richardson, 2014).  
In addition, pomalidomide exhibits greater potency than lenalidomide in anti-proliferative 
effects, augmentation of CD4+ and CD8+ T cell proliferation, Th1 cytokine production and NK
T cell activation (Corral, 1999; Muller, 1999).  These differences allow the administration of 
pomalidomide at relatively lower doses compared with lenalidomide in adult patients with MM
and may allow for lower therapeutic doses in pediatric patients as well.
1.3.2.
Rationale for the Study Design
This is a Phase 2, multicenter, open-label, parallel-group study that will assess the efficacy, 
safety and tolerability of pomalidomide in children and young adults with recurrent or 
progressive brain tumors.  
The proposed age groups to be studied are subjects 1 to < 21 years of age.  Subjects < 1 years of 
age are more likely to be undergoing first line therapy for their brain tumors, are less likely to 
have already experienced recurrence or progression of disease, have a rapidly developing 
immune system and tolerability of pomalidomide is unknown.  The upper age limit was selected 
because the treatment options and number of clinical trials for young adult subjects between 18-
21 years of age are limited due to the significant differences in histologic subtypes and biology
of brain tumors between these subjects and younger children or adults (Bleyer, 2004). In the 
absence of treatment options tailored for adolescents and young adults with brain cancer, 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
27
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
treatments used in younger children tend to have improved efficacy when treated with pediatric 
based regimens rather than those designed for adults.  
A Simon’s Optimal two-stage study design will be applied across the strata (Section 3.1),
conducted in parallel. The design was chosen to limit subject’s exposure to pomalidomide in 
each group prior to confirmation of preliminary efficacy and enrollment of additional subjects 
into that tumor type cohort. Objective response (OR; either complete response [CR] or partial 
response [PR]) rate (ORR) and long-term SD (SD maintained for ≥ 6 cycles [> 3 cycles for 
DIPG]) rate will be evaluated as a combined endpoint for defining antitumor activity in each 
stage. Long-term SD was chosen to be included since it has been reported to correlate with OS
(Warren, 2013).
This study design will provide further information on the antitumor activity and safety of 
pomalidomide in children and young adults and establish if any of these brain tumors are 
sensitive to pomalidomide and should be further explored.
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
In the Phase 1 study conducted by the PBTC (PTBC-043), pomalidomide dose was escalated to 
establish the MTD in children with histologically confirmed diagnosis of recurrent, progressive 
or refractory CNS tumors.  Subjects were treated at dose levels of 1.9, 2.6 and 3.4 mg/m2/day on 
Days 1 through 21 of a 28-day cycle.  A MTD of 2.6 mg/m2/day was reached with three subjects 
each experiencing one DLT at the 3.4 mg/m2/day dose level.  The MTD of 2.6 mg/m2/day is 
comparable to the FDA-approved adult dose (4 mg/day) of pomalidomide taken orally on Days 
1-21 of a 28-day cycle, assuming an average adult body surface area (BSA) of 1.7 m2 (4 mg/1.7 
m2 = 2.35 mg/m2).
The starting dose in this Phase 2 study will be 2.6 mg/m2/day on Days 1 to 21 of a 28-day cycle. 
Four consecutive weeks will constitute one cycle and subsequent cycles will immediately follow 
as long as criteria to continue pomalidomide therapy are met. A cycle may be repeated every 
28 days, for up to 24 cycles or until documented progressive disease (PD), withdrawal of 
consent/assent, treatment becomes intolerable or death, whichever comes first.  
Dosing will be based on the subject’s actual BSA calculated at the beginning of each cycle of 
therapy. 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
28
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective(s)
The primary objective of the study is:
!
To identify potential tumor type(s) for further development by establishing the preliminary efficacy 
of pomalidomide in children and young adults with recurrent or progressive primary brain tumors 
within four distinct tumor types.
Secondary Objective(s)
The secondary objectives are:
!
To evaluate the safety (type and rate of treatment-related toxicity) of pomalidomide within the 
study populations. 
!
To estimate the long-term efficacy of pomalidomide treatment.
Exploratory Objective(s)
The exploratory objectives are:
!
To assess the PK of pomalidomide in children and young adults with recurrent or progressive 
primary brain tumors.
PK= Pharmacokinetics.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
29
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary
Objective response and 
long-term stable disease 
rate
Total number of subjects 
achieving an OR (either CR or 
PR) or a long-term SD under
study treatment, among total 
subjects evaluable for analysis 
per stratum 
Cycle 1, Day 1 to 
completion of Cycle 6
(completion of Cycle 3 
for DIPG)
Secondary
Objective response rate
Total number of subjects 
achieving an OR (either CR or 
PR) under study treatment, 
among total subjects evaluable 
for analysis per stratum
Cycle 1, Day 1 of 
Treatment Period to end 
of Follow-up Period
Long-term stable disease 
rate
Total number of subjects 
achieving a long-term SD under 
study treatment, among total 
subjects evaluable for analysis 
per stratum
Cycle 1, Day 1 to 
completion of Cycle 6 
(completion of Cycle 3 
for DIPG)
Duration of response
The time from first achievement 
of CR or PR under study 
treatment, whichever occurs 
first, until first documentation 
of progressive disease (PD) or 
death of any cause
Cycle 1, Day 1 of 
Treatment Period to end 
of Follow-up Period
Progression-free survival 
The time from enrollment until 
first documentation of PD 
and/or death of any cause
Cycle 1, Day 1 of 
Treatment Period to end 
of Follow-up Period
Overall Survival 
The time from enrollment until 
death of any cause
Cycle 1, Day 1 of 
Treatment Period to end 
of Follow-up Period
Safety 
Type, frequency, and severity 
of AEs and relationship to study 
drug 
Signing of informed 
consent form 
(ICF)/informed assent 
form (IAF) until the end 
of Follow-up Period
Exploratory
Pomalidomide PK 
Plasma PK parameters (eg, 
pomalidomide apparent 
clearance and volume of 
distribution) 
Cycle 1: Days 8 and 15 
AEs = adverse events; CR= complete response; DIPG = diffuse intrinsic pontine glioma; IAF = informed assent 
form; ICF = informed consent form; OR = objective response; PD = progressive disease; PK = pharmacokinetic; 
PR= partial response; SD = stable disease. 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
30
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 2 multi-center, open-label, parallel-group study that will assess the efficacy, 
safety and tolerability of pomalidomide in children and young adults aged 1 to < 21 years with 
recurrent or progressive primary brain tumors after at least one prior standard therapy.  
The study will consist of 4 parallel strata, one for each of the following primary brain tumor 
types: high-grade glioma, medulloblastoma, ependymoma and DIPG.  A Simon’s Optimal two-
stage study design will be applied to each stratum and enrollment will occur as follows:
!
Stage 1: Nine subjects will be enrolled.
!
Stage 2: If during Stage 1, ≥ 2 subjects achieves either an OR (either CR or PR)
within the first 6 cycles of treatment (within first 3 cycles for DIPG), or a long-term 
SD, an additional 11 subjects shall be enrolled; otherwise no additional subjects will 
be enrolled into that stratum.
!
If a total of 5 or more subjects across all 20 subjects in a given stratum (Stage 1 and 
2) evaluable for the primary endpoint are observed as having either an OR (either CR 
or PR) within the first 6 cycles of treatment (within first 3 cycles for DIPG) or a long-
term SD, pomalidomide will be considered effective in that disease indication.
Subjects who withdraw from either stage for reasons other than PD prior to completing Cycle 1 
of study treatment will be replaced.  Subjects completing at least one cycle of study therapy but 
not having at least one post-baseline disease assessment will be considered a non-responder.  
The study will have the following sequential periods for all subjects (Figure 2): Screening Period
(Section 6.1), Treatment Period (Section 6.2) and Follow-up Period (Section 6.3).  Upon 
enrollment, subjects will receive oral pomalidomide for the first 21 days, followed by a 7-day 
rest period, of each 28-day treatment cycle for up to 24 cycles or until documented PD, 
withdrawal of consent/assent, treatment becomes intolerable or death, whichever occurs first. 
Radiographic response (brain and spine) will be assessed by MRI with and without contrast (ie, 
gadolinium). Brain MRI assessments will be conducted during screening (within 21 days prior 
to first dose of study treatment) and then on Day 1 of Cycles 3, 5, 7, 10, 13, 16, 19, 22 (or within 
7 days prior to dosing), after completion of Cycle 24 (or within 7 days prior) and as clinically 
indicated.  Note: For DIPG subjects only, post-baseline brain MRI assessments will be 
performed on Day 1 of Cycles 4, 7, 10, 13, 16, 19, 22 (or within 7 days prior to dosing), after 
completion of Cycle 24 (or within 7 days prior) and as clinically indicated.  
Spine MRI will be also performed during screening (within 21 days prior to first dose of study 
treatment) for all subjects.  If no spinal or leptomeningeal disease is present at screening, 
subsequent spine MRIs will be obtained on Day 1 of Cycles 7, 13, 19 (or within 7 days prior to 
dosing) after completion of Cycle 24 (or within 7 days prior) and as clinically indicated.  If there 
is spinal or leptomeningeal disease present at screening/baseline, spine MRIs will be obtained at 
the same time points as the brain MRI as specified above.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
31
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
A response assessment should also be performed at EOT visit if the subject has discontinued for 
reasons other than progression of disease and it has been more than 8 weeks since their most 
recent scan/response assessment.
Response evaluations will be performed locally and by independent central reviewer according 
to criteria detailed in Section 6.4.1.  
Subjects who discontinue treatment will enter a Follow-up Period which will continue every 
3 months (± 14 days) for up to 5 years from enrollment of the last subject, unless consent/assent
is withdrawn, the subject is lost to follow-up or dies.  Subjects will be followed by phone or 
clinic visits for emergence of second primary malignancies (SPMs) (regardless of causal 
relationship), drug-related SAEs, survival status, and start of any new anticancer therapies.  
Additionally, subjects who discontinue treatment prior to progression will be followed with MRI 
tumor response disease assessments every 6 months from treatment discontinuation for the first 
year off treatment, then annually thereafter, until disease progression or until another anticancer 
therapy is started, whichever comes first.
An external data monitoring committee (DMC) (Section 9.9.2) with multidisciplinary 
representation will evaluate activity of the study treatment and safety data periodically to 
monitor benefit-to-risk of this protocol.  The function of the DMC is to monitor the safety and 
activity of the study treatment and to provide recommendations about the study continuation, as 
appropriate.  Details of the DMC structure, composition, and roles/responsibilities will be 
outlined within a DMC charter. 
The study will be conducted in compliance with the International Council on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
32
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Figure 1:
Simon’s Optimal Two-Stage Parallel Design
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
33
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Figure 2:
Overall Study Design
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
34
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
3.2.
Study Duration for Subjects
The Screening Period will start from the time of obtaining informed consent/assent and last no 
more than 28 days, at which time the Treatment Period will begin (Cycle 1 Day 1, first day of 
actual study drug administration).  Each subject shall receive treatment for up to 24 cycles or 
until documented PD, consent/assent is withdrawn, treatment becomes intolerable, or death, 
whichever occurs first.  Once treatment has been discontinued, subjects will enter into a Follow-
up Period with phone call/clinic visit every 3 months (± 14 days), for up to 5 years from 
enrollment of the last subject, unless consent/assent is withdrawn, the subject is lost to follow-up, 
or death.
Stage 1 portion of the study is expected to last up to approximately 18 months prior to reaching 
the decision point. The Stage 2 portion of the study is expected to last up to approximately 27
months should all strata enroll the maximum number of subjects and assuming no subjects are 
replaced.  
3.3.
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 and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
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as prespec


