Clinical trial NCT02406742
Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
Keywords: CC-122 Pharmacokinetics Safety Ibrutinib Obinutuzumab GA101 Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma
Sponsor: Celgene
Start date: 2015-07-27; Completion date: 2020-07-07
Enrollment: 47 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Safety, pharmacokinetics, and preliminary efficacy of CC-122 alone and in combination with ibrutinib and obinuzutumab.

CC-122 has multiple activities, including immune modulation of several immune cell subsets and antiproliferative activity in CLL. CC-122 has also been shown to have a tolerable safety profile with some preliminary signs of efficacy with early human experience.

Detailed description:
The primary objectives of this Phase 1/2 Study are to determine the safety of single agent CC-122 and the safety, tolerability, and RP2D of CC-122 when administered in combination with ibrutinib and in combination with obinutuzumab to subjects with CLL/SLL. The secondary objectives are to evaluate the PK profiles of subjects administered CC-122 in combination with ibrutinib and in combination with obinutuzumab, to determine ibrutinib concentrations when given alone and in combination with CC-122 and to evaluate the preliminary efficacy of CC-122 at selected dose levels/regimens.

Arms: arm 1: An intrasubject dose escalation design was selected to determine the safety of single agent CC-122 (Arm A) in order to reach an optimal, clinically active dose and to mitigate the risk of early tumor flare reactions, based on earlier experience with lenalidomide monotherapy in CLL. arm 2: Ascending fixed dose cohorts evaluated in a 3 + 3 dose-finding design will be used to determine the safety and tolerability of the combination of CC-122 and ibrutinib to determine the NTD, MTD, and Recommended Phase 2 Dose (RP2D). An intrasubject dose escalation cohort may also be evaluated at the discretion of the Safety Review Committee. The RP2D of the combination may be evaluated in ibrutinib-naïve and high-risk CLL patients in the dose expansion phase to continue to evalute safety and efficacy. arm 3: Ascending fixed dose cohorts evaluated in a 3 + 3 dose-finding design will be used to determine the safety and tolerability of the combination of CC-122 and obinutuzumab to determine the , MTD, and Recommended Phase 2 Dose (RP2D). An intrasubject dose escalation cohort may also be evaluated at the discretion of the Safety Review Committee.. The RP2D of the combination may be evaluated in CLL patients who failed a B-cell receptor pathway inhibitor or venetoclax in the dose expansion phase to continue to evalute safety and efficacy.
Interventions: intervention 1: CC-122 intervention 2: Ibrutinib intervention 3: Obinutuzumab
Intervention descriptions: intervention 1: CC-122 will be administered daily starting at Cycle 1 Day 1 in 28-day cycles until disease progression, unacceptable toxicity, or discontinuation for any other reason. intervention 2: None intervention 3: Obinutuzumab will be administered as an intravenous (IV) infusion at a dose of 100 mg on Cycle 1 Day 1 and 900 mg on Cycle 1 Day 2 and 1000 mg on Cycle 1 Days 8 and 15. The dose of obinutuzumab on Days 1 and 2 of Cycle 1 may be adjusted per institutional practice as long as the combined dose equals 1000 mg. Obinutuzumab will be administered at a dose of 1000 mg on Day 1 of Cycles 2 through 6.

Protocol documents:
Prot_000.pdf: 
EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
1
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
TITLE PAGE
PHASE 1/2 STUDY TO DETERMINE THE SAFETY, 
PHARMACOKINETICS, AND EFFICACY OF SINGLE 
AGENT CC-122 AND THE COMBINATIONS OF CC-122
AND IBRUTINIB AND CC-122 AND OBINUTUZUMAB
IN SUBJECTS WITH CHRONIC LYMPHOCYTIC 
LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA
INVESTIGATIONAL PRODUCT (IP):
CC-122
PROTOCOL NUMBER:
CC-122-CLL-001
DATE FINAL:
15 October 2014
AMENDMENT No. 1:
26 November 2014
AMENDMENT No. 2:
16 February 2015
AMENDMENT No. 3:
30 April 2015
AMENDMENT No. 4:
27 August 2015
AMENDMENT No. 5:
28 March 2016
AMENDMENT No. 6:
06 June 2017
AMENDMENT No. 7:
27 July 2018
EudraCT NUMBER:
2014-003056-31
IND NUMBER:
111489
SPONSOR NAME / ADDRESS:
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.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
2
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
3
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
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.  


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
4
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
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, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
5
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
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.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
6
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
PROTOCOL SUMMARY
On 05 Jul 2018, Celgene informed all study sites that further development of CC-122 in Chronic 
Lymphocytic Leukemia (CLL) will be discontinued after completion of the current Phase 1 Dose 
Escalation Phase. Enrollment into the Phase 2 Dose Expansion Phase will not proceed forward 
as originally planned. The decision was not based on adverse safety findings, and no new safety 
signals for CC-122 have been identified.  Subjects already enrolled and who are receiving 
clinical benefit in the opinion of the treating investigator may continue to receive study treatment 
up to a maximum of 24 cycles of CC-122 irrespective of treatment arm.  Protocol Amendment 7 
is issued to provide further guidance regarding study procedures for the remaining patients on 
study treatment, study closure, and long-term follow-up.
Study Title
Phase 1/2 Study to Determine the Safety, Pharmacokinetics, and Efficacy of Single Agent 
CC-122 and the Combinations of CC-122 and Ibrutinib and CC-122 and Obinutuzumab in 
Subjects with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Objectives
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued. Subjects 
already enrolled who are receiving clinical benefit in the opinion of the treating investigator may 
continue to receive study treatment up to a maximum of 24 cycles of CC-122.
Primary Objectives
!
Determine the safety of single agent CC-122 in subjects with relapsed/refractory 
(R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
!
Determine the safety and tolerability of the combination of CC-122 and 
ibrutinib and determine the recommended Phase 2 dose (RP2D) of the combination in 
ibrutinib naïve CLL/SLL subjects
!
Determine the safety and tolerability of the combination of CC-122 and 
obinutuzumab and determine the RP2D of the combination in subjects with R/R
CLL/SLL
Secondary Objectives
!
Characterize CC-122 pharmacokinetics (PK) in subjects with CLL and assess 
potential drug-drug interactions when CC-122 is given in combination with ibrutinib  
or obinutuzumab
!
Determine ibrutinib plasma concentrations when given alone or in combination with 
CC-122
!
Determine the preliminary efficacy of single agent CC-122, the combination of 
CC-122 and ibrutinib, and the combination of CC-122 and obinutuzumab
 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
7
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Study Design
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued. Phase 2 will 
not proceed.  
CC-122-CLL-001 is a Phase 1/2, multicenter, open-label, dose finding study to determine the 
safety, PK, and preliminary efficacy of CC-122 administered orally to subjects with CLL/SLL.
The following will be evaluated:
!
Arm A:  CC-122 single agent
!
Arm B:  CC-122 in combination with ibrutinib
!
Arm C:  CC-122 in combination with obinutuzumab
The Dose Escalation Phase (Phase 1) will be comprised of an intrasubject dose escalation cohort 
for single agent CC-122 (Arm A) in parallel with ascending fixed-dose cohorts of the 
combinations of CC-122 and ibrutinib (Arm B) and CC-122 and obinutuzumab (Arm C) 
evaluated using a 3 + 3 design to determine the not tolerated dose (NTD) and maximum tolerated 
dose (MTD).
Up to approximately 20 subjects will be evaluated in the intrasubject dose escalation cohort in 
Arm A and three to six subjects will be evaluated in each fixed-dose cohort in Arms B and C; 
therefore, approximately 68 (46-92) subjects are anticipated to be enrolled in Phase 1.  The final 
number of subjects will depend on the number of dose levels tested and the number of dose 
limiting toxicities (DLTs) observed within each cohort. 
For Arm A, subjects will receive a starting dose of 1.0 mg, and may dose escalate every 2 weeks 
in 0.5 mg increments, based on subject tolerability at the discretion of the investigator.  For Arms 
B and C, a safety review committee (SRC) whose members include the sponsor’s medical 
monitor, drug safety physician, and a subset of investigators, will determine a preliminary RP2D 
for each combination treatment arm based on an integrated assessment of the safety, available 
PK and pharmacodynamic data, and preliminary efficacy information.  For the fixed-dose 
cohorts, the SRC will make the recommendation of whether to open the next dose cohort and the 
incremental increase in dose (ie, 0.5 or 1.0 mg) after review of the safety data of the current dose 
cohort (after full enrollment and completion of the DLT evaluation period).  The 1.0 mg 
increment is allowed only after the first two dose cohorts of 0.5 and 1.0 mg have been 
completed.
After completion of the fixed-dose cohorts in Arms B and C, the SRC will make the 
determination whether to evaluate an additional intrasubject dose escalation cohort per each 


EDMS Doc. Number: 22914699 - 19766462
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Protocol CC-122-CLL-001
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Confidential and Proprietary
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CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
combination treatment arm.  The starting dose will be determined by the SRC, with intrasubject 
dose escalation up to a maximum dose of 4.0 mg.
If in the event higher doses of CC-122 are shown to be safe in other hematologic malignancies in 
ongoing CC-122 studies, the maximum dose of 4.0 mg may be increased after approval by the 
SRC.
Once the RP2D is established for Arms B and C, an expansion cohort per arm may be opened in 
the Dose Expansion Phase (Phase 2) to further evaluate the safety and efficacy of CC-122 in 
combination with ibrutinib and/or CC-122 in combination with obinutuzumab:
Arm B (CC-122 in combination with ibrutinib) (N = 50):
!
Expansion Cohort 1:  Subjects who are ibrutinib-naïve and have high-risk CLL
(see Section 7.2)
o
Treatment-naïve (TN) CLL (N = 10) 
o
R/R CLL (N = 40)
Arm C (CC-122 in combination with obinutuzumab) (N = 40):
!
Expansion Cohort 2:  CLL subjects who are B-cell receptor pathway inhibitor 
(BCR PI) or venetoclax failures (see Section 7.2)
In total, approximately 90 subjects are anticipated to enroll in the Dose Expansion Phase.
All active subjects who are receiving clinical benefit in the opinion of the treating investigator 
may continue to receive study treatment up to a maximum of 24 cycles of CC-122, or until 
disease progression (PD), unacceptable toxicity, or discontinuation for any other reason, 
whichever is earlier.  Subjects who achieve minimal residual disease (MRD) negativity (in both 
peripheral blood and bone marrow) lasting for a minimum of 3 months in duration have the 
option to discontinue study treatment; study treatment in these subjects may be resumed at the 
time of MRD positivity (Section 4.1 for additional details).
Study Population
The study population consists of Dose Escalation Phase (Phase 1) subjects who were enrolled 
under previous amendments and were ongoing during Amendment 6, dated 06 Jun 2017. As of 
05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued and Phase 2 will not 
proceed.  
Eligible subjects include those with CLL/SLL requiring treatment as defined by the modified 
International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines for the 
Diagnosis and Treatment of CLL
 
For Arms A and C, subjects must have received at least one prior treatment which must include 
chemoimmunotherapy or an approved Bruton’s tyrosine kinase (BTK) inhibitor unless co-
morbidity or contraindication precludes such a therapy.  
For Arm B, subjects must not have received prior ibrutinib treatment (ie, ibrutinib naïve) or any 
BTK inhibitor.  During the Expansion Phase, subjects must also possess high-risk features.  
Please refer to Section 7.2 for additional details regarding study population for each treatment
arm. 


EDMS Doc. Number: 22914699 - 19766462
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Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
9
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Length of Study
The study is expected to last approximately 5 years and will consist of three phases: Screening, 
Treatment, and Follow-up.  
During the Screening Phase, lasting up to 28 days from the time of signing informed consent to 
first dose administered, subjects will undergo assessments to determine their eligibility.  
Subjects who qualify for enrollment into the study will enter the Treatment Phase, during which 
subjects will receive investigational product(s) [IP(s)] at a predetermined dose and schedule until 
the underlying CLL/SLL has progressed or the subject has discontinued IP treatment for 
unacceptable toxicity or other reasons.  
Subjects enrolled as of 05 Jul 2018 who are receiving clinical benefit in the opinion of the 
treating investigator may continue to receive study treatment up to a maximum of 24 cycles of 
CC-122 irrespective of treatment arm.
The Follow-up Phase will begin at study treatment discontinuation.  Subjects will have a visit at 
the end of treatment as soon as possible once IP has been discontinued and at 28 days after the 
last dose of IP.  All subjects discontinued for any reason other than progressive disease, 
withdrawal of consent, or death, will be contacted every 90 days following the date of the 28-day 
follow-up visit for information regarding the status of their disease and for the type and start date 
for any subsequent anticancer therapy.  Efficacy assessments (including clinical, laboratory tests, 
and CT scans as indicated in the Tables of Events, Table 3 through Table 5) will continue until 
documented PD or initiation of subsequent anti-CLL therapy.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, 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 pre-specified in the protocol and/or the 
statistical analysis plan (SAP), whichever is the later date.
Overview of Efficacy Assessments
!
Best overall response [complete response (CR), complete response with incomplete 
marrow recovery (CRi), nodular partial response (nPR), partial response (PR), partial 
response with lymphocytosis (PRL) (applicable to Arm B only)] as assessed by the 
International Working Group Criteria 
with 
modifications
!
Clinical laboratory evaluations
!
Tumor imaging assessment (CT scan) 
!
Bone marrow aspirate/biopsy
!
MRD assessment (peripheral blood and bone marrow aspirate)
!
Performance status
!
B-Symptom evaluation


EDMS Doc. Number: 22914699 - 19766462
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Protocol CC-122-CLL-001
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Confidential and Proprietary
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Overview of Safety Assessments
!
Adverse events using the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03
!
Vital signs
!
Physical examination
!
Electrocardiogram (ECG)
!
Clinical laboratory assessments
!
Left ventricular ejection fraction (LVEF)
!
Cardiac laboratory testing
!
Ophthalmology examination
 
 
 
 
 
 
 
 


EDMS Doc. Number: 22914699 - 19766462
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Protocol CC-122-CLL-001
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Confidential and Proprietary
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................20
2.
STUDY OBJECTIVES...........................................................................................36
2.1.
Primary Objectives .................................................................................................36
2.2.
Secondary Objectives .............................................................................................36
3.
STUDY ENDPOINTS............................................................................................37
3.1.
Primary Endpoints..................................................................................................37
3.2.
Secondary Endpoints ..............................................................................................37
4.
OVERALL STUDY DESIGN ................................................................................38
4.1.
Study Design ..........................................................................................................38
4.2.
Study Duration .......................................................................................................46
4.3.
End of Trial ............................................................................................................46


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5.
TABLE OF EVENTS.............................................................................................47
6.
PROCEDURES......................................................................................................60
6.1.
Safety Assessments.................................................................................................60
6.1.1.
Demographics / Medical History / Baseline Stage and Prognostic 
Classification..........................................................................................................61
6.1.2.
Adverse Events.......................................................................................................61
6.1.3.
Vital Signs..............................................................................................................62
6.1.4.
Physical Examination .............................................................................................62
6.1.5.
Cardiac Laboratory Testing.....................................................................................62
6.1.6.
12-Lead Electrocardiogram.....................................................................................62
6.1.7.
Left Ventricular Ejection Fraction...........................................................................63
6.1.8.
Clinical Laboratory Tests........................................................................................63
6.1.9.
Prior/Concomitant Medications and Procedures......................................................64
6.1.12.
Ophthalmologic Examinations................................................................................65
6.1.13.
Contraceptive and Risk Counseling ........................................................................66
6.1.14.
Pregnancy Test .......................................................................................................66
6.2.
Efficacy Assessments .............................................................................................67
6.2.1.
Efficacy Parameters................................................................................................67
6.2.2.
Tumor Imaging Assessment....................................................................................67
6.2.3.
Bone Marrow Examination.....................................................................................68
6.2.4.
Minimal Residual Disease (MRD) Assessment.......................................................68
6.2.5.
Performance Status.................................................................................................68
6.2.7.
Efficacy Response Assessment ...............................................................................69


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6.4.1.
Dose Escalation Phase ............................................................................................72
6.4.2.
Dose Expansion Phase............................................................................................73
6.5.
Phase 1 Dose Escalation - Third Cycle of CC-122 Through the Twelfth 
Cycle of CC-122.....................................................................................................74
6.6.
Phase 1 Dose Escalation - Cycle 13 of CC-122 and Beyond....................................74
7.
STUDY POPULATION.........................................................................................76
7.1.
Number of Subjects and Sites .................................................................................76
7.2.
Inclusion Criteria....................................................................................................76
7.3.
Exclusion Criteria...................................................................................................79
8.
DESCRIPTION OF STUDY TREATMENTS........................................................83
8.1.
Description of Investigational Products...................................................................83
8.1.1.
CC-122...................................................................................................................83
8.1.2.
Ibrutinib..................................................................................................................84
8.1.3.
Obinutuzumab ........................................................................................................84
8.1.4.
Premedications .......................................................................................................84
8.2.
Treatment Administration and Schedule .................................................................84
8.2.1.
Safety Review Committee ......................................................................................85
8.2.2.
Dose Escalation Phase ............................................................................................85
8.2.2.1.
Arm A:  CC-122 Single Agent................................................................................85
8.2.2.2.
Arm B:  CC-122 in Combination with Ibrutinib......................................................85
8.2.2.3.
Arm C:  CC-122 in Combination with Obinutuzumab.............................................86
8.2.3.
Dose Expansion Phase (Arms B and C only)...........................................................87
8.2.4.
Definition of Stopping Criteria for Expansion Cohort .............................................88
8.2.5.
Definition of Not Tolerated Dose (NTD) ................................................................88
8.2.6.
Definition of Maximum Tolerated Dose (MTD) .....................................................89
8.2.7.
Definition of Dose Limiting Toxicity (DLT)...........................................................89
8.2.8.
Guidelines for Intrasubject Dose Escalation – Arm A .............................................90
8.2.9.
Dose Interruptions/Modifications............................................................................90
8.2.9.1.
General Dose Modification Guidelines ...................................................................90
8.2.9.2.
Dose Modification Guidelines ................................................................................92
8.2.10.
Management of Select AEs While Receiving Obinutuzumab................................100
8.2.10.1.
Infusion-Related Reactions (IRRs)........................................................................100
8.2.10.2.
Progressive Multifocal Leukoencephalopathy.......................................................101


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8.2.10.3.
Neutropenia, Thrombocytopenia, and Anemia ......................................................101
8.2.10.4.
Gastrointestinal (GI) Perforation...........................................................................102
8.2.11.
Management of Select AEs While Receiving Ibrutinib .........................................102
8.2.11.1.
Interstitial Lung Disease (ILD) .............................................................................102
8.2.12.
Dose Reduction Steps...........................................................................................102
8.2.12.1.
CC-122 Dose Reduction Steps..............................................................................102
8.2.12.2.
Ibrutinib Dose Reduction Steps.............................................................................103
8.2.12.3.
Dose Modification Guidelines for Obinutuzumab .................................................103
8.2.13.
Overdose ..............................................................................................................103
8.3.
Method of Treatment Assignment.........................................................................104
8.4.
Packaging and Labeling........................................................................................104
8.5.
Investigational Product Accountability and Disposal ............................................104
8.6.
Investigational Product Compliance......................................................................104


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10.
STATISTICAL ANALYSES................................................................................109
10.1.
Overview..............................................................................................................109
10.2.
Study Population Definitions ................................................................................109
10.3.
Sample Size and Power Considerations.................................................................110
10.3.1.
Expansion Cohorts................................................................................................110
10.5.
Subject Disposition...............................................................................................111
10.6.
Efficacy Analysis..................................................................................................111
10.7.
Safety Analysis.....................................................................................................112
10.8.
Interim Analysis ...................................................................................................113
11.1.
Monitoring, Recording and Reporting of Adverse Events .....................................115
11.1.1.
Adverse Events of Special Interest........................................................................115
11.1.1.1.
Major Hemorrhage (Arm B) .................................................................................116
11.2.
Evaluation of Adverse Events...............................................................................116
11.2.1.
Seriousness...........................................................................................................116
11.2.2.
Severity / Intensity................................................................................................117
11.2.3.
Causality ..............................................................................................................118
11.2.4.
Duration ...............................................................................................................118
11.2.5.
Action Taken........................................................................................................119
11.2.6.
Outcome...............................................................................................................119
11.3.
Abnormal Laboratory Values................................................................................119
11.4.
Pregnancy.............................................................................................................119
11.4.1.
Females of Childbearing Potential ........................................................................119
11.4.2.
Male Subjects.......................................................................................................120
11.5.
Reporting of Serious Adverse Events....................................................................120
11.5.1.
Adverse Events of Special Interest........................................................................121
11.5.1.1.
Major Hemorrhage (Arm B) .................................................................................121


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11.6.
Safety Queries ......................................................................................................121
11.7.
Expedited Reporting of Adverse Events................................................................121
12.
DISCONTINUATIONS .......................................................................................123
13.
EMERGENCY PROCEDURES...........................................................................124
13.1.
Emergency Contact...............................................................................................124
13.2.
Emergency Identification of Investigational Products ...........................................124
14.
REGULATORY CONSIDERATIONS.................................................................125
14.1.
Good Clinical Practice..........................................................................................125
14.2.
Investigator Responsibilities .................................................................................125
14.3.
Subject Information and Informed Consent...........................................................126
14.4.
Confidentiality......................................................................................................126
14.5.
Protocol Amendments...........................................................................................126
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................126
14.7.
Ongoing Information for Institutional Review Board/Ethics Committee ...............127
14.8.
Closure of the Study .............................................................................................127
15.
DATA HANDLING AND RECORDKEEPING...................................................129
15.1.
Data/Documents...................................................................................................129
15.2.
Data Management.................................................................................................129
15.3.
Record Retention..................................................................................................129
16.
QUALITY CONTROL AND QUALITY ASSURANCE......................................131
16.1.
Study Monitoring and Source Document Verification...........................................131
16.2.
Audits and Inspections..........................................................................................131
16.3.
Product Quality Complaint ...................................................................................132
 
 


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EDMS Doc. Number: 22914699 - 19766462
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LIST OF TABLES
Table 1:
Adverse Events Among NHL Patients Treated with CC-122 Monotherapy at 
3 mg QD or 4 mg on a 5/7-day Schedule in Part B of CC-122-ST-001 Based 
on Data Cutoff of 23SEP2015.................................................................................30
Table 2:
Tolerability in NHL Patients Treated with CC-122 at 3 mg QD or 4 mg on a 
5/7-day Schedule in CC-122-ST-001 Based on Data Cutoff as of 23SEP2015 ........31
Table 3:
Table of Events – Arm A – CC-122 Single Agent...................................................47
Table 4:
Table of Events – Arm B – CC-122 Plus Ibrutinib ..................................................52
Table 5:
Table of Events – Arm C – CC-122 Plus Obinutuzumab.........................................56
Table 10:
Administered Dose and Infusion Rates for Obinutuzumab Infusions.......................87
Table 11:
Expansion Cohort:  Arm B (CC-122 in Combination with Ibrutinib).......................88
Table 12:
Expansion Cohort:  Arm C (CC-122 in Combination with Obinutuzumab) .............88
Table 13:
Grading Scale for Hematologic Toxicity in Chronic Lymphocytic Leukemia 
Studies....................................................................................................................91
Table 14:
Dose Reduction Guidelines.....................................................................................92
Table 15:
CC-122 Dose Reduction Steps..............................................................................103
Table 16:
Ibrutinib Dose Reduction Steps.............................................................................103


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
19
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
LIST OF FIGURES
 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
20
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
1.
INTRODUCTION 
Please refer to the most current version of the CC-122 Investigator’s Brochure (IB), the
obinutuzumab IB, the package inserts (PI) for ibrutinib (IMBRUVICA®) and obinutuzumab 
(GAZYVA®), and the Summary of Product Characteristics (SmPC) for ibrutinib (IMBRUVICA) 
and obinutuzumab (GAZYVARO®) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
respective agents.
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 




























EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
34
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
 
 
 
 
 
 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
35
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
 
 
 
 
 
 
 
 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
36
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
2.
STUDY OBJECTIVES
2.1.
Primary Objectives
The primary objectives of the study are:
!
Determine the safety of single agent CC-122 in subjects with R/R CLL/SLL
!
Determine the safety and tolerability of the combination of CC-122 and ibrutinib and 
determine the RP2D of the combination in ibrutinib-naive CLL/SLL subjects
!
Determine the safety and tolerability of the combination of CC-122 and 
obinutuzumab and determine the RP2D of the combination in subjects with R/R
CLL/SLL
2.2.
Secondary Objectives
The secondary objectives of the study are:
!
Characterize CC-122 PK in subjects with CLL and assess potential drug-drug 
interactions when CC-122 is given in combination with ibrutinib or obinutuzumab
!
Determine ibrutinib plasma concentrations when given alone or in combination with 
CC-122
!
Determine the preliminary efficacy of single agent CC-122, the combination of 
CC-122 and ibrutinib, and the combination of CC-122 and obinutuzumab
 
 
 
 
 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
37
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
3.
STUDY ENDPOINTS
3.1.
Primary Endpoints
!
Incidence and severity of adverse events using the NCI CTCAE criteria (version
4.03), including DLTs
!
CC-122 in combination with ibrutinib and CC-122 in combination with 
obinutuzumab:  Determination of the NTD and MTD
3.2.
Secondary Endpoints
!
CC-122 plasma concentrations when administered alone or in combination with 
ibrutinib or obinutuzumab
!
CC-122 pharmacokinetic parameters when administered in combination with 
ibrutinib
!
Ibrutinib plasma concentrations and/or pharmacokinetic parameters when 
administered in combination with CC-122
!
Best overall response [CR, CRi, nPR, PR, PRL (applicable to Arm B only)]
!
MRD negativity rate
!
Duration of response (DoR)
!
Progression-free survival (PFS)
 
 
 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
38
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
4.
OVERALL STUDY DESIGN 
4.1.
Study Design
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued.  Phase 2 will 
not proceed.  
CC-122-CLL-001 is a Phase 1/2, multicenter, open-label, dose finding study to determine the 
safety, PK, and preliminary efficacy of CC-122 administered orally to subjects with CLL/SLL.  
The following will be evaluated:
!
Arm A:  CC-122 single agent
!
Arm B:  CC-122 in combination with ibrutinib
!
Arm C:  CC-122 in combination with obinutuzumab  
The Dose Escalation Phase (Phase 1) will be comprised of an intrasubject dose escalation cohort 
for single agent CC-122 (Arm A) in parallel with ascending fixed-dose cohorts of the 
combinations of CC-122 and ibrutinib (Arm B) and CC-122 and obinutuzumab (Arm C) 
evaluated using a 3 + 3 design to determine the NTD and MTD.  
Up to approximately 20 subjects will be evaluated in the intrasubject dose escalation cohort in 
Arm A and three to six subjects will be evaluated in each fixed-dose cohort in Arms B and C; 
therefore, approximately 68 (46-92) subjects are anticipated to be enrolled in Phase 1.  The final 
number of subjects will depend on the number of dose levels tested and the number of DLTs
observed within each cohort. 
For Arm A, subjects will receive a starting dose of 1.0 mg, and may dose escalate every 2 weeks 
in 0.5 mg increments, based on subject tolerability at the discretion of the investigator.  For Arms 
B and C, an SRC whose members include the sponsor’s medical monitor, drug safety physician, 
and a subset of investigators, will determine a preliminary RP2D for each combination treatment 
arm based on an integrated assessment of the safety, available PK and pharmacodynamic data, 
and preliminary efficacy information. For the fixed-dose cohorts, the SRC will make the 
recommendation of whether to open the next dose cohort and the incremental increase in dose
(ie, 0.5 or 1.0 mg) after review of the safety data of the current dose cohort (after full enrollment 
and completion of the DLT evaluation period).  The 1.0 mg increment is allowed only after the 
first two dose cohorts of 0.5 and 1.0 mg have been completed. 
After completion of the fixed-dose cohorts in Arms B and C, the SRC will make the 
determination whether to evaluate an additional intrasubject dose escalation cohort per each 
combination treatment arm. The starting dose will be determined by the SRC, with intrasubject 
dose escalation up to a maximum dose of 4.0 mg.
If in the event higher doses of CC-122 are shown to be safe in other hematologic malignancies in 
ongoing CC-122 studies, the maximum dose of 4.0 mg may be increased after approval by the 
SRC.
Once the RP2D is established for Arms B and C, an expansion cohort per arm may be opened in 
the Dose Expansion Phase (Phase 2) to further evaluate the safety and efficacy of CC-122 in 
combination with ibrutinib and/or CC-122 in combination with obinutuzumab:


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
39
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Arm B (CC-122 in combination with ibrutinib) (N = 50):
!
Expansion Cohort 1:  Subjects who are ibrutinib-naïve and have high-risk CLL 
(see Section 7.2)
∀
TN CLL (N = 10) 
∀
R/R CLL (N = 40)
Arm C (CC-122 in combination with obinutuzumab) (N = 40):
!
Expansion Cohort 2:  CLL subjects who are BCR PI or venetoclax failures 
(see Section 7.2)
In total, approximately 90 subjects are anticipated to enroll in the Dose Expansion Phase.
All active subjects who are receiving clinical benefit in the opinion of the treating investigator 
may continue to receive study treatment up to a maximum of 24 cycles of CC-122, or until PD,
unacceptable toxicity or discontinuation for any other reason, whichever is earlier. Subjects who 
achieve MRD negativity (in both peripheral blood and bone marrow) lasting for a minimum of 3 
months in duration have the option to discontinue study treatment, with subsequent MRD tests 
follow-up (in peripheral blood and/or bone marrow) every 3 cycles for the first year, and every 6 
cycles thereafter.  Study treatment in these subjects may be resumed at the time of MRD 
positivity (either in peripheral blood or bone marrow).
Dose Escalation Phase:
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued.
The Dose Escalation Phase will be comprised of an intrasubject dose escalation cohort for single 
agent CC-122 (Arm A) in parallel with ascending fixed-dose cohorts of the combinations of 
CC-122 and ibrutinib (Arm B), and CC-122 and obinutuzumab (Arm C), evaluated using a 3 + 3 
design:
Arm A (CC-122 single agent):
An intrasubject dose escalation cohort of CC-122 starting at the 1.0 mg dose level up to a 
maximum of 4.0 mg will be evaluated.  
In the event higher doses of CC-122 are shown to be safe in other hematologic malignancies in 
ongoing CC-122 studies, the maximum dose of 4.0 mg may be increased after approval by the 
SRC.
Each subject will be permitted to dose escalate by 0.5 mg increments every 2 weeks based on 
investigator assessment of the individual subject’s tolerability (ie, escalation to the next dose 
level requires no DLT or dose reduction at the current dose level in addition to meeting the 
criteria outlined in Section 8.2.8).  
However, dose escalation per cycle is not mandatory if the subject is benefiting (ie, objective 
evidence of disease response based on absolute lymphocyte count [ALC] reduction or shrinkage 
in measurable lesions required) from their current dose in the absence of significant toxicities.
Subjects who are enrolled to fixed dose cohorts (0.25 mg or 0.5 mg) in Arm A under earlier 
protocol amendments (ie, protocol amendment 3 or 4) will be allowed to undertake intrasubject 
dose escalations as described above.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
40
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Subjects in Arm A will have the option to receive the addition of ibrutinib or obinutuzumab if 
there is evidence of PD while on CC-122 monotherapy after the completion of the DLT 
evaluation and CC-122 in combination with these standard agents has been demonstrated to be 
safe in the context of this trial.  These subjects will receive a maximum of 24 cycles of CC-122
(including prior CC-122 monotherapy). The dose of CC-122 may need to be decreased to the 
level that has been shown to be safe in Arms B or C per the SRC (ie, < 2 DLTs/6 subjects).  
Subsequent intrasubject escalation is allowed if higher doses of CC-122 have been deemed 
tolerable in Arms B or C.  This option will also apply to subjects that have enrolled in Arm A 
prior to IRB/EC approval of Amendment 5 after discussion with the Sponsor Medical Monitor.
CC-122 will be administered starting on Cycle 1 Day 1 on a 5/7-day schedule (5 continuous days 
out of 7 days per week) up to a maximum of 24 cycles, or until disease progression,
unacceptable toxicity, or discontinuation for any other reason, whichever is earlier. Each cycle 
consists of 28 days.
Subjects will be observed for early DLTs in Cycle 1 (DLT evaluation period). Monitoring for 
late toxicities necessitating dose reductions or discontinuations will be conducted during
Cycles 2 through 6. 
Arm B (CC-122 + ibrutinib):
The following arm will be evaluated in parallel to Arm A:
Ascending fixed-dose cohorts of CC-122 starting at 0.5 mg up to a maximum of 4.0 mg or NTD, 
whichever occurs first, in combination with ibrutinib will be evaluated.  After completion of the 
0.5 and 1.0 mg fixed-dose cohorts, subsequent cohorts will be allowed to escalate in either 0.5 
mg or 1.0 mg increments.  Escalation to the next dose level requires 0/3 or ≤1/6 DLTs at the 
current dose level. Further, an escalation increment of 1.0 mg requires the absence of any Grade 
3 drug related non-hematologic AEs, any Grade 4 hematological event, and TLS or TFR of any 
grade at the current dose level.  The SRC will make the recommendation of whether to open the 
next dose cohort and the incremental increase in dose (0.5 or 1.0 mg) after review of the safety 
data of the current dose cohort (after full enrollment and completion of the DLT evaluation
period).  
CC-122 will be initiated on Cycle 2 Day 1 and administered on a 5/7-day schedule.  Ibrutinib 
will be administered QD starting on Cycle 1 Day 1 (see Section 8.2 for Treatment Description, 
Administration and Schedule).  
CC-122 and ibrutinib will be administered up to a maximum of 24 cycles of CC-122, or until 
disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever is 
earlier.  In the event CC-122 is discontinued prior to ibrutinib or if patients have surpassed the 24 
cycles of CC-122, Celgene will continue to provide an additional 3 cycles of ibrutinib from the 
investigational supply to allow time for patients to be switched to commercially available 
ibrutinib and/or other therapies at the discretion of the treating physician.  Subjects will be 
observed for early DLTs for 28 days following the initiation of CC-122 combination therapy 
(Cycle 2 Days 1 through 28) (DLT evaluation period).  Monitoring for late toxicities 
necessitating dose reductions or discontinuations will be conducted during the first 6 cycles of 
combination treatment.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
41
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Arm C (CC-122 + obinutuzumab):
The following arm will be evaluated in parallel to Arms A and B:
Ascending fixed-doses cohorts of CC-122 starting at 0.5 mg up to a maximum of 4.0 mg or 
NTD, whichever occurs first, in combination with obinutuzumab will be evaluated.  After 
completion of the 0.5 and 1.0 mg fixed-dose cohorts, subsequent cohorts will be allowed to 
escalate in either 0.5 mg or 1.0 mg increments.  Escalation to the next dose level requires 0/3 or 
≤1/6 DLTs at the current dose level. Further, an escalation increment of 1.0 mg requires the 
absence of any Grade 3 drug related non-hematologic AEs, any Grade 4 hematological event, 
and TLS or TFR of any grade at the current dose level.  The SRC will make the recommendation 
of whether to open the next dose cohort and the incremental increase (0.5 or 1.0 mg) after review 
of the safety data of the current dose cohort (after full enrollment and completion of the DLT 
evaluation period).
CC-122 will be initiated on Cycle 1 Day 9 and administered on a 5/7-day schedule.  For subjects 
on Arm C, Cycle 1 only will consist of 29 days to accommodate the 5/7-day schedule;  
subsequent cycles will consist of 28 days.  Obinutuzumab will be administered intravenously on 
Cycle 1 Days 1, 2, 8, and 15 (see Section 8.2 for Treatment Description, Administration and 
Schedule).  The dose of obinutuzumab on Day 1 and Day 2 of Cycle 1 may be adjusted per 
institutional practice provided the combined dose equals 1000 mg. Obinutuzumab will be 
administered on Day 1 every cycle thereafter up to Cycle 6.
CC-122 will be administered up to a maximum of 24 cycles of CC-122, or until disease 
progression, unacceptable toxicity, or discontinuation for any other reason, whichever is earlier.  
In the event CC-122 is discontinued prior to obinutuzumab, Celgene will continue to supply the 
protocol-specified total of 6 cycles of obinutuzumab.  In addition, for patients that have 
surpassed the 24 cycles of CC-122, Celgene will continue to provide an additional 3 cycles of 
CC-122 to allow time for patients to be switched to commercially available therapies at the 
discretion of the treating physician.  
Subjects will be observed for early DLTs for 28 days following initiation of CC-122 combination 
therapy (Cycle 1 Day 9 through Cycle 2 Day 8) (DLT evaluation period).  Monitoring for late 
toxicities necessitating dose reductions or discontinuations will be conducted during Cycles 2 
through 6.
Early DLT Evaluation of Intrasubject Dose Escalation Cohort in Arm A:
Up to approximately 20 subjects will be enrolled to Arm A to assess an intrasubject dose 
escalation schedule for CC-122.  
If > 20% (eg, > 4 of 20) of subjects meet the criteria for DLT within 28 days of initial escalation 
to a dose level, no further intrasubject dose escalation to that dose level will be permitted.
Early DLT Evaluation for Fixed-Dose Cohorts in Arms B and C:
An initial 3 subjects will be enrolled to each of the fixed-dose escalation cohorts in Arms B and
C.  A dose level will be considered tolerable if 0 of 3 treated subjects experiences a DLT during 
the DLT evaluation period of each respective group.  If 1 of 3 subjects experiences a DLT, 3 
additional subjects will be enrolled to that dose level.  A dose will be considered the NTD when 
≥2 out of 6 evaluable subjects in a cohort experience a DLT.  If DLTs are observed in ≥2 out of 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
42
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
6 evaluable subjects at the first dose level, a lower dose combination may be explored after 
review of safety data by the SRC (see Section 8.2.1).
After full enrollment and completion of the DLT evaluation period of each dose level, the 
number and type of DLTs and AEs occurring during the DLT evaluation period will be 
evaluated.  A dose level will be considered tolerated after discussion of these data by the SRC.  
Subsequent dose cohorts will only be authorized to open for enrollment following a consensus by 
the SRC.  Subjects enrolled in lower CC-122 fixed-dose cohorts will be allowed to escalate 
immediately to the next higher CC-122 dose level upon SRC approval of the subsequent CC-122 
dose.  For example, if the SRC has declared the 1.0 mg dose level tolerable and confirmed the 
opening of the 1.5 or 2.0 mg dose level, the subjects in the lower combination, ie, 0.5 mg CC-
122 dose level may escalate to 1.0 mg. The MTD is defined as the highest dose level below the 
NTD with 0 or 1 of 6 DLT evaluable subjects experiencing a DLT during the specified DLT 
evaluation period.  If only 3 subjects have been enrolled at the last dose level below the NTD, 3 
additional subjects will be enrolled.  A dose level will be declared the MTD when at least 6 
subjects have been enrolled and < 2 subjects have experienced a DLT at that dose level.
An intermediate dose (ie, one between the NTD and the last dose level before the NTD) or 
additional subjects within any dose cohort may be added to determine the MTD and RP2D more 
precisely.
Monitoring for Late Toxicities During the Dose Escalation Phase:
Continuous safety monitoring will continue for all cohorts for late toxicities necessitating dose 
reduction or discontinuation.  If at any time during the first 6 cycles of CC-122 treatment > 20% 
of subjects experience a late toxicity necessitating dose reduction or discontinuation that is 
clearly not related to disease progression, medical procedure, or intercurrent illness, the dose 
level will have been considered to exceed the MTD and the RP2D will be selected at a lower 
dose level.  The SRC will be responsible for monitoring these late toxicities and will make the 
determination that the limit of 20% has been exceeded.
Determination of RP2D:
The SRC will identify a preliminary RP2D for Arms B and C based on an integrated assessment 
of the safety, available PK and pharmacodynamic data, and preliminary efficacy 
information.CC-122 data available from other clinical studies will also be considered by SRC.  
The RP2D selected will not exceed the MTD from the dose escalation cohorts.  
Expansion Phase:
As of 05 Jul 2018, Phase 2 will not proceed.
An expansion cohort may be enrolled at each RP2D for Arms B and C for a total of up to 2
expansion cohorts.  
During the Expansion Phase of the study, the SRC will continue to review safety data regularly 
and make recommendations about the study continuation as appropriate.  The SRC will monitor 
for early DLTs (first cycle of CC-122 dosing during CC-122 combination therapy) and will 
monitor for late toxicities necessitating dose reductions or discontinuations that are clearly not 
related to disease progression, medical procedure, or intercurrent illness through completion of
the first 6 cycles of CC-122 treatment in the expansion cohorts.  If at any time the early DLT rate 
exceeds 20% or the late toxicity rate exceeds 33%, enrollment to that expansion cohort will be 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
43
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
suspended pending evaluation of the safety by the SRC.  The SRC may reopen enrollment into 
that cohort at a lower dose level that has been shown to be tolerated during the dose escalation 
portion of the study.
The expansion cohorts will be conducted with a futility interim analysis for each cohort as 
outlined in Section 10.3.1.
Follow-up Phase:
The Follow-up Phase will begin at study treatment discontinuation.  Subjects will have a visit at 
the end of treatment as soon as possible once IP has been discontinued and at 28 days after the 
last dose of IP.  All subjects discontinued for any reason other than progressive disease, 
withdrawal of consent, or death, will be contacted every 90 days following the date of the 28-day 
follow-up visit for information regarding the status of their disease and for the type and start date 
for any subsequent anticancer therapy.  These contacts will typically be via telephone and will 
not require site visits.  Contact will continue until the subject experiences disease progression, 
starts a new anti-CLL therapy, withdraws consent for further follow-up, or expires.
Efficacy assessments (including clinical, laboratory tests, and CT scans as indicated in the Tables 
of Events, Table 3 through Table 5) will continue until documented PD or initiation of 
subsequent anti-CLL therapy.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
44
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Figure 5:
Overall Study Design
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued.
Screen, 
& ICF 
Dose Escalation 
ARM A
ARM Ba, d
CC-122 
2.0 mg/day + 
ibrutinib
(N = 3-6)
CC-122 
4.0 mg/day f  + 
ibrutinib
(N = 3-6)
ARM Ca,c, d
CC-122 
2.0 mg/day + 
obinutuzumab
(N = 3-6)
CC-122 
3.0 mg/day + 
obinutuzumab
(N = 3-6)
CC-122 
4.0 mg/day f  + 
obinutuzumab
(N = 3-6)
a Cohorts will be evaluated using 3+3 dose escalation.
b Intrasubject sequential dose escalation by cycle as tolerated; each subject will be permitted to dose escalate each cycle by 0.5 mg increments every 2 weeks based on 
investigator assessment of the individual subject’s tolerability.
c Obinutuzumab treatment to Cycle 6 only.
d Escalation in 0.5 mg or 1.0 mg increments as determined by the SRC; the 1.0 mg dose increment is allowed following the completion of the 0.5 and 1.0 mg cohorts (see 
Section 4.1).
e Study treatment may be discontinued after MRD negativity has been achieved in both peripheral blood and bone marrow for ≥ 3 months (see Section 4.1).
f In the event higher doses of CC-122 are shown to be safe in other hematologic malignancies in ongoing CC-122 studies, the maximum dose of 4.0 mg may be increased 
after approval by the SRC.
Treatment until 
a maximum of 
24 cycles of 
CC-122, or 
disease 
progression, 
unacceptable 
toxicity or other 
reason, 
whichever is 
earlier; follow-
up for disease 
progressione
CC-122 
1.0 mg/day + 
ibrutinib
(N = 3-6)
CC-122 
0.5 mg/day + 
ibrutinib 
(N = 3-6)
CC-122 
0.5 mg/day + 
obinutuzumab
(N = 3-6)
CC-122b 0.5 mg/day to 4.0 mg/day f  
(N = 20)
CC-122 
3.0 mg/day + 
ibrutinib
(N = 3-6)
CC-122 
1.0 mg/day + 
obinutuzumab
(N = 3-6)


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
45
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Figure 5: Overall Study Design (Continued)
As of 05 Jul 2018, Phase 2 will not proceed.
ARM B
Dose Expansion 
ARM C
Review Safety, PK 
and preliminary 
efficacy to determine 
RP2D
Review Safety, PK 
and preliminary 
efficacy to determine 
RP2D
Expansion Cohort 1: CC-122 + ibrutinib in ibrutinib-naïve and 
high-risk g CLL subjects: 
!
Treatment-naïve, ibrutinib-naïve, high risk CLL (N = 10)
!
Relapsed/refractory, ibrutinib-naïve, high-risk CLL (N= 40)
Expansion Cohort 2: CC-122 + obinutuzumab in CLL subjects 
who have failed h a B-cell receptor pathway inhibitor 
or venetoclax (N= 40)
g High risk definition: TN CLL: 17p-/TP53 mut; R/R CLL: 17p-/TP53 mut., complex karyotype, progression < 24 mo after 1st line CIT
h Resistant or intolerant (see detailed definition in Section 7.2).
ICF = Informed Consent Form; PK = Pharmacokinetics; RP2D = Recommended Phase 2 Dose; 
CLL = Chronic Lymphocytic Leukemia; SRC = Safety Review Committee; MRD = Minimal Residual Disease.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
46
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
4.2.
Study Duration
The study is expected to last approximately 5 years and will consist of three phases: Screening, 
Treatment and Follow-up.  
During the Screening Phase, lasting up to 28 days from the time of signing informed consent to 
first dose administered, subjects will undergo assessments to determine their eligibility.  
Subjects who qualify for enrollment into the study will enter the Treatment Phase, during which 
subjects will receive IP at a predetermined dose and schedule until the underlying CLL has
progressed or the subject has discontinued IP treatment for unacceptable toxicity or other 
reasons.  
Subjects enrolled as of 05 Jul 2018 and who are receiving clinical benefit in the opinion of the 
treating investigator may continue to receive study treatment up to a maximum of 24 cycles of 
CC-122 irrespective of treatment arm.
The Follow-up Phase will begin at study treatment discontinuation.  
4.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, 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 and/or the SAP, 
whichever is the later date.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
47
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
5.
TABLE OF EVENTS
Table 3:
Table of Events – Arm A – CC-122 Single Agent
(As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued; the procedures below apply to subjects 
continuing in the study.)
Tests and Observations
Screening
Cycle 1 and the first Cycle of 
each Dose Escalationb
Cycle 2 of each Dose 
Levelb
Cycle 3 of each Dose 
Levelb, o
≥Cycle 4b, p
End of 
Treatmentb
Follow-up
≤ 28 Days 
Prior to 
Day 1a
Day 1
Days 2 
and 4
± 1 Day
Days 8, 15 
and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post IP 
discontinuation
Informed Consent
X
-
-
-
-
-
-
-
-
-
-
Demographics/Medical 
History
X
-
-
-
-
-
-
-
-
-
-
Physical Examination
X
X
-
-
X
-
X
-
X
X
X
X
-
-
-
-
-
-
-
-
-
-
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
X
-
X
-
X
X
X
B-symptoms
X
X
-
-
X
-
X
-
X
X
X
Current Stage/Prognostic 
Classification
X
-
-
-
-
-
-
-
-
-
-
CBC & Differential
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
Beta-2 Microglobulin
X
-
-
-
-
-
-
-
-
-
-
C-Reactive Proteinm
X
-
-
X
X
-
X
-
X
-
-
Coagulation
X
X
-
X
X
-
X
-
X
X
-
Urinalysis
X
X
-
-
X
-
X
-
X
X
-


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
48
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Table 3:
Table of Events – Arm A – CC-122 Single Agent (Continued)
Screening
≤ 28 
Days 
Prior to 
Day 1a
Cycle 1 and the first Cycle of 
each Dose Escalationb
Cycle 2 of each Dose
Levelb
Cycle 3 of each Dose 
Levelb, o
≥Cycle 4b, p
End of 
Treatmentb
Follow-up
Screen
Day 1
Days 2 
and 4
± 1 Day
Days 8, 15 and 
22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post IP 
discontinuation
Pregnancy Test as specified 
per PPRMP:
(see Section 6.1.14)
X
X
-
X
X
-
X
-
X
X
X
CC-122 Contraceptive and 
Risk Counseling and 
Education
To be completed prior to each dispensing of IP as per PPRMP
HBsAg, anti-HBc, & HCV 
RNA
X
-
-
-
-
-
-
-
-
-
-
Direct Antiglobulin Test 
X
-
-
-
-
-
-
-
-
-
-
Amylase, lipase, fasting lipid 
profile (eg, cholesterol and 
triglycerides), creatine 
kinase, TSH, FT4, LDH, 
immunoglobulins and T-cell 
subsets (CD4+, CD8+ and 
NK cells)
X
X
-
-
X
-
X
-
X
X
-
Troponin-T and BNP
X
X
-
X
X
-
X
-
X
X
-
12-lead ECG 
X
X
-
X
X
-
X
-
X
X
-
Ophthalmology Examc
X
-
-
-
-
-
-
-
-
-
-
Cardiac ECHO or MUGAd
X
-
-
-
X
-
-
-
Xd
X
-
Tumor Imaging Assessmente
X
-
-
-
-
-
-
-
Xe
Xe
-


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
49
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Table 3:
Table of Events – Arm A – CC-122 Single Agent (Continued)
Screening
≤ 28 
Days 
Prior to 
Day 1a
Cycle 1 and the first Cycle of 
each Dose Escalationb
Cycle 2 of each Dose 
Levelb
Cycle 3 of each Dose 
Levelb, o
≥Cycle 4b, p
End of 
Treatmentb
Follow-up
Screen
Day 1
Days 2 
and 4
± 1 Day
Days 8, 15 
and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post IP 
discontinuation
Efficacy Response 
Assessment f
-
-
-
-
-
-
-
-
Xf
X
-
 
 
X
-
-
-
-
-
-
-
-
-
-
Bone Marrow Aspirate/ 
Biopsy g
X
-
-
-
-
-
-
-
Xg
-
-
Peripheral Blood for MRD 
Assessmenth
X
-
-
-
-
-
-
-
Xh
-
-
X
-
-
-
-
-
-
-
-
-
-
 
-
X
-
-
-
-
-
-
-
-
-
-
X
-
Xk
Xk
Xk
-
Xk
-
-
-
Dispense CC-122 n
-
X
-
-
X
-
X
-
X
-
-
Drug 
Accountability/Compliance
-
-
-
-
X
-
X
-
X
X
-
 
X
X
X
X
X
X
X
X
X
X
X
 
 
-
X
X
X
X
X
X
X
X
X
-


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
50
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Table 3:
Table of Events – Arm A – CC-122 Single Agent (Continued)
Screening
≤ 28 
Days 
Prior to 
Day 1a
Cycle 1 and the first Cycle of 
each Dose Escalationb
Cycle 2 of each Dose 
Levelb
Cycle 3 of each Dose 
Levelb, o
≥Cycle 4b, p
End of 
Treatmentb
Follow-up
Screen
Day 1
Days 2 
and 4
± 1 Day
Days 8, 15 
and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post IP 
discontinuation
 
X
X
X
X
-
-
-
-
-
-
-
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
51
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
 
  
 
 
 
  
 
 
 
 
 
Please refer to Section 6 for a detailed description of Arm A procedures.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
52
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Table 4:
Table of Events – Arm B – CC-122 Plus Ibrutinib
(As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued; the procedures below apply to subjects 
continuing in the study.)
Tests and Observations
Screening
Cycle 1b
Cycle 2b
Cycle 3b
Cycle 4b, n
≥ Cycle 
5b, o
End of 
Treatmentb
Follow-up
≤ 28 Days 
Prior to 
Day 1a
Day 1
Day 1
Days 2 
and 4
± 1 Day
Days, 8, 
15 and 22
± 1 Day
Day 1
Day 8, 15 
and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post IP 
discontinuation
Informed Consent
X
-
-
-
-
-
-
-
-
-
-
-
Demographics/Medical 
History
X
-
-
-
-
-
-
-
-
-
-
-
Physical Examination
X
X
X
-
-
X
-
X
-
X
X
X
CIRS Score Assessment
X
-
-
-
-
-
-
-
-
-
-
-
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
-
-
X
-
X
-
X
X
X
X
X
X
-
-
X
-
X
-
X
X
X
Current Stage/Prognostic 
Classification
X
-
-
-
-
-
-
-
-
-
-
-
CBC & Differential
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Beta-2 Microglobulin
X
-
-
-
-
-
-
-
-
-
-
-
C-Reactive Proteinm
X
-
-
-
X
X
-
X
-
X
-
-
Coagulation
X
X
X
-
X
X
-
X
-
X
X
-
Urinalysis
X
X
X
-
-
X
-
X
-
X
X
-
Pregnancy Test as specified 
per PPRMP:
(see Section 6.1.14)
X
X
X
-
X
X
-
X
-
X
X
X


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
53
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Table 4:
Table of Events – Arm B – CC-122 Plus Ibrutinib (Continued)
Screening
≤ 28 Days 
Prior to 
Day 1a
Cycle 
1b
Cycle 2b
Cycle 3b
Cycle 4b, n
≥ Cycle 
5b, o
End of 
Treatmentb
Follow-up
Screen
Day 1
Day 1
Days 2 
and 4
± 1 
Day
Days, 8, 15 
and 22
± 1 Day
Day 1
Day 8, 15 
and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post IP 
discontinuation
CC-122 Contraceptive and 
Risk Counseling and 
Education
To be completed prior to each dispensing of IP as per PPRMP
HBsAg, anti-HBc, & HCV 
RNA
X
-
-
-
-
-
-
-
-
-
-
-
Direct Antiglobulin Test 
X
-
-
-
-
-
-
-
-
-
-
-
Amylase, lipase, fasting lipid 
profile (eg, cholesterol and 
triglycerides), creatine 
kinase, TSH, FT4, LDH, 
immunoglobulins and T-cell 
subsets (CD4+, CD8+ and 
NK cells)
X
X
X
-
-
X
-
X
-
X
X
-
Troponin-T and BNP
X
-
X
-
X
X
-
X
-
X
X
-
12-lead ECG 
X
X
X
-
X
X
-
X
-
X
X
-
Ophthalmology Examc
X
-
-
-
-
-
-
-
-
-
-
-
Cardiac ECHO or MUGAd
X
-
-
-
-
X
-
-
-
Xd
X
-
Tumor Imaging Assessmente
X
-
-
-
-
-
-
-
-
Xe
Xe
-
Efficacy Response 
Assessmentf
-
-
-
-
-
-
-
Xf
-
Xf
X
-
 
 
X
-
-
-
-
-
-
-
-
-
-
-


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
54
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Table 4:
Table of Events – Arm B – CC-122 Plus Ibrutinib (Continued)
Screening
≤ 28 Days 
Prior to 
Day 1a
Cycle 
1b
Cycle 2b
Cycle 3b
Cycle 4b, n
≥ Cycle 
5b, o
End of 
Treatmentb
Follow-up
Screen
Day 1
Day 1
Days 2 
and 4
± 1 
Day
Days, 8, 15 
and 22
± 1 Day
Day 1
Day 8, 15 
and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post IP 
discontinuation
Bone Marrow Aspirate/
Biopsyg
Xf
-
-
-
-
-
-
-
-
Xg
-
-
Peripheral Blood for MRD 
Assessmenth
X
-
-
-
-
-
-
-
-
Xh
-
-
X
-
-
-
-
-
-
-
-
-
-
-
X
-
-
-
-
-
-
-
-
-
X
-
X
-
Xj
-
Xj
-
Xj
Xj
-
Xj
-
-
-
Xk
Xk
-
Xk
-
Xk
-
-
-
-
-
Dispense Ibrutinib
-
X
X
-
-
X
-
X
-
X
-
-
Dispense CC-122
-
-
X
-
-
X
-
X
-
X
-
-
Drug 
Accountability/Compliance
-
-
X
-
-
X
-
X
-
X
X
-
Concomitant Medications/ 
Procedures
X
X
X
X
X
X
X
X
X
X
X
X
 
-
-
X
X
X
X
X
X
X
X
X
-
Allopurinol Administration 
as Tumor Lysis Prophylaxisl
X
X
X
X
X
-
-
-
-
-
-
-
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
55
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
Please refer to Section 6 for a detailed description of Arm B procedures.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
56
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Table 5:
Table of Events – Arm C – CC-122 Plus Obinutuzumab
(As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued; the procedures below apply to subjects 
continuing in the study.)
Tests and Observations
Screening
Cycle 1b, p
Cycle 2b
Cycle 3b, q
≥ Cycle 
4b, r
End of 
Treatmentb
Follow-up
≤ 28 Days 
Prior to 
Day 1a
Day 1
Day 
2 
Day 
4
Day 8
± 1 Day
Day 9
± 1 Day
Days 10 
and 12
± 1 Day
Days 16
and 23
± 1 Day
Day 1
Days 8, 15 
and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post 
IP discontin-
uation
Informed Consent
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Demographics/Medical 
History
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Physical Examination
X
X
-
-
-
-
-
-
X
-
X
-
X
X
X
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
-
-
-
X
-
X
-
X
X
X
X
X
-
-
-
-
-
-
X
-
X
-
X
X
X
Current Stage/Prognostic 
Classification
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
CBC & Differential
X
X
X
-
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Beta-2 Microglobulin
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
C-Reactive Proteinn
X
-
-
-
X
-
-
X
X
-
X
-
X
-
-
Coagulation
X
X
-
-
X
-
-
X
X
-
X
-
X
X
-
Urinalysis
X
X
-
-
-
-
-
-
X
-
X
-
X
X
-
Pregnancy Test as specified 
per PPRMP:
(see Section 6.1.14)
X
X
-
-
X
-
-
X
X
-
X
-
X
X
X


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
57
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Table 5:
Table of Events – Arm C – CC-122 Plus Obinutuzumab (Continued)
Screening
≤ 28 
Days 
Prior to 
Day 1a
Cycle 1b, p 
Cycle 2b
Cycle 3b, q
≥ Cycle
4b, r
End of 
Treatmentb
Follow-up
Screen
Day 
1
Day 
2 
Day 
4
Day 
8
± 1 
Day
Day 9
± 1 Day
Days 
10 and 
12
± 1 Day
Days 16 and 23
± 1 Day
Day 1
Days 8, 15 
and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post 
IP discontin-
uation
CC-122 Contraceptive and 
Risk Counseling and 
Education
To be completed prior to each dispensing of IP as per PPRMP
HBsAg, anti-HBc, & HCV 
RNA
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Direct Antiglobulin Test 
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Amylase, lipase, fasting lipid 
profile (eg, cholesterol and 
triglycerides), creatine 
kinase, TSH, FT4, LDH, 
immunoglobulins and T-cell 
subsets (CD4+, CD8+ and 
NK cells)
X
X
-
-
-
-
-
-
X
-
X
-
X
X
-
Troponin-T and BNP
X
X
-
-
X
-
-
X
X
-
X
-
X
X
-
12-lead ECG 
X
X
-
-
-
X
-
X
X
-
X
-
X
X
-
Ophthalmology Examc
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Cardiac ECHO or MUGAd
X
-
-
-
-
-
-
-
X
-
-
-
Xd
X
-
X
-
-
-
-
-
-
-
-
-
-
-
Xe
Xe
-
Efficacy Response 
Assessment f
-
-
-
-
-
-
-
-
-
-
-
-
Xf
X
-
 
 
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
58
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
Table 5:
Table of Events – Arm C – CC-122 Plus Obinutuzumab (Continued)
Screening
≤ 28 
Days 
Prior to 
Day 1a
Cycle 1b, p
Cycle 2b
Cycle 3b, q
≥ Cycle 
4b, r
End of 
Treatmentb
Follow-up
Screen
Day 1
Day 
2 
Day 
4
Day 8
± 1 Day
Day 9
± 1 Day
Days 10 
and 12
± 1 Day
Days 16 
and 23
± 1 Day
Day 1
Days 8, 15 
and 22
± 1 Day
Day 1
Days 8, 
15 and 22
± 1 Day
Day 1
28 days post 
IP discontin-
uation
Bone Marrow Aspirate/
Biopsyg
X
-
-
-
-
-
-
-
-
-
-
-
Xg
-
-
Peripheral Blood for MRD 
Assessmenth
X
-
-
-
-
-
-
-
-
-
-
-
Xh
-
-
 
X
-
-
-
-
-
-
-
-
-
-
-
-
-
-
 
X
-
-
-
-
-
-
-
-
-
-
-
-
X
-
 
 
X
-
-
-
-
Xj
-
-
Xj
Xj
-
Xj
Xj
-
-
-
-
-
-
-
X
-
Xk
-
Xk
-
Xk
-
-
-
Administer Obinutuzumabm 
-
X
X
-
X
-
-
X
X
-
X
-
X
-
-
Dispense CC-122
-
-
-
-
-
X
-
-
X
-
X
-
X
-
-
Drug 
Accountability/Compliance
-
-
-
-
-
-
-
-
X
-
X
-
X
X
-
 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
-
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X
X
X
X
X
X
X
X
-
-
-
-
-
-
-
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
59
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
Please refer to Section 6 for a detailed description of Arm C procedures.