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
35
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
4.
STUDY POPULATION
4.1.
Number of Subjects 
The study population will consist of children and young adults aged 1 to < 21 years with 
recurrent or progressive primary brain tumors after at least one prior standard therapy, in 1 of 4
primary brain tumor types: high-grade glioma, medulloblastoma, ependymoma and DIPG.  
Eighty subjects (36 subjects in Stage 1 and 44 subjects in Stage 2) will be included should all 
strata enroll the maximum number of subjects and assuming no subjects are replaced.  
Approximately 80% of subjects across all strata will be < 17 years of age.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is 1 to < 21 years of age at the time of signing the ICF/IAF.
2. Subject (when applicable, parental/legal representative) must understand and voluntarily 
sign an ICF/IAF prior to any study-related assessments/procedures being conducted. 
Note: Adult individuals who lack capacity to consent for themselves will be excluded 
from the study.
3. Subject has received at least one prior standard therapy (or generally accepted upfront 
therapy if no standard exists) and have no known curative therapy. 
4. Subject has a diagnosis of high-grade glioma, medulloblastoma, ependymoma or DIPG 
that is recurrent or progressive with the primary location in the CNS. Subjects with 
neurofibromatosis type 1 (NF-1) associated tumors are eligible if the meet all other 
eligibility criteria. 
5. Subject has histological verification of tumor either at the time of diagnosis or recurrence. 
Subjects with DIPG are exempt from histologic verification if they have typical MRI 
findings of DIPG (ie, hypo- or isointense on T1-weighted imaging, hyperintense on fluid-
attenuated inversion recovery (FLAIR) or T2-weighted imaging, epicenter in the pons, 
> 50% of pons involved).
6. Subject has measurable disease (including subjects that have undergone a surgical 
resection prior to enrollment), defined as a primary brain tumor that is measurable in 2
perpendicular diameters on MRI.  For a lesion to be considered measurable, it must be at 
least twice the slice thickness on MRI (ie, visible on 2 or more axial slices). 
Note: MRI should be performed with cuts of 3 mm or less in slice thickness contiguously.  
Further details regarding MRI acquisition requirements are outlined in the Imaging 
Manual.
7. To document the degree of tumor at study baseline, the following scan(s) must be 
obtained:
!
A brain MRI for all subjects with and without contrast (ie, gadolinium) and a spine 
MRI with contrast (ie, gadolinium) within 21 days prior to first dose of study 
treatment.  For subjects on steroids, baseline MRI scans must be performed while on 
stable or decreasing dose of steroids for at least 5 days.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
36
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
8. Subject has Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status 
score ≥ 50 at screening (Appendix D).
9. Subject has adequate bone marrow function defined as:
!
Peripheral ANC ≥ 1000/mm3
!
Platelet count ≥ 100,000/mm3 (transfusion independent defined as no platelet 
transfusion within 7 days and recovery from nadir)
!
Hemoglobin ≥ 8 g/dL (red blood cell [RBC] transfusion is allowed)
10. Subject has adequate renal function defined as: 
Serum creatinine based on age/gender as described in Table 3.  Subjects that do not 
meet the criteria but who have a 24-hour creatinine clearance or radioisotope 
glomerular filtration rate (GFR) (radioisotope or iothalamate) ≥ 70 mL/min/1.73 m2
are eligible.
Table 3:
Serum Creatinine by Age and Gender
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
1 to <2 years
0.6
0.6
2 to <6 years
0.8
0.8
6 to <10 years
1
1
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 
(Schwartz, 1985) utilizing child length and stature data published by the Centers for Disease Control.
11. Subject has adequate liver function defined as: 
!
Total bilirubin ≤ 1.5 X upper limit of normal (ULN) for current age (≤ 3 X ULN if 
increase in bilirubin is attributable to Gilbert’s Syndrome)
!
Alanine aminotransferase (ALT) (SPGT) is ≤ 3 X ULN for age
!
Serum albumin ≥ 3 g/dL
12. Subject has adequate pulmonary function defined as:
!
No evidence of dyspnea at rest
!
A pulse oximetry ≥ 93% 
13. Subject has recovered from clinically significant acute treatment related toxicities from 
all prior therapies. Recovery is defined as a toxicity Grade ≤ 2 (common terminology 
criteria for adverse events [CTCAE] v. 4.03). 
14. Subject has no significant worsening in clinical status for a minimum of 7 days prior to 
first dose of study drug.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
37
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
15. Subject (and when applicable, with parental/legal representative) is willing and able to 
adhere to the study visit schedule and other protocol requirements.
16. Females of childbearing potential (FCBP), female children of childbearing potential 
(FCCBP), and male subjects who have reached puberty (and when applicable, with 
parental/legal representative) must agree to undergo physician-approved reproductive 
education and discuss the side effects of the study therapy on reproduction.
17. All subjects and/or parents/legal representative must have an understanding that 
pomalidomide 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 female who has achieved menarche at some point, 
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 agree and meet the following conditions below
(Note: amenorrhea following previous anticancer therapy does not rule out childbearing 
potential):
!
Medically supervised (ie, performed in a clinic) pregnancy tests with a sensitivity of 
at least 25 mIU/mL must be conducted in FCCBP/FCBP, including those who 
commit to true abstinence*.  Two pregnancy tests must be conducted prior to starting 
pomalidomide.  The first pregnancy test must be performed 10 to 14 days prior to the 
start of pomalidomide and the second pregnancy test must be performed within 24 
hours prior to starting pomalidomide.  
NOTE: The pregnancy test 10 to 14 days prior to initiation of pomalidomide may be 
omitted, at the discretion of the investigator, for any FCCBP/FCBP who has high 
acuity disease requiring immediate treatment with pomalidomide. The pregnancy test 
within 24 hours prior to the first dose of pomalidomide is required to be performed.
The subject may not receive pomalidomide until the Investigator has verified that the 
results of these pregnancy tests performed on Cycle 1, Day 1 are negative.  Female 
children of childbearing potential/females of childbearing potential with regular or no 
menstrual cycles must agree to have pregnancy tests weekly for the first 28 days
study participation, every 28 days while on study, at study treatment discontinuation 
visit, and at Day 28 following pomalidomide discontinuation.  If menstrual cycles are 
irregular, the pregnancy testing must occur weekly for the first 28 days of study 
participation and then every 14 days while on study, at study treatment 
discontinuation visit, and at Days 14 and 28 following pomalidomide 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 (ie, oral, injectable, 
or implantable hormonal contraceptive; tubal ligation; intrauterine device; 
vasectomized partner) and one additional effective barrier method (ie, male condom, 
diaphragm, cervical cap) 28 days prior to starting pomalidomide, throughout the 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
38
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
entire duration of study treatment including dose interruptions and 28 days after 
discontinuation of pomalidomide.
Note: Only a progestin-suppressing ovulation pill is acceptable as an oral 
contraceptive.  Copper intrauterine devices are not recommended.
!
All male and female subjects must follow all requirements defined in the 
pomalidomide Pregnancy Prevention Program.
18. Male subjects must, as appropriate to age and the discretion of the study physician:
!
Practice true abstinence* (which must be reviewed on a monthly basis) or agree to 
use a condom during sexual contact with a pregnant female or a FCBP while 
participating in the study, during dose interruptions and for at least 28 days following 
pomalidomide discontinuation, even if he has undergone a successful vasectomy or 
practices complete abstinence. 
*True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the 
subject.  Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) 
and withdrawal are not acceptable methods of contraception. 
19. For subjects screened/enrolled in France only: Subject must be affiliated with a Health 
Insurance Scheme or be a beneficiary of one.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has a history of non-central line related thrombosis (arterial or venous), more 
than one prior central-line related thrombosis (excluding small clots in central lines that 
are resolved with tissue plasminogen activator [tPA] flush) or known coagulopathy.
2. Subject has first degree family member with a known hereditary coagulopathy.
3. Subject is actively on anticoagulation therapy.
Note: The use of tPA to flush subject’s central-line is allowed.
4. Subject has had major (per Investigator discretion) surgery, with the exception of tumor 
resection, within 21 days from first dose of study drug.
5. Subject has previously received (presence of any of the following will exclude a subject 
from enrollment):
!
Any prior treatment with pomalidomide.  Subjects who have prior treatment with 
other immunomodulatory compounds (thalidomide, lenalidomide) ARE eligible if 
they meet all other eligibility criteria and did not have allergic reactions or other
“significant toxicity” per Investigator discretion associated with lenalidomide or 
thalidomide use.
!
Myelosuppressive chemotherapy, immunotherapy, or any investigational agent: 
≤21 days (≤ 42 days if a nitrosourea) prior to screening.
!
Biological (anti-neoplastic) therapy: ≤ 7 days prior to screening.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
39
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
Immunomodulatory therapy (ie, thalidomide, lenalidomide): ≤ 28 days prior to 
screening.
!
Monoclonal antibody treatment and agents with known prolonged half-lives: < 3 half-
lives have elapsed or ≤ 28 days prior to screening, whichever is longer.
!
Prior radiation: 
∀
Cranial irradiation, total body irradiation (TBI), or ≥ 50% radiation of pelvis: 
≤3 months prior to screening.
∀
Focal irradiation: ≤ 3 weeks prior to screening if radiation field involved a non-
target lesion; ≤ 6 weeks prior to screening if radiation field involved a target 
lesion.
Note: True disease progression following prior irradiation therapy must be confirmed 
by Investigator prior to screening.  
!
Bone marrow transplant:
∀
Presence of graft versus host disease (GVHD) 
∀
< 6 months since allogeneic bone marrow transplant prior to screening.
∀
< 3 months since autologous bone marrow/stem cell transplant prior to screening.
∀
< 3 months since stem cell transplant (SCT) or Rescue without TBI with no 
evidence of GVHD prior to screening.
!
Radioisotopes: fluorothymidine (18FLT) ≤ 72 hours prior to first dose of study drug
6. Subject has received therapy with a known moderate to potent CYP1A2 inhibitor within 
14 days or 5 half-lives of first dose of study treatment (whichever is longer). The treating 
Investigator should consult a current drug information reference for a complete list 
(http://medicine.iupui.edu/clinpharm/ddis/main-table/). 
7. Subject has received colony-stimulating growth factor(s) within 7 days prior to screening 
(or within 14 days if subject received polyethylene glycol formulations).
8. Subject is pregnant, breast-feeding or lactating. 
9. Subject has an untreated or uncontrolled infection defined as ongoing signs/symptoms 
related to the infection without improvement despite appropriate antibiotics, antiviral 
therapy and/or other treatment. 
10. Subject has active infectious hepatitis, type A, B, or C, or chronic carriers of hepatitis C.  
Note: Hepatitis B serological status must be known prior to enrollment.  If unknown at 
screening, a Hepatitis B serology test must be performed.
11. Subject has any prior history of malignancies, other than high-grade glioma, 
medulloblastoma, ependymoma or DIPG (Note: radiation-associated gliomas are 
excluded from enrollment)
12. Subject who, in the opinion of the Investigator, has any significant medical condition, 
laboratory abnormality, or psychiatric illness that would prevent the subject from 
participating in the study.
13. Subject has any condition including the presence of laboratory abnormalities which, in 
the opinion of the Investigator, places the subject at unacceptable risk if he/she were to 
participate in the study.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
40
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
14. Subject has any condition that confounds the ability to interpret data from the study.
15. Subject has symptomatic cardiac disorders (CTCAE v. 4.03 Grade 3 and 4)
&&,
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
41
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
5.
TABLE OF EVENTS
Table 4:
Table of Events 
Period
Protocol 
Reference 
Section
Screening 
Period
Treatment Periodb
Follow-up Periodb
Screening
a
Each 28-day Cycle
End of 
Treatment
(± 3 days)
28-Day Post 
Treatment
Safety 
Follow-Up
Long-Term
Follow-Up
(± 14 days)
Cycles 1 - 2
(± 3 days)
Cycles 3 - 12
(± 3 days)i
Cycles 13 - 24
(± 3 days)i
Day
-28 to 0
1
8
15
22
1
15
1
Study Entry and General Assessments
Obtain Informed Consent/Assent
13.3
X
-
-
-
-
-
-
-
-
-
-
Interactive Response Technology 
7.3
X
X
-
-
-
X
-
X
X
-
Enrollment 
6.1.5
-
Xo
-
-
-
-
-
-
-
-
-
Demographics
6.1.2
X
-
-
-
-
-
-
-
-
-
-
Inclusion/Exclusion Criteria
4.2, 4.3
X
Xo
-
-
-
-
-
-
-
-
-
Complete Medical History
6.1.3
X
-
-
-
-
-
-
-
-
-
-
Prior Disease Therapies and History
6.1.4
X
-
-
-
-
-
-
-
-
-
-
Prior/Concomitant Medication and 
Procedures
8.0
After signing ICF/IAF and until 28-day post-treatment Safety Follow-up Visit
-
Safety Assessments
Adverse Events 
10
After signing ICF/IAF and until 28-day post-treatment Safety Follow-up Visit
-
Assessment of Second Primary Malignancy 
6.4.2.10
After signing ICF/IAF and until end of Long-term Follow-up Visit
Physical Exam (including vital signs)
6.4.2.1
X
Xc
-
-
-
X
-
X
X
X
-
Pomalidomide Education and Counselingd
6.4.2.9
X
X
-
-
-
X
-
X
X
X
-
Height
6.4.2.2
X
X
-
-
-
X
-
X
X
X
-
Body Weight 
6.4.2.3
X
X
-
-
-
X
-
X
X
X
-
BSA calculation
6.4.2.4
X
X
-
-
-
X
-
X
-
-
-
Lansky/Karnofsky Performance Status
6.4.2.5
X
X
-
-
-
X
-
X
X
X
-
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
42
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 4:
Table of Events (Continued)
Period
Protocol 
Reference 
Section
Screening 
Period
Treatment Periodb
Follow-up Periodb
Screeninga
Each 28-day Cycle
End of 
Treatment
(± 3 days)
28-Day Post 
Treatment
Safety
Follow-Up
Long-Term
Follow-Up
(± 14 days)
Cycles 1 – 2 
(± 3 days)
Cycles 3 - 12
(± 3 days)i
Cycles 13 - 24
(± 3 days)i
Day
-28 to 0
1
8
15
22
1
15
1
Hematologye
6.4.2.6
X
Xc
X
X
X
X
X
X
X
X
-
Serum blood chemistrye
6.4.2.6
X
Xc
X
X
X
X
X
X
X
X
-
Hepatitis B serology (if applicable) 
6.4.2.6
X
-
-
-
-
-
-
-
-
-
-
Pulse oximetry (O2 saturation)
6.4.2.7
X
As clinically indicated
-
Serum or Urine β-hCG Testing
(FCBP/FCCBP)f
6.4.2.9
Xg
Xg
Xo
Xo
Xo
X
-
X
X
X
-
Neurological assessment 
6.4.2.8
X
X
-
-
-
X
-
X
X
X
-
Treatment Administration, Accountability and Compliance
Pomalidomide Dispensing 
7.1
-
X
-
-
-
X
-
X
-
-
-
Pomalidomide Administration 
7.2
-
Days 1-21
-
Days 1-21
Days 1-21
-
-
-
Response Assessments (High-grade glioma, Medulloblastoma and Ependymoma)
Brain MRI with and without gadolinium
6.4.1
Xh
-
-
-
-
Day 1 of Cycles 3, 5, 7, 10, 13, 16, 
19, 22 and after Cycle 24i
Xj
-
Xk
Spine MRI with gadolinium 
6.4.1
Xh
-
-
-
-
Day 1 of Cycles 3, 5, 7, 10, 13, 16, 
19, 22 and after Cycle 24l, i
Xj
-
Xk
Cerebrospinal fluid cytology 
6.4.1
As clinically indicatedm
Response Assessments (DIPG)
Brain MRI with and without gadolinium
6.4.1
Xh
-
-
-
-
Day 1 of Cycles 4, 7, 10, 13, 16, 
19, 22 and after Cycle 24i
Xj
-
Xk
Spine MRI with gadolinium 
6.4.1
Xh
-
-
-
-
Day 1 of Cycles 4, 7, 10, 13, 16, 
19, 22 and after Cycle 24i, l
Xj
-
Xk
Cerebrospinal fluid cytology 
6.4.1
As clinically indicatedm
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
43
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 4:
Table of Events (Continued)
Period
Protocol 
Reference 
Section
Screening 
Period
Treatment Periodb
Follow-up Periodb
Screeninga
Each 28-day Cycle
End of 
Treatment
(± 3 days)
28-Day Post 
Treatment 
Safety
Follow-Up
Long-Term
Follow-Up
(± 14 days)
Cycles 1 – 2 
(± 3 days)
Cycles 3 - 12
(± 3 days)i
Cycles 13 - 24
(± 3 days)i
Day
-28 to 0
1
8
15
22
1
15
1
Pharmacokinetics – Optional 
Optional Pharmacokinetic blood 
sampling 
6.5
-
-
Xo
Xo
-
-
-
-
-
-
-
Follow-Up
PFS, DoR, OS, drug related SAEs, SPMs, 
new anticancer therapies
6.3
-
-
-
-
-
-
-
-
-
-
Xn
β-hcg = beta human chorionic gonadotropin; BSA = body surface area; DoR = duration of response; FCBP = females of childbearing potential; FCCBP = female children of 
childbearing potential; IAF = informed assent form; ICF = informed consent form; MRI = magnetic resonance imaging; O2 = oxygen; OS = overall survival; PFS = progression 
free survival; SAE = serious adverse event; SPM = second primary malignancy. 
a Clinical evaluations to establish eligibility can be obtained up to 28 days prior to Cycle 1, Day 1 (first dose of study drug) unless noted otherwise. Brain/Spine MRI assessments 
can be obtained up to 21 days prior to Cycle 1, Day 1. Assessments should be re-evaluated as needed if there is a change in clinical status.
b Deviations within the provided study visit windows are allowed unless noted otherwise for a particular assessment. 
c Safety laboratory (hematology and serum blood chemistry) and physical examinations do not need to be repeated on Cycle 1, Day 1 if performed within 7 days of starting 
treatment, unless clinically indicated. FCBP/FCCBP must have pregnancy test performed within 24 hours prior to the initial dosing of pomalidomide. 
d Can also be conducted verbally via phone from the site. Subjects must also be counseled against sharing pomalidomide and donating blood, semen or sperm during therapy until 
the 28-day post-treatment Safety Follow-up Visit. Pregnancy counseling and potential risks must be conducted on Day 1 of each cycle prior to pomalidomide dispensing or at a 
minimum of every 28 days during the Treatment Period.  
e Subjects who experience toxicity should have appropriate laboratory testing at least twice weekly (3 to 4 days apart or more frequently) until the toxicity has resolved. It is the 
responsibility of the Investigator to obtain and review laboratory results for subject safety, and follow up with subjects in a timely manner.
f Testing with a sensitivity of at least 25 mIU/mL will be performed in FCBP/FCCBP subjects; refer to Section 6.4.2.9 for details. It is the responsibility of the Investigator to 
obtain and review pregnancy test results for subject safety, and follow up with subjects in a timely manner.  The subject may not receive pomalidomide until the Investigator has 
verified that the result of the pregnancy test performed on Day 1 (within 24 hours prior to treatment) of every cycle is negative.
g Obtain 10 to 14 days prior to first dose of study drug and again within 24 hours prior to first dose of study drug. NOTE: The pregnancy test 10 to 14 days prior to initiation of 
pomalidomide may be omitted, at the discretion of the investigator, for any FCCBP/FCBP who has high acuity disease requiring immediate treatment with pomalidomide. The 
pregnancy test within 24 hours prior to the first dose of pomalidomide is required to be performed.
h Screening/baseline MRI can be obtained up to 21 days prior to Cycle 1 Day 1.
i Brain/Spine MRIs can be performed within 7 days prior to scheduled timepoint.
j Response/MRI assessment will be performed at the End of Treatment Visit only if the subject has discontinued for reasons other than PD and has been more than 8 weeks since 
their most recent scan/response assessment.
k Subjects that discontinue treatment prior to disease progression will be followed with MRI tumor assessments every 6 months from treatment discontinuation for the first year off 
treatment, then annually thereafter until PD, start of a new anticancer therapy, consent/assent is withdrawn, is lost to follow-up, or death.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
44
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
l If no spinal or leptomeningeal disease is present at screening/baseline, subsequent spine MRIs will be obtained on Day 1 of Cycle 7, 13, 19 (or within 7 days prior to dosing),
after completion of Cycle 24 (or within 7 days prior) ) and as clinically indicated at the discretion of the primary treating physician.  If there is spinal or leptomeningeal disease 
present at screening/baseline, spine MRIs will be obtained at the same time points as the brain MRI.
m As clinically indicated to follow disease at the discretion of the primary treating physician.  It is recommended to follow at the same interval as required MRIs if positive at 
screening/baseline.  
n SPMs should be reported regardless of causality. After treatment discontinuation, all subjects will be followed every 3 months from the 28-Day post-treatment Safety Follow-Up 
Visit for up to 5 years after the last subject enrolled.
o Cycle 1 only
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
45
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
6.
PROCEDURES
All procedures will be performed as outlined in the Table of Events (Table 4) and further 
detailed in the respective protocol referenced sections below.  In the table, required assessments 
are indicated with an “X” at the visits for which the assessments are to be performed.  All data 
obtained from these assessments must be supported in the subject’s source documentation.  No 
electronic case report form (eCRF) will be used as a source document.  Scheduled assessments 
should be completed prior to study treatment administration unless noted otherwise.
6.1.
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility.  All 
clinical evaluations to establish eligibility must be performed within 28 days prior to Cycle 1, 
Day 1 (first dose of study drug), unless noted otherwise. MRI assessments must be performed 
within 21 days prior to Cycle 1, Day 1.  Eligibility waivers to the protocol will not be granted 
during the conduct of this trial, under any circumstances.
Safety laboratory analyses and all assessments will be performed locally.  Screening laboratory 
values may be repeated within the screening window, if necessary.  If any laboratory value does 
not meet eligibility criteria prior to the first dose (Cycle 1, Day 1) of study treatment, the subject 
will be considered a screen failure.  Subjects who fail screening may be rescreened 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 rescreening occurs > 28 days prior to the 
original screening date).  A new subject identification (ID) will be issued once the rescreening 
transaction is registered in Interactive Response Technology (IRT). 
The following will be performed at screening as specified in the Table of Events (Table 4), and 
further detailed in the protocol referenced Section 6.4, after informed consent/assent has been 
obtained:
!
Registration of screening via IRT 
!
Demographics 
!
Inclusion/exclusion criteria
!
Complete medical history 
!
Prior disease therapies and history 
!
Prior/concomitant medications and procedures 
!
Assessment of adverse events 
!
Assessment of SPM
!
Physical examination including vital signs
!
Height
!
Body weight
!
BSA calculation
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As
As
!


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
46
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
Lansky/Karnofsky performance status. Karnofsky will be utilized for subjects age 
≥16 years and Lansky will be utilized for subjects age < 16 years. 
!
Hematology 
!
Serum blood chemistry 
!
Hepatitis B serology (if required)
!
Oxygen saturation
!
Serum (or urine) beta human chorionic gonadotropin (β-hCG) pregnancy testing:  
Performed in FCCBP/FCBP at screening within 10 to 14 days prior to first dose of 
study drug and again to assess subject eligibility within 24 hours prior to the first dose 
of study drug (this pregnancy test can be done on Cycle 1 Day 1). NOTE: The 
pregnancy test 10 to 14 days prior to initiation of pomalidomide may be omitted, at 
the discretion of the investigator, for any FCCBP/FCBP who has high acuity disease 
requiring immediate treatment with pomalidomide. The pregnancy test within 24 
hours prior to the first dose of pomalidomide is required to be performed. Negative 
result(s) are required to start treatment administration (see Section 6.4.2.9).
!
Neurological assessment
!
Brain MRI with and without gadolinium (for tumor evaluation of response 
assessment).  
!
Spine MRI with gadolinium (for tumor evaluation of response assessment) 
!
Cerebrospinal fluid cytology (if clinically indicated)
!
Pomalidomide education and counseling is required for all subjects at screening.  
Education and counseling about pregnancy precautions and the potential risks of fetal 
exposure must be conducted by trained personnel at the site prior to each dispensing 
of pomalidomide.  The individual conducting the training must sign the appropriate 
counseling form prior to administration of study treatment to document that the 
education and counseling was performed.
6.1.1.
Information to be Collected on Screen Failures
!
Informed consent/assent date 
!
Demographics
!
Inclusion and exclusion criteria eligibility information 
!
Reason for screen failure
!
Adverse events.  Concomitant medications to treat the AE(s) will be recorded on the 
eCRF and captured in the source document.
6.1.2.
Demographics
Demographics including gender, race, ethnicity, and date of birth, where allowed by local 
regulations, will be documented at screening only.
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2


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
47
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
6.1.3.
Complete Medical History
A complete medical history including evaluation for preceding medical disorders and past (up to 
5 years) or present cardiovascular, respiratory, gastrointestinal, renal, hepatic, neurological, 
endocrine, lymphatic, hematological, immunological, dermatological, psychiatric, genitourinary, 
obstetrical, surgical history (including those related to disease under study) or any other disorders 
will also be documented at screening.  
6.1.4.
Prior Disease History and Therapies
The subject’s current disease (ie, diagnosis, date of diagnosis, grading/staging, and histology), as 
well as all prior disease therapies including surgery, radiation, SCT, chemotherapy, systemic or 
any other therapy for the subject’s disease will be recorded on the respective eCRF at screening.  
6.1.5.
Enrollment
Prior to enrolling a subject, written informed consent/assent must be obtained, all screening 
evaluations must be completed, and eligibility criteria must be verified by the Investigator.  Once 
these actions have been completed, the Investigator or designated staff will log into IRT and 
confirm that the subject still fulfills all the inclusion and exclusion criteria.  After enrollment, the 
subject will retain his/her Subject ID number (Section 7.3.1) during participation in the study.
6.2.
Treatment Period
The subject will begin treatment upon re-confirmation of eligibility (ie, safety assessments) and 
subsequent enrollment.  The subject must start treatment within 28 days of signing the ICF/IAF. 
For all subsequent visits, an administrative window of ± 3 days is permitted unless noted 
otherwise for a particular assessment. Brain and spine MRI assessments can be conducted within 
7 days prior to the scheduled timepoint (ie, during study drug rest period). Study visit windows 
should take into account the subject’s investigational product (IP) supply and administration.  
Note: Safety laboratory (hematology, serum blood chemistry) and physical examinations do not 
need to be repeated on Cycle 1, Day 1 if performed within 7 days of starting treatment unless 
clinically indicated; however, for FCCBP/FCBP subjects, a urine or serum pregnancy test must 
be performed to assess subject eligibility 10 to 14 days prior to and again within 24 hours prior to 
the first administration of pomalidomide. The pregnancy test 10 to 14 days prior to initiation of 
pomalidomide however may be omitted, at the discretion of the investigator, for any 
FCCBP/FCBP who has high acuity disease requiring immediate treatment with pomalidomide. 
The pregnancy test within 24 hours prior to the first dose of pomalidomide is required to be 
performed (refer to Section 6.4.2.9).
The Treatment Period is defined as the time starting from first study drug administration 
(Cycle 1, Day 1) until permanent study treatment discontinuation.  Subjects will be administered 
pomalidomide on Days 1 to 21 of each 28-day treatment cycle for a maximum of 24 cycles. 
Pomalidomide will not be administered on Days 22 through 28 of the 28-day treatment cycle.  
The following evaluations will be performed at the frequency specified in the Table of Events 
(Table 4) and further detailed in the protocol referenced Section 6.4. The evaluations should be 
performed prior to dosing on the visit day, unless otherwise specified.
!
Reconfirm eligibility (Cycle 1, Day 1 only)
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
48
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
IRT registration (Day 1 of each treatment cycle)
!
Enrollment via IRT: Day 1, Cycle 1 only
!
Concomitant medications and procedures
!
Adverse event evaluation 
!
Assessment of SPM
!
Physical examination (including vital signs)
!
Height
!
Body weight
!
BSA calculation
!
Lansky/Karnofsky performance status.  Karnofsky will be utilized for subjects age 
≥16 years and Lansky will be utilized for subjects age < 16 years. 
!
Hematology 
!
Serum blood chemistry 
!
Oxygen saturation (as clinically indicated)
!
Serum (or urine) β-hCG pregnancy testing in FCCBP/FCBP (see Section 6.4.2.9)
!
Neurological assessment
!
Pomalidomide administration 
!
Brain MRI with and without gadolinium (for tumor evaluation of response 
assessment)  
!
Spine MRI with gadolinium (for tumor evaluation of response assessment) 
!
Cerebrospinal fluid cytology (as clinically indicated)
!
Pomalidomide education and counseling.  For applicable subjects, confirmation of 
use of two effective methods of birth control, agree to use condom (male) or 
confirmation of complete abstinence 
!
Optional PK blood sampling (Cycle 1, Day 8 and 15 only)
6.2.1.
End of Treatment
All subjects discontinuing treatment, regardless of reason, should undergo treatment 
discontinuation procedures and evaluation as soon as possible after the decision to permanently 
discontinue treatment has been made.  
The following evaluations will be performed as specified in the Table of Events (Table 4) and 
further detailed in protocol referenced Section 6.4:
!
Registration of treatment discontinuation via IRT
!
Concomitant medications and procedures 
&&,
for subject
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urther
urther


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
49
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
Adverse event evaluation
!
Assessment of SPM
!
Physical examination (including vital signs)
!
Pomalidomide education and counseling
!
Height 
!
Body weight 
!
Lansky/Karnofsky performance status.  Karnofsky will be utilized for subjects age 
≥16 years and Lansky will be utilized for subjects age < 16 years. 
!
Hematology 
!
Serum blood chemistry 
!
Oxygen saturation (as clinically indicated)
!
Serum (or urine) β-hCG pregnancy testing for FCCBP/FCBP (see Section 6.4.2.9) 
!
Neurological assessment
!
Brain MRI with and without gadolinium (for tumor evaluation of response 
assessment) will be performed only if subject has discontinued for reasons other than 
progression of disease and it has been more than 8 weeks since their most recent 
scan/response assessment
!
Spine MRI with gadolinium (if applicable, for tumor evaluation of response 
assessment) will be performed only if subject has discontinued for reasons other than 
progression of disease and has been more than 8 weeks since their most recent 
scan/response assessment
!
Cerebrospinal fluid cytology (as clinically indicated)
6.3.
Follow-up Period 
6.3.1.
Safety Follow-up
All subjects will be followed for 28 days after the last dose of treatment for AE reporting, as well 
as concomitant medications/procedures used to treat the AEs.  SAEs made known to the 
Investigator at any time thereafter that are suspected of being related to study drug will be 
reported, as described in Section 10.1.  At this visit, the following evaluations will be performed 
as specified in the Table of Events (Table 4) and further detailed in the protocol referenced 
Section 6.4:  
!
Concomitant medications and procedures
!
Adverse event evaluation 
!
Assessment of SPM
!
Physical examination (including vital signs)
&&,
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6.4: 
!
C


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
50
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
Pomalidomide education and counseling 
!
Height
!
Body weight
!
Lansky/Karnofsky performance status.  Karnofsky will be utilized for subjects age 
≥16 years and Lansky will be utilized for subjects age < 16 years. 
!
Hematology 
!
Serum blood chemistry
!
O2 saturation (as clinically indicated)
!
Serum (or urine) β-hCG pregnancy testing for FCCBP/FCBP (see Section 6.4.2.9) 
!
Neurologic examination
6.3.2.
Second Primary Malignancy Follow-up Period
Second primary malignancies will be monitored as events of interest and must be reported as 
SAEs.  This includes any SPM, regardless of causal relationship to study drug, occurring 
throughout the subject’s entire participation in the study.  Subjects that do not receive treatment 
(eg, screen failures) will not be followed for SPM. Further details are described in Section 
6.4.2.10.
6.3.3.
Long-term Follow-up
After permanent study drug discontinuation, all subjects will be followed every 3 months 
(± 14 days) from the 28-day post-treatment Safety Follow-up Visit for SPMs (regardless of 
causal relationship), any drug-related SAEs, OS, and start of any new anticancer therapies.  
Follow-up will continue every 3 months for up to 5 years after the last subject enrollment, unless 
consent/assent is withdrawn, the subject is lost to follow-up, or death.  
Note: The Long-term Follow-up Period may not be terminated because of starting a new 
anticancer treatment.
In addition, subjects that discontinue treatment prior to disease progression will be followed for
MRI tumor response assessments every 6 months from treatment discontinuation for the first 
year off treatment, then annually thereafter until PD, withdrawal of consent/assent, start of new 
anticancer therapy, lost to follow up or death, whichever occurs first.  These MRI scans will 
continue to be sent for independent central review.
Survival/long-term follow-up may be conducted by clinic visits, by record review (including 
public records) and/or telephone contact with the subject, family, or the subject’s treating 
physician.
6.4.
Assessment Types
6.4.1.
Efficacy Assessments
Brain tumor assessments will be conducted by MRI with and without contrast (ie, gadolinium) 
using 3 standard MRI sequences (T1-weighted pre- and postcontrast, T2-weighted, FLAIR).  A 
&&,
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6.4


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
51
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
spine MRI with contrast (ie, gadolinium) will also be performed as specified in Table 4.  The 
neuroradiologist may select the appropriate sequence that best highlights the tumor (T1-weighted 
postcontrast or T2-weighted or FLAIR) and the same sequence should be used for serial 
measurements (Section 6.4.1.2). Further details regarding MRI acquisition requirements are 
outlined in the Imaging Manual.
Brain MRI assessments will be conducted during screening (within 21 days prior to first dose of 
study treatment) and then on Day 1 of Cycles 3, 5, 7, 10, 13, 16, 19, 22 (or within 7 days prior to 
dosing), after completion of Cycle 24 (or within 7 days prior) and as clinically indicated.  Note:
For DIPG subjects only, post-baseline brain MRI assessments will be performed on Day 1 of 
Cycles 4, 7, 10, 13, 16, 19, 22 (or within 7 days prior to dosing), after completion of Cycle 24 (or 
within 7 days prior) and as clinically indicated.  
Spine MRI will be also performed during screening (within 21 days prior to first dose of study 
treatment) for all subjects.  If no spinal or leptomeningeal disease is present at screening, 
subsequent spine MRIs will be obtained on Day 1 of Cycles 7, 13, 19 (or within 7 days prior to 
dosing), after completion of Cycle 24 (or within 7 days prior) and as clinically indicated.  If there 
is spinal or leptomeningeal disease present at screening/baseline, spine MRIs will be obtained at 
the same brain MRI time points specified above.
In addition, if clinically indicated and at the discretion of the Investigator, CSF cytology will also 
be assessed to follow disease. It is recommended to follow at the same interval as required brain 
MRIs if positive at initiation of treatment.  Corticosteroid use and clinical assessments (ie,
neurologic status) will also be considered when determining overall response (Section 6.4.1.7).
A response assessment should be performed at EOT visit if the subject has discontinued for 
reasons other than progression of disease and it has been more than 8 weeks since their most 
recent scan/response assessment. Subjects that discontinue treatment prior to disease progression 
will be followed for MRI tumor response every 6 months from treatment discontinuation for the 
first year off treatment, then annually thereafter until PD, start new anticancer therapy, 
withdrawal of consent/assent, lost to follow-up or death, whichever occurs sooner.  
The same method of assessment and sequence/technique must be used to characterize each 
reported target and non-target lesions at baseline and subsequent scans after start of study 
treatment.  
Tumor response will be assessed both locally and by an independent central reviewer
(Section 6.4.1.7) according to the criteria described below. The local Investigator’s radiological 
assessment will be used for subject eligibility and treatment decisions.  Efficacy based endpoints 
incorporating tumor assessments (primary and secondary) will be based on the independent 
central assessment.  
6.4.1.1.
Selection of Target and Non-Target Lesions
Screening/baseline requirement:
Screening MRI evaluations will be performed within 21 days of first dose of study treatment.  
For subjects on steroids, screening MRI scans must be performed while on a stable or decreasing 
&&,
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
52
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
dose of steroids for at least 5 days.  Subjects must have measurable disease (including subjects 
that have undergone a surgical resection prior to enrollment).  
!
Measurable disease is defined as lesions that are (all criteria below are met):
∀
Brain lesions which are the primary tumors
∀
Measurable in 2 perpendicular diameters
∀
At least twice the slice thickness on MRI (ie, visible on 2 or more axial slices)
Note: MRI should be performed with cuts of 3 mm or less in slice thickness 
contiguously.  
∀
Do not include cavity or cyst in measurement (see Section 6.4.1.2)
!
Nonmeasurable disease is defined as (any criteria below are met): 
∀
Spinal lesions 
∀
Lesions with poorly defined margin on MRI
∀
Cerebrospinal fluid 
∀
Cystic or necrotic components (see Section 6.4.1.2)
All target and non-target lesions should be identified and recorded at screening.
!
For most CNS tumors, only one lesion/mass is present and therefore this single lesion
is considered a “target” for measurement to assess tumor response and progression.
!
Spinal lesions should be considered as nonmeasurable disease (ie, non-target lesions); 
however, size should be noted and change in size should be evaluated.  
!
All subjects should have at least one measurable, target lesion confirmed by MRI.  
Target lesions should be selected on the basis of size (eg, largest) and suitability for 
accurate repeated measurements.  All other lesions will be followed as non-target 
lesions. 
!
Leptomeningeal tumor spread is usually not a target lesion, and cannot be measured 
accurately; however, presence and location of leptomeningeal tumor spread should be 
noted and change in extent/thickness should be evaluated on assessments.
6.4.1.2.
Methodology to Determine Tumor Measurement
Tumor dimensions will be determined by two-dimensional measurement of the longest diameter 
(width [W]) and the longest perpendicular diameter (transverse [T]) for each target lesion 
(Figure 3). Radiologist at each institution may select the appropriate sequence that best 
highlights the tumor (T1-weighted postcontrast or T2-weighted or FLAIR) and the same 
sequence should be used for serial measurements.
Radiographic response determination will be based on a comparison of an area (W x T) between 
the baseline assessment (or smallest disease measurements recorded since the start of protocol 
therapy [nadir]) and the assessments post-treatment.  Assessments post treatment should reiterate 
the measurements obtained at baseline for each target lesion.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
53
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Tumor response criteria are determined by changes in size using the longest tumor diameter and 
its perpendicular diameter (W x T).  The following describes the measurement method:
!
The longest diameter measurement (W) can be measured from the axial plane or the 
plane in which the tumor is best seen or measured.  The same plane chosen at 
baseline should be used in subsequent assessments. 
!
The perpendicular diameter measurement (T) is maximal perpendicular to the W in 
the selected plane.
!
The cystic or necrotic components of a tumor are not considered in tumor
measurements. Therefore, only the solid component of cystic tumors should be 
measured.  If cyst/necrosis composes the majority of the lesion, the lesion may not be 
“measurable.” In general, such lesions should be considered non-target. 
Options:
∀
If the cyst/necrosis is eccentric, the W and T of the solid portion should be 
measured, and the cyst/necrosis portion should be excluded from measurement.
∀
If the cyst/necrosis is central but represents a small portion of the tumor (< 25%), 
the cyst/necrosis should be disregarded, and the entire tumor should be measured.
∀
If the cyst/necrosis is central and represents a large portion of the tumor, identify 
a solid aspect of the tumor mass that can be reproducibly measured.
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an be repro


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
54
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Figure 3:
Guidelines for Measurement of Tumor Size
Source: Children’s Oncology Group (COG) guideline
6.4.1.3.
Tumor Response Criteria for Target Lesions
1. Response criteria are assessed in 2 dimensions - the product of W x T
2. The overall measurement of target lesions for a particular assessment is quantified by 
the sum of the products of the perpendicular diameters of all target lesions 
(eg, W1 x T1 + W2 x T2 + ….).
3. To assess response/progression, the ratio is calculated:
                                 
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4. Radiographic response should be made in comparison to the tumor measurement 
obtained at baseline for the determination of response, and the smallest tumor 
measurement (nadir) either at baseline or after initiation treatment for determination 
of progression.
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0$7,21