EDMS Doc. Number: 22914699 - 19766462
CC-122
Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary
60
CC-122-CLL-001 Amendment 7 Final: 27 Jul 2018
6.
PROCEDURES
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued, and Phase 2 
will not proceed. Subjects already enrolled who are receiving clinical benefit in the opinion of 
the treating investigator may continue to receive study treatment up to a maximum of 24 cycles 
of CC-122.
The screening period begins on the date the Informed Consent Document (ICD) is signed and 
will last for up to 28 days.  The ICD must be obtained prior to beginning any assessments solely 
for the purpose of this study.  Standard of care assessments performed prior to signing the ICD
(as described in the protocol) may be used for this study, assuming they meet the protocol 
requirements and following discussion with the sponsor’s medical monitor.  Recording of 
AEs/serious adverse events (SAEs) will begin once the subject has signed the ICD.  All prior 
anticancer treatments (eg, chemotherapy, surgeries) and medical history, including approximate 
dates of treatment or diagnosis, must be recorded during screening. 
All study-required procedures should be performed as outlined in Table 3 through Table 5, 
depending on the arm to which the subject is assigned:
Table
Arm
Table 3
Arm A:  CC-122 single agent with intrasubject dose escalation
Table 4
Arm B:  CC-122 in combination with ibrutinib
Table 5
Arm C:  CC-122 in combination with obinutuzumab
As of Protocol Amendment 7, some clinic visits and assessments may be omitted as noted in
Table 3 through Table 5, and in Section 6.6 below.
Excursions from the timing of assessments will be considered protocol deviations and should be 
recorded in the source document along with the reason for the excursion. 
All scheduled laboratory assessments are to be performed at the designated central laboratory.
However, local laboratories may be used for the biweekly assessments (Days 8 and 22) during 
the third cycle of CC-122 dosing, and for decisions affecting treatment and dose modifications.  
For subjects on Arm A who dose escalate every 2 weeks, local laboratories may be used however 
the designated central laboratory is recommended.  
All laboratory values should be carefully monitored, especially following the initial treatment, 
throughout the first two cycles and for dose escalations of CC-122.  Serum creatinine and 
creatinine clearance, uric acid, phosphorus, calcium, and potassium labs should be monitored 
closely on Days 1, 2, 4, and 8 during the first cycle of CC-122 (ie, Cycle 1 in Arms A and C) and 
(Cycle 2 in Arm B)
 and unscheduled 
assessments performed as needed.
6.1.
Safety Assessments
Study safety evaluations will occur in accordance with Table 3 through Table 5, and should be 
performed in accordance with this section of the protocol.  The safety of CC-122 single agent 


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and CC-122 in combination with ibrutinib and in combination with obinutuzumab will be 
assessed using AEs, physical examinations (PEs), concomitant medications and procedures, 
clinical laboratory tests, vital signs, electrocardiograms (ECGs), and an echocardiogram/multi-
gated acquisition scan (MUGA).
Detailed procedures for obtaining each assessment are provided below.  
6.1.1.
Demographics / Medical History / Baseline Stage and Prognostic Classification
Demographics (gender, race, ethnicity, and date of birth), medical history, and the Cumulative 
Illness Rating Scale (CIRS) Score (Appendix G) will be documented by a qualified clinician at 
the time of the Screening visit.  The medical history will be general enough to document 
common comorbid conditions as well as specific enough to reveal any conditions listed as 
participation exclusion criteria, and will document whether the identified conditions are active or 
inactive at the time of enrollment.  The CIRS score will be collected to assess the performance 
status and fitness of subjects. 
 
6.1.1.1.
Prognostic Classification
Chronic lymphocytic leukemia-specific international prognostic classification reflecting the 
subject’s status at the time of enrollment will be documented 
 
 
 
 
 
6.1.2.
Adverse Events
All subjects will be evaluated for AEs during all scheduled visits starting at the signing of the 
ICD until 28 days after the last dose of study treatment. 


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6.1.3.
Vital Signs
Vital sign measurements will be obtained at each visit as indicated in Table 3 through Table 5.  
These assessments include systolic and diastolic blood pressure, heart rate, respiration rate, body 
temperature and body weight.  Measurements of height will be recorded only at the Screening 
visit.
Vital signs should be measured after the subject has rested for at least 5 minutes.  Vital sign 
measurements should be repeated for confirmation if clinically significant observations or 
changes from baseline occur.  All confirmed, clinically significant vital sign measurements must 
be recorded as an AE.
After the first 12 cycles of CC-122, in the absence of Grade ≥ 2 adverse events related to
CC-122, and as clinically indicated, some clinic visits and assessments may become less frequent 
as detailed in Section 6.6.
6.1.4.
Physical Examination
Complete PEs, including evaluation of lymph nodes, spleen and liver will be performed during 
Screening, on Cycle 1 Day 1 and will continue to be performed on Day 1 of each subsequent 
treatment cycle under Protocol Amendment 7 as part of the assessment for response (in the 
absence of imaging), at the EOT visit and at 28 days after the last IP discontinuation.  
Measurements of lymph nodes and documentation of any enlargement of the spleen and/or liver 
should be recorded in the source document and eCRF.
Symptom driven limited PEs will be performed as clinically indicated at any study visit.
6.1.5.
Cardiac Laboratory Testing
Subjects will undergo laboratory monitoring of plasma troponin-T and B-type natriuretic peptide
(BNP) to evaluate for potential early evidence of cardiac toxicity.  Testing will be performed at 
Screening, weekly during the first cycle of CC-122 treatment and for the first cycle of each dose 
escalation (Days 1, 8, 15, and 22), Day 1 of each subsequent cycle, and at the EOT visit.  A 
significant elevation of troponin-T is defined as a value greater than the upper limit of normal 
(ULN) for the assay with associated elevation of BNP or other significant cardiac symptoms or 
findings.  A significant elevation of BNP is defined as a ≥20% increase over baseline with an 
absolute value > 100 pg/mL.  Subjects who are found at Screening to have baseline troponin-T 
> ULN or BNP > 100 pg/mL must have a baseline evaluation by a cardiologist during screening 
to optimize cardioprotective therapy.
After the first 12 cycles of CC-122, in the absence of Grade ≥ 2 adverse events related to
CC-122, and as clinically indicated, some clinic visits and assessments may become less frequent 
as detailed in Section 6.6.
6.1.6.
12-Lead Electrocardiogram 
Triplicate or single standard 12-lead ECGs will be recorded at the visits listed in Table 3 through 
Table 5.  The 12-lead ECGs (12-lead at 25 mm/sec reporting rhythm, ventricular rate, 
PR-interval, QRS complex, QT interval, and QTc interval) will be performed after the subject 
has been in the supine position for at least 5 minutes.  


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Triplicate ECGs (3 recordings within 2±1 minute intervals) will be performed at Screening for 
all subjects.  In addition, triplicate ECGs will be collected as follows:
Arm A:
Cycle 1 Day 1:  0 and 1.5 hours (±15 minutes) after CC-122 dosing
Arm B: 
Cycle 1 Day 1: 0 and 1.5 hours (±15 minutes) after ibrutinib dosing
Cycle 2 Day 1:  0 and 1.5 hours (±15 minutes) after CC-122 dosing
Cycle 2 Day 15: 0 and 1.5 hours (±15 minutes) after CC-122 dosing
Arm C:
Cycle 1 Day 1:  0 and 1.5 hours (±15 minutes) after obinutuzumab dosing
Cycle 1 Day 9 and Cycle 1 Day 23:  0 and 1.5 hours (±15 minutes) after CC-122
dosing
A single ECG will be performed on all other visits where an ECG is indicated per Table 3
through Table 5 approximately 1.5 hours (±15 minutes) after dosing.
After the first 12 cycles of CC-122, in the absence of Grade ≥ 2 adverse events related to
CC-122, and as clinically indicated, some clinic visits and assessments may become less frequent 
as detailed in Section 6.6.
6.1.7.
Left Ventricular Ejection Fraction
Left ventricular ejection fraction (LVEF) MUGA, or echocardiogram (ECHO) will be conducted 
at Screening, after the first cycle of CC-122, and every 3 cycles thereafter (± 7 days), and at the 
EOT if not performed within the previous 8 weeks.
After the first 12 cycles of CC-122, in the absence of Grade ≥ 2 adverse events related to
CC-122, and as clinically indicated, some clinic visits and assessments may become less frequent 
as detailed in Section 6.6.
6.1.8.
Clinical Laboratory Tests
The following laboratory assessments will be performed at the Screening visit and during the 
study at the time points as described in Table 3 through Table 5.  All samples will be analyzed at 
a central laboratory unless otherwise specified.  All samples should be drawn predose unless 
otherwise specified.  Laboratory assessments will be recorded in the source document and eCRF: 
!
Amylase, lipase, fasting lipid profile, creatine kinase, thyroid-stimulating hormone
(TSH), free T4 (FT4), immunoglobulins (IgG, IgM and IgA only), T-cell subsets
!
CBC:  hemoglobin, hematocrit, red blood cell count with indices, white blood cell 
count with absolute differential and platelet count.  
!
Serum chemistry: albumin, total protein, bicarbonate, calcium, phosphorus, serum 
creatinine, serum urea/blood urea nitrogen (BUN), glucose (fasting), potassium, 
sodium, magnesium, chloride, total bilirubin, alkaline phosphatase, aspartate 
aminotransferase (AST or serum glutamic oxaloacetic transaminase [SGOT]), alanine 
aminotransferase (ALT or serum glutamate pyruvic transaminase [SGPT]), and 
lactate dehydrogenase (LDH) and uric acid.  
!
Beta-2 Microglobulin


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!
C-reactive protein
!
Direct antiglobulin test (local laboratory only)
!
Coagulation tests:  prothrombin time, international normalized ratio, and partial 
thromboplastin time
!
Urinalysis: dipstick, with microscopy in event of positive (1+ or greater) blood or 
protein and 24-hour collection for creatinine clearance and protein quantification in 
the event of 2+ or greater protein. 
!
Virus Serology:  hepatitis B antigen (HBsAg), hepatitis B core antibody (anti-HBc), 
and hepatitis C virus (HCV) RNA 
After the first 12 cycles of CC-122, in the absence of Grade ≥ 2 adverse events related to
CC-122, and as clinically indicated, some clinic visits and assessments may become less 
frequent as detailed in Section 6.6.
6.1.9.
Prior/Concomitant Medications and Procedures
All subjects will be evaluated for any concomitant medications and procedures during all 
scheduled visits from the signing of the ICD until 28 days after the last dose of study treatment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.1.12.
Ophthalmologic Examinations
An ophthalmologic examination will be performed by a qualified ophthalmologist at Screening 
as described below in all subjects. The Screening ophthalmologic exam will include:
!
Visual acuity
!
Slit-lamp examination with fluorescein staining following pupillary dilation (unless 
fluorescein and pupillary dilatation are contraindicated)


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!
Ophthalmologic examination focusing on the anterior chamber, iris and anterior 
vitreous 
Subsequent ophthalmologic examinations will be performed as clinically indicated.  If there are 
any clinically significant findings, a full ophthalmologic exam will be conducted by a qualified 
ophthalmologist. 
6.1.13.
Contraceptive and Risk Counseling
Subjects will be counseled about appropriate contraception during Screening.  Complete 
abstinence or double contraceptive methods (one of which must be a barrier method) for females 
(eg, oral, injectable, or implantable hormonal contraceptive; intra-uterine device; barrier 
contraceptive with spermicide; or vasectomized partner) must be used from the time ICF is 
signed, throughout the study and for 28 days after the last dose of CC-122.  A single 
contraceptive method for males (complete abstinence or a condom) must be used from the time 
the ICF is signed, throughout the study, and for 3 months after the last dose of CC-122.  
Counseling should be documented in source documents.
The CC-122 Pregnancy Risk Minimization Plan for Celgene Clinical Trials (Appendix F) applies 
to all subjects receiving CC-122 therapy and will be given to sites as a separate document. 
CC-122 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, or designee, in requirements specific to counseling of subjects.  
Once trained, these healthcare staff will counsel subjects prior to the administration of CC-122 to 
ensure that the subject has complied with all requirements including use of birth control and that 
the subject understands the risks associated with CC-122.  This step will be documented with a 
completed Education and Counseling Guidance Document, and CC-122 will not be administered 
until this step occurs.  
A CC-122 Information Sheet will be provided to each subject before IP is dispensed.  
Females of childbearing potential and males, other than the subject, should not handle or 
administer CC-122 unless they are wearing gloves. 
Arm C:  Females of childbearing potential should use effective contraception during 
obinutuzumab treatment and for 18 months following obinutuzumab therapy (GAZYVA, 
GAZYVARO).
Arm B:  Females of childbearing potential should avoid becoming pregnant while taking 
ibrutinib because ibrutinib can cause fetal harm (IMBRUVICA).
6.1.14.
Pregnancy Test
A female of child bearing potential (FCBP) is defined as a sexually mature woman who has: 
1. Not undergone a hysterectomy or bilateral oophorectomy, and 
2. Not been naturally postmenopausal (amenorrhea following cancer therapy does not rule 
out childbearing potential) for at least 24 consecutive months (ie, has had menses at any 
time in the preceding 24 consecutive months).  


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The investigator will classify a female subject as a FCBP according to this definition.  Pregnancy 
testing is not required for non-FCBP subjects but justification must be recorded in the eCRF and 
the source document.  Pregnancy testing will be conducted by the local laboratory.
For a FCBP, pregnancy testing will be conducted at the visits listed in Table 3 through Table 5:
!
A serum pregnancy test with sensitivity of at least 25 mIU/mL is to be obtained at 
Screening.  
!
A serum or urine pregnancy test (based on investigator’s discretion and minimum test 
sensitivity [25 mIU/mL]) should be done weekly for the first cycle, within 72 hours 
prior to Day 1 of every cycle (with the exception of the first day of CC-122 dosing on 
which it must be performed within 24 hours of first dose), EOT visit and 28 days post 
IP discontinuation.  
!
The subject may not receive IP until the investigator has verified the Screening 
pregnancy tests to be negative.
!
A FCBP must avoid activities that could lead to conception for 28 days after the last 
dose of CC-122 or a male subject whose partner is an FCBP must avoid activities that 
could lead to conception for 3 months after the last dose of CC-122.
!
Please refer to the ibrutinib and the obinutuzumab  PI(s) or SmPC(s) for additional 
recommendations.
Note: FCBP receiving CC-122 will undergo pregnancy testing according to the schedule 
described in the CC-122 Pregnancy Prevention Risk Management Plan (PPRMP) and CC-122 
Information Sheet.
Results for pregnancy tests will be recorded in the source document and eCRF.  
6.2.
Efficacy Assessments
6.2.1.
Efficacy Parameters
The following efficacy assessments will be performed at scheduled intervals throughout the 
study as described in Table 3 through Table 5.
6.2.2.
Tumor Imaging Assessment
Tumor imaging assessment by CT scan is mandatory at Screening (neck, chest, abdomen, and 
pelvis), and after the first 6 cycles of CC-122 dosing [the 2nd scan is mandatory only for the 
affected regions with abnormal findings at baseline; Week 25 (for subjects on Arms A and C) or 
Week 29 (for subjects on Arm B), +4 weeks/-1 week], and is recommended if the subject 
discontinues study treatment due to an adverse event (if the subject shows signs of preliminary 
efficacy).  Additional CT scan(s) is allowed if clinically indicated until documented disease 
progression or initiation of subsequent CLL therapy.  The unscheduled CT scan(s) should be 
documented in the CRF.  A CT scan with contrast is the recommended imaging modality.  MRI 
may be used only if CT with contrast is medically contraindicated or if the frequency of CT 
scans exceeds local standards.  Standard of care CT scans or MRI performed up to 56 days prior 
to Cycle 1 Day 1 may be acceptable for Screening, even if performed prior to signing the ICD.  
All imaging assessments will be evaluated by a reader at the local institution.  


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6.2.3.
Bone Marrow Examination
A bone marrow aspirate and biopsy are optional for all subjects at Screening.  A bone marrow 
aspirate and biopsy must be collected for all subjects at the time of the CR/CRi confirmation visit 
within 12 weeks after clinical, imaging, and laboratory response criteria have been met.
6.2.4.
Minimal Residual Disease (MRD) Assessment
Peripheral blood for MRD assessment should be collected during Screening, every 6 cycles (only 
if subject is receiving CC-122, up to a maximum of 24 cycles), and at the time of CR/CRi 
confirmation visit (within 12 weeks after clinical and laboratory response criteria have been 
met).  For those subjects found to be MRD positive in the peripheral blood at the CR/CRi 
confirmation visit, a peripheral blood sample for MRD assessment should be collected 
approximately every 6 cycles thereafter until MRD negativity is achieved or relapse/progression 
is documented. Peripheral blood for MRD assessment should also be collected at the time of PR 
(within 12 weeks after clinical, imaging, and laboratory response criteria have been met).  A 
bone marrow aspirate for MRD assessment should be collected at the time of CR/CRi 
confirmation visit and once MRD-negativity is achieved in peripheral blood unless MRD 
negativity in bone marrow was documented earlier.  Peripheral blood for MRD assessment 
should also be collected at the time of relapse/progression in subjects who previously achieved 
MRD negativity in peripheral blood.
MRD analyses will be performed by a central laboratory.
 
 
 
 
 
 
 
 


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6.2.7.
Efficacy Response Assessment
Response assessment for CLL will be completed according to the updated IWCLL guidelines for 
the diagnosis and treatment of CLL as described in Appendix A with modifications.  Subjects 
with SLL will be assessed according to the lymphoma guidelines as described in Appendix B.  
Lymph node responses will be assessed separately and independently of increases in blood 
lymphocyte counts.  
Efficacy response according to the respective criteria for CLL/SLL will be formally assessed at 
the same schedule as CT scans and at the End of Treatment visit.  In addition, efficacy 
assessment should also be performed every 3 cycles (+4 weeks/-1 week) during the first two 
years and every 6 cycles (+4 weeks/-1 week) thereafter at the time of physical examinations until 
documented progression or initiation of subsequent CLL therapy.  CR/CRi confirmation by bone 
marrow examination must be completed within 12 weeks after clinical criteria have been met.
 
 
 
 
 
 
 
 
 
 


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6.5.
Phase 1 Dose Escalation - Third Cycle of CC-122 Through the 
Twelfth Cycle of CC-122 
During the third cycle of CC-122, the Day 8 and/or Day 22 clinic visits and assessments may be 
omitted at the discretion of the investigator in the absence of any Grade ≥ 2 toxicity related to 
CC-122.  
Thereafter, the minimum frequency of visits is once monthly (until the first 12 cycles of CC-122 
have been completed, see Section 6.6) and appropriate procedures/tests are expected to be 
performed. Note that the drug dispensed at a given visit should cover the anticipated time to the 
next scheduled visit.  Owing to the requirements of the PPRMP and its proscriptions concerning 
the availability of drug and the importance of pregnancy testing and counseling, a subject must 
visit with a minimum frequency of every 28 days. 
6.6.
Phase 1 Dose Escalation - Cycle 13 of CC-122 and Beyond
Beginning with Cycle 13 of CC-122, the following Day 1 clinic visits and assessments may be
performed on a less frequent schedule at the discretion of the investigator in the absence of any 
Grade ≥ 2 toxicity related to CC-122.


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!
Tests to occur every cycle (can be up to 7 days prior to Day 1) in order for CC-
122 to be dispensed:
∀
Serum or urine pregnancy test in females of childbearing potential as per CC-122 
PPRMP (Appendix F, Section 19).
∀
CC-122 Contraceptive and Risk Counseling and Education (Appendix F, 
Section 19).
∀
Hematology: CBC with differential and platelet counts. 
∀
Laboratory test may be performed up to 48 hours before the visit.
∀
Physical Examination.
∀
Recording of adverse events:

Subjects will be queried on any new adverse events that were experienced by 
the subject and recorded in the source documents and CRFs.
∀
Recording of concomitant medications and procedures
!
Tests to occur every 1-3 months (± 7 days) in the absence of any Grade ≥ 2 
toxicity related to CC-122:
∀
Vital signs and weight
∀
Laboratory tests (may be performed up to 48 hours before the visit):

Serum chemistries: albumin, total protein, bicarbonate, calcium, phosphorus, 
serum creatinine, serum urea/BUN, glucose (fasting), potassium, sodium, 
magnesium, chloride, total bilirubin, alkaline phosphatase, AST, ALT, LDH, 
and uric acid  

C-Reactive Protein 

Cardiac-specific troponin-T, BNP

PT/INR/PTT

Amylase, lipase, fasting lipid profile, creatine kinase, TSH, FT4, 
immunoglobulins 

Urinalysis with microscopy
 
∀
12-lead single ECG (3 recordings within 2 ± 2 minute intervals) will be 
performed both at predose (within 90 minutes prior to dosing) and at 1.5 hours 
post dose
∀
LVEF by ECHO or MUGA only if clinically indicated
∀
T-cell subsets should continue to be obtained on Day 1 of each cycle


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7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
The study population consists of Dose Escalation Phase (Phase 1) subjects who were enrolled 
under previous amendments and were ongoing during Amendment 6, version dated 06 Jun 2017.
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued and Phase 2 
will not proceed.  
Depending on the tolerability of each dose level, this study will enroll approximately 158 
(136-182) subjects.  The Dose Escalation Phase will include the following:
!
Arm A:  20 subjects
!
Arm B:  24 (18 to 36) subjects
!
Arm C:  24 (18 to 36) subjects
The Dose Expansion Phase may enroll up to 50 subjects in Arm B and/or 40 subjects in Arm C
for a total of up to 90 subjects. 
Subjects will be enrolled in the US, Canada and Europe.
7.2.
Inclusion Criteria
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued and Phase 2 
will not proceed.
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subjects ≥18 years age and ≤80 years of age at the time of signing the informed consent 
form.
2. Understand and voluntarily sign an informed consent form prior to any study related 
assessments/procedures being conducted.
3. Able to adhere to the study visit schedule and other protocol requirements.
4. Must have a documented diagnosis of CLL/SLL requiring treatment (IWCLL Guidelines 
for the Diagnosis and Treatment of CLL [Hallek, 2008]).  In addition:
a.
Presence of at least one clinically measurable lesion:
i. nodal lesion that measures ≥ 1.5 cm in longest dimension (LD) and 
≥ 1.0 cm in longest perpendicular dimension (LPD), or
ii. spleen that measures ≥ 14 cm in longest vertical dimension (LVD) with a 
minimum of 2 cm enlargement, or
iii. liver that measures ≥20 cm in LVD with a minimum of 2 cm
enlargement, or
iv. peripheral blood B lymphocyte count > 5000/uL


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5. Must meet the criteria for relapsed and/or refractory disease according to the IWCLL 
guidelines 
to ≥ 1 prior treatment (with the exception of Arm B) and have 
evidence of disease progression requiring treatment at the time of study entry as follows:  
a.
For Arms A and C, subjects must have received either prior 
chemoimmunotherapy or therapy with an approved BTK inhibitor with the 
following exceptions: 
i. Chemoimmunotherapy is not required if subjects have specific co-  
morbidities that preclude the use of standard chemoimmunotherapy 
meeting at least 1 of the following criteria;
1. CIRS ≥ 6;
2. Creatinine Clearance < 70 mL/min;
3. Subject is not a candidate for a chemoimmunotherapy in the 
opinion of investigator. 
The reason for not being a candidate must be documented in the CRF.
ii. Treatment with an approved BTK inhibitor is not required if subject has
contraindications or is not a candidate for such a therapy in the opinion of 
the investigator. 
The reason for not being a candidate must be documented in the CRF. 
b. For Arm B, subjects with treatment-naïve or R/R CLL must meet the following 
criteria:
i. Dose Escalation Phase: Subjects must not have received prior treatment 
with ibrutinib (or any other BTK inhibitors) and must have: 
1. R/R CLL: has 17p- and/or TP53 mutation; or 
2. Treatment naïve: is unfit for standard chemoimmunotherapy 
meeting at least 1 of the following co-morbidity criteria:
a.
CIRS ≥ 6;
b. Creatinine Clearance < 70 mL/min;
c.
Subject is not a candidate for a chemoimmunotherapy in 
the opinion of the investigator. 
The reason for not being a candidate must be documented in CRF.
ii. Dose Expansion Phase: Subjects must not have received prior treatment 
with ibrutinib (or any other BTK inhibitors) and must have high risk CLL. 
High risk is defined as:
1)
17p- and/or TP53 mutation positive in treatment naïve CLL; or 
2) 17p- and/or TP53 mutation positive, and/or complex karyotype, 
and/or progression < 24 months after completion of 1st line 
chemoimmunotherapy in R/R CLL


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c.
Subjects with R/R SLL or CLL with bulky disease (at least one lymph node 
measuring > 5.0 cm in diameter) are considered at higher risk for developing TFR 
and may only be enrolled upon discussion with the sponsor’s medical monitor and 
agreement to close medical management.
6. Subjects must have the following lab values:
a.
Absolute neutrophil count (ANC) ≥1,500 cells/mm3 or ≥1000 cells/mm3 if secondary 
to bone marrow involvement by disease.
b. Platelet count ≥100,000 cells/mm3 (100 x 109/L) or ≥50,000 cells/mm3 (50 x 109/L) 
if secondary to bone marrow involvement by disease.
c.
Serum aspartate transaminase (AST/SGOT) or alanine transaminase 
(ALT/SGPT) < 3.0 x upper limit of normal (ULN) unless due to disease.
d. Serum bilirubin < 1.5 x ULN unless due to Gilbert’s syndrome.
o
Serum bilirubin ≤1.0 x ULN unless due to Gilbert’s syndrome, 
Treatment Arm B only (CC-122 in combination with ibrutinib)
e.
Calculated creatinine clearance of ≥60 ml/min.
f.
No evidence of TLS per the Cairo-Bishop definition of laboratory TLS (Appendix E) 
(subjects may be enrolled upon correction of electrolyte abnormalities).
8. Ability to swallow oral capsules without difficulty.
9. Pregnancy Prevention Risk Management Plan:
a.
Females of childbearing potential (FCBP) must undergo pregnancy testing based on 
the frequency outlined in the PPRMP and pregnancy results must be negative. 
b. Unless practicing complete abstinence from heterosexual intercourse, sexually active 
FCBP must agree to use adequate contraceptive methods as specified in the PPRMP. 
o
For Arm C, subjects must agree to use adequate contraceptive methods for 18 
months (please refer to the obinutuzumab IB, PI, and SmPC).
∀
Complete abstinence is only acceptable in cases where this is the preferred and 
usual lifestyle of the subject.  
∀
Periodic abstinence (calendar ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable. 
c.
Males (including those who have had a vasectomy) must practice complete 
abstinence or use barrier contraception (condoms) when engaging in sexual activity 
with FCBP as specified in the PPRMP. 
d. Males must agree not to donate semen or sperm for the duration of the study and for 3 
months after the last dose of CC-122. 
e.
All subjects must: 
∀
Understand that the IP could have a potential teratogenic risk. 


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∀
Agree to abstain from donating blood while taking IP and following 
discontinuation of IP. 
∀
Agree not to share IP with another person. 
f.
Other than the subject, FCBP and males should not handle the IP or touch the 
capsules, unless gloves are worn.
g. Be counseled about pregnancy precautions and risks of fetal exposure (see 
Section 6.1.13).  
Arm B only:
10. Enrollment into Arm B will be permitted if ibrutinib is considered the standard of care in 
the clinical practice.
Expansion Cohort 2 of Arm C:
11. Subjects in Cohort 2 of Arm C must meet the following criteria:
a.
Subject must have received at least one BCR PI (ibrutinib, idelalisib, or other 
approved BTK or PI3K inhibitor) and/or venetoclax;
b. Subject must be either resistant to or intolerant of (ie., treatment failures) the last 
BCR PI and/or venetoclax. Resistant is defined as relapsed or refractory per 
IWCLL2008:
i.
Relapse is defined as a patient who has previously achieved a CR or PR, but 
after a period of 6 or more months, demonstrates evidence of disease 
progression.
ii.
Refractory is defined as failing to achieve a CR or PR, or disease progression 
within 6 months after initiation of treatment with an approved BTK or PI3K 
inhibitor (eg, ibrutinib, idelalisib) or venetoclax.
iii.
Intolerance is defined as the inability to continue treatment with a BCR PI or 
venetoclax due to toxicities or due to development of a contraindication that 
makes the subject ineligible to receive further treatment with a BCR PI or 
venetoclax.
7.3.
Exclusion Criteria
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued and Phase 2 
will not proceed.  
The presence of any of the following will exclude a subject from enrollment:
1. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study.
2. Any condition including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study.
3. Any condition that confounds the ability to interpret data from the study.