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
55
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
5. Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions, eg, when multiple lesions 
show opposite responses, the progressive disease takes precedence.
The tumor response categories for target lesions are CR, PR, SD and PD and are further defined 
in Appendix B.  
6.4.1.4.
Tumor Response Criteria for Non-Target Lesions
The tumor response categories for non-target lesions are CR, incomplete response (IR)/SD and 
PD and are further defined in Appendix B.  Non-target lesions are assessed subjectively and the 
decision when progression is evident is at the discretion of the radiologist/Investigator.
6.4.1.5.
Clinical Status (Neurologic Symptoms/Examination)
The definition of clinical status and deterioration is left to the discretion of the Investigator.  
Clinical deterioration should be attributable to neurologic abnormalities or worsening neurologic 
status not explained by causes unrelated to tumor progression (eg, anticonvulsant or 
corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.) or changes in 
corticosteroid dose.
6.4.1.6.
Corticosteroid Administration
An increase in corticosteroid dose alone will not cause determination of progression in the 
absence of clinical deterioration or radiographically documented lesion growth. For 
corticosteroid dose to be considered “stable or decreasing,” it should not be a greater dose than 
compared with baseline. For overall assessment of response (Section 6.4.1.7), physiologic 
replacement doses of corticosteroids, defined as no more than 0.75 mg/m2/day of dexamethasone 
or equivalent, will be considered. 
6.4.1.7.
Overall Response Assessment 
The overall response assessment takes into account response in both target and non-target
lesions, the appearance of new lesions, current corticosteroid use (compared to 
screening/baseline) and neurologic symptoms/examination (clinical status) according to the 
criteria described in Appendix C.
Subjects who do not meet the criteria for an objective response or disease progression by the end 
of Cycle 6 (end of Cycle 3 for DIPG subjects) will be considered as having long-term SD.
6.4.1.8.
Independent Central Response Review
Response evaluations will be based on MRI results obtained at each site and will assessed locally 
and by an independent central reviewer.  Corticosteroid use and clinical assessments (ie, 
neurologic status) will also be considered when determining overall response.  The local 
Investigator’s assessment will be used for subject eligibility and treatment decisions.  Efficacy 
based endpoints incorporating tumor assessments (primary and secondary) will be based on the 
independent central assessment.  
Imaging/response data will be centrally collected and checked for quality by an imaging contract 
research organization (CRO) designated by Celgene.  Independent central review (screening/
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
56
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
baseline and post-baseline assessments) will be performed for all MRIs collected for response 
assessment.  Further details regarding MRI acquisition requirements and image submission 
procedures are outlined in the Imaging Manual.
Details of the central review process and requirements for central imaging review will be 
described in the independent review charter.  Results of the central review will not be provided 
to the sites.  
6.4.2.
Safety and Tolerability Assessments 
Safety assessments will consist of monitoring and recording all AEs, including SAEs, 
concomitant medications, SPMs, dose discontinuations, reductions and interruptions, the regular 
monitoring of hematology and blood chemistry, regular monitoring of vital signs and physical 
condition.  These assessments should be performed within the prescribed window of the 
scheduled day of assessment (Table 4) and at any unscheduled visit if clinically indicated; 
however, AEs, concomitant medications and review for SPMs will be evaluated and recorded 
continuously throughout the study.
Note:  Pomalidomide experience in subjects < 3 years of age is limited.  As such, subjects 
< 3 years of age should be carefully monitored for safety and side effects (adverse effects).  In 
addition, as pomalidomide is metabolized hepatically, subjects with hepatic impairment should 
also be carefully monitored.  In response to any safety concerns in subjects with hepatic 
impairment, Investigators should have a low threshold for performing additional safety 
evaluations (ie, hematology, blood chemistry, physical exams, vital signs, etc) as needed.  
6.4.2.1.
Physical Examinations (Including Vital Signs)
A complete physical examination will include (as applicable) the examination of general 
appearance, skin, neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological (Section 6.4.2.8).  For other indicated areas, based on 
medical history and/or symptoms, examinations will be performed. 
Physical examination will be source documented only; however significant findings that were 
present prior to the signing of the ICF/IAF must be included in the Medical History page on the 
subject’s eCRF.  Clinically significant new findings that begin or worsen after informed 
consent/assent must be recorded on the AE page of the subject’s eCRF.  
At screening, the Investigator or designee performing the physical examination will characterize 
the findings as either normal or abnormal in the source.  If abnormal, a description of the 
abnormality and clinical importance should be source documented.  Clinically significant 
changes from screening/baseline will be recorded in the AE section of the eCRF.
Vital signs assessment will include temperature, blood pressure, heart rate and respiratory rate. 
On-treatment vital sign measurements will be source documented only; however, if an abnormal 
(out of range) value is reported at any given visit and clinically significant, that parameter should 
be collected in the eCRF at every subsequent scheduled visit until it returns to normal or not 
clinically significant (NCS), and recorded as an AE if appropriate.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
57
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
6.4.2.2.
Height 
Height in centimeters (cm) without shoes will be measured. For each height assessment, 
measurements should be performed three times and the average taken for calculation of BSA. 
6.4.2.3.
Weight
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured.  For each weight assessment, measurements should be performed three times and the
average taken for calculation of BSA.
6.4.2.4.
Body Surface Area Calculation
Body surface area, in m2, will be calculated using the following formula, where weight (W) is in 
kg and height (H) is in cm (Dubois, 1916):
BSA= (W0.425x H0.725) x 0.007184
The subject’s pomalidomide dose should be calculated on the first day of Cycle 1 based upon the 
subject’s current BSA.  Measurements of the subject’s height and body weight will be repeated 
on Day 1 of each subsequent cycle and BSA recalculated at these visits.  
6.4.2.5.
Lansky/Karnofsky Performance Status
For subjects < 16 years of age, the Lansky performance status will be determined.  For subjects 
≥16 years of age, the Karnofsky performance status will be determined (Appendix D).  Each 
subject must continue to be assessed with the same performance status scale used at screening 
throughout his/her duration in the study (regardless of changing age over time).
6.4.2.6.
Laboratory Evaluations
Screening and other laboratory assessments will be performed locally at each scheduled visit 
according to Table of Events (Table 4) and collection plan in Table 5 below.
Note: Additional assessments should be performed between visits as clinically required to follow 
AEs or determine dose modifications.  All laboratory assessments should be performed prior to 
treatment administration on that particular visit unless indicated otherwise.
It is the responsibility of the Investigator to obtain and review laboratory results for subject 
safety, and follow up with subjects in a timely manner.  The Investigator will evaluate the 
clinical significance of each applicable laboratory value outside of the reference range.  This 
decision shall be based upon the nature and degree of the observed abnormality.  Values which 
are considered clinically significant and/or related to study treatment will be noted in source 
document(s). The Investigator may choose to repeat any abnormal result, in order to rule out 
laboratory error.  “Not clinically significant” or “NCS” will be recorded on the original 
laboratory sheet for all laboratory values which are outside the reference range, but are judged 
“not clinically significant.”  The Investigator making these assessments shall date and initial each 
form.
Hematology, serum chemistry and viral serology laboratory values will not be collected on the 
laboratory eCRF; instead, laboratory abnormalities that are considered AEs should be reported 
on the AE eCRF (see Section 10).
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
58
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 5:
Local Clinical Laboratory Parameters Collection Plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Mean corpuscular volume, Platelets, RBC, White 
Blood Cells (WBC) absolute and differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils)
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, 
Blood Urea Nitrogen, Calcium, Chloride, Creatinine, Direct Bilirubin, Total 
Bilirubin, Glucose, Potassium, Phosphorous, Magnesium, Sodium, Total Protein
Viral Serology
Hepatitis B serology is required at screening if status is not known
ALT = alanine aminotransferase; AST = aspartate transaminase; RBC = red blood cell; SGPT = serum glutamic-
pyruvic transaminase; SGOT = serum glutamic-oxaloacetic transaminase.
6.4.2.7.
Pulse Oximetry (Oxygen Saturation)
Oxygen (O2) saturation will be measured by pulse oximetry at screening and repeated as 
clinically indicated throughout the study.  
6.4.2.8.
Neurological Assessment
A basic neurological exam (including, but not limited to, cranial nerve examination, motor 
function, sensory function, reflexes and cerebellar function) will be conducted as part of the 
physical examination.
6.4.2.9.
Pregnancy Testing and Pregnancy Risk Counseling
Medically supervised (ie, performed in a clinic) serum or urine pregnancy tests with a sensitivity 
of at least 25 mIU/mL must be conducted in FCCBP/FCBP, including those who commit to 
complete abstinence. Female children of childbearing potential is 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). 
A female of childbearing potential is defined as a female who has achieved menarche at some 
point, 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). 
For all applicable subjects during the Screening Period, 2 pregnancy tests (with sensitivity of at 
least 25 mIU/mL) must be conducted prior to starting treatment. The first pregnancy test in both 
FCCBP and FCBP must be performed within 10 to 14 days prior to the start of treatment 
(Screening Period) and the second pregnancy test must be performed within 24 hours prior to the 
start of treatment (Cycle 1, Day 1).  Amenorrhea following cancer therapy does not rule out 
childbearing potential. 
Note: The pregnancy test 10 to 14 days prior to initiation of pomalidomide may be omitted, at 
the discretion of the investigator, for any FCCBP/FCBP who has high acuity disease requiring 
immediate treatment with pomalidomide. The pregnancy test within 24 hours prior to the first 
dose of pomalidomide is required to be performed.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
59
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Female children of childbearing potential and FCBP with regular or no menstrual cycles must 
agree to have subsequent pregnancy tests weekly for the first 28 days of study participation and
then every 28 days while on study, at End of Treatment Visit and at day 28 following treatment 
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 End of Treatment Visit, and at 
Days 14 and 28 following treatment discontinuation.   It is the responsibility of the Investigator 
to obtain and review pregnancy test results for subject safety, and follow up with subjects in a 
timely manner.
The subject must not receive pomalidomide until the Investigator has verified that the results of 
the pregnancy test performed are negative. See inclusion criteria (Section 4.2) for pregnancy 
testing requirements.
The Investigator must confirm the FCCBP/FCBP subject 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 
pomalidomide must be conducted at screening, on Day 1 (within 24 hours prior to treatment) of 
each cycle prior to pomalidomide dispensing or at a minimum of every 28 days (can also be 
conducted verbally from the site), at the End of Treatment Visit, and at the 28-day post-treatment
Safety Follow-up Visit.  If pregnancy or a positive pregnancy test does occur in a study subject, 
treatment 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. Treatment must be discontinued during this evaluation as well.  Female children and 
adult females must agree to abstain from breastfeeding during study participation and for at least 
28 days after treatment 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.
Furthermore, FCCBP/FCBP and male subjects that have reached puberty must agree to undergo 
physician-approved reproductive education and discuss the side effects of pomalidomide on 
reproduction with parent(s) and/or guardian(s) when appropriate.  Pregnancy testing is not 
required for non-FCCBP subjects, unless deemed necessary by the Investigator.
Any pregnancy occurring in either a female subject or partner of a male subject while in the 
Treatment Period, or within 28 days thereafter, are considered immediately reportable events 
(see Section 10.4).  
6.4.2.10.
Assessment of Second Primary Malignancy
Second primary malignancies will be monitored as events of interest and must be reported as 
SAEs.  This includes any SPM, regardless of causal relationship to treatment, occurring at any 
time for the duration of the study, for at least 5 years from enrollment of the last subject, unless 
consent/assent is withdrawn, the subject is lost to follow-up, or death.  Subjects that do not 
receive treatment (eg, screen failures) will not be followed for SPM.
Events of SPM are to be reported using the SAE report form and must be considered an 
“Important Medical Event” if no other serious criteria apply; these events must also be 
documented in the appropriate page(s) of the eCRF (ie, AE and SPM eCRF) and subject’s source 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
60
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
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, CT scans, etc).
6.5.
Pharmacokinetics – Optional 
Sparse whole blood samples for PK analysis will be collected from consenting subjects at the 
time points specified in Table 6.  Blood samples MUST be drawn from the arm contra lateral to 
the arm with the intravenous infusion of concomitant medications (if applicable).  For each PK 
sample, draw approximately 1 mL blood and prepare plasma by centrifugation at 4°C.  The dose 
of pomalidomide (Cycle 1: Day 8 and 15) should be administered to subjects in the morning after 
the collection of the pre-dose PK blood samples.  To reduce PK variability on PK sampling days, 
subjects will be asked not to eat for 2 hours prior and 2 hours after pomalidomide administration.  
Specific details regarding the collection, processing, storage, and shipment of PK samples are 
provided in Appendix E.
Note: Blood samples for PK analysis can be obtained through a central line, if applicable. The 
use of the central line to collect PK samples and any concomitant medications given via the 
central line prior to sampling must be captured in the appropriate section of the subject’s eCRF
and source documents. 
Table 6:
Pharmacokinetic Sampling Time Points
Collection Time Relative to 
Pomalidomide Administration
Collection 
Window
Cycle 1, Day 8
Cycle 1, Day 15
0 hour (pre-dose)
-90 min
x
x
2 hours
± 30 min
x
x
The following information must be captured on the PK visit days:
!
Actual date and time for PK blood collections
!
Administered dose of pomalidomide
!
Actual date and time of pomalidomide oral administration
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
61
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product
Investigational product will be provided as capsule formulation and oral suspension. 
Pomalidomide oral capsules for this clinical study will be supplied by Celgene Corporation in 
0.5 mg gelatin capsules (size 4 reddish brown), 1 mg hard gelatin capsules (size 4 reddish brown)
and 2 mg, 3 mg and 4 mg hard gelatin capsules (size 2 reddish brown) labeled appropriately as 
IP for this study. Each bottle contains 21 capsules with each capsule containing pomalidomide 
as the active ingredient and the following inactive ingredients: mannitol, pre-gelatinized starch 
and sodium stearyl fumarate.  The capsules are supplied in tamper-evident, child-resistant, 
opaque, high density polyethylene (HDPE bottles) with polypropylene caps.  
Celgene Corporation will also supply pomalidomide active pharmaceutical ingredient in 
individually sealed vials for constitution to an oral suspension. Each vial contains 20 mg of 
pomalidomide, mannitol, pre-gelatinized starch and sodium stearyl fumarate. The pomalidomide 
powder in each vial is constituted with 4 ml of water and 5 ml of suspending agent to create a 
pomalidomide oral suspension with a final volume of 10 mL and a concentration of 2
mg/ml. This suspension is intended for oral administration only.
Please refer to the pomalidomide study drug label for more details on preparation, storage 
conditions, approved indications, known precautions, warnings and adverse reactions. Additional 
information may be included on the label as needed or applicable.  Label(s) for study drug will 
contain information as required per local health authority.  The pomalidomide dispensing, 
administration, dosing schedule and dose adjustments to be followed for this study are described 
in Section 7.2.
7.2.
Treatment Administration and Schedule
The starting dose of pomalidomide will be 2.6 mg/m2/day, based on the subject’s actual BSA 
calculated at the beginning of each cycle.  Pomalidomide (oral capsules or suspension) will be 
administered daily for the first 21 days of every 28-day cycle and only enough pomalidomide for 
1 cycle (21-day supply) of treatment will be dispensed on Day 1 of each new cycle of therapy.
The oral suspension is available for use in subjects who are unable to swallow the capsules or at 
the discretion of the Investigator.  On Day 1 of each cycle, pomalidomide will be dispensed and 
administered after completion of all clinical procedures required for that day.  Subsequent 
pomalidomide administration (ie, Days 2-21 of each cycle) may occur at the subject’s home.
Pomalidomide will not be administered on Days 22 through 28 of the 28-Day treatment cycle
even if a subject experiences a toxicity that requires dose interruption (see Section 7.2.2).  
Counting of days should continue uninterrupted and the rest period (Days 22 to 28) should be 
continued as planned.  For example, if a subject experiences a toxicity that requires interruption 
and does not recover until Day 22, pomalidomide should be restarted on Day 1 of the subsequent 
cycle if other protocol parameters are met. Subjects will continue treatment for up to 24 cycles or 
until documented PD, withdrawal of consent/assent, treatment becomes intolerable or death, 
whichever comes first.
For subjects receiving capsules, the pomalidomide dose should be calculated and rounded up or 
down to the nearest 0.5 mg as the prescribed dose before each new dosing cycle.  The dose 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
62
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
prescribed should be based on the subject’s BSA and yield the minimum number of capsules to 
achieve the prescribed dose. However, if a subject is unable to swallow larger capsules, varying 
appropriate strength combinations may be considered during medication assignment.  
Pomalidomide capsules should not be broken, chewed or opened and should be taken at 
approximately the same time every day for 21 consecutive days in a cycle. If a dose is vomited 
within 15 minutes of taking the dose and the capsule(s) are visible in the emesis, the dose should 
be repeated and the Investigator should be notified to have replacement capsule(s) provided. If 
vomiting occurs beyond 15 minutes of dosing, do not repeat the dose and that day’s dose should 
be skipped.  Any vomiting of the capsules should be described in the subject dosing diary.
For subjects receiving the oral suspension of pomalidomide, the dose administered should 
correspond with a volume that is a 0.1 mL increment.  The oral suspension should be taken at 
approximately the same time every day for 21 consecutive days in a cycle. If the dose is 
vomited, the dose should not be repeated for that dosing day and details entered in the subject 
dosing diary. If a subject is receiving the pomalidomide 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 Pomalyst Oral Suspension Preparation Administration and Handling 
Guide for additional guidance. 
Pomalidomide (capsules or oral suspension) can be taken with or without food or beverage; 
however, to reduce PK variability on PK sampling days in Cycle 1 (Days 8 and 15), consenting 
subjects should not eat for 2 hours prior and 2 hours after pomalidomide administration. A 
pomalidomide dosing table is provided in Appendix F to facilitate dosing calculation for both 
capsules and oral suspension. If a dose is forgotten but remembered within 8 hours, the missed 
dose should be taken/given immediately.  If more than 8 hours have passed since the time the 
dose was due, that day’s dose should be skipped.
Treatment 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 childbearing potential should not handle or administer pomalidomide unless they are 
wearing gloves.  All subjects should not extensively handle the pomalidomide capsule
formulation or oral suspension and should maintain storage in the packaging until ingestion.  In 
investigational studies, pomalidomide 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 pomalidomide being dispensed to 
ensure that the subject has complied with all requirements (including use of birth control and 
pregnancy testing) and that the subject understands the risks associated with pomalidomide.  This 
step will be documented with a completed Education and Counseling Guidance Document and 
no pomalidomide will be dispensed until this step occurs. Counseling includes verification with 
the subject that required pregnancy testing was performed and results were negative. 
A Pomalidomide Information Sheet will be supplied each time pomalidomide is dispensed.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
63
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
7.2.1.
Criteria for Starting Subsequent Treatment Cycles
Prior to the start (within 48 hours) of each treatment Cycle (Day 1) the following parameters
MUST be met:
!
ANC ≥ 1,000/mm3
!
Platelet count ≥ 100,000/mm3 (transfusion independent, defined as no platelet 
transfusion within 7 days and recovery from nadir)
!
Does not meet PD or treatment interruption/discontinuation criteria
In addition, subjects MUST meet the following within 24 hours prior to the start of each 
treatment cycle: 
∀
Confirmation of negative serum or urine pregnancy test (sensitivity of at least 25 
mIU/mL) in FCCBP/FCBP.
∀
Confirmation of the use of 2 forms of effective birth control for FCCBP/FCBP
and sexually mature males or confirmation of commitment to complete 
abstinence.
∀
Completion and documentation of required pomalidomide education and 
counseling.
If a subject does not meet the above parameters by Day 28 of a treatment cycle, then the 
subsequent cycle should not be started until these parameters are met.  Refer to Section 7.2.2 for 
dose interruptions/reductions or next cycle delays due to count recovery or non-hematological 
toxicities.
7.2.2.
Dose Reductions, Interruptions and Discontinuation Criteria for Toxicities
Hematological and non-hematological toxicity will be graded using CTCAE version 4.03.  In all 
cases, the reason for dose modification/interruption/discontinuation must be recorded in the 
subject’s medical record.  If the subject discontinues the protocol-prescribed therapy due to an 
AE, this event must be reported in accordance with the procedures outlined in Section 10.
Subjects who experience significant toxicity as listed below (Table 8) will have pomalidomide 
interrupted or reduced as specified in Table 7.  Up to two dose reductions of pomalidomide are 
allowed across the Treatment Period in the event of specific protocol defined toxicity with no 
evidence of disease progression.  
In addition: 
!
If a subject experiences a toxicity that requires interruption and does not recover until 
Day 22, pomalidomide (dose-reduced) should be restarted on Day 1 of the subsequent
cycle if other protocol parameters are met. 
!
The dose will not be re-escalated following a dose reduction, even if there is minimal 
or no toxicity with the subsequent reduction in dose. 
!
Subjects who again experience dose modifying toxicity after 2 dose reductions will be 
taken off pomalidomide therapy.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
64
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
Subjects who experience hematologic toxicity (eg, neutropenia or thrombocytopenia) 
should have appropriate laboratory testing at least twice weekly (3 to 4 days apart) 
until the toxicity has resolved.  
!
If there is a > 14-day delay in starting the subsequent cycle for a pomalidomide-
related toxicity, the investigator should consider pomalidomide dose reduction or 
pomalidomide discontinuation, based upon clinical judgment and the required dose 
modification criteria outlined in Table 8.
Table 7:
Dose Reductions of Pomalidomide
Dose Level
Dose
Starting dose
2.6 mg/m2/day
Dose Level -1
1.9 mg/m2/day
Dose Level -2
1.3 mg/m2/day
Dose Level -3
Discontinue treatment
7.2.2.1.
Dose Modifications
Table 8:
Dose Modification Criteria
Toxicity
Dose Modification and Discontinuation
Grade 4 neutropenia that occurs during 
the 21-day dosing period 
Grade 3 or 4 febrile neutropenia
Grade 4 neutropenia of ≥ 5 days 
duration during the treatment rest period
!
Interrupt pomalidomide until the neutrophil count recovers to 
≥1000/mm3 and no fever (≤ 38.3 °C) (if applicable).
!
If the toxicity resolves and the subject meets eligibility
parameters to resume as described in the protocol within 14 days 
(eg, ANC ≥ 1000/mm3; platelets ≥100,000/mm3), the subject 
should re-initiate treatment at one dose level lower.
!
If the dose modifying toxicity does not resolve to meet the 
parameters as described in the protocol within 14 days of 
treatment being held, pomalidomide should be permanently
discontinued.
Grade 3 or 4 platelet count decreased 
that occurs during the 21 day dosing 
period
!
Transfuse platelets to a post-transfusion plate target of 
≥100,000/μL if platelet count is < 50,000/mm3.
!
Interrupt pomalidomide until the platelet count recovers to 
≥100,000/mm3 unsupported (defined as no platelet transfusion 
within 7 days and recovery from nadir).
!
If the toxicity resolves and the subject meets eligibility 
parameters to resume as described in the protocol within 14 days 
(eg, ANC ≥ 1000/mm3; platelets > 100,000/mm3), the subject 
should re-initiate treatment at one dose level lower.
!
If the toxicity does not resolve to meet the eligibility parameters 
as described in the protocol within 14 days of treatment being 
held, pomalidomide should be permanently discontinued.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
65
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 8:
Dose Modification Criteria (Continued)
Toxicity
Dose Modification and Discontinuation
Any Grade 4 non-hematological toxicity
related to pomalidomide
Any Grade 3 non-hematological toxicity 
related to pomalidomide with the 
specific exclusion of following: 
!
Grade 3 nausea and vomiting 
controlled by anti-emetics
(≤3 days) 
!
Grade 3 fever or infection
(≤3 days)
!
Grade 3 hypophosphatemia, 
hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral 
supplementation 
!
Interrupt pomalidomide until toxicity returns to baseline or 
≤Grade 2. 
!
If the toxicity resolves and the subject meets eligibility 
parameters to resume as described in the protocol within 14 days
the subject should re-initiate treatment at one dose level lower.
!
If the toxicity does not resolve to ≤Grade 2 or meet the 
eligibility parameters as described in the protocol within 14 days 
of treatment being held, the investigator, based on clinical 
judgment, should consider discontinuing pomalidomide 
permanently.
Any other medically significant or 
sufficiently intolerable AEs ≥ Grade 2
related to pomalidomide that requires 
treatment interruption
Interrupt pomalidomide until resolution of symptoms.  
!
If resolves (< Grade 2) ≤ 3 days, the subject may resume 
treatment at the same pomalidomide dose level. 
!
If the toxicity recurs upon drug re-challenge, treatment should be 
interrupted again until the toxicity resolves (< Grade 2), and 
subject should re-initiate treatment at a lower dose level. 
!
If the ≥ Grade 2 toxicity recurs at the lower dose level and is 
considered medically significant or intolerable, pomalidomide
should be interrupted again until the toxicity resolves
(< Grade 2), and the subject should re-initiate at the next lower 
dose level. 
!
If the ≥ Grade 2 toxicity recurs after two dose reductions 
(Dose level -2) and is considered medically significant or 
intolerable, pomalidomide should be permanently discontinued.
!
If the toxicity resolves (< Grade 2) after > 3 days but ≤ 14 days, 
subject may resume treatment at a lower dose level.
!
If the toxicity does not resolve (< Grade 2) within 14 days of 
treatment being held, the investigator, based on clinical 
judgment, should consider discontinuing pomalidomide 
permanently.
Grade 4 rash or blistering, Steven’s 
Johnson or TEN (toxic epidermal 
necrolysis) or anaphylaxis
Pomalidomide should be discontinued permanently.
Non-central line related thromboembolic 
event
Pomalidomide should be discontinued permanently.
AEs = adverse events; ANC = absolute neutrophil count. 
7.2.3.
Overdose
Overdose, as defined in this protocol, refers to pomalidomide dosing. 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of pomalidomide assigned to a given subject, regardless of any associated AE(s) or 
sequelae.
!
> 10% over the protocol-specified dose.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
66
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol-required schedule or frequency.
Complete data about treatment administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the eCRF.  See Section 10 for the 
reporting of AEs associated with overdose.
7.3.
Method of Treatment Assignment
Subjects will be enrolled (Section 6.1.5) into the study via IRT.  For detailed IRT screening and 
enrollment procedures, please refer to the IRT User Manual. Subjects will enroll and be assigned 
to one of 4 parallel strata based on the following tumor types: high-grade glioma, 
medulloblastoma, ependymoma and DIPG.  
7.3.1.
Subject Numbering
All subjects will be screened and subsequently enrolled into the study using IRT.  The 
Investigator or designated site staff will be assigned password protected, coded identification 
numbers that give them authorization to log into IRT.  At screening, the Investigator or 
designated staff will log into the IRT and provide the requested identifying information for the 
subject.  IRT will then confirm the assignment of a 2-part unique subject ID number consisting 
of 7 digits. The first part is a 3-digit site number and the second part is a 4-digit number (always 
starting with “1” for the initial screening) assigned sequentially to subjects at that site 
(eg, 101-1001, 101-1002, etc).  If the subject is not eligible for enrollment into the study, the site 
is required to register the subject as a screen failure in IRT.  Subjects who fail screening may be 
rescreened 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 rescreening occurs 
> 28 days from original screening date).  A new Subject ID will be issued once the rescreening 
transaction is registered in IRT.  To identify subjects that rescreen, the 4-digit number identifier 
will start with “2” (eg, 101-2001) for 2nd rescreen, “3” (eg, 101-3001) for third rescreen, etc. 
Once the subject is enrolled into the study, the subject will retain their Subject ID number which 
will be used to identify that specific subject during participation in the study.  
7.4.
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.
7.5.
Investigational Product Accountability and Disposal 
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for IP return, disposal, and/or destruction including responsibilities for the site versus Celgene 
(or designee).
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
67
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the Investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and/or in the Investigator’s Brochure. 
Accountability for all treatment administered during the course of the study is the responsibility 
of the Investigator (or designee).  The Investigator (or designee) is responsible for taking an 
inventory of each shipment pomalidomide received, and comparing it with the accompanying 
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 
treatment received, to whom it was administered (subject-by-subject accounting), and accounts 
of any pomalidomide accidentally or deliberately destroyed or returned.  Accurate recording of 
all treatment administration will be made in the appropriate section of the subject’s eCRF and 
source documents.  
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, dose information, date 
dispensed, numbers of capsules or oral suspension kit components dispensed/returned, date 
returned, etc. should be collected as well as information provided by the subject or the caregiver 
(eg, subject dosing diary).  Treatment accountability should be completed on Cycle 1 Day 1, at 
the end of every treatment cycle (Day 1 of subsequent cycle) and at the end of treatment (EOT)
Visit.
Unless otherwise notified, all pomalidomide both used and unused must be saved for study 
treatment accountability.
7.6.
Investigational Product Compliance
Compliance for pomalidomide administrated during the course of the study is the responsibility 
of the Investigator or designee and accurate recording of all treatment will be captured in the 
appropriate section of the subject’s eCRF and source document.  Compliance will be defined as 
taking between 75% and 110% of the intended quantity of study treatment.
Compliance of the IP will be based on what drug is returned and/or written in the subject dosing
diary.
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ll be base


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
68
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from study treatments or disease progression. 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the Investigator. 
All concomitant treatments, including blood and blood products, used from 28 days prior to first 
dose of study drug, except for those taken for the subject’s disease, must be reported on the 
eCRF.  Medications and procedures associated with the disease under study prior to screening 
will be captured under “Prior disease therapies.” Concomitant treatments must be reported until 
the 28-day post-treatment Safety Follow-up Visit on the eCRF. 
For information regarding other drugs that may interact with treatment and affect its metabolism, 
pharmacokinetics, or excretion, please see the Investigator’s Brochure and/or local package 
insert and prescribing information.
8.1.
Permitted Concomitant Medications and Procedures
All supportive care (eg, antibiotics, blood products, anti-emetics, fluids, electrolytes, etc.), with 
exception of prohibited concomitant medicines and procedures listed in Section 8.2, is permitted 
when necessary and clinically indicated. This includes but not limited to:
8.1.1.
Anti-emetics
Anti-emetics should not be administered prophylactically prior to the first dose of pomalidomide.  
Subsequent use of anti-emetics should be given as needed at the Investigator’s discretion.  
8.1.2.
Corticosteroids
Corticosteroid therapy should be used at the lowest dose consistent with good management for 
treatment of increased intracranial pressure or physiologic replacement.  Physiologic 
replacement doses will be defined on this protocol as no more than 0.75 mg/m2/day of 
dexamethasone or equivalent of corticosteroids.  Doses higher than this will be considered 
therapeutic. 
Corticosteroids should not be used as a first-line anti-emetic.  Subjects on steroids who require 
an increase in steroid dose for worsening neurologic symptoms should have a brain and/or spine 
MRI performed within 72 hours to rule out tumor progression. 
Note: Subjects who are receiving corticosteroids at screening must be on a stable or decreasing 
dose for at least 5 days prior to the screening/baseline MRI. 
8.1.3.
Colony Stimulating Growth Factors
Routine use of growth factors (eg, filgrastim, sargramostim) in clinically well subjects awaiting 
count recovery is not recommended. Therapeutic use of growth factors in subjects with serious 
neutropenic conditions (eg, ANC < 500/mm3), such as sepsis, may be considered at the 
Investigator’s discretion. 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
69
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
8.1.4.
Anticonvulsants
Subjects on anti-epileptic drugs (AEDs) may continue taking these medications as clinically 
indicated.  Due to the unknown effects of pomalidomide on the metabolism of AEDs, it is 
recommended that anticonvulsant levels be followed closely while on this study.
8.1.5.
Neurosurgical or Other Surgical Procedure
If a neurosurgical procedure or other surgical procedure is required for a reason other than tumor 
progression (ie, the onset of hydrocephalus), these procedures should be documented, but will 
not constitute criteria for declaring the subject “off therapy.”  Pomalidomide should be held until 
the subject is clinically stable and has recovered from the acute effects of surgery.  Holding and 
restarting pomalidomide for these neurosurgical interventions should be discussed with the 
Sponsor and Principal Investigator when possible, and documented in the eCRF and source 
documents.
8.1.6.
Alternative Supplements
Subjects on alternative supplements should strongly be encouraged to discontinue them prior to 
first dosing of treatment.  If subjects opt to continue, they may be enrolled into the study as long 
as they have been receiving the supplement for at least 30 days, with no evidence of hepatic, 
renal or other organ dysfunction, and the administration is approved by the Investigator.
8.1.7.
Antibiotics Associated with Febrile Neutropenia
Febrile neutropenia should be managed according to the local institutional guidelines; however,
pomalidomide dosing should be modified as described in Table 8.
8.2.
Prohibited Concomitant Medications and Procedures
Subjects must be instructed not to take any additional medications (over-the-counter, herbal or 
other products) during the study without prior consultation with the Investigator.  Concurrent 
cancer therapy, including investigational, chemotherapy, immunotherapy, live vaccines (with 
exception to nasal influenza vaccine) or biologic therapy may NOT be administered to subjects 
while on this study.  The use of alternative or complementary therapies is also discouraged, but if 
given, should be recorded in the database.  
8.2.1.
Radiotherapy
Radiotherapy is not permitted.
8.2.2.
Deep Venous Thrombosis Prophylaxis
The use of medication for deep vein thrombosis prophylaxis is not allowed for this study.  In the 
event of non-central line related thrombosis, pomalidomide will be discontinued permanently 
and not restarted.
Drugs known to be pro-thrombotic (ie, erythropoietic stimulating agents) should be avoided.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
70
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
8.2.3.
Anti-coagulation Medications
The use of anticoagulation medications is not permitted, with the exception of tPA (ie, 
Alteplase), which may be used to dissolve central-line related thrombosis.
8.2.4.
Moderate to Strong CYP1A2 Inhibitors
Co-administration with moderate to strong CYP1A2 inhibitors (eg, ciprofloxacin, enoxacin, 
fluvoxamine, etc) are not permitted due to the potential drug interactions with pomalidomide.  
Subjects taking a known moderate to strong CYP1A2 inhibitor are excluded from this study. 
Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a 
substrate for P-glycoprotein. Therefore, use of CYP1A2 inhibitors may increase pomalidomide 
exposure.  The treating Investigator should consult a current drug information reference for a 
complete list (http://medicine.iupui.edu/clinpharm/ddis/main-table/).  
Note: As an exception, subjects can be administered propofol (an inhibitor of CYP1A2) for 
sedation procedures such as a MRI. 
8.3.
Required Concomitant Medications and Procedures
Not Applicable.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
71
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This study consists of 4 independent strata for each of a distinct disease indication (high-grade 
glioma, medulloblastoma, ependymoma and DIPG).  Each stratum will enroll up to 20 subjects 
in total that are eligible for analysis of the primary endpoint, ie, a maximum of 80 subjects across 
the 4 strata assuming no subjects are replaced.  A Simon’s Optimal two-stage study design will 
be applied to each stratum.  All baseline and efficacy based endpoints (ORR, long-term SD rate, 
DoR, OS, and PFS) will be presented by stratum; safety data shall be presented by stratum and in 
aggregate. A DMC will be used to monitor the study conduct.  
9.2.
Study Population Definitions
Informed Consent/Assent Population
The Informed Consent/Assent Population will consist of all subjects with signed informed 
consent/assent provided. The Informed Consent/Assent Population will be used for describing 
the disposition of subjects with signed informed consent/assent.
Response Population
The Response Population will consist of all subjects enrolled, receiving at least 1 cycle of 
pomalidomide, if not discontinued therapy earlier due to PD. Subjects who withdraw from the 
Treatment Period for any reason other than PD prior to completing Cycle 1 of study treatment 
will be replaced. Subjects completing at least one cycle of study therapy but not having at least 
one post-baseline disease assessment will be considered a non-responder. The Response 
Population shall be used for analysis of the primary endpoint.
Intent-to-Treat Population
The Intent to Treat (ITT) Population will consist of all subjects enrolled regardless of whether 
the subject received the assigned study treatment or not. The ITT population will be used for 
analysis of efficacy endpoints.  This analysis population will only be used if there is at least one 
subject that enrolled into the study but did not receive study medication.
Safety Population
The Safety Population will consist of all subjects who received at least one dose of 
pomalidomide. The safety population will be applied for the analysis of all safety and efficacy 
endpoints.
Pharmacokinetic Population 
The PK Population will include all subjects who received at least one dose of pomalidomide and 
have at least one measurable pomalidomide plasma concentration. The evaluable subjects in the 
PK population will be included in the PK data analysis.  
9.3.
Sample Size and Power Considerations
Under Simon’s Optimal two-stage design with a 5% significance level and 90% power, assuming 
a lower boundary of interest in the response rate of 10% and an upper boundary of interest in the 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
72
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
response rate of 40%, a total of 20 subjects evaluable for the primary endpoint (ie, Response 
Population) are required per stratum; 9 per stratum in Stage 1 and an additional 11 per stratum in 
Stage 2.  
Enrollment will proceed as follows:
1. Stage 1: Nine subjects will be enrolled into each of the strata.
2. Stage 2: If during Stage 1, ≥ 2 subjects in a given stratum achieve either an OR (either 
CR or PR) within the first 6 cycles of treatment (within 3 cycles for DIPG) or a long-term 
SD, an additional 11 subjects shall be enrolled to that stratum; otherwise no additional 
subjects will be enrolled.
3. If a total of 5 or more subjects across all 20 subjects in a given stratum (Stage 1 and 2) 
evaluable for the primary endpoint are observed as having either an OR (either CR or PR)
within the first 6 cycles of treatment (within 3 cycles for DIPG) or long-term SD, 
pomalidomide will be considered effective in that disease indication.
Up to 80 subjects (36 subjects in Stage 1 and 44 subjects in Stage 2) will be included should all 
strata enroll the maximum number of subjects (ie, 20 per stratum), assuming no subjects are 
replaced.  
9.4.
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. 
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for the Screening 
Period, Treatment Period and Follow-up Period.  A summary of subjects enrolled by site will be 
provided.  Protocol deviations and violations will be summarized using frequency tabulations. 
9.6.
Efficacy Analysis
Objective Response and Long-term Stable Disease Rate
Objective response and long-term SD rate (ORSDR), is defined as the total number of subjects 
achieving either an OR (either CR or PR) within the first 6 cycles of treatment (within 3 cycles 
for DIPG) or a long-term SD (SD maintained for ≥ 6 cycles [> 3 cycles for DIPG]), over the total 
number of subjects evaluable for analysis. Evaluable is defined as a subject completing at least 
one cycle of study therapy or discontinuing treatment earlier due to a PD.  Subjects completing at 
least one cycle of study therapy but not having at least one subsequent (post-baseline) disease 
assessment will be considered a non-responder. The corresponding Clopper Pearson 95% 
confidence interval (CI) shall be calculated for each rate per stratum. Each stratum will be 
analyzed separately.  Analysis of this endpoint will be based on the Response Population, with 
secondary analyses based on the ITT Population and/or Safety Population.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
73
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Objective Response Rate
The ORR is defined as the total number of subjects achieving an OR (either CR or PR), over the 
total number of subjects evaluable for the analysis.  Disease responses occurring after start of a 
new anticancer therapy shall not be considered. Each stratum will be analyzed separately.
Analysis of this endpoint will be based on the ITT Population and/or Safety Population.
Long-term Stable Disease Rate
The long-term SD rate is the proportion of subjects achieving long-term SD, defined as a SD 
maintained for ≥ 6 cycles (≥ 3 cycles for DIPG), over the total number of subjects evaluable for 
the analysis.  The corresponding Clopper Pearson 95% CI shall be calculated for each rate per 
stratum.  Each stratum shall be analyzed separately.  Analysis of this endpoint will be based on 
the ITT Population and/or Safety Population.
Duration of Response
Duration of response is defined as the time from first observed response (either CR or PR, 
whichever comes first) until either disease progression, or death. Only subjects observed with a 
response shall be included in the analysis of DoR.  The median DoR time and the proportion of 
subjects remaining with a response at 3, 6, 9, 12, 18 and 24 months, and at close of study along 
with the corresponding 95% CI will be calculated using Kaplan-Meier methods.  Subjects who 
are alive and remain in disease response at the time of analysis will be censored at the time of 
their last adequate disease assessment or at the time of starting a new anticancer therapy, 
whichever is first. Due to the low number of subjects to be included in the analysis, additional 
summary statistics will be presented.  Each stratum shall be analyzed separately.  Analysis of this 
endpoint will be based on the ITT Population and/or Safety Population.
Progression-Free Survival
Progression-free survival is defined as the time from enrollment until either disease progression, 
or death of any cause, whichever occurs first.  The median PFS time and proportion of subjects 
remaining progression-free at 3, 6, 9, 12, 18 and 24 months, and at close of study along with the 
corresponding 95% CI calculated using Kaplan-Meier methods will be presented.  Subjects 
remaining progression-free at the time of analysis will be censored at the time of their last 
adequate disease assessment. Additionally, subjects will be censored at the time of starting a 
new anticancer therapy if having not had disease progression previously.  Due to the low number 
of subjects to be included in the analysis, additional summary statistics will be presented.  Each 
stratum shall be analyzed separately.  Analysis of this endpoint will be based on the ITT 
Population and/or Safety Population.
Overall Survival
Overall survival is defined as the time from enrollment until death of any cause.  The median OS 
time and proportion of subjects remaining alive at 3, 6, 9, 12, 18 and 24 months, and at close of 
study, along with the corresponding 95% CI, calculated using Kaplan-Meier methods will be 
presented.  Subjects remaining alive at the time of analysis will be censored at the time they were 
last known to be alive.  Due to the low number of subjects to be included in the analysis, 
additional summary statistics will be presented. Each stratum shall be analyzed separately.  
Analysis of this endpoint will be based on the ITT Population and/or Safety Population.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
74
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
9.7.
Safety Analysis
Toxicity Assessment
Toxicity, including SPMs, will be monitored in real time during the course of the study.  
Descriptive statistics will be used to summarize the proportion of subjects experiencing any 
Grade 3 or higher non-hematologic toxicities and infections.
Adverse Events 
Adverse Events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) (latest version).  This study will utilize the NCI CTCAE (version 4.03) for toxicity
grading and performance reporting.  All AE data shall be presented by disease stratum and in 
aggregate, based on the Safety Population, ie, all subjects receiving at least one dose of 
pomalidomide.
Treatment-emergent adverse events are defined as any AE occurring or worsening on or after the 
first dose of the study medication until the 28-day post-treatment Safety Follow-up Visit.  All 
TEAEs, AEs leading to study medication discontinuation, AEs leading to dose reduction/ 
interruption, AEs related to the study treatment, SAEs, and AEs leading to death will be 
summarized by cycle and 28-day follow-up period after permanent treatment discontinuation as 
well as by subject (worse recorded grade) per event type (organ class and preferred term) and 
grade.  A summary of AEs with NCI CTCAE (version 4.03) Grade 3 or higher, as well as the 
most frequent preferred terms, will also be provided by grade and term.
Cross tabulations will be provided to summarize frequencies of abnormalities.  
By-subject listings will be provided for all relevant safety data.  Graphical displays and figures 
will be provided where useful to assist in the interpretation of results.
Deaths
Deaths during the Treatment Period (defined as the time between enrollment until the 28-day 
post-treatment Safety Follow-up Visit) and during the Follow-up Period shall be summarized by 
frequency of occurrence and corresponding percentage by cause of death per study period 
(during treatment or follow-up) as well as overall. All death data shall be presented by disease 
stratum and in aggregate.
9.8.
Interim Analysis
For each stratum, there is one interim analysis planned at the end of Stage 1. The interim analysis 
will be informal, performed internally by Celgene personnel with input, only if needed, from the 
DMC and steering committee (SC). Enrollment will be suspended for each interim analysis,
once the first 9 subjects evaluable for the primary endpoint have been enrolled.  Enrollment for 
each stratum will be re-opened/closed based upon the following criteria:
!
Should only one or no subjects be observed as having either an OR (either CR or PR) or a 
long-term SD, that stratum shall be closed to further enrollment.  
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Should at least 2 subjects across Stage 1 have either an OR (either CR or PR) or a long-
term SD, then that stratum will continue into Stage 2 to include up to 11 more additional 
subjects evaluable for the primary endpoint.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
75
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
9.9.
Other Topics
9.9.1.
Pharmacokinetic Analysis
If warranted, population PK analysis (eg, CL/F and Vd/F) of pomalidomide plasma 
concentrations will be conducted, with possible pooling of data from other clinical studies with 
pomalidomide.  
9.9.2.
Data Monitoring Committee
An external DMC with multidisciplinary representation will be established to evaluate safety 
data periodically to monitor the overall benefit-to-risk of this protocol.  The DMC will be 
comprised of medical oncologists with experience in treating pediatric subjects with brain tumors
and a statistician, all of whom are not otherwise involved in the study conduct.  During the 
course of the study, the DMC will review the safety data regularly as well as safety and efficacy 
data in accordance with the guidelines for the preplanned interim analyses (ie, end of Stage 1 and 
Stage 2).
The DMC will advise on serious safety considerations and any other issues important to the safe 
conduct of the study, and will make recommendations about the continuing safety of current 
participants and those yet to be enrolled.  The DMC will also provide recommendations about 
stopping the study, or continuing the study as planned, or with modifications for safety reasons, 
and may advise on ways to improve quality. 
Details regarding the operational aspects, structure, composition, roles and responsibilities of the 
DMC will be outlined in a DMC charter.
9.9.3.
Steering Committee 
The SC will be established comprising of Investigators participating in the study (ie, not being 
members of a DMC and Celgene representatives from the clinical study team).
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical study team, the SC will also 
develop recommendations for publications of study results including authorship rules (if 
applicable). The details of the role of the SC are defined in a SC charter.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
76
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
10.
ADVERSE EVENTS
10.1.
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 in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to the IP should be reported as an AE. Overdose, 
accidental or intentional, whether or not it is associated with an AE should be reported on the 
overdose eCRF. (See Section 7.2.3 for the definition of overdose.) Any sequela of an accidental 
or intentional overdose of the IP should be reported as an AE on the AE eCRF. If the sequela of 
an overdose is an SAE, then the sequela must be reported on an SAE report form and on the AE 
eCRF. The overdose resulting in the SAE should be identified as the cause of the event on the 
SAE report form and eCRF but should not be reported as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for pomalidomide
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 findings from 
other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed 
consent/assent until the 28-day post-treatment Safety Follow-up Visit as well as those SAEs 
made known to the Investigator at any time thereafter while in Long-term Follow-up that are 
suspected of being related to study drug.  Adverse events and SAEs will be recorded on the AE 
page of the eCRF 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.  
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
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risk of death from the AE);
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
77
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
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subject’s ability to conduct normal life functions);
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Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
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. 
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routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
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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 eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
!
an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 
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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 eCRF 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.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
78
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
10.2.2.
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 the CTCAE, Version 4.03); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to 
the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
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 AE to the 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 the 
IP caused the AE.  ‘Reasonable possibility’ means there is 
evidence to suggest a causal relationship between the IP and the 
AE.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
&&,
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calal
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or de
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ine
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d:d:
a cau
a c
un
un
Suspected
Suspected