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4. Prior autologous or allogeneic stem cell transplant (SCT)/bone marrow transplant within 
12 months of signing the ICD. Subjects who received allogeneic SCT ≥ 12 months before 
signing the ICD may be eligible provided there is no ongoing graft-versus-host disease 
and no ongoing immune suppression therapy. 
5. Uncontrolled intercurrent illness including, but not limited to:
a.
Ongoing or active infection requiring parenteral antibiotics.
b. Uncontrolled diabetes mellitus.
i. The glycemic targets for subjects with diabetes should take into 
consideration age, comorbidities, life expectancy, and functional status of 
the subjects and follow established guidelines (eg, International Diabetes 
Federation, the European Diabetes Working Party guidelines, and the 
American Diabetes Association).  For younger (< 70 years old) or subjects 
with life expectancy ≥10 years, the target glycosylated hemoglobin, type 
A1C (HbA1c) should be < 7.0%. The target HbA1c for older (≥ 70 years 
old) subjects or subjects with life expectancy < 10 years should be < 8.0%.  
Consultation with an endocrinologist is recommended when deciding if 
diabetes is optimally controlled.  Subjects with a stable HbA1c greater than 
the suggested target may be enrolled upon discussion with the medical 
monitor.  
c.
Chronic symptomatic congestive heart failure (Class III or IV of the New York 
Heart Association Classification for Heart Disease).
d. Active central nervous system involvement as documented by spinal fluid 
cytology or imaging.  
e.
Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
f.
Other concurrent severe and/or uncontrolled concomitant medical conditions that 
could cause unacceptable safety risks or compromise compliance with protocol.
6. History of second malignancies with life expectancy of < 2 years or requirement of 
therapy that would confound study results.  This does not include the following:
a.
Basal cell carcinoma of the skin.
b. Squamous cell carcinoma of the skin.
c.
Carcinoma in situ of the cervix.
d. Carcinoma in situ of the breast.
e.
Carcinoma in situ of the bladder.
f.
Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b).
7. Known seropositivity for or history of active viral infection with human 
immunodeficiency virus (HIV), or hepatitis B or C virus (HBV, HCV).
a.
Hepatitis B screening is mandatory for all patients (HBsAg and anti-HBc). 
Patients with active hepatitis B disease should not be treated with obinutuzumab. 
Patients should be referred to a specialist if they are carriers before treatment 


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starts (see PI or SmPC).  Subjects who are positive for anti-HBc and/or anti-HBs 
but negative for HBsAg and HBV DNA may be treated after consultation with a 
hepatologist.
8. Any peripheral neuropathy ≥ NCI CTCAE Grade 2.
9. Use of systemic corticosteroids in doses greater than prednisone equivalent to 20 mg/day.
10. Medicines with high probability to cause QT prolongation or torsades de pointes. 
Subjects on chronic medications in this category may enroll after discussion with the 
medical monitor if changing these medications are not in the best medical interest of the 
patient.
11. History of hypersensitivity to IMiDs® (lenalidomide, pomalidomide, thalidomide).
12. Impaired cardiac function or clinically significant cardiac diseases, including any of the 
following:
a.
LVEF < 45% as determined by MUGA scan or ECHO.
b. Complete left bundle branch, or bifasicular, block.
c.
Congenital long QT syndrome.
d. Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation.
e.
QTcF > 470 msec on Screening ECG (mean of triplicate recordings).
f.
Unstable angina pectoris or myocardial infarction ≤ 6 months prior to starting 
CC-122.
g. Uncontrolled congestive heart failure or uncontrolled hypertension.
h. Troponin-T value >0.4 ng/mL or BNP >300 pg/mL.
Subjects with baseline troponin-T >ULN or BNP >100 pg/mL are eligible but 
should have cardiologist evaluation prior to enrollment in the trial for baseline 
assessment and optimization of cardioprotective therapy and after discussion with 
the sponsor’s medical monitor.
13. Chemotherapy, radiotherapy, investigational anticancer therapy or major surgery within 
28 days of Day 1 dosing with the following exceptions:
a.
Arm A: A minimum 5-day washout after discontinuation of ibrutinib (or other 
BTK inhibitors) is required; only those subjects without rapid disease progression 
during the 5-day washout will be allowed to enroll into Arm A.
i. Rapid disease progression is defined as follows:
1. For subjects with measurable nodal disease, the increase in the sum 
of diameters of the largest lymph nodes (up to 3 nodes) exceeds 
1 cm per day OR the diameter of the largest lymph node exceeds 
5 cm during the 5 day wash out. 
2. For subjects with lymphocytosis, the increase in the ALC exceeds 
2x109/L per day OR the ALC exceeds 100,000 x109/L during the 
5-day wash out;


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b. Arm C: No minimum washout is required after discontinuation of ibrutinib 
(or other BTK inhibitors)
c.
Approved PI3 kinase inhibitors: Subjects may start study treatment within 3 days 
of discontinuation of approved PI3 kinase inhibitors.
14. Persistent diarrhea or malabsorption ≥ NCI CTCAE Grade 2, despite medical 
management.
15. Active disease transformation (ie, Richter’s Syndrome); subjects with Richter’s 
Syndrome that has resolved > 2 years from signing the ICD are eligible.
16. Known acute or chronic pancreatitis
17. Pregnant or lactating females
Arm B only (CC-122 in combination with ibrutinib):
18. Prior treatment with a BTK inhibitor
19. Presence of transfusion-dependent thrombocytopenia or a history of bleeding disorders or 
clinical conditions (eg, gastrointestinal bleeding or constitutional disorders) that may 
increase risk of life-threatening bleeding when thrombocytopenic
20. History of stroke or intracranial hemorrhage within 6 months prior to signing the ICD
21. Medications that are strong inhibitors or inducers of CYP3A4/5 (eg, itraconazole, 
ketoconazole, clarithromycin, ritonavir, phenytoin, pentobarbital, and rifampin) should be 
changed; subjects who cannot change these medications must be excluded (see 
Appendix H for a list of strong and moderate inhibitors/strong inducers of CYP3A).
22. Use of concomitant anticoagulation with warfarin or other vitamin K antagonists is 
prohibited, as is treatment with these agents in the 7 days prior to signing the ICD.  The 
use of other anticoagulants (eg, heparins) and anti-platelet agents is allowed per 
investigator’s discretion.  Investigator questions regarding this should be addressed to the 
sponsor’s medical monitor or the study national Principal Investigators.
Arm C only (CC-122 in combination with obinutuzumab):
23. Hypersensitivity to obinutuzumab


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8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Products
8.1.1.
CC-122
Celgene Corporation will supply CC-122 in appropriate strengths.  The active pharmaceutical 
ingredient in capsules (AIC) was employed from the beginning of the current study 
(non-formulated, white opaque gelatin capsules). There are no other excipients in the capsules. 
During the course of the current study, a new formulation, Formulation 6 [F6] of CC-122 is 
being developed at various strengths (0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 
4.0 mg) to be made available over the course of the study. The F6 formulations have different 
CC-122 base free amounts compared to the CC-122 AIC that was employed from the beginning 
of the current study. CC-122 AIC 0.5, 1, and 3 mg strengths were based on CC-122 HCl and are 
equivalent to 0.44, 0.88, and 2.64 mg CC-122 base free, respectively. CC-122 formulated 
capsules of 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4 mg strengths are based on CC-122 base free and are 
equivalent to 0.56, 1.13, 1.69, 2.25, 2.81, 3.38 , 3.95 and 4.51 mg CC-122 HCl, respectively.
Study CC-122-CP-002 Part 2 was an open-label, randomized, three-period, six-sequence, 
three-way single-dose crossover study in healthy adult subjects to evaluate the PK of CC-122 
after administration of formulated (test formulations: Formulation 4 [F4] and F6) and AIC 
CC-122 capsules.
Following a single oral administration of CC-122 at the dose level of 3 mg from reference AIC 
formulation and formulated capsule F-6 formulation in healthy adult subjects (N=18), the total 
plasma exposures (AUCinf) is 16.29% higher and the peak plasma exposure (Cmax) is 35.58% 
higher from the F-6 formulation as compared to that from the reference AIC formulation. The 
CC-122 F-6 formulation has been selected for further development (Data on File, 2015).
For subjects on Arm A, subjects who start with AIC will continue to receive AIC; subjects who 
start with F6 will continue to receive F6 for all dose levels.
For subjects on Arms B and C, F6 will be introduced in the 1.0 mg cohorts after the 0.5 mg AIC 
fixed-dose cohort has been completed, and will continue to receive F6 thereafter. The 0.5 mg 
fixed dose cohorts will use AIC.  Any subjects requiring doses of 0.25 mg or lower due to dose 
reductions will use AIC.
The formulated capsules will be provided in reddish brown gelatin capsules and contain the 
following excipients: Avicel PH 102, spray dried mannitol, crospovidone, areosil, and stearic 
acid.
Celgene will continue to provide up to 24 cycles of CC-122 for ongoing patients experiencing 
clinical benefit.  
Please refer to the CC-122 IB and pharmacy manual for detailed information concerning the 
physical properties of CC-122.
The IP will be labeled per local regulations. Store as directed on package label. 


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8.1.2.
Ibrutinib
Ibrutinib will be supplied by Celgene and labeled appropriately as investigational material for the 
study. Ibrutinib is supplied as 140 mg capsules.  The recommended dose of ibrutinib for subjects 
with CLL according to the ibrutinib package insert or SmPC (IMBRUVICA) is 420 mg (three 
140 mg capsules) orally once daily.  Refer to Section 8.2.2.2 for administration information.  
Celgene will continue to provide an investigational supply of ibrutinib for ongoing patients 
experiencing clinical benefit, for up to 24 cycles of CC-122.  For patients who discontinue
CC-122 prior to 24 cycles or if patients have surpassed the 24 cycles of CC-122, Celgene will 
continue to provide an additional 3 cycles of ibrutinib from the investigational supply to allow 
time for patients to be switched to commercially available ibrutinib and/or other therapies at the 
discretion of the treating physician.
Refer to the Pharmacy manual, package insert, or SmPC for stability and storage information.
8.1.3.
Obinutuzumab
Obinutuzumab will be supplied by Celgene and labeled appropriately as investigational material 
for the study. 
Refer to the obinutuzumab IB, package insert or SmPC (GAZYVA, GAZYVARO) for 
preparation and administration information.  Refer to Section 8.2.2.3 for timing of obinutuzumab 
administration.  Premedicate according to the PI, SmPC, or institutional standards.  
Recommended premedications will be provided by the investigational site.  The sponsor will not 
provide these medications.
Obinutuzumab is to be administered only as an intravenous (IV) infusion.
Celgene will continue to provide the protocol-specified total of 6 cycles of investigational supply 
of obinutuzumab for ongoing patients experiencing clinical benefit.  In the event CC-122 is 
discontinued prior to obinutuzumab, subjects may continue to receive the protocol-specified total 
of 6 cycles of obinutuzumab at the discretion of the treating physician.  In addition, for patients 
that have surpassed the 24 cycles of CC-122, Celgene will continue to provide an additional 3 
cycles of CC-122 to allow time for patients to be switched to commercially available therapies at 
the discretion of the treating physician.
Refer to the Pharmacy manual, PI, or SmPC for stability and storage information.
8.1.4.
Premedications
Other recommended medications such as allopurinol will be provided by the investigative site.  
The sponsor will not provide these medications.
Please refer to Section 9.3.3 for required premedications for obinutuzumab infusions.
8.2.
Treatment Administration and Schedule
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued and Phase 2 
will not proceed.  


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CC-122-CLL-001 is a Phase 1/2 open-label, dose finding study evaluating CC-122 administered 
orally to subjects with CLL/SLL.  Subjects who are eligible for the study will be assigned to one 
of the following arms:
!
Arm A:  CC-122 single agent
!
Arm B:  CC-122 in combination with ibrutinib  
!
Arm C:  CC-122 in combination with obinutuzumab
Cycle 1 Day 1 treatment may begin if the following parameters are met:
!
All eligibility criteria
!
The ANC is ≥1,500 cells/mm3 (1.5 x 109/L) or ≥1,000 cells/mm3 (1.0 x 109/L) if 
secondary to bone marrow involvement by disease
!
The platelet count is ≥100,000 cells/mm3 (100 x 109/L) or ≥50,000 cells/mm3
(50 x 109/L) if secondary to bone marrow involvement by disease
!
AST/ALT < 3 x ULN
8.2.1.
Safety Review Committee
Safety considerations, including decisions to open a new dose level cohort will be made by an
SRC.  The SRC membership will be comprised of the sponsor’s medical monitor and drug safety 
physician, the lead coordinating investigator (or designee), European coordinating investigator
(or designee) and 2 additional physicians participating in the study and nominated by the 
coordinating investigators as having sufficient prior experience in early phase studies in CLL and 
in the use of lenalidomide in CLL.  Other study team members (eg, study statistician) may also 
participate in SRC meetings as needed.  Discussions and outcomes of SRC meetings will be 
documented and provided to all study investigators.
8.2.2.
Dose Escalation Phase
8.2.2.1.
Arm A:  CC-122 Single Agent
Subjects assigned to Arm A will be administered a starting dose of 1.0 mg CC-122 orally on a 
5/7-day (5 continuous days out of 7 days per week) schedule starting at Cycle 1 Day 1 with 
intrasubject dose escalation every 2 weeks at 0.5 mg increments at the discretion of the 
investigator as tolerated up to a maximum dose of 4.0 mg for a total of 24 cycles of CC-122, or 
until disease progression, unacceptable toxicity or discontinuation for any other reason, 
whichever is earlier.  All treatment cycles are 28 days.  Each dose will be taken in the morning 
with about 8 ounces of water.  CC-122 may be taken up to 12 hours late if dosing has been 
delayed on a single day; otherwise that day’s dose should be omitted.
8.2.2.2.
Arm B:  CC-122 in Combination with Ibrutinib
Subjects in Arm B will be administered CC-122 orally on a 5/7-day schedule.  
CC-122 will be initiated on Cycle 2 Day 1 and on Day 1 of each cycle thereafter up to a 
maximum of 24 cycles of CC-122, or until disease progression, unacceptable toxicity or 
discontinuation for any other reason, whichever is earlier.  Each dose will be taken in the 


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morning with about 8 ounces of water.  CC-122 may be taken up to 12 hours late if dosing has 
been delayed on a single day; otherwise that day’s dose should be omitted.  
Dosing of ibrutinib is as described in the IMBRUVICA package insert or SmPC.  Subjects will 
take orally three 140 mg capsules of ibrutinib daily for a total daily dose of 420 mg.  Ibrutinib 
should be taken once daily at approximately the same time each day.  The capsules should be 
swallowed whole with water and subjects should not open, break or chew capsules.  Ibrutinib 
will be administered daily starting Cycle 1 Day 1 up to a maximum of 24 cycles of CC-122, or 
until disease progression, unacceptable toxicity or discontinuation for any other reason,
whichever is earlier.  For patients who discontinue CC-122 prior to 24 cycles or if patients have 
surpassed the 24 cycles of CC-122, Celgene will continue to provide an additional 3 cycles of 
ibrutinib from the investigational supply to allow time for patients to be transitioned to 
commercially available ibrutinib and/or other therapies at the discretion of the treating physician.
Toxicity-related dose interruptions and modifications for ibrutinib are described in Section
8.2.12.2.
8.2.2.3.
Arm C:  CC-122 in Combination with Obinutuzumab
Subjects in Arm C will be administered CC-122 orally on a 5/7-day schedule.  
CC-122 will be initiated on Cycle 1 Day 9 and on Day 1 of each cycle thereafter up to a 
maximum of 24 cycles of CC-122, or until disease progression, unacceptable toxicity or 
discontinuation for any other reason, whichever is earlier.  Each dose will be taken in the 
morning with about 8 ounces of water.  CC-122 may be taken up to 12 hours late if dosing has 
been delayed on a single day; otherwise that day’s dose should be omitted.
Celgene will continue to provide the protocol-specified total of 6 cycles of investigational supply 
of obinutuzumab for ongoing patients experiencing clinical benefit.  In the event CC-122 is 
discontinued prior to obinutuzumab, subjects may continue to receive the protocol-specified total 
of 6 cycles of obinutuzumab at the discretion of the treating physician.  In addition, for patients 
that have surpassed the 24 cycles of CC-122, Celgene will continue to provide an additional 3 
cycles of CC-122 to allow time for patients to be switched to commercially available therapies at 
the discretion of the treating physician.  
Dosing of obinutuzumab is as described in the GAZYVA package insert or GAZYVARO SmPC. 
Obinutuzumab will be administered as an IV infusion at a dose of 100 mg on Cycle 1 Day 1 and 
900 mg on Cycle 1 Day 2 and 1000 mg on Cycle 1 Days 8 and 15.  The dose of obinutuzumab 
on Days 1 and 2 of Cycle 1 may be adjusted per institutional practice as long as the combined 
dose equals 1000 mg.  Obinutuzumab will be administered at a dose of 1000 mg on Day 1 of 
Cycles 2 through 6. 
Obinutuzumab may be administered in either an inpatient or outpatient clinical setting.  Full 
emergency resuscitation facilities must be immediately available in the event of a severe infusion 
reaction and subjects must be under close supervision of the investigator or appropriately trained 
staff during the infusions and the post-infusion period.
Please refer to the GAZYVA package insert or GAZYVARO SmPC for instructions for the
preparation of each obinutuzumab dose. All transfer procedures during preparation require strict 
adherence to aseptic techniques. For microbiological stability, the diluted obinutuzumab


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infusion solution should be used immediately. If not used immediately, the solution may be 
stored in a refrigerator at 2oC to 8oC (36oF to 46oF) for up to 24 hours prior to use. 
Subjects will be premedicated prior to each infusion as described in Section 9.3.3.  
Obinutuzumab will only be administered as a slow IV infusion through a dedicated line and 
never as an IV push or bolus. Infusion pumps should be used to control the infusion rate. Do 
not use an additional in-line filter because of the potential for adsorption. Infusion rates are 
outlined in Table 10.
After the end of the first infusion, the IV line or central venous catheter should remain in place 
for ≥ 2 hours to be able to administer IV treatments for infusion reactions if necessary. For 
subsequent infusions during Cycle 1, the IV line or central venous catheter should remain in 
place for at least 1 hour after the end of the infusion. For Cycles 2 and later, subjects who 
tolerate the infusion well without infusion reactions can have the IV line removed or the central 
venous catheter de-accessed immediately after the end of each infusion. 
Table 10:
Administered Dose and Infusion Rates for Obinutuzumab Infusions
Day of treatment cycle
Dose of 
obinutuzumab
Rate of infusion (in the absence of infusion reactions/ 
hypersensitivity during previous infusions)
Cycle 1
Day 1
100 mg
Administer at 25 mg/hr over 4 hours.  Do not increase 
the infusion rate.
Day 2
900 mg
Administer at 50 mg/hr.  The rate of infusion can be 
escalated in increments of 50 mg/hr every 30 minutes to 
a maximum rate of 400 mg/hr.
Day 8
1000 mg
Infusions can be started at a rate of 100 mg/hr and 
increased by 100 mg/hr increments every 30 minutes to 
a maximum of 400 mg/hr.
Day 15
1000 mg
Cycles 2-6
Day 1
1000 mg
Please refer to Table 14 for instructions on how to modify the dose in the event of an infusion 
reaction.
8.2.3.
Dose Expansion Phase (Arms B and C only)
As of 05 Jul 2018, Phase 2 will not proceed.
When the Dose Escalation Phase is fully enrolled, and the evaluation completed, the preliminary 
RP2Ds for CC-122 in combination with ibrutinib and CC-122 in combination with 
obinutuzumab will be established for possible further evaluation of safety and preliminary 
efficacy in the Expansion Phase of the study.  
Expansion cohorts at the RP2D may be conducted with a futility interim analyses as outlined in 
Section 10.3.1 and as shown below (Table 11 and Table 12).


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Table 11:
Expansion Cohort:  Arm B (CC-122 in Combination with Ibrutinib)
Expansion 
cohort
Populationa
N
1
Treatment-naïve, ibrutinib-naïve, and high risk
CLL subjects
Futility Interim:  6
Total: 10
R/R, ibrutinib-naïve, and high-risk CLL subjects
Futility Interim:  16
Total: 40
a Subjects must meet all other criteria for study entry.
Table 12:
Expansion Cohort:  Arm C (CC-122 in Combination with Obinutuzumab)
Expansion cohort
Populationa
N
2
BCR PI or venetoclax resistant or 
intolerant subjects
Futility Interim:  17
Total: 40
a Subjects must meet all other criteria for study entry.
Each subject will remain on the study until disease progression, unacceptable toxicity or 
treatment discontinuation for any other reason.  A subject may discontinue one of the study 
treatments and remain on study with the other treatment in compliance with all study 
requirements if in the judgment of the investigator the subject will derive benefit from continued 
study treatment. Subjects who achieve MRD negativity (in both peripheral blood and bone 
marrow) lasting for a minimum of 3 months in duration have the option to discontinue study 
treatment; study treatment in these subjects may be resumed at the time of MRD positivity (see 
Section 4.1).
8.2.4.
Definition of Stopping Criteria for Expansion Cohort
If at any time the early DLT rate (first 28 days of CC-122 dosing during CC-122 combination 
therapy) exceeds 20% or the late toxicity rate (AEs identified during the first 6 cycles of CC-122 
dosing necessitating dose reduction or discontinuation that are clearly not related to disease 
progression, medical procedure, or intercurrent illness) exceeds 33%, enrollment to that 
expansion cohort will be suspended pending evaluation of the safety by the SRC.  The SRC may 
reopen enrollment into that cohort at a lower dose level that has shown to be tolerated during the 
dose escalation portion of the study.
In addition, an interim analysis will be performed for each expansion cohort as outlined in 
Section 10.3.1.  If criteria as specified are not met at the time of interim analysis, enrollment to 
that cohort will be stopped.
8.2.5.
Definition of Not Tolerated Dose (NTD)
A dose level will be considered NTD when ≥2 out of 6 DLT evaluable subjects in a fixed-dose 
cohort experience an IP-related DLT.


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8.2.6.
Definition of Maximum Tolerated Dose (MTD)
The MTD is defined as the last dose level below the NTD with ≤1 out of 6 DLT evaluable 
subjects experiencing DLT during the DLT evaluation period.
8.2.7.
Definition of Dose Limiting Toxicity (DLT)
National Cancer Institute CTCAE Version 4.03 are used as a guide for the grading of severity of 
adverse events (except as otherwise specified).  Dose-limiting toxicities are described below:
!
A non-hematologic AE that is clearly not related to disease progression, medical 
procedure or intercurrent illness and that commences within 28 days of first CC-122 
dose and is ≥ Grade 3 EXCEPT for:
∀
Alopecia
∀
Grade 3 rash of the acneiform or maculopapular type of not more than 4 days 
durations (with optimal medical management)
∀
Grade 3 diarrhea or vomiting lasting less than 72 hours (with optimal medical 
management)
o
Grade 3 diarrhea requiring hospitalization and Grade 3 nausea or vomiting
that required tube feeding, total parenteral nutrition, or hospitalization will be 
considered DLTs
!
Tumor lysis syndrome (TLS), unless TLS does not progress to Grade 2 and resolves 
in less than 7 days with medical management
!
≥ Grade 3 tumor flare reaction (per NCI CTC AE Version 3.0) 
!
Laboratory abnormality that is clearly not related to disease progression, medical 
procedure or intercurrent illness and that commences within 28 days of first dose of 
CC-122 and is ≥ Grade 3 (unless otherwise specified below)
!
Hematological toxicities as follows (grading as per IWCLL criteria):
∀
Any febrile neutropenia
∀
Grade 4 neutropenia lasting > 7 days 
∀
Any Grade 3 or 4 thrombocytopenia with clinically significant bleeding
∀
Any cytopenia that requires dose reduction during the DLT evaluation period
!
Grade 4 liver function tests or Grade 3 ALT with Grade 2 or higher bilirubin will be 
considered a DLT irrespective of underlying attribution
!
Any AE assessed as clearly not related to disease progression, medical procedure or 
intercurrent illness and necessitating dose-level reduction during the DLT evaluation 
period.


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8.2.8.
Guidelines for Intrasubject Dose Escalation – Arm A
For Arm A, intrasubject dose escalation of CC-122 is permitted every 2 weeks at 0.5 mg 
increments at the discretion of the investigator as tolerated.  Dose escalation may occur every 2 
weeks if:
!
The ANC is ≥1500 cells/mm3 (1.5 x 109/L) or ≥1000 cells/mm3 (1.0 x 109/L) if 
secondary to bone marrow involvement by disease
!
The platelet count is ≥100,000 cells/mm3 (100 x 109/L) or ≥50,000 cells/mm3 (50 x 
109/L) if secondary to bone marrow involvement by disease
!
Any IP-related AE not requiring discontinuation has resolved to ≤Grade 1 severity or 
baseline
!
AST/ALT is < 3x ULN and total bilirubin is < 1.5x ULN 
!
Subject does not meet any other criteria for dose reduction or modification
During the every 2 week dose escalation visit, the following safety assessments will include but 
are not limited to: 
!
Hematology
!
Chemistry
!
Vital signs
!
Tumor Flare and Tumor Lysis Monitoring
!
Adverse Event and Concomitant Medication Reporting 
!
CC-122 Contraceptive and Risk Counseling and Education 
(requirement at each CC-122 dispensation visit)
8.2.9.
Dose Interruptions/Modifications
Dose modifications are permitted in any cycle, including Cycle 1 and the DLT evaluation period:
!
Dose reductions that occur during the DLT evaluation period will constitute a DLT, 
but subjects will be allowed to continue on IP at a reduced dose.  
!
Dose reductions are allowed for CC-122 and ibrutinib.  No dose reduction is allowed 
for obinutuzumab, but treatment may be discontinued at the discretion of the 
investigator for severe infusion or allergic reactions. 
8.2.9.1.
General Dose Modification Guidelines
Subjects will be evaluated for AEs at each visit with the NCI CTCAE (version 4.03) used as a 
guide for the grading of severity, with the exception of tumor flare (NCI CTCAE version 3.0), 
 and laboratory abnormalities as recommended by the IWCLL
guidelines for the diagnosis and treatment of chronic lymphocytic leukemia
 as 
listed below:


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Subjects experiencing related AEs or SAEs ≥ Grade 3 must interrupt dosing of the responsible IP 
or both IPs until resolution of the toxicity to ≤ Grade 1 or baseline severity unless as otherwise 
indicated in Table 14. If IP-related events do not resolve to ≤ Grade 1 or baseline severity within 
28 days despite adequate medical management, the sponsor’s study medical monitor should be 
notified.  
The dose of CC-122 may be reduced successively by one level from the starting dose.  There will 
be no more than one dose level reduction from one cycle to the next unless otherwise permitted 
after consultation with the sponsor medical monitor.  In addition, if a subject continues to 
experience unacceptable toxicity after two dose reductions (with the exception of CC-122 per 
Table 15 where up to 3 dose reductions may be allowed for selected doses), IP will be 
discontinued permanently.  If a dose is reduced for toxicity other than a Grade 4 non-
hematological toxicity, re-escalation is permitted after the toxicity is resolved.  If the toxicity 
recurs after re-escalation, the subject should remain at the lower dose level.  Subjects who 
experience a Grade 4 non-hematological toxicity may not have their dose re-escalated.
For the combination of CC-122 and ibrutinib or obinutuzumab, in the event of a toxicity 
requiring dose modification, CC-122 should be considered for interruption and dose reduction 
first if possible.  If the subject continues to require dose modification after a dose hold and/or 
reduction of CC-122 a dose interruption of obinutuzumab or ibrutinib or reduction of ibrutinib 
may be considered.
Dose interruptions lasting beyond 28 days should be discussed with the sponsor’s study medical 
monitor.


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If it becomes necessary to permanently stop administration of one of the IPs, continuation on the 
other IP will require discussion and agreement between the sponsor’s study medical monitor and 
the investigator.
8.2.9.2.
Dose Modification Guidelines 
Any IP-related toxicity meeting the definition of DLT will require dose reduction or interruption.  
The criteria for dose reduction are listed in Table 14, should be used for dose modifications.  
Chronic Grade 2 toxicity (other than specified below) may warrant dose reduction or interruption
of one or both IP.  Such cases should be discussed with the sponsor’s medical monitor before 
changes are made.  
Dose modification decisions for patients with cytopenia (below the lower limit of the normal 
range) at baseline will be based on the IWCLL guideline (Table 13). For patients with a normal
neutrophil count, platelet count and/or hemoglobin value at baseline, the NCI CTCAE (version 
4.03) will be used.
Any dose modifications must be recorded on the respective Study Drug Record eCRF.  
Table 14:
Dose Reduction Guidelines
Adverse Event
Grade
Action
Agent to be considered 
for interruption/
reduction (in descending 
order)
Thrombocytopenia
≥ Grade 3
!
Hold all IP
!
Follow CBC at least every 7 days
!
If thrombocytopenia resolves to ≤Grade 2, 
restart IP and reduce CC-122 to the next 
lower dose level. Ibrutinib may be 
restarted after thrombocytopenia resolves 
to ≤Grade 1 or baseline at original dose 
after the 1st occurrence, and reduce by one 
dose level at each subsequent recurrence
with a maximum of 2 dose reductions 
allowed. A 4th recurrence requires 
permanent discontinuation of ibrutinib.
!
Obinutuzumab should be restarted at the 
full dose after thrombocytopenia resolves 
to ≤Grade 2, no dose reduction is 
allowed.
!
CC-122
!
Ibrutinib/obinutuzumab


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Table 14:
Dose Reduction Guidelines (Continued)
Adverse Event
Grade
Action
Agent to be considered 
for interruption/
reduction (in descending 
order)
Neutropenia 
≥Grade 3
with infection
OR
Sustained (≥ 7 
days) Grade 3
OR
≥ Grade 3 
associated 
with fever 
(temperature 
≥38.5ºC)
OR
Grade 4
!
Hold all IP  
!
Follow CBC at least every 7 days
!
If neutropenia resolves to ≤Grade 2, 
restart IP at the same or reduced dose 
level at the investigator’s discretion 
(restarting at the same dose level is 
permitted only one time for those subjects 
with Grade 4 neutropenia.  If Grade 4 
neutropenia recurs, the IP dose must be 
reduced upon resolution). Ibrutinib may 
be restarted after neutropenia resolves to ≤ 
Grade 1 or baseline at original dose (420 
mg per day) after the 1st occurrence, and 
reduce by one dose level (to 280 mg per 
day) at each subsequent recurrence with a 
maximum of 2 dose reductions (to 140 mg 
per day) allowed. A 4th recurrence 
requires permanent discontinuation of 
ibrutinib.
Obinutuzumab should be restarted at the 
full dose after neutropenia resolves to ≤ 
Grade 2, no dose reduction is allowed.
!
Use of growth factors (G-CSF, GM-CSF) 
is permitted at the discretion of the 
investigator
!
CC-122
!
Ibrutinib/obinutuzumab
Troponin-T/BNP
Troponin-T > 
ULN with 
associated 
significant 
elevation in 
BNP or with 
cardiac 
symptoms or 
significant 
changes in 
ECG or LVEF
!
Hold CC-122
!
Cardiology evaluation
!
Follow troponin-T, BNP, and ECG at 
least every 7 days
!
If troponin-T and BNP stabilize and there 
are no other significant cardiac findings, 
restart CC-122 at the same or next lower 
dose level
!
Permanently discontinue CC-122 if 
Troponin-T > ULN with cardiac 
symptoms or significant changes in ECG 
or LVEF
Please refer to Section 8.2.9.2.3 for 
additional guidance
!
CC-122