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
79
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
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.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with the IP as a result of an AE or SAE, as 
applicable (eg, discontinuation, interruption, or dose reduction of the IP, as appropriate) and 
report if concomitant and/or additional treatments were given for the event. 
10.2.6.
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, or death (due to 
the SAE).
10.3.
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 the IP dose, or any other therapeutic 
intervention; or
!
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a 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 eCRF.  If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a FCBP/FCCBP 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 
pomalidomide is also an immediately reportable event.
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Pr
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All pregn
All pregn
hildbe
hildb


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
80
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated βhCG or positive pregnancy test in a 
FCBP/FCCBP regardless of disease state) occurring while the subject is on IP, or until the 28-day 
post-treatment Safety Follow-up Visit are considered immediately reportable events.  
Investigational product is to be discontinued immediately and the subject instructed to return any 
unused portion of the IP to the Investigator. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by email, phone or 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form.  
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or any 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 methods, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.4.2.
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.  
10.5.
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 eCRF.  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. This includes any SPM, regardless of causal relationship to treatment, occurring at any 
time for the duration of the study, for at least 5 years from enrollment of the last subject, unless 
consent/assent is withdrawn, the subject is lost to follow-up, or death. Subjects that do not 
receive treatment (eg, screen failures) will not be followed for SPM.  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 
&&,
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
81
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
page(s) of the eCRF (ie, AE and SPM eCRF) and subject’s source document(s). Documentation 
on the diagnosis of the SPM 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 the IP) that occur during the 
study (from the time the subject signs informed consent/assent until the 28-day post-treatment
Safety Follow-up Visit) or any SAE made known to the Investigator at any time 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 a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the Investigator is responsible for informing the 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.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
10.6.
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 pomalidomide based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and ECs concerned, 
SUSARs in accordance with Directive 2001/20/EC and the Detailed Guidance on collection, 
verification and presentation of adverse reaction reports arising from clinical trials on the IP for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.  
Celgene or its authorized representative shall notify the Investigator of the following 
information:
!
Any AE suspected of being related to the use of the 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.
&&,
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
82
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
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 14.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the SAE Report Form Completion 
Guidelines or to the Pregnancy Report Form Completion Guidelines.
&&,


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
83
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the IP(s):
!
Adverse Event
!
Withdrawal of consent/assent by subject/parent(s)/legal guardian(s) - under this 
situation, the Investigator should clarify if the family also wishes to withdraw the 
study ICF/IAF for continued participation in the Long-term Follow-up Period and 
data collection
!
Death
!
Lost to follow-up
!
Pregnancy
!
Non-compliance with IP 
!
Progressive disease
!
Physician decision
!
Protocol violation
!
Completion of the Treatment Period (24 cycles)
!
Study or site terminated by Sponsor
!
Other (to be specified on the eCRF)
The reason for discontinuation of treatment, last dose of treatment and date subject taken off 
treatment should be recorded in the eCRF and in the source documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician and 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 
documentation for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
!
Withdrawal of consent/assent by subject/parent(s)/legal guardian(s) for any further 
data collection
!
Death
!
Lost to follow-up
!
Completion of the Follow-up Period
&&,
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
84
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
Study or site terminated by Sponsor
!
Other (to be specified on the eCRF)
The date and reason for study discontinuation should be recorded in the eCRF 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.
Since the follow-up of subjects who discontinue prematurely is of particular importance, every 
attempt should be made to collect all survival information and new anticancer treatment/therapy, 
unless the subject has specifically withdrawn consent/assent from further follow-up.  
Note: The Long-term Follow-up Period may not be terminated because of new anticancer 
treatment.  
For subjects whose status is unclear because they fail to appear for study visits without stating an 
intention to withdraw consent/assent, the Investigator should show "due diligence" by contacting 
the subject, family or family physician as agreed in the informed consent/assent and by 
documenting in the source documents steps taken to contact the subject, eg, dates of telephone 
calls, registered letters, etc. A subject should not be considered lost to follow-up until due 
diligence has been completed.  Subjects lost to follow-up should be recorded as such on the 
appropriate eCRF.  
&&,
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eg, da
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to follo
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
85
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Celgene 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, 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 Physicians or Medical Monitor or designee for emergency 
calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, the IP will be identified on the package labeling.
&&,
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d on the p