EDMS Doc. Number: 22914699 - 19766462
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Table 14:
Dose Reduction Guidelines (Continued)
Adverse Event
Grade
Action
Agent to be considered 
for interruption/
reduction (in descending 
order)
AST/ALT/
Bilirubin
≥ Grade 3
!
Hold one or more IPs at investigator’s 
discretion 
!
Follow labs at least every 7 days
!
If abnormalities resolve to ≤Grade 1 or 
baseline, restart IPs and reduce CC-122 to 
the next lower dose level
!
For ibrutinib, once the toxicity has
resolved to Grade 1 or baseline 
(recovery), ibrutinib therapy may be 
reinitiated at the starting dose (420 mg per 
day). If the toxicity reoccurs, reduce dose 
to 280 mg per day. A second reduction of 
dose to 140 mg per day may be 
considered as needed. If these toxicities 
persist or recur following two dose 
reductions, discontinue ibrutinib.
!
CC-122
!
Ibrutinib
ALT and/or 
AST ≥3x 
ULN and total 
bilirubin > 2x 
ULN 
(potential 
Hy’s Law)
!
Hold all IPs
!
Conduct medical work up to determine the 
cause of abnormalities
!
Follow labs at least every 7 days until 
resolution to ≤Grade 1 or baseline severity 
for all AST, ALT and total bilirubin
!
In case of confirmed Hy’s Law, dosing 
will not be resumed
Stomatitis/Nausea/
Vomiting / 
Constipation
≥ Grade 3
!
Hold one or more IPs at investigator’s 
discretion if AE fails to respond to 
symptomatic treatment 
!
When the toxicity resolves to ≤Grade 1 or 
baseline restart both IP.
!
For ibrutinib, once the toxicity has
resolved to Grade 1 or baseline 
(recovery), ibrutinib therapy may be 
reinitiated at the starting dose (420 mg per 
day). If the toxicity reoccurs, reduce dose 
to 280 mg per day. A second reduction of 
dose to 140 mg per day may be 
considered as needed. If these toxicities 
persist or recur following two dose 
reductions, discontinue ibrutinib.
!
CC-122
!
Ibrutinib


EDMS Doc. Number: 22914699 - 19766462
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Table 14:
Dose Reduction Guidelines (Continued)
Adverse Event
Grade
Action
Agent to be considered 
for interruption/
reduction (in descending 
order)
Diarrhea
≥ Grade 3
!
Hold one or more IPs at the investigator’s 
discretion
!
Strongly recommend to perform a 
colonoscopy and biopsy
!
When the toxicity resolves to ≤Grade 1 
restart IPs and reduce CC-122 to the next 
lower dose level.
!
For ibrutinib, once the toxicity has
resolved to Grade 1 or baseline 
(recovery), ibrutinib therapy may be 
reinitiated at the starting dose (420 mg per 
day). If the toxicity reoccurs, reduce dose 
to 280 mg per day. A second reduction of 
dose to 140 mg per day may be 
considered as needed. If these toxicities 
persist or recur following two dose 
reductions, discontinue ibrutinib.
!
CC-122
!
Ibrutinib
Rash
≥ Grade 3
!
Discontinue suspected IP for 
desquamating (blistering) Grade 3 or any 
Grade 4 rash
!
For maculopapular, acneiform, or pustular 
rashes lasting ≤ 7 days medical 
management is warranted
!
CC-122
!
Ibrutinib
Allergic Reaction 
or Hypersensitivity
≥ Grade 3
!
For obinutuzumab:
Grade 3:  premedicate future doses and 
adjust infusion rates per standard practice
Recurring Grade 3 or Grade 4:  
permanently discontinue
!
CC-122 or ibrutinib, discontinue one or 
more suspected IPs
!
Obinutuzumab
!
CC-122
!
Ibrutinib
Venous 
Thrombosis / 
Embolism
≥ Grade 3
!
Hold CC-122 at investigator’s discretion 
and start anticoagulation; restart CC-122 
at investigator’s discretion (maintain dose 
level)
!
Discontinue ibrutinib
!
CC-122
!
Ibrutinib
Peripheral 
Neuropathy
(applies only to 
those neuropathies 
which begin or 
worsen while on 
study)
Newly 
developed 
≥Grade 3
!
Hold CC-122 at investigator’s discretion 
!
When the toxicity resolves to ≤Grade 2 or 
to baseline, restart CC-122 at the next 
lower dose level
!
CC-122


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Table 14:
Dose Reduction Guidelines (Continued)
Adverse Event
Grade
Action
Agent to be considered 
for interruption/
reduction (in descending 
order)
Bleeding Events
≥ Grade 2
!
Hold one or more IPs at investigator’s 
discretion
!
When the toxicity resolves to ≤Grade 1, 
restart one or more IPs
!
Ibrutinib
!
CC-122
Tumor Lysis 
Syndrome
Laboratory or 
Grade 1 TLS
!
Continue treatment at same dose level or 
one dose level dose reduction
!
Provide vigorous intravenous hydration 
and appropriate medical management 
according to the local standard of care, 
until correction of electrolyte 
abnormalities.  Treat appropriately as 
needed to reduce hyperuricemia
!
Hospitalization will be at investigator’s 
discretion
!
CC-122
!
Ibrutinib/obinutuzumab
Grade 2-4
!
Hold CC-122 and ibrutinib/obinutuzumab
!
When symptoms resolve to Grade 0, 
restart IPs at the next lower dose level
(CC-122 and ibrutinib) or full dose 
(obinutuzumab).
!
If IPs resumed prior to the start of a 
subsequent cycle, a chemistry test should 
be performed every other day for the first 
week following re-initiation of IPs
Tumor Flare 
Reaction (TFR)*
*assessed 
according  to NCI 
CTCAE Version 
3.0
Grades 1-2
!
Continue CC-122, maintain dose level
!
Initiate therapy with corticosteroids at the 
investigator’s discretion
!
NSAIDs and/or narcotics may also be 
used as per investigator’s discretion
!
CC-122
Grades 3-4
!
Hold CC-122
!
Initiate therapy with corticosteroids
!
NSAIDs and/or narcotics may also be 
used per investigator’s discretion
!
When symptoms resolve ≤Grade 1, restart 
CC-122 at the same dose level
Other
≥ Grade 3
!
Hold one or more IPs at investigator’s 
discretion 
!
When the toxicity resolves to ≤Grade 2, 
restart both IPs and reduce CC-122 to the 
next lower dose level. Refer to package 
inserts or SmPCs for the approved 
products for dose modification 
instructions (ibrutinib  and 
obinutuzumab).
--


EDMS Doc. Number: 22914699 - 19766462
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Protocol CC-122-CLL-001
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Table 14:
Dose Reduction Guidelines (Continued)
Adverse Event
Grade
Action
Agent to be considered 
for interruption/
reduction (in descending 
order)
Renal and urinary
CrCl 
decreased 
from ≥50
mL/min to 
30-49 mL/min
and 30% drop 
from baseline
!
Decrease dose to next dose level 
!
CC-122
CrCl decrease 
to < 30
mL/min
!
Hold CC-122
!
When CrCl improves to ≥30 mL/min,
restart CC-122 at the next lower dose
level 
!
CC-122
Surgical 
Procedures
Minor
!
Hold one or more IPs at investigator’s
discretion on day of surgery
!
IPs may be restarted at same dose level 
upon recovery
!
Ibrutinib
!
CC-122
Major
!
Hold one or more IPs for 3 to 7 days prior 
to surgery through 3 to 7 days post 
surgery
!
Restart IPs upon recovery and at least 3 to 
7 days post surgery at the same dose level
Infusion Reaction
Grade 1-2
!
Reduce infusion rate (≤ 50% prior rate) or 
interrupt infusion and treat symptoms
!
Upon resolution, continue or resume 
infusion; infusion rate increments and 
intervals may resume at the increments 
and intervals as appropriate for the 
treatment dose if no further infusion 
reaction symptoms
!
Obinutuzumab
Grade 3 
(severe) 
infusion 
reaction
!
Interrupt infusion and manage symptoms
!
Upon resolution, restart infusion at ≤ 50% 
prior rate; infusion rate escalations can 
resume at the increments and intervals as 
appropriate for the treatment dose if no 
further infusion reaction symptoms
!
Permanently discontinue if Grade 3 or 
higher infusion-related symptom occurs 
with re-challenge
Grade 4 (life 
threatening) 
infusion 
reaction
!
Stop infusion immediately; permanently 
discontinue 


EDMS Doc. Number: 22914699 - 19766462
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Protocol CC-122-CLL-001
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Table 14:
Dose Reduction Guidelines (Continued)
Adverse Event
Grade
Action
Agent to be considered 
for interruption/
reduction (in descending 
order)
Progressive 
Multifocal 
Leukoencephalo-
pathy
All
!
Permanently discontinue 
!
Obinutuzumab
Pneumonitis
Grade 2
!
Hold one or more IPs at investigator’s 
discretion
!
Once symptoms have resolved 
completely, CC-122 and/or ibrutinib may 
be restarted at the next lower dose level.
!
CC-122
!
Ibrutinib
≥ Grade 3
!
Discontinue one or more suspected IPs 
permanently
Atrial Fibrillation
Grade 3 or 4 
or persistent 
atrial 
fibrillation of 
any grade
!
Consider the risks and benefits of ibrutinib 
treatment. If clinically indicated, the use 
of non-prohibited anticoagulants or 
antiplatelet agents may be considered for 
the thromboprophylaxis of atrial 
fibrillation.  
!
If dose of ibrutinib is reduced, at the 
investigator’s discretion, the dose of 
ibrutinib may be escalated after 2 cycles 
of a dose reduction in the absence of a 
recurrence of the toxicity that led to the 
reduction.  
!
Ibrutinib
Abbreviations:  BNP = B-type Natriuretic Peptide; CBC = Complete Blood Count; CrCl = Creatinine Clearance; ECG =
Electrocardiogram; G-CSF = Granulocyte Colony-Stimulating Factor; GM-CSF = Granulocyte-Macrophage Colony-Stimulating 
Factor; IP = Investigational Product; LVEF = Left Ventricular Ejection Fraction; NSAID = Non-steroidal Anti-inflammatory 
Drug; TLS = Tumor Lysis Syndrome; ULN = Upper Limit Normal.
 
 
 
  
 
 
 
 
 
 
 


EDMS Doc. Number: 22914699 - 19766462
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8.2.9.2.3. Cardiac Laboratory Abnormalities
In addition to routine ECG monitoring in all treatment arms, additional monitoring for potential 
cardiac toxicity is included for subjects treated with CC-122.  This includes routine monitoring 
of troponin-T and BNP as well as more intensive monitoring of ECGs and LVEF as described in 
Section 6.  Elevations of troponin-T or BNP warrant further investigation including assessment 
of the subject for signs and symptoms of cardiac injury, consideration of a cardiology 
consultation, other cardiac evaluations (such as an exercise stress test, additional evaluation of 
LVEF, or other cardiac tests recommended by a cardiologist), and the addition of 
cardioprotective therapy (eg, beta blockers) as appropriate.  Laboratory evaluation to assess for 
assay interference may also be warranted.  Isolated asymptomatic elevations of troponin-T or 
BNP without associated ECG or LVEF changes or other cardiac findings do not require that 


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CC-122 dose be held.  For any elevation of troponin-T > ULN associated with either significant 
elevation of BNP (20% increase from baseline with an absolute value > 100 pg/mL) or 
associated cardiac symptoms or findings, CC-122 dosing should be held and the sponsor should 
be notified.  Additional cardiac monitoring should be performed as described in Table 14 and as 
medically indicated. CC-122 may be restarted at the same dose or a reduced dose, in consultation 
with the sponsor, based on troponin-T/BNP guidelines in Table 14 and general guidelines 
provided in Section 6. 
8.2.9.2.4. Pneumonitis
Pneumonitis has been observed in patients taking CC-122. The diagnosis should be considered in 
subjects presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural 
effusion, cough, dyspnea, or interstitial pulmonary infiltrates, and in whom infectious, neoplastic 
and other causes are excluded by appropriate investigations. Subjects should be specifically
advised to report promptly any new or worsening respiratory symptoms they experience. 
Those with radiological features suggestive of non-infectious pneumonitis but with minimal
(Grade 1) symptoms may continue CC-122 without dose alteration. For drug-related Grade 2 
pneumonitis, CC-122 treatment should be interrupted and corticosteroids may be indicated. Once 
symptoms have resolved completely, CC-122 may be reintroduced at the next lower dose level. 
For drug-related Grade 3 or 4 pneumonitis CC-122 must be permanently discontinued and 
corticosteroids are recommended until clinical symptoms have resolved.
 
 
8.2.10.
Management of Select AEs While Receiving Obinutuzumab
8.2.10.1.
Infusion-Related Reactions (IRRs)
Two-thirds of patients experienced IRRs with the first infusion of obinutuzumab; reactions can 
also occur with subsequent infusions, but the frequency is lower (GAZYVA, GAZYVARO).
Infusion reactions typically occur within 24 hours of receiving obinutuzumab. Symptoms may 
include anaphylaxis, acute life-threatening respiratory symptoms, hypotension, tachycardia, 
dyspnea, bronchospasms, larynx and throat irritation, wheezing, and laryngeal edema. Additional 
potential symptoms include nausea, vomiting, diarrhea, hypertension, flushing, skin rash, 
urticaria, headache, pyrexia, and chills.
To minimize the potential for these reactions, premedication is administered as described in 
Section 9.3.3. Full emergency resuscitation facilities should be immediately available in the 
event of a severe and life-threatening infusion reaction and subjects should be under close 
supervision of the investigator or appropriately trained staff during the infusions. Medical 


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management of infusion reactions should be instituted according to standard medical practice 
using glucocorticoids, epinephrine, oxygen, intravenous fluids and other medications as 
medically indicated.  Subsequent infusions should be administered with appropriate 
premedications as in Section 9.3.3.
Subjects with pre-existing cardiac or pulmonary conditions should be monitored more frequently 
throughout the infusion and after the infusion. Hypotension may occur and investigators should 
consider withholding antihypertensive agents (for subjects not at risk for hypertensive crisis) for 
12 hours prior to, during the infusion, and for 1 hour after the infusion until blood pressure is 
stable. 
8.2.10.2.
Progressive Multifocal Leukoencephalopathy
John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy 
(PML), which can be fatal, has been observed in patients treated with obinutuzumab. Subjects 
with new onset or changes to pre-existing neurologic manifestations should be evaluated for 
PML. The symptoms of PML are unspecific and can vary depending on the affected region of 
the brain. Motor symptoms with corticospinal tract findings (eg, muscular weakness, paralysis, 
and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects 
are common. Some signs/symptoms regarded as “cortical” (eg, aphasia or visual-spatial 
disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a 
neurologist, brain MRI, and lumbar puncture 
 
Obinutuzumab and CC-122 should be discontinued in subjects who develop PML. 
The subject should be referred to a neurologist for the evaluation and treatment of PML.
8.2.10.3.
Neutropenia, Thrombocytopenia, and Anemia
 
  
 
Severe and life-threatening thrombocytopenia, including acute thrombocytopenia (occurring 
within 24 hours after the infusion), has been observed during treatment with obinutuzumab. Fatal 
hemorrhagic events have also been reported in Cycle 1 in patients treated with obinutuzumab
(GAZYVA, GAZYVARO). A clear relationship between thrombocytopenia and hemorrhagic 
events has not been established. Subjects should be closely monitored for thrombocytopenia, 
especially during the first cycle. Regular laboratory tests should be performed until the event 
resolves, and dose delays should be considered in case of severe or life-threatening 
thrombocytopenia. Transfusion of blood products (ie, platelet transfusion) according to 
institutional practice is at the discretion of the treating physician. Use of all concomitant 
therapies, which could possibly worsen thrombocytopenia-related events such as platelet 
inhibitors and anticoagulants, should also be taken into consideration, especially during the first 
cycle. 
Hematopoietic growth factors or other hematologic support, such as erythropoietin, darbepoetin, 
granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating 
factor (GM-CSF), RBC- or platelet- transfusions are allowed in the study with therapeutic intent. 


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Therapeutic use of G-CSF is allowed at any time for subjects experiencing Grade 3 or 4 
neutropenia or any grade febrile neutropenia.  Prophylactic use of granulocyte (or granulocyte-
macrophage) growth factors is not allowed during Cycle 1.
8.2.10.4.
Gastrointestinal (GI) Perforation
Cases of gastrointestinal perforation have been reported in patients receiving obinutuzumab 
(GAZYVA, GAZYVARO) mainly in NHL. Monitor patients with GI involvement for GI 
perforation.
8.2.11.
Management of Select AEs While Receiving Ibrutinib
Fatal bleeding events have occurred in patients treated with ibrutinib (IMBRUVICA). Grade 3 or 
higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post 
procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, 
including bruising and petechiae, occurred in approximately half of patients treated with 
IMBRUVICA.  The mechanism for the bleeding events is not well understood.  IMBRUVICA
may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. 
Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-
surgery depending upon the type of surgery and the risk of bleeding.
Inform subjects of the possibility of bleeding, and report any signs or symptoms (blood in stools 
or urine, prolonged or uncontrolled bleeding). Inform the subject that IMBRUVICA may need to 
be interrupted for medical or dental procedures. 
Subjects should be closely monitored for hemorrhagic events. Regular laboratory tests should be 
performed until the event resolves, and dose delays should be considered in the event of ≥Grade 
2 hemorrhage (Table 14). Transfusion of blood products (ie, RBC- or platelet- transfusions) 
according to institutional practice is at the discretion of the treating physician.
For any subjects receiving ibrutinib (Arm B), major hemorrhages as defined in Section 11.1 are 
considered adverse events of special interest and must be reported on the Serious Adverse Event 
Report Form using the “Important Medical Event” as the seriousness criteria and sent via email 
or fax to Celgene and/or designee, within 24 hours of awareness (see Section 11.5.1).
8.2.11.1.
Interstitial Lung Disease (ILD)
Cases of ILD have been reported in patients treated with ibrutinib.  Monitor patients for 
pulmonary symptoms indicative of ILD. Should symptoms develop, follow the protocol dose 
modification guidelines as outlined in Table 16.
8.2.12.
Dose Reduction Steps
If a subject develops toxicity, the dose of CC-122 may be reduced as outlined in Table 15 and
ibrutinib as outlined in Table 16.
8.2.12.1.
CC-122 Dose Reduction Steps
Recommendations for dose reduction steps for CC-122 are presented in Table 15.  Up to 3 dose 
reductions will be permitted for patients who receive an initial starting dose of 3.0 mg, 3.5 mg or 
4.0 mg, provided data from the fixed-dose cohorts during the escalation phase demonstrates that 


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1.5 mg, 2.0 mg and 2.5 mg are active (i.e. at least 1 objective response (CR or PR/PRL) was 
observed).
Table 15:
CC-122 Dose Reduction Steps
Current Dose
0.5 mg
1.0 mg
1.5 mg
2.0 mg
2.5 mg
3.0 mg
3.5 mg
4.0 mg
Dose Reduction 1
0.25 mg
0.5 mg
1.0 mg
1.5 mg
2.0 mg
2.5 mg
3.0 mg
3.5 mg
Dose Reduction 2
0.1 mg 
0.25 mg 
0.5 mg
1.0 mg
1.5 mg
2.0 mg
2.5 mg
3.0 mg
Dose Reduction 3
D/C
D/C
D/C
D/C
D/C
1.5 mg
2.0 mg
2.5 mg
Abbreviation:  D/C = Discontinue.
8.2.12.2.
Ibrutinib Dose Reduction Steps
Ibrutinib dose reduction steps are shown in Table 16.
Table 16: Ibrutinib Dose Reduction Steps
Non-Hematologic Adverse Events
Toxicity Occurrence
Action to be Taken
First
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 
original dose level, 420 mg daily
Second 
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 
dose level lower, 280 mg daily
Third
Withhold ibrutinib until recovery to Grade ≤1 or baseline; may restart at 1 
dose level lower, 140 mg daily
Fourth
Discontinue Ibrutinib
8.2.12.3.
Dose Modification Guidelines for Obinutuzumab
There is no allowable dose reduction schedule for obinutuzumab.  In the event of toxicities or 
adverse events, dose modification should be based on Section 8.2.9.1.
8.2.13.
Overdose
Overdose, as defined for this protocol, refers to CC-122, ibrutinib and obinutuzumab dosing 
only.  
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of CC-122 or ibrutinib assigned to a given subject, regardless of any associated adverse 
events or sequelae.  
!
PO
any amount over the protocol-specified dose
!
IV
10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.  
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate.


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Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.  See 
Section 11 for the reporting of AEs associated with overdose.  
8.3.
Method of Treatment Assignment
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued.
Assignment of subjects to Arms A, B, or C will be based on current open dose levels, 
investigator choice, and available slots.
An interactive web response system (IWRS) will be used to track subject assignments to the 
treatment arms and dose levels.
8.4.
Packaging and Labeling
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
8.5.
Investigational Product Accountability and Disposal
The investigator(s) is responsible for taking an inventory of each shipment of IP received and 
comparing it with the accompanying IP shipping order form.  The investigator(s) will verify the 
accuracy of the information on the form to register the IP received at the site and retain a copy of 
the form in the study file.
At the study site, all investigational IP will be stored in a locked, safe area to prevent 
unauthorized access.  The IP should be stored as directed on the package label.
Celgene (or designee) will review with the investigator and relevant site personnel the process 
for Investigational Product return, disposal, and/or destruction including responsibilities for the 
site versus Celgene (or designee).
8.6.
Investigational Product Compliance
Subjects will return all IP at the Day 1 scheduled visit of each cycle to assess treatment 
compliance.  Subjects must miss no more than 5 scheduled doses of IP during the DLT 
evaluation period (eg, forget to take or lose their IP; or if discontinued early due to progressive 
disease) to be considered evaluable for DLT, unless the missed doses were due to IP-related 
AE(s), in which case they remain evaluable for DLT.  During subsequent cycles, a subject will 
be considered compliant with each IP and overall if the IPs taken are ≥80% to ≤120% of the 
assigned dosage.  IP accountability will be evaluated on Day 1 of each cycle; full and/or partial 
bottles may be re-dispensed once IP accountability has been performed.










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10.
STATISTICAL ANALYSES
10.1.
Overview
The primary objectives of this Phase 1/2 Study are to determine the safety of single agent 
CC-122 and the safety, tolerability, and RP2D of CC-122 when administered in combination 
with ibrutinib and in combination with obinutuzumab to subjects with CLL/SLL.  The secondary 
objectives are to evaluate the PK profiles of subjects administered CC-122  in combination with 
ibrutinib and in combination with obinutuzumab, to determine ibrutinib concentrations when 
given alone and in combination with CC-122, and to evaluate the preliminary efficacy of CC-122 
at selected dose levels/regimens.
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued. Subjects 
already enrolled who are receiving clinical benefit in the opinion of the treating investigator may 
continue to receive study treatment up to a maximum of 24 cycles of CC-122.
In the following, statistical analyses will be performed by study arm, dose level and visit cycle as 
needed or applicable.
10.2.
Study Population Definitions
For the purpose of statistical analysis and data presentation, the study populations are defined as 
follows:
!
Safety Population – all subjects who take at least one dose of IP.
!
Dose-Limiting Toxicity Evaluable Population –
∀
Arm A:  all subjects who completed at least one cycle of treatment and did not 
miss more than 5 days of CC-122 dosing during the first cycle are to be 
considered evaluable for DLT, unless the missed doses were due to IP related 
AE(s) or the cycle was not completed due to a DLT, in which case they remain 
evaluable for DLT.
∀
Arm B:  all subjects who completed at least one cycle of CC-122 (Cycle 2 Day 1 
through Cycle 2 Day 28) and did not miss more than 5 days of CC-122 treatment 
are to be considered evaluable for DLT, unless the missed doses were due to IP 
related AE(s) or the cycle was not completed due to a DLT, in which case they 
remain evaluable for DLT.
∀
Arm C:  all subjects who completed at least one cycle of CC-122 (Cycle 1 Day 9 
through Cycle 2 Day 8) and did not miss more than 5 days of CC-122 treatment 
are to be considered evaluable for DLT, unless the missed doses were due to IP 
related AE(s) or the cycle was not completed due to a DLT, in which case they 
remain evaluable for DLT.
!
Efficacy Evaluable (EE) Population – all subjects who complete at least one cycle of 
their assigned treatment regimen, and have a baseline and at least one post-baseline 
efficacy assessment.
!
Pharmacokinetic Population – all subjects who have at least 1 measurable CC-122 
and/or ibrutinib concentration datum.


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10.3.
Sample Size and Power Considerations
During the Dose Escalation Phase of the study, an intrasubject dose escalation schedule and
standard “3 + 3” dose escalation design will be used to identify initial toxicities and safety of 
single agent CC-122 and to determine the MTD of the combination treatments.  The final 
number of subjects needed in the Dose Escalation Phase depends on number of DLTs observed 
within each cohort.  Non-DLT evaluable subjects withdrawn prior to completion of the DLT 
evaluation period due to reasons other than DLT will be replaced.  After the MTD and 
preliminary RP2D have been determined for CC-122 in combination with ibrutinib and CC-122 
in combination with obinutuzumab, 2 additional cohorts may be enrolled to further evaluate the 
safety and efficacy of the combination therapy in specific subject populations at the preliminary 
RP2D in the Expansion Phase.  
10.3.1.
Expansion Cohorts
As of 05 Jul 2018, Phase 2 will not proceed.
The sample size of 50 subjects/cohort for Expansion Cohort 1 and 40 subjects/cohort for 
Expansion Cohort 2 are not based on formal statistical calculation to have adequate power for 
hypothesis testing.  Rather it is to provide additional efficacy and safety information beyond the 
limited number of subjects in the Dose Escalation Phase. To reduce the risk that subjects 
exposure to less efficient IP, a futility interim analysis will be conducted for each expansion 
cohort.
Estimates of expected response rate were calculated for each patient population to be evaluated 
in the expansion cohorts based on currently available published data, when available:
!
Arm B, Expansion Cohort 1, will evaluate subjects with high risk CLL (n=10 for TN 
CLL, n=40 for R/R CLL). A design with futility interim will be applied to both TN 
(n=10) and R/R CLL cohorts (n=40).  An estimated ORR of 97% (including both PR 
and PRL) and CR of 12% is projected for single agent ibrutinib in TN CLL with 17p-
/TP53 mutation (Farooqui, 2015).  An estimated ORR of 60% is projected based on
single agent ibrutinib data in R/R high risk CLL.  Four studies with ibrutinib in 17p-
/TP53 mutation positive R/R CLL reported response rates ranging from 40% to 71% 
(Pollyea, 2014; IMBRUVICA; Preetesh, 2015; Farooqui, 2015).  The total number of 
responders was divided by the total number of subjects from the four studies to 
estimate an ORR of 60% for this cohort.
!
Arm C, Expansion Cohort 2, will evaluate patients who are resistant to or intolerant 
of prior ibrutinib/idelalisib/venetoclax or alternate BTK or PI3K inhibitors.  Limited 
data is available on the response of patients post-treatment failure with ibrutinib and 
idelalisib. One study reported 25% to 76% response rates with kinase inhibitors 
(idelalisib or ibrutinib if not previously experienced) or non-kinase inhibitors (anti-
CD20 antibody, chemotherapy, BCL-2 inhibitor, etc) in patients who were resistant or 
intolerant of idelalisib or ibrutinib (Mato, 2015), therefore an ORR of 50% is 
projected for this cohort.
Based on the above assumptions, a design with a futility interim analysis will be applied in the 
expansion cohorts: 


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!
Arm B, TN CLL cohort: Considering 97% of TN CLL patients are expected to have a 
response with monotherapy ibrutinib, the stopping rule will be based on either 
excessive toxicity or lack of efficacy. Specifically, the enrollment to the TN CLL 
cohort will be stopped if  ≥ 2 DLTs are observed among the first ≤ 6 patients or if < 5 
responses (CR, PR/PRL) are observed among the first 6 efficacy evaluable subjects.
!
Arm B, Expansion Cohort 1, the hypotheses for the true ORR to be tested are p ≤ 0.5
versus p ≥ 0.7. An interim analysis for futility purpose will be conducted on the first
16 efficacy evaluable subjects. If there are at least 10 responders, the cohort will be 
completed to include a total of 40 subjects. The probability of early termination of the 
study at the interim analysis is not less than 0.77 if the true ORR rate is 0.5 or less. If 
the true ORR is 0.7 or greater and there are at least 10 responders at the futility 
interim, the expected lower boundary of exact 95% confidence interval is larger than 
0.5.
!
Arm C, Expansion Cohort 2, the hypotheses for the true ORR to be tested are p ≤ 0.4 
versus p ≥ 0.6. A futility interim analysis will be conducted when there are 17 
subjects that are efficacy evaluable. If there are at least 9 responders, the trial will be 
completed to include a total of 40 subjects. The probability of early termination of the 
study at the interim analysis is not less than 0.80 if the true ORR rate is 0.4 or less. If 
the true ORR is 0.6 or greater and there are at least 9 responders at the futility interim, 
the expected lower boundary of exact 95% confidence interval is larger than 0.4.
10.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations.  Medical history data will be summarized using frequency tabulations by SOC and 
preferred term (PT).
10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site will be provided. Protocol 
deviations will be summarized using frequency tabulations.
10.6.
Efficacy Analysis
All efficacy evaluable subjects will be included for efficacy analysis.
Response, including evaluation of MRD, will be assessed by IWCLL guidelines for diagnosis 
and treatment of CLL 
with modifications. The 
response rate based on the best response during the treatment period and the relative proportions 
in each response category will be examined. Distributions of the responses into the response 
categories (CR, CRi, nPR, PR, PRL, SD, PD) will be provided for each arm and dose level. 
Response at selected time points (eg, end of Cycle 3, end of Cycle 6, end of Cycle 12, end of 
treatment) may also be provided for each arm and dose level. Overall response rate (CR + CRi +
PR + nPR + PRL [PRL is applicable to Arm B only]) and MRD negativity rate together with 


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confidence intervals will be provided for each treatment arm and dose level. For subjects having 
brief signs of progression while off CC-122, or combination of this with ibrutinib or 
obinutuzumab, which resolves with reinitiation of therapy, this will not be considered 
progression.
Duration of response is defined as the time from first PRL [applicable to Arm B only], nPR, PR, 
CRi, or CR to PD.  Duration of response will be censored at the last date that the patient was 
known to be progression-free for: 1) patients who have not progressed at the time of analysis; 2) 
patients who have withdrawn consent or are lost to follow-up prior to documentation of 
progression. Duration of response will be analyzed using the Kaplan-Meier method. Median 
duration of response along with two-sided confidence interval will be provided for each
treatment arm and dose level.
Progression-free survival is calculated as the time from first IP dose to the first documented 
progression or death due to any cause during or after the treatment period, whichever occurs 
first. Median PFS will be estimated using Kaplan-Meier estimates and the 95% confidence 
intervals (CI) will be computed by the method of Klein and Moeschberger 
with
log-log transformation with each treatment arm and dose level. 
10.7.
Safety Analysis
All subjects who receive at least one dose of any assigned IP will be included in the safety 
analyses. Adverse events, vital sign measurements, physical exam findings, clinical laboratory 
information, ECG interpretations, LVEF assessments, pregnancy tests for FCBP, concomitant 
medications and procedures will be tabulated and summarized by study phase, treatment arm, 
and dose level, as appropriate. 
In the Dose Escalation Phase, during the 28 days following initiation of CC-122, DLTs and all 
available safety information will be reviewed on an ongoing basis by the investigators and 
sponsor and summarized at the conclusion of each dose level for each treatment arm.  Treatment 
arms will be evaluated independently.  After completion of each dosing cohort the SRC will 
review the summarized data to determine the next step.  Dose-limiting toxicity occurrence will 
be summarized by treatment arm and dose level as appropriate.
Adverse events observed will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA). The severity or intensity of adverse events will be graded according to the 
CTCAE version 4.03 unless otherwise specified.
The frequency of AEs will be tabulated by MedDRA SOC and PT. In the by-subject analysis, a 
subject having the same event more than once will be counted only once. Adverse events leading 
to discontinuation from treatment, events classified as CTCAE Grade 3 or higher, IP-related 
events, and serious AEs will be tabulated and listed separately. By-subject listings of all AEs, 
serious AEs, and their attributes will be provided.
Clinical laboratory data will be summarized. Laboratory data will be graded according to 
CTCAE version 4.03 criteria for select analytes unless otherwise specified. The frequencies of 
the worst severity grade observed during treatment will be displayed in cross-tabulations by 
screening status. 


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Vital signs, ECG data and LVEF data will be summarized by cross-tabulations presenting normal 
and abnormal values by number of subjects at pre- and post-IP initiation.
Graphical displays will be provided where useful in the interpretation of results.
10.8.
Interim Analysis
Futility interim analysis is planned for the expansion cohorts as described in Section 10.3.1.
10.9.
Other Topics
10.9.1.
Assessment of Pharmacokinetics
The PK population includes all subjects who have at least 1 measurable CC-122 and/or ibrutinib 
plasma concentration datum. The evaluable subjects in the PK population will be included in the 
PK data analysis.
Noncompartmental analysis will be performed on the drug concentration data for subjects with 
intensive PK sampling. Pharmacokinetic parameters include, but are not limited to, the 
following:
Cmax
Peak (maximum) drug plasma concentration
Tmax
Time to peak (maximum) drug concentration 
AUCt
Area under the concentration -time curve calculated to the last observable 
concentration at time t
AUC∞
Area under the plasma concentration-time curve from time zero to infinity, 
AUCτ
Area under the plasma concentration-time curve during the dosing interval (τ) at 
steady state
t½
Terminal elimination half-life
CL/F
Apparent clearance of drug from plasma
Vz/F
Apparent volume of distribution during the terminal phase after extravascular 
administration 
Rac
Accumulation ratio based on AUC after multiple dose administration relative to 
single dose administration
Details of statistical analyses of drug concentration data and PK parameters are included in the 
statistical analysis plan.
 
 
 


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11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 8.2.9), 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 an investigational product 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 8.2.13 for the definition of overdose). Any sequela 
of an accidental or intentional overdose of an investigational product 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 CC-122, 
obinutuzumab, or ibrutinib 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 
until 28 days after the last dose of IP and those SAEs made known to the investigator at any time 
thereafter that are suspected of being related to IP.  Adverse Events and serious adverse events 
(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.  
Additionally, for any subject receiving obinutuzumab, the site will simultaneously send the SAE 
Report Form to Celgene and Hoffmann-La Roche within the same timeframe and method.
11.1.1.
Adverse Events of Special Interest
Specific adverse events, or groups of adverse events, will be followed as part of safety 
monitoring activities by the Sponsor. 


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11.1.1.1.
Major Hemorrhage (Arm B)
For any subjects receiving ibrutinib (Arm B), major hemorrhages as defined below are 
considered adverse events of special interest and must be reported on the Serious Adverse Event 
Report Form using the “Important Medical Event” as the seriousness criteria and sent via email 
or fax to Celgene and/or designee, within 24 hours of awareness (see Section 11.5.1).
Major hemorrhage is defined as any of the following: 
!
Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher* 
!
Any treatment-emergent serious adverse events of bleeding of any grade
!
Any treatment-emergent central nervous system hemorrhage/hematoma of any grade
*All hemorrhagic events requiring transfusion of red blood cells should be reported as a Grade 3 
or higher AE per CTCAE.
 
 
 
 
11.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all adverse events as to: 
11.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the investigator, the subject is at immediate 
risk of death from the AE);
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  


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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.
!
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
A procedure for protocol/disease-related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE.
!
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
A procedure that is planned (ie, planned prior to starting 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. 
!
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 IP, action taken regarding IP, and outcome.
11.2.2.
Severity / Intensity
For both AEs and SAEs, the investigator must assess the severity / intensity of the event. 
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the current active minor version of the CTCAE Version 4.03 with the exception of TFR (NCI 
CTCAE version 3.0), 
 and laboratory abnormalities as recommended by the 
IWCLL guidelines for the diagnosis and treatment of CL
AEs that are not defined in the CTCAE should be evaluated for severity / intensity according to 
the following scale:


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!
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.
11.2.3.
Causality 
The investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means a causal relationship of the adverse event to IP
administration is unlikely or remote, or other medications, 
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event.
Suspected:
Means there is a reasonable possibility that the administration 
of IP caused the adverse event.  ‘Reasonable possibility’ means 
there is evidence to suggest a causal relationship between the IP 
and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
11.2.4.
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.


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11.2.5.
Action Taken
The investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
11.2.6.
Outcome
The investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered or death (due to the 
SAE). 
11.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE and reported if the abnormality:
!
results in discontinuation from the study; or
!
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
!
considered clinically significant by the investigator, regardless of the severity. 
Grade 3/4 laboratory abnormalities will be reported as adverse events independent of associated 
signs or symptoms, if it requires treatment, modification or interruption of IP dose, or any other 
therapeutic intervention, or results in discontinuation from the study. The associated signs and 
symptoms will be considered as additional event terms and graded according to their own 
criteria.
Regardless of severity grade, laboratory abnormalities that fulfill a seriousness criterion need to 
be documented as a serious adverse event.  
Note: 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).
11.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject or partner of a 
male subject are immediately reportable events.
11.4.1.
Females of Childbearing Potential
The following are considered immediately reportable events:
!
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject is 
on study drugs, or within at least 28 days of the subject’s last dose of CC-122.


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!
Pregnancies of female subjects occurring while the subject is on study drug, or within 
at least 18 months after the subject’s last dose of obinutuzumab.  
IP is to be discontinued immediately and the subject instructed to return any unused portion of 
the IP to the investigator as applicable.  The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, using the Pregnancy Initial Report Form, or approved equivalent form.  
The exposure of any pregnant female (eg, caregiver or pharmacist) to CC-122 is also an 
immediately reportable event.
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 other appropriate 
method, within 24 hours of the investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
Additionally, for any subject receiving obinutuzumab, the site will simultaneously send the SAE 
Report Form to Celgene and Hoffmann-La Roche within the same timeframe and method.
11.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP 
should notify the investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately.  
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the 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, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE reports as well as any follow-up reports.
The investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) or any 
SAE made known to the investigator at any time thereafter that are suspected of being related to 
IP.  Serious AEs occurring prior to treatment (after signing the ICF) will be captured.


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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.
11.5.1.
Adverse Events of Special Interest 
Specific adverse events, or groups of adverse events, will be followed as part of safety 
monitoring activities by the Sponsor. 
11.5.1.1.
Major Hemorrhage (Arm B)
For any subjects receiving ibrutinib (Arm B), major hemorrhages as defined in Section 11.1.1.1
are considered adverse events of special interest and must be reported on the Serious Adverse 
Event Report Form using the “Important Medical Event” as the seriousness criteria and sent via 
email or fax to Celgene and/or designee, within 24 hours of awareness. 
 
 
 
 
 
11.6.
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.
11.7.
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 CC-122 based on the IB.
In the US, 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 Ethics 
Committees concerned, SUSARs in accordance with Directive 2001/20/EC and the Detailed 


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Guidance on collection, verification and presentation of adverse reaction reports arising from 
clinical trials on investigational products for human use (ENTR/CT3) and also in accordance 
with country-specific requirements.  
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to ibrutinib based on the EU SmPC and to 
obinutuzumab based on the IB.
Events of disease progression for the disease under study (including deaths due to disease 
progression for indications that are considered to be fatal) will be assessed as expected adverse 
events and will not be reported as expedited safety reports to regulatory authorities.
Celgene or its authorized representative shall notify the investigator of the following 
information: 
!
Any AE suspected of being related to the use of IP in this study or in other studies
that is both serious and unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC. (See Section 15.3 for record retention 
information.)
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.


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12.
DISCONTINUATIONS
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:
!
Adverse event
!
Disease progression
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Protocol violation
!
Start of a new anti-CLL therapy (with the exception of rituximab for the treatment of 
autoimmune hemolytic anemia)
!
Upon completion of a maximum of 24 cycles of CC-122
!
For subjects on Arm B, subjects who have discontinued CC-122 prior to the 
maximum of 24 cycles and have received an additional 3 cycles of investigational 
supply of ibrutinib
The reason for discontinuation should be recorded in the eCRF and in the source documents.
The decision to discontinue a subject remains the responsibility of the treating physician, which 
will not be delayed or refused by the sponsor.  However, prior to discontinuing a subject, the 
investigator may contact the medical monitor and forward appropriate supporting documents for 
review and discussion.


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13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the investigator should contact the responsible clinical research
physician/medical monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the clinical research physician/medical monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page).This global Emergency 
Call Center is available 24 hours a day and 7 days a week. The representatives are responsible 
for obtaining your call-back information and contacting the on call Celgene/contract research 
organization (CRO) medical monitor, who will then contact you promptly.
Note: The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the clinical research physician(s) or medical monitor or designee for emergency 
calls. 
13.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.


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14.
REGULATORY CONSIDERATIONS
14.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative,
and investigator abide by GCP, as described in International Council for Harmonization (ICH) 
Guideline E6 and in accordance with the general ethical principles outlined in the Declaration of 
Helsinki. The study will receive approval from an IRB/EC prior to commencement. The 
investigator will conduct all aspects of this study in accordance with applicable national, state, 
and local laws of the pertinent regulatory authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions. 
The investigator should maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties.
The investigator is responsible for keeping a record of all subjects who sign an informed consent 
document 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 IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.


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14.3.
Subject Information and Informed Consent
The investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original informed consent document 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, the 
informed consent document must be revised.  Study subjects participating in the study when the 
amended protocol is implemented must be re-consented with the revised version of the informed 
consent document.  The revised informed consent document 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.  
14.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent document, it is the responsibility of the investigator to obtain 
such permission in writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene clinical research 
physician/medical monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document, 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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Investigational product can only be supplied to an investigator by Celgene or its authorized 
representative after documentation on all ethical and legal requirements for starting the study has 
been received by Celgene or its authorized representative. This documentation must also include 
a list of the members of the IRB/EC and their occupation and qualifications. If the IRB/EC will 
not disclose the names, occupations and qualifications of the committee members, it should be 
asked to issue a statement confirming that the composition of the committee is in accordance 
with GCP. For example, the IRB General Assurance Number may be accepted as a substitute for 
this list. Formal approval by the IRB/EC should mention the protocol title, number, amendment 
number (if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the informed consent document 
should also be revised.
The investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
14.7.
Ongoing Information for Institutional Review Board/Ethics 
Committee
If required by legislation or the IRB/EC, the investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
14.8.
Closure of the Study
Celgene reserves the right to terminate this study 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 addition, the investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;


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Falsification of records;
!
Failure to adhere to the study protocol.


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15.
DATA HANDLING AND RECORDKEEPING
15.1.
Data/Documents
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
15.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene SOPs. This 
data will be electronically verified through use of programmed edit checks specified by the 
clinical team.  Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary.  Resolutions to these issues will be reflected in the 
database.  An audit trail within the system will track all changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. 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 informed consent documents for all subjects;
!
Subject identification code list, screening log (if applicable), and enrollment log;
!
Record of all communications between the investigator and the IRB/EC;
!
Composition of the IRB/EC;
!
Record of all communications between the investigator, Celgene, and their authorized 
representative(s);
!
List of sub-investigators and other appropriately qualified persons to whom the 
investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 


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!
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/Institution should take measures to prevent accidental or premature destruction of 
these documents.


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16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1.
Study Monitoring and Source Document Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the investigator and the staff at a study 
initiation visit and/or at an investigator meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the investigator.  Monitoring will 
include on-site visits with the investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product 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, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs 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/IECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives.  The investigator should make every effort to be available 
for the audits and/or inspections.  If the investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene immediately.


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16.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
after it is released for distribution.  PQCs may reduce the usability of the product for its intended 
function or affect performance of the product and therefore pose a significant risk to the patient.  
Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
seal/packaging breach, product missing/short/overage, contamination, suspected falsified, 
tampered, diverted or stolen material, and general product/packaging damage. If you become 
aware of a suspected PQC, you are obligated to report the issue immediately. 
 
 


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SAP_001.pdf: 
Statistical Analysis Plan for 
 
Official Title of Study 
PHASE 1/2 STUDY TO DETERMINE THE SAFETY, PHARMACOKINETICS, AND 
EFFICACY OF SINGLE AGENT CC-122 AND THE COMBINATIONS OF CC-122 AND 
IBRUTINIB AND CC-122 AND OBINUTUZUMAB IN SUBJECTS WITH CHRONIC 
LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA 
NCT02406742 
29-June-2020 


EDMS Doc. Number: 24891129 - 24890820
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Statistical Analysis Plan: Protocol CC-122-CLL-001                                     Celgene Corporation
Confidential and Proprietary
STATISTICAL ANALYSIS PLAN
PHASE 1/2 STUDY TO DETERMINE THE SAFETY, PHARMACOKINETICS, AND 
EFFICACY OF SINGLE AGENT CC-122 AND THE COMBINATIONS OF CC-122 AND 
IBRUTINIB AND CC-122 AND OBINUTUZUMAB IN SUBJECTS WITH CHRONIC 
LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA
STUDY DRUG:
CC-122
PROTOCOL NUMBER: 
CC-122-CLL-001
DATE DRAFT:
Jun-2020
CONFIDENTIAL
The information contained in this document is regarded as confidential and, 
except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be informed 
that the information is confidential and may not be further disclosed by 
them.


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                              2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1. 
LIST OF ABBREVIATIONS...................................................................................7
2. 
INTRODUCTION..................................................................................................12
3. 
STUDY OBJECTIVES AND ENDPOINTS...........................................................13
4. 
INVESTIGATIONAL PLAN.................................................................................15
4.1. 
Study Design and Plan............................................................................................15
4.1.1. 
Dose Escalation Phase: 
...........................................................................................15
4.1.2. 
Expansion Phase:....................................................................................................18
4.1.3. 
Follow-up Phase: 
....................................................................................................18
4.2. 
Study Treatments....................................................................................................19
4.3. 
Stratification and Randomization............................................................................22
4.4. 
Sample Size Determination.....................................................................................23
5. 
GENERAL STATISTICAL CONSIDERATIONS.................................................24
5.1. 
Reporting Conventions...........................................................................................24
5.2. 
Analysis Populations..............................................................................................25
5.2.1. 
Safety Population....................................................................................................26
5.2.2. 
Dose Limiting Toxicity (DLT) Evaluable Population..............................................26
5.2.3. 
Efficacy Evaluable (EE) Population........................................................................26
5.2.4. 
Pharmacokinetic (PK) Population...........................................................................26
6. 
SUBJECT DISPOSITION......................................................................................27
7. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................29
7.1. 
Demographics.........................................................................................................29
7.2. 
Baseline Characteristics..........................................................................................29
7.3. 
Medical History......................................................................................................30
7.4. 
Prior Therapies 
.......................................................................................................30
8. 
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................31
8.1. 
Treatment Duration.................................................................................................31
8.2. 
Cumulative Dose and Dose Intensity ......................................................................31
8.3. 
Relative Dose Intensity...........................................................................................32
8.4. 
Dose Reduction/Interruptions.................................................................................32
9. 
PRIOR/CONCOMITANT MEDICATIONS AND PROCEDURES.......................34
9.1. 
Prior Medications ...................................................................................................34


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Statistical Analysis Plan: Protocol CC-122-CLL-001
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10. 
EFFICACY ANALYSIS........................................................................................35
10.1. 
Objective Response Rate (ORR) and Minimal Residual Disease (MRD).................35
10.2. 
Duration of Response (DoR)...................................................................................39
10.3. 
Time to Response and Time to Best Overall Response............................................40
10.4. 
Progression-Free Survival (PFS).............................................................................40
10.5. 
Bone Marrow Examination.....................................................................................41
10.6. 
ECOG Performance Status......................................................................................41
10.7. 
B-symptoms Evaluation..........................................................................................41
10.8. 
Physical Examination for Efficacy Analysis............................................................42
11. 
SAFETY ANALYSIS............................................................................................43
11.1. 
Adverse Events.......................................................................................................43
11.1.1. 
Summary of Adverse Events...................................................................................43
11.1.2. 
Dose-limiting Toxicities (DLTs).............................................................................45
11.1.3. 
Adverse Events Subgroup Analysis........................................................................45
11.2. 
Clinical Laboratory Evaluations..............................................................................46
11.3. 
Vital Sign Measurements........................................................................................47
11.4. 
Electrocardiograms (ECG)......................................................................................47
11.5. 
Left Ventricular Ejection Fraction (LVEF) Assessment..........................................47
14. 
INTERIM ANALYSIS...........................................................................................52
15. 
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................53
17. 
APPENDICES........................................................................................................55


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17.1. 
Dose Escalation Rules ............................................................................................55
17.2. 
Handling of Dates...................................................................................................55
17.2.1. 
Calculation Using Dates.........................................................................................55
17.2.2. 
Calculation of Cycles..............................................................................................56
17.3. 
Baseline, Repeated Measurements, and End of Trial...............................................56
17.4. 
Date Imputation Guideline......................................................................................57
17.6. 
Laboratory Data Handling ......................................................................................61
17.7. 
Study Procedures....................................................................................................61
17.7.1. 
Modification of the International Workshop Lymphoma Response Criteria : 
Small Lymphocytic Lymphoma Diagnosis and Response.......................................62
17.8. 
Laboratory Abnormalities Toxicity Grading as Recommended by IWCLL 
Guidelines ..............................................................................................................63
17.9. 
Cumulative Illness Rating Scale (CIRS).................................................................64


EDMS Doc. Number: 24891129 - 24890820
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LIST OF TABLES
Table 1: Abbreviations and Specialist Terms..........................................................................7
Table 2: Objectives and Endpoints.......................................................................................13
Table 3: Response Definition after Treatment for Chronic Lymphocytic 
Leukemia Subjects..................................................................................................36
Table 4: Summary of Revised Criteria for Response Assessment for Small 
Lymphocytic Lymphoma........................................................................................38
Table 5: Censoring Method for Progression-Free Survival Time...........................................40
Table 6: Normal Ranges of Vital Sign Measurements...........................................................47
Table 7: Biomarker Endpoints, Sample Collection Schedule and Hints for Statistical 
Analysis..................................................................................................................50
Table 8: Intrasubject Dose Escalation and Fixed-Doses Cohort Escalation Rules..................55
Table 9: General Data Handling Conventions for Pharmacodynamic Biomarkers.................60
Table 10: BM Assay-Specific Data Handling Conventions for Pharmcodynamic 
Biomarkers 
.............................................................................................................61
Table 11: Data Handling Conventions for Laboratory Parameters...........................................61
Table 12: Revised Staging System for Primary Nodal Lymphomas ........................................62
Table 13: Grading Scale for Hematologic Toxicity in Chronic Lymphocytic Leukemia 
Studies....................................................................................................................63
Table 14: Cumulative Illness Rating Scale..............................................................................64
Table 15: CIRS Rating Scale..................................................................................................65
LIST OF FIGURES
Figure 1: Overall Study Design..............................................................................................20




EDMS Doc. Number: 24891129 - 24890820
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Statistical Analysis Plan: Protocol CC-122-CLL-001
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                              7
1. 
LIST OF ABBREVIATIONS
Table 1: 
Abbreviations and Specialist Terms
Abbreviation or specialist term 
Explanation
5PS
5-point scale
AE
 Adverse
 
Event
 
ALC
Absolute Lymphocyte Count
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
ANC
Absolute Neutrophil Count
AST
Aspartate Transaminase
ATC 
Anatomical Therapeutic Chemical 
AUC
Area Under Concentration
BCR PI
B-Cell Receptor Pathway Inhibitor
BQL
Below the Quantification Limit
BMI
Body Mass Index
BNP
B-type Natriuretic Peptide
bpm
beats per minute 
BPM
Breaths per Minute 
BSA
Body Surface Area 
BTK
Bruton’s tyrosine kinase
BUN
Blood urea nitrogen
CBC
Complete Blood Count
CI
Confidence Interval 
CIRS
Cumulative Illness Rating Scale
CL/F
Apparent clearance of drug from plasma
CLL
Chronic Lymphocytic Leukemia 
Cmax
Peak (maximum) drug plasma concentration
CR
Complete Response 
CRF
Case Report Form 
CRi
Complete Response with incomplete marrow recovery
CTCAE
Common Terminology Criteria for Adverse Events 
CT
Computerized Tomography


EDMS Doc. Number: 24891129 - 24890820
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Statistical Analysis Plan: Protocol CC-122-CLL-001
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Table 1: 
Abbreviations and Specialist Terms (continued)
Abbreviation or specialist term 
Explanation
CV
Coefficient of Variation
DBP
Diastolic Blood Pressure
DLT
 Dose
 
Limiting
 
Toxicity
 
DNA
Deoxyribonucleic Acid
DoR 
Duration of Response 
EC
Ethics Committee
ECG
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EE 
Efficacy Evaluable  
EOT
End of Treatment
Esc
Escalation Level
FISH
Fluorescent In Situ Hybridization
FDG
Fluorodeoxyglucose
fT4
Free T4
G-CSF
Granulocyte Colony-Stimulating Factor
GM-CSF
Granulocyte-Macrophage Colony-Stimulating Factor
HBsAg
Hepatitis B surface Antigen
anti-HBc
Hepatitis B core antibody
HCV 
Hepatitis C Virus 
HGB
Hemoglobin
IFN-γ
Interferon-gamma
Ig
Immunoglobulin
IgVH
Immunoglobulin Heavy Chain
IL
Interleukin
INR 
International Normalized Ratio 
IP
Investigational Product
IRB
Institutional Review Board
IVRS
Interactive Voice Response System 
IWCLL
International Workshop on Chronic Lymphocytic Leukemia 
LD
Longest Diameter
LDH
Lactate Dehydrogenase


EDMS Doc. Number: 24891129 - 24890820
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Statistical Analysis Plan: Protocol CC-122-CLL-001
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Table 1: 
Abbreviations and Specialist Terms (continued)
Abbreviation or specialist term 
Explanation
LLOQ
Low Limit Of Quantification
LOD
Limit Of Detection
LPD
Longest Perpendicular Diameter
LVD
Longest Vertical Dimension
LVEF 
Left Ventricular Ejection Fraction 
Max
 Maximum
 
MedDRA
Medical Dictionary for Regulatory Affairs
Min
 Minimum
 
MRD
Minimum Residual Disease
MTD 
Maximum Tolerated Dose 
NCA
Non-compartmental analysis
NCI 
National Cancer Institute 
nPR
nodular Partial Response
NTD
 Non-Tolerated
 
Dose
 
ORR 
Objective Response Rate 
PBMC
Peripheral blood mononuclear cell
PD
 Progressive
 
Disease
PDwH
PD with histologic transformation
PDw/oH
PD without histologic transformation
PET
Positron Emission Tomography
PFS
 Progression-Free
 
Survival
 
PK
 Pharmacokinetic
 
PR
 Partial
 
Response
 
PRL
Partial Response with Lymphocytosis
PT
 Preferred
 
Term
 
PTT
Partial Thromboplastin Time
QD
Daily Dose
QNS
Quantity Not Sufficient
QTc 
Corrected QT Interval 
QTcB
Bazett Corrected QT Interval
QTcF
Fridericia Corrected QT Interval


EDMS Doc. Number: 24891129 - 24890820
CC-122
Statistical Analysis Plan: Protocol CC-122-CLL-001
Celgene Corporation
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                              10
Table 1: 
Abbreviations and Specialist Terms (continued)
Abbreviation or specialist term 
Explanation
Rac
Accumulation Ratio 
RBC
Red Blood Cell
RNA
Ribonucleic Acid
RP2D 
Recommended Phase 2 Dose 
RR
R wave to R wave interval
R/R
Relapsed/Refractory
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD
 Stable
 
Disease
 
SE
Standard Error
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamate pyruvic transaminase
SLL
Small Lymphocytic Lymphoma
SMQ
Standardized MedDRA Queries
SOC 
System Organ Class 
SPD
Sum of the product of the Perpendicular Diameters for 
multiple lesions
SRC
Safety Review Committee 
StdDev
 Standard
 
Deviation
 
t½
 Terminal
 
elimination
 
half-life
TEAE 
Treatment Emergent Adverse Event 
TFR
Tumor Flare Reaction 
TLS
Tumor Lysis Syndrome 
Tmax
Time to peak (maximum) drug concentration
TN
Treatment Naïve
TNF
Tumor Necrosis Factor
TSH
Thyroid Stimulating Hormone
Vz/F
Apparent volume of distribution during the terminal phase 
after extravascular administration
WBC
White Blood Cell
WHO 
World Health Organization 


EDMS Doc. Number: 24891129 - 24890820
CC-122
Statistical Analysis Plan: Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary 
                              11
Table 1: 
Abbreviations and Specialist Terms (continued)
Abbreviation or specialist term 
Explanation
WHODrug
World Health Organization Drug Dictionary
ZAP 70
Zeta-Chain-Associated Protein Kinase


EDMS Doc. Number: 24891129 - 24890820
CC-122
Statistical Analysis Plan: Protocol CC-122-CLL-001
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                              12
2. 
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s protocol 
amendment 7 “Phase 1/2 study to determine the safety, pharmacokinetics, and efficacy of single agent CC-
122 and the combinations of CC-122 and ibrutinib and CC-122 and obinutuzumab in subjects with chronic 
lymphocytic leukemia/small lymphocytic lymphoma” that was issued on 27 July 2018. 
The main focus of the dose escalation phase of the study CC-122-CLL-001 is to determine the safety of 
single agent CC-122 (Arm A) and the safety and tolerability of CC-122 when administered in combination 
with ibrutinib (Arm B) and when administered in combination with obinutuzumab (Arm C), and to define 
the Non-Tolerated Dose (NTD), Maximum Tolerated Dose (MTD), and the Recommended Phase 2 Dose 
(RP2D) of CC-122 for each of those combinations. The RP2D may be the MTD or lower dose depending 
on tolerability, the pharmacokinetic (PK) profile, and the pharmacodynamic profile observed. The Safety 
Review Committee (SRC) will identify a preliminary RP2D for Arms B and C based on an integrated 
assessment of the safety, available PK, pharmacodynamics data and preliminary efficacy information.  The 
RP2D selected will not exceed the MTD from the dose escalation cohorts.
The principal objectives of the dose expansion phase are to further assess the safety profile and to provide 
preliminary efficacy information of CC-122 in combination with ibrutinib, and CC-122 in combination 
with obinutuzumab in subjects with Relapsed/Refractory
 (R/R)
 chronic
 lymphocytic
 leukemia (CLL)/Small
 
Lymphocytic Lymphoma (SLL). Since the Phase 2 dose expansion phase will not proceed per Protocol 
Amendment 7, further characterization of the MTD and RP2D in the dose expansion phase will not be
conducted.
The purpose of this SAP is to ensure the credibility of the study findings by pre-specifying the statistical 
approaches
 to
 the
 analysis
 of
 study
 data
 prior
 to
 database
 lock.
 This
 SAP
 contains
 definitions
 for
 the
 analysis
 
populations and derived variables, as well as the description of the strategy, rationale and statistical 
techniques to be used to achieve the objectives of the dose escalation of the study. The analysis for dose 
expansion will not be conducted and is not included in this SAP.
This SAP will be finalized and signed prior to the clinical database lock at the end of the dose escalation 
phase. All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.2 or higher.