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
86
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
13.
REGULATORY CONSIDERATIONS
13.1.
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 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.
13.2.
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 ICF/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 eCRFs 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 Investigator’s Brochure 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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espons
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
87
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
13.3.
Subject Information and Informed Consent/Assent
The Investigator must obtain informed consent/assent of a subject and/or a subject’s legal 
representative prior to any study related procedures.
Documentation that informed consent/assent occurred prior to the study subject’s entry into the 
study and of the informed consent/assent process should be recorded in the study subject’s 
source documents including the date.  The original ICF/IAF signed and dated by the study 
subject and by the person consenting the study subject prior to the study subject’s entry into the 
study, must be maintained in the Investigator’s study files and a copy given to the study subject.  
In addition, if a protocol is amended and it impacts on the content of the informed 
consent/assent, the ICF/IAF must be revised.  Study subjects participating in the study when the 
amended protocol is implemented must be re-consented/assented with the revised version of the 
ICF/IAF.  The revised ICF/IAF signed and dated by the study subject and by the person 
consenting the study subject must be maintained in the Investigator’s study files and a copy 
given to the study subject.
13.4.
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 ICF/IAF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval. 
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/EC approval but will be submitted to the IRB/EC for 
information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, 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.
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dates o
gh


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
88
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
The 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 ICF 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.  
13.7.
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 AEs 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
13.8.
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).
In the case where there are subjects still being administered the investigational product, and it is 
the opinion of the Investigator(s) that these subjects continue to receive benefit from treatment, 
the Sponsor may choose to initiate an open-label, extension study under a separate protocol to 
allow these subjects continued access to pomalidomide following their participation in this study 
(CC-4047-BRN-001).
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
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
89
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
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:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
90
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
14.
DATA HANDLING AND RECORDKEEPING
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the IP 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 eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (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.
14.3.
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 eCRFs 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.)
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
91
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial)
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. The 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
he
ruction of 
uction of


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
92
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
15.
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.
15.1.
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 Investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, 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, facsimile, or telephone.  During monitoring visits, the facilities, 
IP storage area, eCRFs, subject’s source documents, and all other study documentation will be 
inspected/reviewed by the Celgene representative in accordance with the Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs 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 eCRFs 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.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, European Medicines 
Agency [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:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
93
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
16.
PUBLICATIONS
As described in Section 13.2, 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 SC (when 
applicable) and contribution to abstract, presentation and/or publication development.
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
94
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
17.
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fects
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lidomide a
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donald C
ependently 
ependently
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ois EF. A fo
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16.6. Arch In
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Jungnelius
ungneliu
natatioi n wi
with
th
i
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orac Onco
Escoubet
Escoubet
21
21 WAF
WA


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
95
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
96
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
97
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
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Sie M, den Dunnen WF, Hoving EW, et al. Anti-angiogenic therapy in pediatric brain tumors: an 
effective strategy?  Crit Rev Oncol Hematol. 2014;89(3):418-32.
Teo SK, Stirling DI, Zeldis JB.  Thalidomide as a novel therapeutic agent: new uses for an old 
product.  Drug Discov Today. 2005;10(2):107-14.
Walker DA, Punt JA, Sokal M.  Clinical management of brain stem glioma.  Arch Dis Child. 
1999;80(6):558-64.
Warren KE, Goldman S, Pollack IF, et al.  Phase I trial of lenalidomide in pediatric patients with 
recurrent, refractory, or progressive primary CNS tumors:  Pediatric Brain Tumor Consortium 
study PBTC-018.  J Clin Oncol. 2011;29(3):324-9.
Warren KE.  Novel therapeutic delivery approaches in development for pediatric gliomas. CNS 
Oncol. 2013;2(5):427-35.
Xu Y, Li J, Ferguson GD, et al.  Immunomodulatory drugs reorganize cytoskeleton by 
modulating Rho GTPases.  Blood. 2009;114(2):338-45.
&&,
rugs.  
ugs. 
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escent b
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tic agent: n
c agent: n
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rain stem 
trial o
trial of lena
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S tumors:  
S tumors:  
324
324-9.
-9.
approaches
approaches
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od
od.d 2009;1
2009;1


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
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18.
APPENDICES
Appendix A: Table of Abbreviations
Table 9:
Abbreviations and Specialist Terms 
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
AED
Anti-epileptic drugs
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
ATRT
Atypical teratoid rhabdoid tumor 
AUC
Area under the curve
β-FGF
Basic fibroblast growth factor
β-Hcg
β-subunit of human chorionic gonadotropin
BSA
Body surface area
CDK
Cyclin-dependent kinase
CI
Confidence interval
CL/F
Clearance
Cmax
Maximum plasma concentration of drug
CNS
Central nervous system
COG
Children oncology group
CR
Complete response
CRBN
Cereblon protein
CRO
Contract research organization
CSF
Cerebrospinal fluid
CTCAE
Common terminology criteria for adverse events
CUL4
Cullin 4
CYP
Cytochrome P450
DDB1
DNA Damage-binding protein 1 
DIPG
Diffuse intrinsic pontine glioma
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
DoR
Duration of response
EC
Ethics Committee
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52
Contract
Contract
35
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( 3
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1(
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DLT
DL
&(
&


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
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CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 9:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
eCRF
Electronic case report form
EEA
European Economic Area
EMA
European Medicines Agency
EOT
End of treatment
EU
European Union
FCBP
Females of childbearing potential
FCCBP
Female children of childbearing potential
FDA
Food and Drug Administration
FLAIR
Fluid-attenuated inversion recovery
GBM
Glioblastoma multiforme
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GFR
Glomerular filtration rate
GTR
Gross total resection 
GVHD
Graft versus host disease
HDPE
High density polyethylene
IAF
Informed assent form
ICF
Informed consent form
ICH
International Council on Harmonisation
ID
Identification number
IIT
Investigator initiated trial
IL
Interleukin
IND
Investigational new drug
IFN-γ
Interferon-gamma
IP
Investigational product
IR
Incomplete response
IRF4
Interferon regulatory factor 4
IRB
Institutional review board
IRT
Interactive Response Technology
ITT
Intent to treat
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RB
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
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Confidential and Proprietary
100
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 9:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
MAA
Marketing authorization application
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
MF
Myelofibrosis
MM
Multiple myeloma 
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National cancer institute 
NCS
Not clinically significant 
NF1
Neurofibromatosis type 1
NHL
non-Hodgkin’s lymphoma
NK
Natural killer 
NLME
Nonlinear mixed-effect 
O2
Oxygen
OAT
Organic anion transporter
OCT
Organic cation transporter
OR
Objective response
ORR
Objective response rate
ORSDR
Objective response and long-term stable disease rate
OS
Overall survival
PA
Pilocytic astrocytoma
PBTC
Pediatric Brain Tumor Consortium 
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
PK
Pharmacokinetics
PNET
Primitive neuroectodermal tumor 
RBC
Red blood cell count
RP2D
Recommended phase 2 dose
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
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CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 9:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
SAE
Serious adverse event
SC
Steering committee
SCT
Stem cell transplant
SD
Stable disease
SOP
Standard operating procedure
SPM
Second primary malignancy 
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Half-life
TBI
Total body irradiation
TEAE
Treatment emergent adverse event
TEN
Toxic epidural necrolysis
TGF-α
Transforming growth factor alpha
Th1
T helper cell type 1
Tmax
Time to maximum plasma concentration
TNF-α
Tumor necrosis factor-alpha
tPA
Tissue plasminogen activator
ULN
Upper limit of normal
Vd/F
Volume of distribution
VEGF
Vascular endothelial growth factor
WBC
White blood cell
WHO
World Health Organization 
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EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
102
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Appendix B: Tumor Response Categories for Target and Non-target Lesions
Target Lesions
For the purpose of this study, response criteria for target lesions are defined as follows: 
!
Complete Response (CR): 
∀
Complete disappearance on MRI of all measurable lesions.
!
Partial Response (PR):
∀
A reduction of ≥ 50% in tumor size by bi-dimensional measurement (taking as 
reference the baseline measurements) quantified by the sum of the products of the 
perpendicular diameters of measurable lesions.
!
Stable Disease (SD):  
∀
A decrease of < 50% or an increase of < 25% in the sum of the products of the 
perpendicular diameters of measurable lesions and no evidence of new lesions.  
Response does not meet the criteria for CR, PR or PD.  
!
Progressive Disease (PD):
∀
≥ 25% increase in the bi-dimensional measurement as quantified by the sum of 
the products of the largest diameters of the measurable lesions taking as a 
reference the smallest disease measurement recorded since the start of protocol 
therapy (nadir).
Non-target Lesions
For the purpose of this study, response criteria for non-target lesions are defined as follows:
!
Complete Response (CR):
∀
Disappearance of all non-target lesions.
∀
If spine MRI and/or lumbar CSF cytology were previously positive, it must be 
negative at time of assessment.
!
Incomplete Response/Stable Disease (IR/SD):  
∀
The persistence of non-target lesions, stable (no progression) or decrease in size.
∀
If spine MRI and/or lumbar CSF cytology were previously positive at baseline
and remains positive with no other evidence of PD.
!
Progressive Disease (PD): 
∀
The appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.
∀
If spine MRI and/or lumbar CSF cytology were previously negative and became 
positive.
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∀


EDMS Doc. Number:
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
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Appendix C: Overall Response Assessment
The overall response assessment takes into account response in both target (Appendix B) and non-target lesions (Appendix B), the 
appearance of new lesions, current corticosteroid use (compared to baseline) and neurologic symptoms/examination (clinical status)
according to the criteria below (Table 10).  Subjects who do not meet the criteria for an objective response or disease progression by 
the end of Cycle 6 (end of Cycle 3 for DIPG subjects) will be considered as having long-term SD.
Table 10:
Overall Response Assessment
Overall Response
Criterion
Complete Response
Partial Response
Stable Disease 
Progression 
Target lesions 
CR
PR
CR
SD
PD
Non-Target lesions 
CR
CR or IR/SD
IR/SD
CR or IR/SD
PD
New Lesion
None
None
None
None
Present
Corticosteroids
None
a
Stable or 
Decreasingb
Stable or 
Decreasingb
Stable or 
Decreasingb
Not Applicablec
Clinical Status (neurologic 
examination)
Stable or Improved
Stable or 
Improved
Stable or 
Improved
Stable or 
Improved
Decreasingd
Requirement for Response 
All
All
All
All
Anye
CR = complete response; IR = incomplete response; PR = partial response; SD = stable disease; PD = progressive disease.
a Only physiologic replacement doses allowed, defined as no more than 0.75 mg/m2/day of dexamethasone or equivalent.
b Not greater dose than compared with baseline.
c An increase in corticosteroid dose alone will not cause a determination of progression in the absence of clinical deterioration or radiographically documented 
lesion growth.
d Neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (eg, anticonvulsant or corticosteroid toxicity 
wean, electrolyte disturbances, sepsis, hyperglycemia, etc.) or changes in corticosteroid dose.
e Progression occurs when any of these criteria are met present.
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are met pre


EDMS Doc. Number
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
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104
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Appendix D: Performance Status
Table 11:
Performance Status
Karnofsky Scale (age ≥ 16 years)
Lansky Scale (age < 16 years)
Able to carry on normal activity and to work; no 
special care needed.
Able to carry on normal activity; no special care 
is needed
100
Normal no complaints; no evidence of 
disease
100
Fully active
90
Able to carry on normal activity; minor 
signs or symptoms of disease
90
Minor restriction in physically strenuous 
play
80
Normal activity with effort; some signs or 
symptoms of disease
80
Restricted in strenuous play, tires more 
easily, otherwise active
Unable to work; able to live at home and care for 
most personal needs; varying amount of 
assistance needed.
Mild to moderate restriction
70
Cares for self; unable to carry on normal 
activity or to do active work
70
Both greater restrictions of, and less time 
spent in active play
60
Requires occasional assistance, but is able 
to care for most of his personal needs
60
Ambulatory up to 50% of the time, 
limited active play with 
assistance/supervision
50
Requires considerable assistance and 
frequent medical care
50
Considerable assistance required for any 
active play, fully able to engage in quiet 
play
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly.
Moderate to severe restriction
40
Disabled; requires special care and 
assistance
40
Able to initiate quiet activities
30
Severely disabled; hospital admission is 
indicated although death not imminent
30
Needs considerable assistance for quiet 
activity
20
Very sick; hospital admission necessary; 
active supportive treatment necessary
20
Limited to very passive activity initiated 
by others (eg, television)
10
Moribund; fatal processes progressing 
rapidly
10
Completely disabled, not even passive 
play
0
Dead 
0
Unresponsive
Source: Karnofsky, 1949; Lansky 1987.
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
105
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Appendix E: Plasma PK Sample Handling Instruction
Each participating institution will be provided with PK sample collection kits along with a PK 
laboratory manual.
Preparation of Collection Tubes and Storage Vials
All labels will be provided by central laboratory.  The labels will contain the following 
information:
!
Protocol No.: CC-4047-BRN-001
!
Subject ID number: (To be added by site)
!
Nominal Time (eg, 2 hours postdose)
!
Sample Type (eg, Plasma Primary or Backup) 
All plasma collection tubes and storage vials should be labeled and chilled on wet ice prior to
sample collection and processing.
Pomalidomide 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 two pre-labeled, pre-chilled, 
polypropylene citric acid 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 –20oC freezer, where the tubes will remain stored until shipping.
!
Immediately record the time of sample entry into the freezer.
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Immed
med
m


EDMS Doc. Number
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
106
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
PK Plasma 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 on dry ice from the sites 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-4047-BRN-001
!
Subject ID Numbers
!
Collection date (eg, dd mmm yyyy)
!
Nominal collection time (ie, 2 hours postdose)
!
Sample types (eg, Plasma Primary or Backup)
The central lab will then ship the samples to XBL for sample analysis of pomalidomide.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
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pomali


EDMS Doc. Number
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
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Appendix F: Pomalidomide Dosing 
Table 12:
Pomalidomide Capsule Dosing Tables
2.6 mg/m2/day (Starting Dose)
Minimum BSA (m2)
Maximum BSA (m2)
Daily Pomalidomide Dose (mg)
0.55
0.66
1.5
0.67
0.86
2.0
0.87
1.05
2.5
1.06
1.25
3.0
1.26
1.44
3.5
1.45
1.63
4.0
1.64
1.82
4.5
1.83
2.01
5.0
2.02
2.21
5.5
2.22
2.40
6.0
2.41
2.50
6.5
1.9 mg/m2/day (Dose Level -1)
Minimum BSA (m2)
Maximum BSA (m2)
Daily Pomalidomide Dose (mg)
0.55
0.66
1.0
0.67
0.92
1.5
0.93
1.18
2.0
1.19
1.44
2.5
1.45
1.71
3.0
1.72
1.97
3.5
1.98
2.23
4.0
2.24
2.49
4.5
2.50
2.50
5.0
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
108
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 12:
Pomalidomide Capsule Dosing Tables (Continued)
1.3 mg/m2/day (Dose Level -2)
Minimum BSA (m2)
Maximum BSA (m2)
Daily Pomalidomide Dose (mg)
0.55
0.66
0.5
0.67
0.96
1.0
0.97
1.34
1.5
1.35
1.73
2.0
1.74
2.11
2.5
2.12
2.50
3.0
BSA = body surface area.
&&,
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5