EDMS Doc. Number: 24891129 - 24890820
CC-122
Statistical Analysis Plan: Protocol CC-122-CLL-001
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3. 
STUDY OBJECTIVES AND ENDPOINTS
The study objectives and endpoints for the dose escalation phase and the dose expansion phase are listed 
in Table 2. The analysis for the dose expansion objectives and endpoints will not be conducted and is not 
included in this SAP.
Table 2: 
Objectives and Endpoints  
Objectives
Endpoints
Phase of Analysis
Primary
Determine the safety of single agent CC-
122 in subjects with R/R CLL/SLL.
Incidence and severity of adverse 
events using the National Cancer 
Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) 
criteria (version 4.03), including Dose-
Limiting Toxicities (DLTs).
Dose escalation
Determine the safety and tolerability of 
the combination of CC-122 and ibrutinib 
and determine the RP2D of the 
combination in ibrutinib-naïve CLL/SLL 
subjects.
CC-122 in combination with ibrutinib: 
Determination of the NTD and MTD.
Dose escalation and 
safety
 and refinement 
of the RP2D in the 
dose expansion*.
Determine the safety and tolerability of 
the combination of CC-122 and 
obinutuzumab and determine the RP2D of 
the combination in subjects with R/R 
CLL/SLL.
CC-122 in combination with 
obinutuzumab: Determination of the 
NTD and MTD.
Dose escalation and 
safety and refinement 
of the RP2D in the 
dose expansion*.
Secondary
Characterize CC-122 PK in subjects with 
CLL and assess potential drug-drug 
interactions when CC-122 is given in 
combination with ibrutinib, or 
obinutuzumab.
CC-122 plasma concentrations when 
administered alone or in combination 
with ibrutinib, or obinutuzumab.
CC-122 PK parameters when 
administered in combination with 
ibrutinib**
Dose escalation and 
dose expansion*
Determine ibrutinib concentrations when 
given alone or in combination with CC-
122
Ibrutinib plasma concentrations and/or 
PK parameters when administered in 
combination with CC-122.**
Dose escalation and 
dose expansion*
Determine the preliminary efficacy of 
single agent CC-122, the combination of 
CC-122 and ibrutinib, and the 
combination of CC-122 and 
obinutuzumab.
Rates for best overall response 
(Complete Response [CR], Complete 
Response with incomplete marrow 
recovery [CRi], nodular Partial 
Response [nPR], Partial Response 
[PR], Partial Response with 
Lymphocytosis [PRL] – applicable to 
Arm B only)
Dose escalation and 
dose expansion*
Minimal Residual Disease (MRD) 
negativity rate in bone marrow and 
peripheral blood.
Dose escalation and 
dose expansion*
Duration of response (DoR).
Dose escalation and 
dose expansion*
Progression-Free Survival (PFS).
Dose escalation and 
dose expansion*


EDMS Doc. Number: 24891129 - 24890820
CC-122
Statistical Analysis Plan: Protocol CC-122-CLL-001
Celgene Corporation
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                              14


EDMS Doc. Number: 24891129 - 24890820
CC-122
Statistical Analysis Plan: Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary 
                              15
4.
INVESTIGATIONAL PLAN
4.1. 
Study Design and Plan
CC-122-CLL-001 is a Phase 1/2 multicenter, open-label, dose finding study to determine the safety and 
preliminary efficacy of CC-122 administered orally to subjects with CLL/SLL. The following will be 
evaluated:
! Arm
 A:  CC-122 single agent
! Arm B:  CC-122 in combination with ibrutinib.  
! Arm C: CC-122 in combination with obinutuzumab
The Dose Escalation Phase (Phase 1) will be comprised of an intrasubject dose escalation cohort for single 
agent CC-122 (Arm A) in parallel with ascending fixed-doses cohorts of the combinations of CC-122 and 
ibrutinib (Arm B) and CC-122 and obinutuzumab (Arm C) evaluated using a 3 + 3 design to determine the 
NTD and MTD.  
Up to approximately 20 subjects will be evaluated in the intrasubject dose escalation cohort in Arm A and 
3 to 6 subjects will be evaluated in each fixed-doses cohort in Arms B and C; therefore, approximately 68
(46-92) subjects are anticipated to be enrolled in Phase 1. The final number of subjects will depend on the 
number of dose levels tested and the number of DLTs observed within each cohort.
An SRC whose members include the sponsor’s medical monitor, drug safety physician, and a subset of 
investigators, will determine a preliminary RP2D for each combination treatment arm based on an 
integrated assessment of the safety, available PK and pharmacodynamic data, and preliminary efficacy 
information. For the fixed-doses cohorts, the SRC will make the recommendation of whether to open the 
next dose cohort and the incremental increase in dose (i.e., 0.5 or 1.0 mg) after review of the safety data of 
the current dose cohort (after full enrolment and completion of the DLT evaluation period). The 1.0 mg 
increment is allowed only after the first two dose cohorts of 0.5 and 1.0 mg have been completed.
After completion of the fixed-doses cohorts in Arms B and C, the SRC will make the determination whether 
to evaluate an additional intrasubject dose escalation cohort per each combination treatment arm. The 
starting dose will be determined by the SRC, with intrasubject dose escalation up to a maximum dose of 
4.0 mg.
The same rules governing dose escalations in Arm A (see below) will be applied for intrasubject dose 
escalation cohorts in the combination arms.
All active subjects who are receiving clinical benefit in the opinion of the treating investigator may 
continue to receive study treatment up to a maximum of 24 cycles of CC-122, oruntil progressive disease 
(PD), unacceptable toxicity or discontinuation for any other reason, whichever is earlier. Subjects who 
achieve MRD negativity (in both peripheral blood and bone marrow) lasting for a minimum of 3 months 
in duration have the option to discontinue study treatment, with subsequent MRD tests follow-up (in 
peripheral blood and/or bone marrow) every 3 cycles for the first year, and every 6 cycles thereafter. 
Study treatment in these subjects may be resumed at the time of MRD positivity (either in peripheral 
blood or bone marrow).
4.1.1. 
Dose Escalation Phase:
As of 05 Jul 2018, enrollment of new subjects into Phase 1 has been discontinued (per protocol amendment 
7).


EDMS Doc. Number: 24891129 - 24890820
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Statistical Analysis Plan: Protocol CC-122-CLL-001
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                              16
The Dose Escalation Phase will be comprised of an intrasubject dose escalation cohort for single agent CC-
122 (Arm A) in parallel with ascending fixed-doses cohorts of the combinations of CC-122 and ibrutinib 
(Arm B), and CC-122 and obinutuzumab (Arm C), evaluated using a 3 + 3 design:
Arm
 A (CC-122 single agent):  
An intrasubject dose escalation cohort of CC-122 starting at the 1.0 mg dose level up to a maximum of 4.0 
mg will be evaluated. (Previous protocol has starting CC-122 dose as 0.25 mg and 0.5 mg).
In the event higher doses of CC-122 are shown to be safe in other hematologic malignancies in ongoing 
CC-122 studies, the maximum dose of 4.0 mg may be increased after approval by the SRC.
Each subject will be permitted to dose escalate by 0.5 mg increments every 2 weeks based on investigator 
assessment of the individual subject’s tolerability (i.e., escalation to the next dose level requires no DLT or 
dose reduction at the current dose level in addition to meeting the criteria outlined in Protocol Section 
8.2.8).
However, dose escalation per cycle is not mandatory if the subject is benefiting (i.e., objective evidence 
of disease response based on Absolute Lymphocyte Count [ALC] reduction or shrinkage in measurable 
lesions required) from their current dose in the absence of significant toxicities. Subjects who are enrolled 
to fixed dose cohorts (0.25 mg or 0.5 mg) in Arm A under earlier protocol amendments (i.e., protocol 
amendment 3 or 4) will be allowed to undertake intrasubject dose escalations as described above. Subjects 
in Arm A will have the option to receive the addition of ibrutinib or obinutuzumab if there is evidence of 
PD while on CC-122 monotherapy after the completion of the DLT evaluation and CC-122 in 
combination with these standard agents has been demonstrated to be safe in the context of this trial. These 
subjects will receive a maximum of 24 cycles of CC-122 (including prior CC-122 monotherapy). The 
dose of CC-122 may need to be decreased to the level that has been shown to be safe in Arms B or C per
the SRC (i.e., < 2 DLTs/6 subjects). Subsequent intrasubject escalation is allowed if higher doses of CC-
122 have been deemed tolerable in Arms B or C. This option will also apply to subjects that have enrolled 
in Arm A prior to Institutional Review Board (IRB) and/or Ethics Committee (EC) approval of 
Amendment 5 after discussion with the Sponsor Medical Monitor.
CC-122 will be administered starting on Cycle 1 Day 1 on a 5/7-day schedule (5 continuous days out of 7 
days per week) up to a maximum of 24 cycles, or until PD, unacceptable toxicity, or discontinuation for 
any other reason, whichever is earlier. Each cycle consists of 28 days.
Subjects will be observed for early DLTs in Cycle 1 (DLT evaluation period). Monitoring for late toxicities 
necessitating dose reductions or discontinuations will be conducted during Cycles 2 through 6. 
Arm B (CC-122 + ibrutinib):  
The following arm will be evaluated in parallel to Arm A:
Ascending fixed-dose cohorts of CC-122 starting at 0.5 mg up to a maximum of 4.0 mg or NTD, whichever 
occurs first, in combination with ibrutinib will be evaluated. After completion of the 0.5 mg and 1.0 mg 
fixed-doses cohorts, subsequent cohorts will be allowed to escalate in either 0.5 mg or 1.0 mg increments. 
Escalation to the next dose level requires 0/3 or ≤ 1/6 DLTs at the current dose level. Further, an escalation 
increment of 1.0 mg requires that absence of any Grade 3 drug related non-hematologic AEs, any Grade 4 
hematological event, and TLS or TFR of any grade at the current dose level. The SRC will make the 
recommendation of whether to open the next dose cohort and the incremental increase in dose (0.5 or 1.0 
mg) after review of the safety data of the current dose cohort (after full enrolment and completion of the 
DLT evaluation period).


EDMS Doc. Number: 24891129 - 24890820
CC-122
Statistical Analysis Plan: Protocol CC-122-CLL-001
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                              17
CC-122 will be initiated on Cycle 2, Day 1 and administrated on a 5/7-day schedule. Ibrutinib 420 mg daily 
dose (QD) will be administered starting on Cycle 1, Day 1 (see Protocol Section 8.2 for treatment 
description, administration and schedule). 
CC-122 and ibrutinib will be administered up to a maximum of 24 cycles of CC-122, or until PD, 
unacceptable toxicity, or discontinuation for any other reason, whichever is earlier. In the event CC-122 is 
discontinued prior to ibrutinib or if patients have surpassed the 24 cycles of CC-122, Celgene will continue 
to provide an additional 3 cycles of ibrutinib from the investigational supply to allow time for patients to 
be switched to commercially available ibrutinib and/or other therapies at the discretion of the treating 
physician.
Subjects will be observed for early DLTs for 28 days following the initiation of CC-122 combination 
therapy (Cycle 2, Days 1 through 28) (DLT evaluation period). Monitoring for late toxicities necessitating 
dose reductions or discontinuations will be conducted during the first 6 cycles of combination treatment 
(see Section 17.2.2 for CC-122 Cycle definition).
Arm C (CC-122 + obinutuzumab): 
The following arm will be evaluated in parallel to Arms A and B:
Ascending fixed-doses cohorts of CC-122 starting at 0.5 mg up to a maximum of 4.0 mg or NTD, whichever 
occurs first, in combination with obinutuzumab will be evaluated. After completion of the 0.5 and 1.0 mg 
fixed-dose cohorts, subsequent cohorts will be allowed to escalate in either 0.5 mg or 1.0 mg increments. 
Escalation to the next dose level requires 0/3 or ≤ 1/6 DLTs at the current dose level. Further, an escalation 
increment of 1.0 mg requires the absence of any Grade 3 drug related non-hematologic AEs, any Grade 4 
hematological event, and TLS or TFR of any grade at the current dose level. The SRC will make the
recommendation of whether to open the next dose cohort and the incremental increase (0.5 or 1.0 mg) after 
review of the safety data of the current dose cohort (after full enrolment and completion of the DLT 
evaluation period). 
CC-122 will be initiated on Cycle 1 Day 9 and administered on a 5/7-day schedule. For subjects on Arm C, 
Cycle 1 only will consist of 29 days to accommodate the 5/7-day schedule; subsequent cycles will consist 
of 28 days. Obinutuzumab will be administered intravenously on Cycle 1 Days 1, 2, 8 and 15 (see Protocol 
Section 8.2 for treatment description, administration and schedule). The dose of obinutuzumab on Day 1 
and Day 2 of Cycle 1 may be adjusted per institutional practice provided the combined dose equals 1000 
mg.  Obinutuzumab will be administered on Day 1 every cycle thereafter up to Cycle 6. 
CC-122 will be administered up to a maximum of 24 cycles of CC-122, or until PD, unacceptable toxicity, 
or discontinuation for any other reason, whichever is earlier. In the event CC-122 is discontinued prior to 
obinutuzumab, Celgene will continue to supply the protocol-specified total of 6 cycles of obinutuzumab. 
In addition, for patients that have surpassed the 24 cycles of CC-122, Celgene will continue to provide an 
additional 3 cycles of CC-122 to allow time for patients to be switched to commercially available therapies 
at the discretion of the treating physician.
Subjects will be observed for early DLTs for 28 days following initiation of CC-122 combination therapy 
(Cycle 1 Day 9 through Cycle 2 Day 8) (DLT evaluation period). Monitoring for late toxicities necessitating 
dose reductions or discontinuations will be conducted during Cycles 2 through 6.
Early DLT Evaluation of Intrasubject Dose Escalation Cohort in Arm
 A:
Up to approximately 20 subjects will be enrolled to Arm A to assess an intrasubject dose escalation 
schedule for CC-122.


EDMS Doc. Number: 24891129 - 24890820
CC-122
Statistical Analysis Plan: Protocol CC-122-CLL-001
Celgene Corporation
Confidential and Proprietary 
                              18
If > 20% (e.g., >4 of 20) of subjects meet the criteria for DLT within 28 days of initial escalation to a dose 
level, no further intrasubject dose escalation to that dose level will be permitted. 
Early DLT Evaluation for Fixed-Doses Cohorts in Arms B and C:
An initial 3 subjects will be enrolled to each of the fixed-doses escalation cohorts in Arms B and C. A dose 
level will be considered tolerable if 0 of 3 treated subjects experiences a DLT during the DLT evaluation 
period of each respective group. If 1 of 3 subjects experiences a DLT, 3 additional subjects will be enrolled 
to that dose level. A dose will be considered the NTD when ≥ 2 out of 6 evaluable subjects in a cohort 
experience a DLT. If DLTs are observed in ≥ 2 out of 6 evaluable subjects at the first dose level, a lower 
dose combination may be explored after review of safety data by the SRC (see Protocol Section 8.2.1).
After full enrolment and completion of the DLT evaluation period of each dose level, the number and type 
of DLTs and AEs occurring during the DLT evaluation period will be evaluated. A dose level will be 
considered tolerated after discussion of these data by the SRC. Subsequent dose cohorts will only be 
authorized to open for enrolment following a consensus by the SRC. Subjects enrolled in lower CC-122 
fixed-dose cohorts will be allowed to escalate immediately to the next higher CC-122 dose level upon SRC 
approval of the subsequent CC-122 dose. For example, if the SRC has declared the 1.0 mg dose level 
tolerable and confirmed the opening of the 1.5 or 2.0 mg dose level, the subjects in the lower combination, 
ie, 0.5 mg CC- 122 dose level may escalate to 1.0 mg.
The MTD is defined as the highest dose level below the NTD with 0 or 1 of 6 DLT evaluable subjects 
experiencing a DLT during the specified DLT evaluation period. If only 3 subjects have been enrolled at 
the last dose level below the NTD, 3 additional subjects will be enrolled. A dose level will be declared the 
MTD when at least 6 subjects have been enrolled and less than 2 subjects have experienced a DLT at that 
dose level.
An intermediate dose (i.e. one between the NTD and the last dose level before the NTD) or additional 
subjects within any dose cohort may be required to determine the MTD and RP2D more precisely.
Monitoring for Late Toxicities during the Dose Escalation Phase: 
Continuous safety monitoring will continue for all cohorts for late toxicities necessitating dose reduction 
or discontinuation. If at any time during the first 6 cycles of CC-122 treatment greater than 20% of subjects 
experience a late toxicity necessitating dose reduction or discontinuation that is clearly not related to PD, 
medical procedure, or intercurrent illness, the dose level will have been considered to exceed the MTD and 
the RP2D will be selected at a lower dose level. The SRC will be responsible for monitoring these late 
toxicities and will make the determination that the limit of 20% has been exceeded. 
Determination of RP2D: 
The SRC will identify a preliminary RP2D for Arms B and C based on an integrated assessment of the 
safety, available PK and pharmacodynamic data, and preliminary efficacy information. CC-122 data 
available from other clinical studies will also be considered by SRC. The RP2D selected will not exceed 
the MTD from the dose escalation cohorts. 
4.1.2. 
Expansion Phase: 
As of Protocol Amendment 7, Phase 2 Expansion Phase will not proceed.
4.1.3. 
Follow-up Phase:
The Follow-up Phase will begin at study treatment discontinuation. Subjects will have a visit at the End of 
Treatment (EoT) as soon as possible once Investigational Product (IP) has been discontinued and at 28 days 


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after the last dose of IP.  All subjects discontinued for any reason other than PD, withdrawal of consent, or 
death, will be contacted every 90 days following the date of the 28-day follow-up visit for information 
regarding the status of their disease and for the type and start date for any subsequent anticancer therapy.  
These contacts will typically be via telephone and will not require site visits. Contact will continue until the 
subject experiences PD, starts a new anti-CLL therapy, withdraws consent for further follow-up, or expires.
Efficacy assessments (including clinical examination, laboratory test, and Computerized Tomography (CT) 
scans as indicated in the tables of scheduled events) will continue until documented PD or initiation of 
subsequent anti-CLL therapy.
4.2. 
Study Treatments
The overall study design is presented in Figure 1.
Per Protocol Amendment 7, Phase 2 Dose Expansion Phase will not proceed.


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Figure 1: 
Overall Study Design




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Arm
 A (Single agent CC-122):
Subjects assigned to Arm A will be administered a starting dose of 1.0 mg CC-122 orally on a 5/7-day (5 
continuous days out of 7 days per week) schedule starting at Cycle 1 Day 1 up to a maximum of 24 cycles 
of each cycle with intrasubject dose escalation permitted up to a maximum dose of 4.0 mg until PD, 
unacceptable toxicity or discontinuation for any other reason. Each subject will be permitted to dose 
escalate by 0.5 mg increments every 2 weeks based on investigator assessment of the individual subject’s 
tolerability. Subjects will have the option to receive the addition of ibrutinib or obinutuzumab if there is 
evidence of PD while on CC-122 monotherapy after the completion of the DLT evaluation and CC-122 in 
combination with these standard agents has been demonstrated to be safe in the context of this trial. Each 
cycle consists of 28 days.
Subjects who are enrolled to fixed dose cohorts (0.25 mg or 0.5 mg daily) in Arm A under earlier protocol 
amendments (i.e., protocol amendment 3 or 4) will be allowed to undertake intrasubject dose escalations as 
described above. Those subjects will switch to a 5/7 schedule as soon as the protocol amendment 5 has 
been approved at their site. 
Arm B (CC-122 + ibrutinib):  
Subjects in Arm B will be administered CC-122 orally on a 5/7-day schedule starting on Cycle 2 Day 1. 
CC-122 will be initiated until PD, unacceptable toxicity or discontinuation for any reason.
Subjects will take orally three 140 mg capsules of ibrutinib daily for a total dose of 420 mg. Ibrutinib will 
be administered daily starting Cycle 1 Day 1 up to a maximum of 24 cycles of CC-122 until PD, 
unacceptable toxicity or discontinuation for any other reason. For subjects who discontinue CC-122 prior 
to 24 cycles or if subjects have surpassed the 24 cycles of CC-122, Celgene will continue to provide an 
additional 3 cycles of ibrutinib from the investigational supply to allow time for subjects to be switched to 
commercially available ibrutinib and/or other therapies at the discretion of the treating physician.
Arm
 C (CC-122 + obinutuzumab):    
Subjects in Arm C will be administered CC-122 orally on a 5/7-day schedule. CC-122 will be initiated on 
Cycle 1 Day 9 and on Day 1 of each cycle thereafter up to a maximum of 24 cycles of CC-122 until PD, 
unacceptable toxicity or discontinuation for any other reason. 
Obinutuzumab will be administered as an IV infusion at a dose of 100 mg on Cycle 1 Day 1 and 900 mg 
on Cycle 1 Day 2 and 1000 mg on Cycle 1 Days 8 and 15. The dose of obinutuzumab on Days 1 and 2 of 
Cycle 1 may be adjusted per institutional practice as long as the combined dose equals 1000 mg. 
Obinutuzumab will be administered at a dose of 1000 mg on Day 1 of Cycles 2 through 6. In the event CC-
122 is discontinued prior to obinutuzumab, subjects may continue to receive the protocol-specified total of 
6 cycles of obinutuzumab at the discretion of the treating physician. In addition, for subjects that have 
surpassed the 24 cycles of CC-122, Celgene will continue to provide an additional 3 cycles of CC-122 to 
allow time for subjects to be switched to commercially available therapies at the discretion of the treating 
physician.
Please refer to Protocol Section 8 for detailed description of study treatment.
4.3. 
Stratification and Randomization
This study is an open-label study. Treatment assignment does not require randomization, blinding, or 
stratification. 


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4.4. 
Sample Size Determination
During the Dose Escalation Phase of the study, an intrasubject does escalation schedule and standard “3 + 
3” dose escalation design will be used to identify initial toxicities and safety of single agent CC-122 and 
to determine the MTD of the combination treatments. The final number of subjects needed in the Dose 
Escalation Phase depends on number of DLTs observed within each cohort.  Non-DLT evaluable subjects 
withdrawn prior to completion of the DLT evaluation period due to reasons other than DLT will be 
replaced.  






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Efficacy analyses including Eastern Cooperative Oncology Group (ECOG) performance status (except for 
PK) will be based on the Safety population. Key Efficacy analyses [summary of ORR, DoR and PFS] will 
be based on both the Safety population and the Efficacy Evaluable (EE) population. 
PK analyses will be based on the PK population. 
All listings will use all enrolled subjects.
5.2.1. 
Safety Population
Safety population – all subjects who take at least one dose of any IP. Subjects will be summarized under 
the treatment arm and starting dose of CC-122 they initially received.
5.2.2. 
Dose Limiting Toxicity (DLT) Evaluable Population
DLT Evaluable population –
! Arm A:  is defined as all subjects who completed at least one cycle of treatment and did not miss 
more than 5 days of CC-122 dosing during the first cycle are to be considered evaluable for DLT, 
unless the missed doses were due to IP related AE(s) or the cycle was not completed due to a DLT, 
in which case they remain evaluable for DLT.
! Arm B:  is defined as all subjects who completed at least one cycle of CC-122 (Cycle 2 Day 1 
through Cycle 2 Day 28) and did not miss more than 5 days of CC-122 treatment are to be 
considered evaluable for DLT, unless the missed doses were due to IP related AE(s) or the cycle 
was not completed due to a DLT, in which case they remain evaluable for DLT.
! Arm C:  is defined as all subjects who completed at least one cycle of CC-122 (Cycle 1 Day 9 
through Cycle 2 Day 8) and did not miss more than 5 days of CC-122 treatment are to be considered 
evaluable for DLT, unless the missed doses were due to IP related AE(s) or the cycle was not 
completed due to a DLT, in which case they remain evaluable for DLT.
Subjects will be summarized under the starting treatment arm and starting dose of CC-122 they initially 
received.
5.2.3. 
Efficacy Evaluable (EE) Population
EE population – all subjects who completed at least one cycle (CC-122) of their assigned treatment 
regimen and have a baseline and at least one post-baseline efficacy assessment. Subjects will be 
summarized under the treatment arm they were enrolled.
5.2.4. 
Pharmacokinetic (PK) Population
PK population - all subjects who have at least one measurable
 CC-122
 and/or
 ibrutinib
 concentration
 datum. 
Subjects will be summarized under the actual dose level corresponding to the PK sample collection.
Intensive PK Population is defined as all subjects who have at least one measurable CC-122 concentration 
datum from intensive sampling. Intensive PK population will be used to support summaries for CC-122 PK
concentrations and parameters from the intensive sampling.


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6. 
SUBJECT DISPOSITION
The total number of subjects who are considered screen failures will be summarized. 
A summary of subject disposition will be presented by treatment arm, and dose cohort.
A tabulated summary of all analysis populations in Section 0will be presented together with the subject 
disposition. A summary of Safety population subjects by site, treatment arm, dose cohort, and overall will 
be presented. 
Reasons for discontinuation from the IP (CC-122, ibrutinib and obinutuzumab) will be summarized by 
treatment arm, dose cohort, and overall with the following categories: 
! Progressive disease
! Adverse event
! Death
! Pregnancy
! Lack of efficacy
! Withdrawal by Subject
! Non-compliance with study drug
! Lost to follow up
! Study terminated by sponsor
! Transition to commercially available treatment
! Physician decision
! Disease relapse
! Symptomatic deterioration
! Protocol violation
! Start of a new anti-CLL therapy (with the exception of rituximab for the treatment of autoimmune 
hemolytic anemia) *
! Upon completion of a maximum of 24 cycles of CC-122 *
! For subjects on Arm B, subjects who have discontinued CC-122 prior to the maximum of 24 
cycles and have received an additional 3 cycles of investigational supply of ibrutinib *
! Other
Note the three reasons marked with “*” are allowed for treatment discontinuation in Protocol Amendment 
7 and will be derived using corresponding standard wordings from the text field for “Other” specified 
reason: ‘Start of new anti-CLL therapy’, ‘Maximum number of CC-122 cycles completed’, ‘CC-122 
discontinued, additional 3 cycles of ibrutinib completed’.
Reasons for discontinuation from the study will be summarized by, treatment arm, dose cohort, and overall 
with the following categories: 
! Death


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! Adverse event
! Pregnancy
! Progressive disease
! Lack of efficacy
! Withdrawal by Subject
! Non- compliance with study drug
! Lost to follow up
! Study terminated by sponsor
! Transition to commercially available treatment
! Physician decision
! Disease relapse
! Symptomatic deterioration
! Protocol violation
! Start of a new anti-CLL therapy (with the exception of rituximab for the treatment of autoimmune 
hemolytic anemia) *
! Upon completion of a maximum of 24 cycles of CC-122 *
! For subjects on Arm B, subjects who have discontinued CC-122 prior to the maximum of 24 cycles 
and have received an additional 3 cycles of investigational supply of ibrutinib *
! Other 
Similarly, the three reasons marked with “*” are allowed for study discontinuation in Protocol Amendment 
7 and will be derived using corresponding standard wordings from the text field for “Other” specified 
reason: ‘Start of new anti-CLL therapy’, ‘Maximum number of CC-122 cycles completed’, ‘CC-122 
discontinued, additional 3 cycles of ibrutinib completed’.
Protocol violations (PV) and protocol deviations (PD) will be identified and assessed by the clinical 
research physician or designee following company standard operational procedure. Protocol deviations and 
violations will be summarized by category and sub-category for the Safety population. 
The following by-subject listing of subjects with demographic information included will be provided:
! Subject listing of discontinuation for any reason. 
! Subject listing of screen failures. 
! Subject listing of protocol violations and protocol deviations with an additional column to flag the 
protocol deviations that are identified as protocol violations.


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7. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be summarized by treatment arm, dose cohort, and overall 
for all populations defined in Section 0, if not otherwise specified. Individual subject listings for the all 
enrolled subjects will be provided to support the summary tables.
7.1. 
Demographics
The continuous demographic variables, age (year), weight (kg), height (cm), Body Mass Index (BMI) 
(kg/m
2) and Body Surface Area (BSA) (m
2) will be summarized using descriptive statistics (e.g. n, mean, 
standard deviation, median, minimum, and maximum) by treatment arm, dose cohort and overall. BMI 
category (<25 kg/m
2, ≥25 kg/m
2, Missing) will be summarized with frequency counts. 
Age is calculated based on the date of birth and the date of informed consent. In the case date of birth is 
missing or partial, age collected in the Case Report Form (CRF) will be used. Age category (≤70, >70) will 
be summarized with frequency counts. 
BSA (m2) is calculated as follows: 
(
)×
( ) /
(based on the Mosteller formula). 
BMI is calculated as follows: 
ℎ( )
ℎ( )
Race, sex and ethnicity will be summarized with frequency tabulations by treatment arm, dose cohort and 
overall.  
7.2. 
Baseline Characteristics
Baseline clinical characteristics include temperature (°C), systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), pulse rate (beats per minute [bpm]), respiration rate (breaths per minute [BPM]), overall 
interpretation of Electrocardiogram (ECG), ECOG performance status (0, 1 or >1), B-symptoms, disease 
diagnosis (CLL or SLL), current stage/prognostic classification and Minimal Residual Disease (MRD)
(provided from eCRF).
The Cumulative Illness Rating Scale (CIRS) score will be documented by a qualified clinician at the time 
of the screening visit. The CIRS score will be collected to assess the performance status and fitness of 
subjects. Baseline CIRS will be presented as below: 
! The total score category: 0, 1-3, 4-6, 7-9, 10-11, > 11;
! At least one grade 3 or higher comorbidities: Yes, No.
 
 
Baseline best corrected visual acuity, slit lamp examination results and ophthalmologic examination results
will be summarized in an additional table for Safety population only.
For Safety population only, summary statistics will be provided for baseline Left Ventricular Ejection 
Fraction (LVEF), overall interpretation of LVEF, laboratory data (Hemoglobin [HGB]*, Potassium*, Total 
Bilirubin*, Aspartate Aminotransferase* [Aspartate Transaminase (AST) or serum glutamic oxaloacetic 


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transaminase (SGOT)], Alanine Aminotransferase* [Alanine Transaminase (ALT) or serum glutamate 
pyruvic transaminase (SGPT)], Lactate Dehydrogenase [LDH] , Uric Acid, Troponin-T, C-Reactive 
Protein, Direct Antiglobulin test, White Blood Cell (WBC) count*, ALC*, Absolute Neutrophil Count 
(ANC)*, Calcium*, Phosphorous, Serum Creatinine, Alkaline Phosphatase [ALP]*) and Creatinine 
Clearance. Frequency counts for NCI-CTCAE grades will be also provided for the laboratory tests above 
with asterisk sign (*).
Categorical baseline variables will be summarized using
 frequency
 counts
 and
 percentage
 by
 treatment
 arm, 
dose cohort and overall. Continuous baseline variables will be summarized by descriptive statistics in the 
same way as continuous demographic variables (e.g., n, mean, standard deviation, median, minimum, and 
maximum).  Listings will be presented for all enrolled subjects.
7.3. 
Medical History
Medical history will be summarized by frequency counts and percentage for the Safety population. The 
summary will be tabulated by System Organ Class (SOC) and Preferred Term (PT) using the Medical 
Dictionary for Regulatory Affairs® (MedDRA) Version 22.0 or higher and presented by treatment arm, 
dose cohort and overall. Listings will be presented for all enrolled subjects.
7.4. 
Prior Therapies
The number of prior therapies for CLL/SLL collected in the CRF will be summarized for prior radiation 
therapies, prior systemic anti-cancer therapies and prior stem cell transplants separately by frequency 
tabulations for each treatment arm, dose cohort and overall for the Safety population. The therapies with 
the same sequence/regimen number are counted as one prior therapy. Listings will also be presented by 
treatment arm and dose cohort for all enrolled subjects.
Novel agent failure, information collected for resistance/intolerance of BTK inhibitor, PI3K inhibitor and 
Venetoclax, will be listed by treatment arm and dose cohort for all enrolled subjects.