EDMS Doc. Number
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
109
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 13:
Pomalidomide Dosing Table – Oral Suspension
For subjects receiving pomalidomide as an oral suspension, please refer to the Pomalyst Oral 
Suspension Preparation Administration and Handling Guide for additional guidance.
Calculated Dose
(mg/day)
Actual Dose Administered
(mg/day)
Volume Administered 
(mL)
0.50 to 0.69
0.6
0.3
0.70 to 0.89
0.8
0.4
0.90 to 1.09
1.0
0.5
1.10 to 1.29
1.2
0.6
1.30 to 1.49
1.4
0.7
1.50 to 1.69
1.6
0.8
1.70 to 1.89
1.8
0.9
1.90 to 2.09
2.0
1.0
2.10 to 2.29
2.2
1.1
2.30 to 2.49
2.4
1.2
2.50 to 2.69
2.6
1.3
2.70 to 2.89
2.8
1.4
2.90 to 3.09
3.0
1.5
3.10 to 3.29
3.2
1.6
3.30 to 3.49
3.4
1.7
3.50 to 3.69
3.6
1.8
3.70 to 3.89
3.8
1.9
3.90 to 4.09
4.0
2.0
4.10 to 4.29
4.2
2.1
4.30 to 4.49
4.4
2.2
4.50 to 4.69
4.6
2.3
4.70 to 4.89
4.8
2.4
4.90 to 5.09
5.0
2.5
5.10 to 5.29
5.2
2.6
5.30 to 5.49
5.4
2.7
5.50 to 5.69
5.6
2.8
5.70 to 5.89
5.8
2.9
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Protocol CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
110
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
Table 13:
Pomalidomide Dosing Table – Oral Suspension (Continued)
Calculated Dose
(mg/day)
Actual Dose Administered
(mg/day)
Volume Administered 
(mL)
5.90 to 6.09
6.0
3.0
6.10 to 6.29
6.2
3.1a
6.30 to 6.49
6.4
3.2a
6.50-6.69
6.6
3.3a
a For administered volumes > 3.0 mL, the dose should be split. For example, a volume of 3.2 mL can be 
administered as two doses of 1.6 mL each. A dose of 3.3 can be administered as two doses of 1.6 mL and 1.7 mL 
each.
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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
Pomalyst® (Pomalidomide)
Summary of Changes CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
3
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Clarified that only subjects with brain as the primary site of disease (primary brain 
tumors) will be allowed to participate
The inclusion criteria and the definition of measurable disease was updated to clarify that 
subjects must have brain tumor as a primary target lesion.  This was revised to exclude 
subjects with metastatic brain lesions, as this trial is only targeting subjects with primary 
brain tumors.
Revised sections: Section 4.2 Inclusion Criteria, No. 6; Section 6.4.1.1 Selection of Target 
and Non-Target Lesions
!
Updated language regarding the required screening pregnancy testing 
Amended language to state that the pregnancy test 10 to 14 days prior to initiation of 
pomalidomide may be omitted, at the discretion of the investigator, for any females of 
childbearing potential (FCBP)/female children of childbearing potential (FCCBP) who have
high acuity disease requiring immediate treatment with pomalidomide. This change was 
made to accommodate any potential subjects with high-risk disease, who may need
immediate treatment with pomalidomide. The pregnancy test within 24 hours prior to the first 
dose of pomalidomide is still required to be performed.
Revised sections: Section 4.2 Inclusion Criteria, No. 17; Section 5 Table of Events (Table 4); 
Section 6.1 Screening Period; 6.2 Treatment Period; Section 6.4.2.9 Pregnancy Testing and 
Pregnancy Risk Counseling
!
Clarified the use of anti-coagulation therapy 
Provided clarification that small clots in central lines that are resolved with tissue 
plasminogen activator (tPA) flush will not be considered a central-line related thrombosis.  In 
addition, the use of tPA (eg, Alteplase) to flush subject’s central-line is allowed and would 
not be considered a prohibited concomitant medication. 
Revised sections: Section 4.3 Exclusion Criteria, Nos.1 and 3; Section 8.2.3 Anti-coagulation 
Medications
!
Updated language regarding the collection of pharmacokinetic samples
Clarified that blood samples for pharmacokinetic (PK) analysis can be obtained through a 
central line, if applicable.  The use of the central line to collect PK samples and any 
concomitant medications given via the central line prior to sampling must be captured in the 
appropriate section of the subject’s electronic case report form (eCRF) and source 
documents. In addition, removed the requirement that pomalidomide needs to be 
administered “at the study center” on Cycle 1, Day 8 and 15.
Revised section: Section 6.5 Pharmacokinetics - Optional
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Summary of Changes CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
4
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
Extended the collection time window for the pre-dose PK sample
To avoid the potential for an additional blood draw on PK days, the collection window for 
the 0-hour (pre-dose) PK sample on Cycle 1, Day 8 and Cycle 1, Day 15 was updated from   
-30 minutes to -90 minutes in order to allow the PK blood sample to be collected with the 
other labs that day (ie, hematology and chemistry labs).
Revised section: Section 6.5 Pharmacokinetic Sampling Time Points (Table 6)
!
Added the Informed Consent/Assent Population
The Informed Consent/Assent Population was added to be consistent with the CC-4047-
BRN-001 Statistical Analysis Plan.  The Informed Consent/Assent Population will consist of 
all subjects with signed informed consent/assent provided and used for describing the 
disposition of subjects with signed informed consent/assent.
Revised section: Section 9.2 Study Population Definitions 
The amendment also includes other minor clarifications and corrections including: 
!
Clarified that 2.6 mg/m2/day was the maximum tolerated dose (MTD), not the 
recommended Phase 2 dose, from the Phase 1 trial conducted by the Pediatric Brain 
Tumor Consortium (PBTC-043).  (Protocol Summary; Section 1.2.4; Section 1.3.3). 
!
Updated the current approval status of pomalidomide (Section 1.2).
!
Clarified that brain and spine magnetic resonance imaging (MRI) assessments can be 
performed within 7 days prior to the completion of Cycle 24 (Section 3.1; Section 5 
Table of Events [Table 4]; Section 6.4.1).
!
Clarified that prior immunomodulatory therapy refers to thalidomide and 
lenalidomide (Section 4.3).
!
Corrected the word “Secondary” to “Second” as Second Primary Malignancy is the 
correct phrase to use (Section 3.1; Section 5 Table of Events [Table 4]).
!
Defined FCBP = females of childbearing potential and FCCBP = female children of 
childbearing potential (Section 5 Table of Events [Table 4]).
!
Clarified that it is the responsibility of the Investigator to obtain and review 
laboratory/pregnancy results for subject safety, and follow up with subjects in a 
timely manner (Section 5 Table of Events [Table 4], Section 6.4.2.6, Section 6.4.2.9).
!
Removed “initials” from the demographic data to be collected since initials are not 
being captured in the study (Section 6.1.2).   
!
Clarified that cerebrospinal fluid, positive or negative for tumor cells, will be 
followed as nonmeasurable disease (Section 6.4.1.1). 
!
Corrected that a new informed consent/assent and screening procedures will need to 
be repeated if rescreening occurs > 28 days (not 21 days) from original screening date
(Section 7.3.1).
!
Clarified the safety population will be applied for the analysis of all safety and 
efficacy endpoints (Section 9.2). 
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Summary of Changes CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
5
CC-4047-BRN-001 Amendment 3 Final: 20 Dec 2017
!
Clarified that subject disposition will be summarized for the Screening Period, 
Treatment Period and Follow-up Period (Section 9.5). 
!
Clarified that the analysis of Objective Response and Long-term Stable Disease Rate 
will be based on the Response Population, with secondary analyses based on the 
Intent-to-Treat (ITT) Population and/or Safety Population (Section 9.6). 
!
Clarified that the analysis of Objective Response Rate, Long-term Stable Disease 
Rate, Duration of Response (DoR), Progression-free Survival (PFS) and Overall 
Survival (OS) will be based on the ITT Population and/or Safety Population (Section 
9.6).
!
Added that the analysis of median PFS time and proportion of subjects remaining 
progressive-free will also be collected at 3, 9 and 18 months (Section 9.6).
!
Added that the analysis of median DoR time and proportion of subjects remaining 
with a response will also be collected at 3, 9 and 18 months (Section 9.6).
!
Added that the analysis of median OS time and proportion of subjects remaining alive
will also be collected at 3, 9 and 18 months (Section 9.6).
!
Clarified that the safety analysis of adverse events will be based on the Safety 
Population, ie, all subjects receiving at least one dose of pomalidomide (Section 9.7).
!
Clarified that the interim analysis for each stratum will be “informal,” performed 
internally by Celgene personnel with input, only if needed, from the data monitoring 
committee and steering committee (Section 9.8).
!
Clarified that the plasma obtained follow pharmacokinetic blood sample processing 
should be transferred to polypropylene citric acid storage tubes (Appendix E).
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Summary of Changes CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
3
CC-4047-BRN-001 Amendment 2 Final: 18 Aug 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Updated Inclusion Criteria #17 regarding highly effective contraceptive methods
In response to health authority recommendation from the French National Agency for
Medicines and Health Products Safety (ANSM), the below guidance was added regarding the 
use of highly effective contraceptive methods for female subjects of childbearing potential:
!
Only a progestin-suppressing ovulation pill is acceptable as an oral contraceptive
!
Copper intrauterine devices are not recommended
Revised sections: Section 4.2, Inclusion Criteria #17
!
Clarified how subjects may continue pomalidomide following study termination
In response to health authority recommendation from the French ANSM, the below text was 
added to clarify how subjects may continue treatment with pomalidomide who would 
continue to benefit from it at the time of the trial closure: 
!
In the case where there are subjects still being administered the investigational 
product, and it is the opinion of the Investigator(s) that these subjects continue to 
receive benefit from treatment, the Sponsor may choose to initiate an open-label, 
extension study under a separate protocol to allow these subjects continued access to 
pomalidomide following their participation in this study (CC-4047-BRN-001).
Revised sections: Section 13.8, Termination of the Study
!
Inclusion #19 for affiliation to a health insurance scheme (France only) was added
In response to health authority recommendation from the French Central Ethics Committee , 
the country-specific inclusion criteria was added: 
!
For subjects screened/enrolled in France only: Subject must be affiliated with a 
Health Insurance Scheme or be a beneficiary of one
Revised sections: Section 4.2, Inclusion Criteria #19
!
Clarified Exclusion Criteria #10 regarding hepatitis B serological status
In response to health authority recommendation from the French ANSM, it was further 
clarified that hepatitis B serology must be known or performed at screening if unknown.  The 
below exclusion criteria was updated: 
!
Subject has active infectious hepatitis, type A, B, or C, or chronic carriers of hepatitis 
C.  Note: Hepatitis B serological status must be known prior to enrollment.  If 
unknown at screening, a hepatitis B serology must be performed. 
Revised sections: Section 4.3, Exclusion Criteria #10; Section 5, Table 4; Section 6,1, 
Screening Period; Section 6.4.2.6, Table 5
&&,
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Summary of Changes CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
4
CC-4047-BRN-001 Amendment 2 Final: 18 Aug 2017
!
Extended the initial weekly blood count testing for an additional four weeks
In response to health authority recommendation from the French ANSM, safety blood testing 
(i.e., hematology and blood chemistry) will be now be performed weekly during the first 8 
weeks of treatment (and not only during the first 4 weeks). 
Revised sections: Section 5, Table 4
!
Updated Inclusion Criteria #2 regarding adult subjects who lack capacity to consent 
In response to a request from the
 adult 
subjects who lack the capacity to consent for themselves will be excluded from enrolling into 
the study.   The below inclusion criteria was updated:
!
Subject (when applicable, parental/legal representative) must understand and 
voluntarily sign an ICF/IAF prior to any study-related assessments/procedures being 
conducted. Note: Adult individuals who lack capacity to consent for themselves will 
be excluded from the study.
Revised sections: Section 4.2, Inclusion Criteria #2
The amendment also includes other minor clarifications and corrections including: 
!
Clarified that subjects will be followed for 28 days, not 28 days (± 3 days), after the 
last dose of treatment for adverse events (Section 5 [Table 4]; Section 6.3.1). 
!
Added footnote “o” to clarify which assessments are performed in Cycle 1 only (i.e., 
enrollment, inclusion/exclusion criteria, weekly pregnancy testing and 
pharmacokinetics) (Section 5, Table 4).  
!
Clarified that prior to enrolling a subject, written informed consent/assent must be 
obtained, all screening evaluations must be completed, and eligibility criteria must be 
verified by the Investigator, not the Sponsor (Section 6.1.5)
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Summary of Changes CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
3
CC-4047-BRN-001 Amendment 1 Final:  0116 Jun 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Pharmacokinetic assessments made optional
Pharmacokinetics (PK) assessments are also included in the ongoing Phase 1 pomalidomide 
trial conducted under the Pediatric Brain Tumor Consortium (PBTC-043).  As the Phase 1 
trial remains open, additional subjects are planned to be enrolled and samples obtained to 
satisfy the PK requirements. Therefore, PK assessments in this Phase 2 study will not be 
mandatory.
Revised sections: Table 4, Table of Events; Section 6.2 Treatment Period; Section 6.5, 
Pharmacokinetics; Section 9.9.1, Pharmacokinetics Analysis
!
Removed requirement to obtain spine MRIs without contrast
It has been recommended by the study Steering Committee to remove the requirement to 
obtain spine MRIs without contrast as it would not provide any additional benefit to the 
subject in evaluating response.  This further provides flexibility to sites to perform imaging 
assessments per institutional procedures.
Revised sections: Section 4.2, Inclusion Criteria #7; Table 4, Table of Events; Section 6.1, 
Screening Period; Section 6.2, Treatment Period; Section 6.2.1, End of Treatment; Section 
6.4.1, Efficacy Assessments
!
Updated study visit window for brain and spine MRIs performed during Treatment 
Period
To provide site the flexibility when scheduling MRIs during the Treatment Period, brain and 
spine MRI assessments can be performed within 7 days prior to dosing on Day 1 of Cycles 3, 
5, 7, 10, 13, 16, 19, and 22.  For DIPG subjects only, brain and spine MRI assessments can 
be performed within 7 days prior to dosing on Day 1 of Cycles 4, 7, 10, 13, 16, 19, and 22.
Revised sections: Section 3.1, Study Design; Table 4, Table of Events; Section 6.4.1, 
Efficacy Assessments
!
Updated Exclusion Criteria #5 (prior therapy)
1. The time frame from the last dose of prior therapy for a subject to be excluded, was 
reduced from ≤ 28 days to ≤ 21 days prior to screening for subjects receiving prior 
myelosuppressive chemotherapy, immunotherapy, or any investigational agent.  This was 
updated to accommodate the target population(s) that have highly aggressive disease and 
may require more rapid intervention with pomalidomide.
2. Clarified that subjects cannot have received prior focal radiation ≤ 6 weeks prior to 
screening for target lesions and ≤ 3 weeks prior to screening for non-target lesions 
identified at baseline. 
Revised sections: Section 4.3, Exclusion Criteria #5
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Summary of Changes CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
4
CC-4047-BRN-001 Amendment 1 Final:  0116 Jun 2017
!
Exclusion Criteria #15 for pre-existing cardiac disorders was added
In response to health authority recommendation from the Spanish Agency for Medicinal 
Products and Medical Devices (AEMPS), the following exclusion criteria has been added:
!
Subject has symptomatic cardiac disorder (CTCAE v. 4.03 Grade 3 and 4)
Revised sections: Section 4.3, Exclusion Criteria #15
!
Screening Period extended to 28 days 
The Screening Period was increased from 21 to 28 days to accommodate the protocol
requirement for female subjects of child bearing potential to use 2 reliable forms of 
contraception (or abstinence) for at least 28 days before starting pomalidomide. 
Revised sections: Protocol Summary; Figure 2, Overall Study Design; Section 3.2, Study 
Duration for Subjects; Table 4, Table of Events; Section 6.1, Screening Period
!
Provided guidance if pomalidomide dosing is vomited or forgotten
Additional guidance was included to clarify what to do if a dose of pomalidomide is vomited 
or forgotten. 
For subjects receiving capsules: 
!
If a dose is vomited within 15 minutes of taking the dose and the capsule(s) are 
visible in the emesis, the dose should be repeated and the Investigator should be 
notified to have replacement capsule(s) provided.  If vomiting occurs beyond 15 
minutes of dosing, do not repeat the dose and that day’s dose should be skipped.  Any 
vomiting of the capsules should be described in the subject dosing diary.
For subjects receiving the oral suspension:
!
If the dose is vomited, the dose should not be repeated for that dosing day and details 
entered in the subject dosing diary.  
If a dose (capsules or oral suspension) is forgotten but remembered within 8 hours, the 
missed dose should be taken/given immediately.  If more than 8 hours have passed since the 
time the dose was due, that day’s dose should be skipped.
Revised sections: Section 7.2, Treatment Administration and Schedule
!
Revised dose modification criteria
3. Clarified febrile neutropenia must be Grade 3 or 4.
4. Clarified in Table 8 that study drug should be permanently discontinued for subjects 
experiencing the following toxicities, which do not resolve per protocol within 14 days of
treatment being held: Grade 3 or 4 febrile neutropenia, Grade 4 neutropenia, or Grade 3 
or 4 platelet count decrease.
5. Removed Grade 4 anemia dose modification criteria.   Subjects being considered for 
enrollment into this trial are often heavily pretreated with multiple chemotherapeutic 
agents. As a consequence of prior therapy, it is expected that subjects will be anemic and 
difficult to distinguish study drug effect.  In addition, Grade 4 anemia is unlikely to occur 
alone in the absence of neutropenia or thrombocytopenia which specifically have 
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EDMS Doc. Number
Pomalyst® (Pomalidomide)
Summary of Changes CC-4047-BRN-001
Celgene Corporation
Confidential and Proprietary
5
CC-4047-BRN-001 Amendment 1 Final:  0116 Jun 2017
parameters that must be met before each treatment cycle as well as additional dose 
modification criteria.
Revised sections: Table 8, Dose Modification Criteria 
The amendment also includes several other minor clarification and corrections including: 
!
Change of Medical Monitor.
!
Updated the word “CRF” to “eCRF” throughout the document.
!
Updates to the Introduction in line with current literature and to provide further 
clarification (Section 1).
!
Removed “having documented PD” from the study population description to align 
with inclusion criteria in Section 4.2 (Protocol Summary, Section 3.1, Section 4.1).
!
Updated the study visit window for the Long-term Follow-up Period from ± 7 days to 
± 14 days (Section 3.2, Table 4, Section 6.3.3).
!
Clarified pharmacokinetic objectives are exploratory (Protocol Summary, Table 1).
!
Additional reference to Imagining Manual for details regarding MRI acquisition and 
image submission procedures (Section 4.2, Section 6.4.1.8).
!
Clarified that spinal lesions should be considered nonmeasurable disease (ie, a non-
target lesion); however, size should be noted and change in size should be evaluated
(Section 6.4.1.1).
!
Removed reference to “Versa Plus” as the suspending agent of the pomalidomide oral 
suspension (Section 7.1). 
!
Removed the requirement that pomalidomide needs to be administered at study center 
by designated site staff on Day 1 of each treatment cycle (Section 7.2).
!
Clarified pomalidomide (capsules or oral suspension) can be taken with or without 
food or beverage with exception to PK days (Section 7.2).
!
Clarified that the following parameters must be met within 48 hours (updated from 
within 24 hours) of Day 1 to start of subsequent treatment cycles: ANC ≥ 1,000/mm3, 
platelet count ≥ 100,000/mm3, and does not meet PD or treatment interruption/ 
discontinuation criteria (Section 7.2.1).
!
Clarified compliance of the study drug will be based on drug returned and/or written 
in the subject dosing diary (Section 7.6).
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