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8. 
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Study treatment and extent of exposure summaries will be provided based on the Safety population. 
Descriptive statistics will be provided for treatment duration, number of cycles, cumulative dose, actual 
dose intensity and relative dose intensity by treatment arm, dose cohort and overall. Relative dose intensity 
is used in place of the treatment compliance. The distribution of treatment duration and number of cycles 
will be analyzed by frequency counts on different intervals of treatment duration and number of cycles. 
For subjects in Arm A who switch treatment, the convention outlined in Section 5.1 will be applied. A by-
subject listing will be provided for the subjects who received progressive disease subsequent treatment in 
Arm A.
8.1. 
Treatment Duration
Treatment duration is presented in days or weeks as appropriate. For each treatment arm the treatment 
duration is:
Arm
 A:
Treatment duration (days) = [(Last non-missing dose date of CC-122) - (First non-missing dose date of 
CC-122) + 1], where the first non-missing dose date of CC-122 is Cycle 1 Day 1.
Arm B:
CC-122 treatment duration (days) = [(Last non-missing dose date of CC-122) - (First non-missing dose 
date of CC-122) + 1], where the first non-missing dose date of CC-122 is Cycle 2 Day 1;
Ibrutinib treatment duration (days) = [(Last non-missing dose date of ibrutinib) - (First non-missing 
dose date of ibrutinib) + 1].
Arm
 C:
CC-122 treatment duration (days) = [(Last non-missing dose date of CC-122) - (First non-missing dose 
date of CC-122) + 1], where the first non-missing dose date of CC-122 is Cycle 1 Day 9;
Obinutuzumab treatment duration (days) = Minimal(28 days × number of cycles of non-zero/non-
missing Obinutuzumab dose, End of study date – First dose date of any IP +1.
8.2. 
Cumulative Dose and Dose Intensity
The cumulative actual dose and actual dose intensity for each
 study
 drug
 (CC-122,
 ibrutinib,
 obinutuzumab)
 
will be presented by dose cohort for each arm. The actual dose intensity is defined as the cumulative actual 
dose divided by the total length of treatment for the IP.
CC-122:
The cumulative actual dose of CC-122 is defined as the sum of all doses of CC-122 taken across the 
treatment period. 
The cumulative expected dose of CC-122 is calculated as below:
! For the cycles on daily schedule of CC-122 (only applicable to Arm A subjects): 
Expected dose = (stop date - start date of CC-122 administration +1) × planned daily dose;
! For the cycles on 5/7 days schedule of CC-122: 


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=
 
 
×[
×5+min 5
,
 −
×7 ], where 
Duris the treatment duration for CC-122. 
Repeat this derivation for each planned dose (i.e. take into account the dose escalation but not the decrease 
due to AE) and sum up.
The Expected dose intensity for CC-122 is the cumulative expected dose divided by the total length of
treatment duration for CC-122.
Ibrutinib (Arm B)
The cumulative actual dose of ibrutinib is the sum of all doses of Ibrutinibtaken across the treatment period.
The cumulative expected dose of ibrutinib is the (planned daily dose × Ibrutinib treatment duration in days).
The expected dose intensity for Ibrutinib is the planned daily dose – 420 mg/day.
Obinutuzumab (Arm C): 
The cumulative actual dose of obinutuzumab is the sum of all doses of obinutuzumab taken across the 
treatment period. The cumulative expected dose of obinutuzumab is the sum of the planned dose per Table 
10 in the protocol Section 8.2.2.3 based onthe last visit which has been completed: 
Last visit 
completed   
Cycle 1 
Day 1
Cycle 1 
Day 2
Cycle 1 
Day 8
Cycle 1 
Day 15
Cycle 2 
Day 1
Cycle 3 
Day 1
Cycle 4 
Day 1
Cycle 5 
Day 1
Cycle 6 
Day 1
Cumulative 
expected 
dose (mg)
100 
1000 
2000 
3000 
4000 
5000 
6000 
7000 
8000
The Expected dose intensity for obinutuzumab is the cumulative expected dose divided by the total length 
of treatment duration for obinutuzumab.
8.3. 
Relative Dose Intensity
Relative dose intensity is used in place of the treatment compliance.  Relative dose intensity is defined as 
actual dose intensity divided by expected dose intensity.
Additionally, the number and percentage of subjects will be summarized by ≤80% and >80% for relative 
total dose intensity of CC-122, for CC-122 and ibrutinib in Arm B, for CC-122 and obinutuzumab in Arm 
C, the actual category can be data driven. 
8.4. 
Dose Reduction/Interruptions
Dose reduction is defined as a decrease in dose (non-zero) relative to the immediately previous dose (or 
assigned dose if the first dose). Dose interruption occurs if the record of actual administered dose is zero 
except as required by the protocol(i.e. for CC-122 the 2 out of 7 days when the subject does not receive 
CC-122 drug). If an interruption happens at the start of a cycle and causes the cycle to be postponed, it is 
also called dose delay. Consecutive zeros are counted as one interruption. The reductions will be derived 
from the data collected.
Dose modifications are permitted in any cycle, including Cycle 1 and the DLT evaluation period:
! Dose reductions that occur during the DLT evaluation period will constitute a DLT, but subjects 
will be allowed to continue on IP at a reduced dose.  


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! Dose reductions are allowed for CC-122 and ibrutinib. No dose reductions are allowed for 
obinutuzumab, but treatment may be discontinued at the discretion of the investigator for severe 
infusion or allergic reactions. 
Dose reduction, where applicable, and interruption will be summarized separately by dose cohort and 
overall for each arm. Summaries include the following:  
! Number of subjects with dose reductions or interruptions; 
! Number of dose reductions/interruptions due to AE;
! Descriptive statistics of time to the first dose reduction or interruption (from the first dose) due to 
an AE for those who have at least one dose reduction or interruption due to an AE;  
! Descriptive statistics of total days of dose reduction or interruption due to an AE for those who 
have at least one dose reduction or interruption of CC-122 and Ibrutinib due to an AE; 
! Number and percentage of subjects who have at least two dose reductions or interruptions.


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9. 
PRIOR/CONCOMITANT MEDICATIONS AND PROCEDURES
Medications initiated prior to the start of first dose of IP (i.e. any study drug) and are continued after the 
first dose of IP will be counted as both prior and concomitant medications.
Summary tables of prior and concomitant medications and prior and concomitant procedures will be 
provided for the Safety population. Listings will also be provided for all enrolled subjects.
The Anatomical Therapeutic Chemical (ATC) coding scheme of the World Health Organization (WHO) 
Drug Dictionary (WHODrug) will be used to group medications into relevant categories for these 
tabulations. Individual listings of prior and concomitant medications/procedures will be provided to support 
the tables.  
9.1. 
Prior Medications
Prior medications are defined as medications that were started before the first dose of the study drug and 
either ended before the start of the study treatment or continued after initiation of study treatment.  Prior 
medications will be summarized in frequency tabulations by dose cohort and overall for each treatment arm 
and by ATC level 2 category and preferred drug name.
9.2. 
Concomitant Medications
Concomitant medications are defined as non-study medications that were either initiated before first dose 
of any study drug and continued during the study treatment or initiated during the study treatment exposure
period, defined as the interval between the date of first administration of any study treatment and the last 
dose of any study treatment plus 28 days. Concomitant medications will be summarized in frequency 
tabulations by treatment arm, dose cohort and overall and by ATC level 2 category and preferred drug 
name. 
In addition, the number of subjects with concomitant growth factor will be summarized in frequency 
tabulations by treatment arm, dose cohort and overall and by ATC level 2 category and preferred drug 
name.
9.3. 
Concomitant Procedures and Surgeries
Concomitant procedures/surgeries will be summarized by SOC and PT coded with the MedDRA dictionary 
Version 22.0 or higher using frequency tabulations by treatment arm, dose cohort and overall. Concomitant 
procedures/surgeries are defined as procedures/surgeries that were performed during the study treatment
exposure period, defined as the interval between the date of first administration of any study treatment and 
the last dose of any study treatment plus 28 days. Concomitant procedures/surgeries will be listed. 
 
 
 
 


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10. 
EFFICACY ANALYSIS
The efficacy endpoints of this study include ORR, MRD, DoR and PFS based on the International 
Workshop on Chronic Lymphocytic Leukemia (IWCLL)
 with modifications
 
for subjects with CLL and based on the revised International Workshop Lymphoma criteria 
for response assessment 
 for subjects with SLL. For subjects with CLL see Table3 for 
details and for subjects with SLL see Table4 for details. Lymph node responses will be assessed separately 
and independently of increases in blood lymphocyte counts. 
Efficacy response according to the respective criteria for CLL/SLL will be formally assessed every three 
cycles during the first two years and every 6 cycles thereafter at the time of physical examinations until 
documented progression or initiation of subsequent CLL therapy. PD based on physical and/or laboratory 
tests at any time should be confirmed by CT scan. CR/CRi confirmation by bone marrow examination must 
be completed within 12 weeks after clinical criteria have been met. Furthermore, CT scans at Screening, 
end of Cycle 6 are mandatory (the 2nd scan is mandatory only for the affected regions with abnormal 
findings at baseline; Week 25 (for subjects on Arms A and C) or Week 29 (for subjects on Arm B), +4 
weeks/-1 week).  
Tables and listings will be provided to describe the efficacy endpoints tabulated by dose cohort and overall 
for each treatment arm. Efficacy analysis will include a summary of ORR, MRD, DoR and PFS.
For each subject the survival status will be provided in a listing.
In addition, a waterfall of the best percentage change from baseline sum of the product of the perpendicular 
diameters for multiple lesions will be provided for subjects with measurable nodal lesions at baseline. Each 
subject’s best percent change will be represented by a bar, with a pattern specific to the dose level to which 
they were initially assigned to (in dose escalation phase).
10.1. 
Objective Response Rate (ORR) and Minimal Residual Disease (MRD) 
For subjects treated with CC-122 and CC-122 in combination with ibrutinib or obinutuzumab, investigators 
will use the updated IWCLL guidelines for diagnosis and treatment of CLL 
 with 
modifications
 for subjects with CLL and the revised International Workshop 
Lymphoma criteria for response assessment 
 for subjects with SLL.


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Table 3: 
Response Definition after Treatment for Chronic Lymphocytic Leukemia Subjects
Parameter
Complete Response*
Partial Response*
Partial Response with 
Lymphocytosis*
Progressive Disease***
Group A
Lymphadenopathy  
None > 1.5 cm 
Decrease ≥ 50% from the 
baseline in the SPD of the 
index nodal lesions
Decrease ≥ 50% from the 
baseline in the SPD of the 
index nodal lesions
Increase from the nadir by 
≥ 50% in the SPD of lesions 
or new lesion**
Hepatomegaly
 None
 
Decrease in the enlargement of 
the liver by ≥ 50% (minimum 
2 cm decrease) from baseline 
or LVD decrease to ≤ 18 cm 
by imaging
Decrease in the 
enlargement of the liver by 
≥ 50% (minimum 2 cm 
decrease) from baseline or 
LVD decrease to ≤ 18 cm 
by imaging
Increase ≥ 50% in the 
enlargement of the liver 
from nadir (with a 
minimum 2 cm increase 
and a minimum LVD of 20
cm) or new lesion**
Splenomegaly
 None
 
Decrease in the enlargement of 
spleen by ≥ 50% (minimum 2 
cm decrease) from baseline or 
LVD decrease to ≤ 12 cm by 
imaging.
Decrease in the 
enlargement of spleen by ≥ 
50% (minimum 2 cm 
decrease) from baseline, or 
LVD decrease to ≤ 12 cm 
by imaging.
Increase ≥ 50% in splenic 
enlargement from nadir 
(with a minimum 2 cm 
increase and a minimum 
LVD of 14 cm) or new 
lesion**
Blood Lymphocytes  
< 4000/μL 
Decrease ≥ 50% from baseline
Persistent lymphocytosis 
due to mechanism of action 
of IP
Increase ≥ 50% over nadir 
(with at least ALC of 5000/ 
μL)
Marrow 
Normocellular, < 30% 
lymphocytes, no B-lymphoid 
nodules 
Hypocellular marrow defines 
Cri
50% reduction in marrow 
infiltrate, or B-lymphoid 
nodules
50% reduction in marrow 
infiltrate, or B-lymphoid 
nodules
-


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Confidential and Proprietary                                                                      37
Table 3:  
Response Definition after Treatment for Chronic Lymphocytic Leukemia Subjects (Continued)
Parameter
Complete Response*
Partial Response*
Partial Response with 
Lymphocytosis*
Progressive Disease***
Group B
Platelet count
> 100,000/μL
> 100,000/μL or increase 
≥50% over baseline
> 100,000/μL or increase 
≥50% over baseline
Current platelet is < 100 x
109/L and there has been a
decrease of ≥ 50% from
baseline secondary to CLL
Hemoglobin
> 11.0 g/dL
> 11.0 g/dL or increase ≥50% 
over baseline
> 11.0 g/dL or increase 
≥50% over baseline
The current hemoglobin is
< 11 g/dL and there has
been a decrease of
> 2g/dL from baseline
secondary to CLL
Neutrophils
> 1500/μL
> 1,500/μL or increase ≥ 50% 
over baseline
> 1,500/μL or increase
≥ 50% over baseline
-
Abbreviations: ALC = absolute lymphocyte count; CLL = chronic lymphocytic leukemia; CRi = complete response with incomplete marrow recovery; IP = investigational product; 
LD = longest diameter; LPD = longest perpendicular diameter; LVD = longest vertical dimension; SPD = sum of the product of the perpendicular diameters for multiple lesions.
Notes:
* Complete Response (CR): all of the criteria have to be met, and subjects have to lack disease-related constitutional symptoms; Partial Response (PR) and Partial Response with 
Lymphocytosis (PRL): at least two of the criteria of Group A
 plus one of the criteria of Group B have to be met. There are two exceptions in which only 1 criterion is needed: 1) 
only lymphadenopathy is present at baseline (applicable to PR only); 2) only lymphadenopathy and lymphocytosis are present at baseline. In these two scenarios (applicable to 
PRL only), only lymphadenopathy must improve to the extent outlined in the Group A criteria in the table; Stable Disease (SD) is the absence of Progressive Disease (PD) and 
failure to achieve at least PR; PD: at least one of the above criteria of Group A or Group B has to be met. Lymphocytosis as a criterion for PD is not applicable to ibrutinib treated 
subjects and generally requires other supportive evidence of PD. Response or PD assessment of lymphadenopathy may also be based on longest diameters of the enlarged lymph 
nodes and the same method should be applied consistently to all lesions.
**New lesion is defined as any
 of the following: a new node that measures >1.5cm in the LD and >1.0 cm in the LPD; new or recurrent hepatomegaly ≥20 cm in LVD; new or 
recurrent splenomegaly ≥14 cm in LVD; unequivocal appearance or re-appearance of an extra-nodal lesion of any size; New non-index disease (ascites, pleural effusion, or other 
abnormalities) confirmed to be related to CLL progression.
***Additional criteria for PD include: 1) transformation to a more aggressive histology (e.g., Richter syndrome) as established by biopsy (the date of biopsy being the date of 
progression in the subject who has no earlier objectively documented CLL progression). 2) Unequivocal increase in size of non-index disease (e.g., effusions, ascites, or other 
organ abnormalities confirmed to be related to CLL).


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Table 4: 
Summary of Revised Criteria for Response Assessment for Small 
Lymphocytic Lymphoma
Response 
Category
PET-CT-Based Response
CT-Based Response
CR
Complete metabolic response
Score 1, 2, or 3 with or without a residual mass on 
5PS
A complete metabolic response even with a 
persistent mass is considered a complete 
remission
Target nodes/nodal masses must regress to ≤1.5 cm in 
longest diameter
No extralymphatic sites of disease
PR
Partial metabolic response
Score 4 or 5 with reduced uptake compared with 
baseline and residual masses of any size
All of the following:
≥ 50% decrease in SPD of up to 6 target measurable 
nodes and extranodal sites
Spleen must have regressed by > 50% in length beyond 
normal
SD
No metabolic response
Score 4 or 5 with no significant change in FDG 
uptake from baseline 
< 50% decrease from baseline in SPD of up to 6 
dominant, measurable nodes and extranodal sites
No criteria for PD are met
PD
Progressive metabolic disease
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or
New FDG-avid foci consistent with lymphoma
Bone marrow:  New or recurrent FDG-avid foci
At least 1 of the following:
An individual node/lesion must be abnormal with:
Longest diameter > 1.5 cm and increase by ≥50% from 
nadir and 
An increase by longest diameter or shortest diameter  
from nadir
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase 
beyond baseline
New or recurrent splenomegaly
New or clear progression of pre-existing non-measured 
lesions 
Regrowth of previously resolved lesions
Bone marrow:  New or recurrent involvement
Abbreviations:  5PS:  5-point scale; CR=complete response; CT = computed tomography; FDG = fluorodeoxyglucose; 
PET = positron emission tomography; PR = partial response; PD = progressive disease; SPD = sum of the product of the 
perpendicular diameters for multiple lesions.
Definition: nadir = the smallest value from all previous lesion size assessments (not including the current assessment).
 
Peripheral blood for MRD assessment will be collected during screening, every 6 cycles (only if subjects 
is receiving CC-122, up to a maximum of 24 cycles), and at the time of Complete Response (CR) and/or 
Complete Response with incomplete marrow recovery (CRi) confirmation visit (within 12 weeks after 
clinical and laboratory response criteria have been met).  For those subjects confirmed to be MRD positive 
in the peripheral blood at the CR/CRi confirmation visit, a peripheral blood sample for MRD assessment 
will be collected approximately every 6 cycles thereafter until MRD negativity is achieved or 
relapse/progression is documented. 
Peripheral blood for MRD assessment will also be collected at the time of Partial Response (PR), including 
Partial Response with Lymphocytosis (PRL), within 12 weeks after clinical, imaging, and laboratory 


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response criteria have been met.  Peripheral blood for MRD assessment should also be collected at the time 
of relapse/progression in subjects who previously achieved MRD negativity in peripheral blood. MRD 
analyses will be performed by a central laboratory.
Response will
 be
 assessed
 by
 the
 investigator
 using
 modified
 IWCLL
 guidelines
 for
 diagnosis
 and
 treatment
 
of CLL for CLL subjects and the revised International Workshop Lymphoma criteria for response 
assessment for SLL subjects. The response rate based on the best response during the treatment period and 
the relative proportions in each response category will be examined. Distributions of the responses into the 
response categories (CR, CRi, nodular Partial Response [nPR], PR, PRL, stable disease [SD], PD with 
histologic transformation [PDwH] and PD without histologic transformation [PDw/oH], not evaluable, not 
evaluable due to TFR and other) will be provided for each treatment arm and dose level. 
ORR will be the proportion of subjects with (CR + CRi + PR + nPR + PRL [PRL is only applicable to Arm 
B]). ORR will be summarized by dose cohort and overall for each treatment arm for the Safety and the EE 
populations. The corresponding two-sided 95% CI will be calculated for CLL/SLL cohorts using Clopper-
Pearson 
 method. 
Response rate will also be presented for end of cycle 3, end of cycle 6 and end of cycle 12 assessments. As 
the length of cycles can be varied due to dose escalation, following rules will be applied to the summary: 
‒ for the best response at the end of cycle 3, responses collected up to Day 85 will be used; 
‒ for the best response at the end of cycle 6, responses collected up to Day 169 will be used; only 
subjects who have assessment beyond Cycle 3 (Day 85) are included in this summary;
‒ for the best response at the end of cycle 12, responses collected up to Day 337 will be used; only 
subjects who have assessment beyond Cycle 6 (Day 169) are included in this summary.
MRD negativity rate will be presented using frequency counts and percentages together with CIs for each 
treatment arm and dose level for the Safety and EE populations. The corresponding two-sided 95% CI will 
be calculated using Clopper-Pearson
 method. The MRD negativity rate will be presented 
by source of sample collection (BM, PB, BM and/or PB).
10.2. 
Duration of Response (DoR) 
For subjects with response as PR, nPR, PRL (applicable to Arm B only), CRi or CR, the Duration of 
Response (DoR) is measured from the time the response is first met until the first date that PD or death is 
documented. Subjects who neither progress nor die or who withdrew consent or are lost to follow-up prior 
to documentation of progression will be censored at the date of their last adequate response assessment. 
Adequate efficacy assessment encompasses protocol defined assessments of tumor lesions (lymph nodes, 
spleen, and liver), peripheral blood test, bone marrow assessment when indicated, and clinical assessment.
The Kaplan-Meier estimate of median DoR along with a two-sided 95% CI will be provided by dose cohort 
and overall for each treatment arm in a table using Safety and EE populations. 
A listing of all subjects with their response and best overall response will be provided. A separate listing 
will also include the DoR (for subjects with response as CR, CRi, PR, nPR or PRL [PRL applicable to Arm 
B only], based on the criteria defined above for CLL and SLL). 


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10.3. 
Time to Response and Time to Best Overall Response
Time to Response
For subjects with response as PR, nPR, PRL (applicable to Arm B only), CRi or CR, the time to response 
is measured from the first dose date of any treatment to the date a response is first met (PR, nPR, PRL 
[applicable to Arm B only], CRi or CR). Subjects who did not have a response are not included in the 
analysis.
The median, mean, standard deviation, minimum and maximum of the time to response will be provided 
by dose cohort and overall for each treatment arm in a table using Safety and EE populations. 
Time to Best Overall Response
For subjects with response as PR, nPR, PRL (applicable to Arm B only), CRi or CR, the time to best overall 
response is measured from the first dose date of any treatment to the date the best overall response is first 
met.
The best overall response is the best response amongst the following response: CR, CRi, nPR, PR and then 
PRL. Subjects who did not have a response are not included in the analysis.
The median, mean, standard deviation, minimum and maximum time to response will be provided by dose 
cohort and overall for each treatment arm in a table using Safety and EE populations. 
A by-subject listing will be displayed for the time to response and time to best response for responder 
alongside the DoR.
10.4. 
Progression-Free Survival (PFS) 
Progression-Free Survival (PFS) will be calculated as the time from first IP (i.e. any study drug) dose date 
to the first documented progression or death due to any cause during or after the treatment period,
 whichever
 
occurs first. PD is determined by criteria defined in Table3  for CLL and Table4 for SLL.
A subject who has neither progressed nor died will be censored on the date of his or her last adequate tumor
response assessment. Subjects without adequate baseline or post-baseline efficacy assessments will be 
censored on their first dose dates. Table 5summarizes the different scenarios for consideration for 
censoring.
Table 5: 
Censoring Method for Progression-Free Survival Time
Situation
Date of Progression or Censoring
Situation 
Outcome
No post-baseline response assessments 
Date of the treatment start
Censored
Progression documented before subsequent 
anti-CLL/SLL therapy
Earliest of sample collection date, target and non-target 
lesions date for samples supported the response assessment 
Events
Death before first PD and subsequent anti-
CLL/SLL therapy
Date of death
Events
No progression nor death
Date of last adequate response assessment with evidence of 
no progression
Censored
Study
 discontinuation for reasons other than 
PD or death
Date of last adequate response assessment with evidence of 
no progression
Censored


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New anti-CLL/SLL treatment started with no 
claim of progression
Date of last adequate assessment with evidence of no 
progression prior to the start of new anti-CLL/SLL 
treatment
Censored
Analysis of PFS will be provided for different dose cohorts and overall by treatment arm in a table. Median 
and 1
stquartile PFS will be estimated using Kaplan-Meier estimates and the 95% CI will be computed using 
the method of Klein and Moeschberger 
with log-log transformation for each treatment arm 
and dose level. The number of events, subjects censored, and the Kaplan-Meier estimates of PFS rates at 
the time points of three, six months, one, two and three years along with the 95% CIof rate estimates, will 
also be provided.(For selecting timepoints: 1 month = 30 days, 1 year = 365 days.)
A listing of subjects who progressed based on the criteria defined above for CLL and SLL, and who died 
will be presented. 
10.5. 
Bone Marrow Examination 
Bone marrow aspirate is optional at screening and bone marrow aspirate and biopsy will be mandatorily
collected for all subjects at the time of the CR/CRi confirmation visit (within 12 weeks after clinical, 
imaging and laboratory response criteria have been met). Listings for bone marrow aspirate and biopsy (all 
parameters collected) will be provided by dose cohort for each treatment arm for all enrolled subjects. 
Bone marrow collected for MRD assessment (MRD -, MRD + and not done) will be listed for all enrolled 
subjects. Frequency counts and percentages will be provided for MRD negativity by dose cohort and overall 
for each treatment arm for the Safety and EE populations.
10.6. 
ECOG Performance Status
Shift table from baseline to best post-baseline in ECOG performance status will be displayed by dose cohort 
and overall by treatment arm for the Safety population. A listing of ECOG grade will be provided as well.
10.7. 
B-symptoms Evaluation
Assessment of the presence or absence of B-symptoms will be performed at screening and on Day 1 for 
all cycles, at EoT and 28 days post last dose of IP.  After the first 12 cycles of CC-122, in the absence of 
adverse events related to CC-122, and as clinically indicated, some Day 1 clinic visits and assessments 
may become less frequent. 
B-symptoms are defined as any one or more of the following disease-related symptoms or signs: 
! Unintentional weight loss ≥ 10% within the previous six months.
! Significant fatigue (i.e., ECOG performance status of two or higher; cannot work or unable to 
perform usual activities).
! Fevers
 of
 greater
 than 100.5°F or 38.0°C for two or more weeks without other evidence of infection.
! Night sweats for more than one month without evidence of infection.
Summary tables for B-symptoms for weight loss, fatigue, fever and night sweats will be provided by visit, 
dose cohort and overall for each treatment arm using Safety population. Listing of B-symptoms will be 
provided to support the tables.  


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10.8. 
Physical Examination for Efficacy Analysis
Data collected from physical examination for measurable lymph node assessment, physical examination
for non-measurable lymph node assessment will be listed.


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11. 
SAFETY ANALYSIS
The purpose of this section is to define the safety parameters for the study and to summarize the safety 
results of the study. All summaries of safety data will be conducted using the Safety population and will be 
presented by treatment arm, dose cohort and overall. Safety measurements will include AEs, clinical 
laboratory information, vital sign measurements, cardiac laboratory assessment, 12-lead ECGs, LVEF 
assessments, monitoring for TLS and tumor flare, ophthalmological and pregnancy status evaluation. 
Individual subject listings (including coagulation tests such as Prothrombin Time, International Normalized 
Ratio (INR) and Partial Thromboplastin Time (PTT) assessment) will be provided to support the tables.  
If an EoT measurement is conducted for those subjects who discontinue from the study, the data from the 
EoT visit will be included as a separate visit in the summary table.  In addition, the data from the EoT visit 
as well as follow-up at 28 days visit will also be included in plots for parameters of individual subjects over 
time, unless otherwise specified.
11.1. 
Adverse Events
11.1.1. 
Summary of Adverse Events
AEs will be analyzed in terms of Treatment-Emergent Adverse Events (TEAEs) which are defined as any 
AEs that begin or worsen on or after the start of IP through 28 days after the last dose of IP. All AEs will 
be coded using the MedDRA
®dictionary Version 22.0 or higher. 
If a subject experiences the same AE more than once with a different toxicity grade, then the event with the 
highest grade will be tabulated in “by grade” tables. If a subject experiences multiple AEs under the same 
PT (SOC), then the subject will be counted only once for that PT (SOC). In addition, AEs with a missing 
intensity will be presented in the summary table as an intensity category of “Missing” and will not be 
imputed. 
The incidence of TEAEs will be summarized by MedDRA SOC and PT. The intensity of AEs will be 
graded 1 to grade 5 by investigator according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) Version 4.03 with the exception of tumor flare (NCI CTCAE 
version 3.0), tumor lysis 
 and laboratory abnormalities as recommended by the IWCLL 
guidelines for the diagnosis and treatment of chronic lymphocytic leukemia
 For all other 
AEs, the intensity will be determined by the investigator as mild(Grade 1), moderate (Grade 2), severe 
(Grade 3), life-threatening (Grade 4) or death (Grade 5). 
Tables summarizing the incidence of TEAEs by dose cohort will be generated for each treatment arm with 
the following:
! TEAEs;
! TEAEs related to CC-122, other combination drug (ibrutinib or obinutuzumab) and CC-122 and/or 
other combination drug; 
! TEAEs of NCI CTCAE grade 3 or 4 by maximum NCI CTCAE grade; 
! TEAEs related to CC-122, other combination drug (ibrutinib or obinutuzumab) and CC-122 and/or 
other combination drug with NCI CTCAE grade 3 or 4 by maximum NCI CTCAE grade; 
! TEAEs with death outcome;


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! TEAEs with death outcome related to CC-122, other combination drug (ibrutinib and 
obinutuzumab) and CC-122 and/or other combination drug;
! Serious TEAEs; 
! Serious TEAEs related to CC-122, other combination drug (ibrutinib and obinutuzumab) and CC-
122 and/or other combination drug;
! TEAEs leading to discontinuation of CC-122, of other combination drug (ibrutinib and 
obinutuzumab), of CC-122 or other combination drug, of CC-122 and other combination drug; 
! TEAEs leading to dose reduction of CC-122, of other combination drug (ibrutinib), of CC-122 or 
other combination drug, of CC-122 and other combination drug;
! TEAEs leading to dose interruption of CC-122, of other combination drug (ibrutinib and 
obinutuzumab), of CC-122 or other combination drug, of CC-122 and other combination drug. 
As well as
! TEAEs by cycle of onset; 
! Febrile Neutropenia, TFR, TLS by cycle of onset and overall;
! TEAEs related to CC-122, other combination drug (ibrutinib or obinutuzumab) and CC-122 and/or 
other combination drug, by cycle of onset;
! TEAE with onset from second to sixth CC-122 cycle leading to dose reduction/discontinuation of 
CC-122, of other combination drug (ibrutinib and obinutuzumab), of CC-122 or other combination 
drug, of CC-122 and/or other combination drug;
! TEAE by CC-122 cycle of onset and leading to dose reduction/discontinuation of CC-122, of other 
combination drug (ibrutinib and obinutuzumab), of CC-122 and/or other combination drug, of CC-
122;
! TEAEs by maximum NCI CTCAE grade; 
! TEAEs related to CC-122, other combination drug (ibrutinib or obinutuzumab) and CC-122 and/or 
other combination drug, by maximum NCI CTCAE grade;
! Common (≥10%) TEAEs; 
! Common (≥20%) TEAEs; 
! Common (≥10%) TEAEs related to CC-122, other combination drug (ibrutinib and obinutuzumab) 
and CC-122 and/or other combination drug;
! Common (≥20%) TEAEs related to CC-122, other combination drug (ibrutinib and obinutuzumab) 
and CC-122 and/or other combination drug;
! Selected TEAE of interest by aggregated terms;
! TEAEs by PT.
Selected TEAEs/ serious AEs (SAEs) of interest as determined by the mechanism of action, known class 
effects, or TEAEs observed to date will be summarized by treatment arm and dose cohort, and then grade 
or cycle of onset. Standardized MedDRA queries (SMQs) will be used in the search strategy for some of 
the selected AEs of special interest, intending to aid in case identification. The groupings of selected AEs, 


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described by one phrase or topic term will be determined by clinicians based on SMQ or relevant search 
terms and provided to statistician, prior to database lock.
The selected TEAEs of interest include:
! Cardiac Failure (SMQ)
! Embolic or Thrombotic Events (SMQ) including ATE (Sub-SMQ), VTE (Sub-SMQ), and 
Mixed Embolic and Thrombotic Events (Sub-SMQ)
! Hemorrhage (SMQ)
! Interstitial Pneumonitis (SMQ)
! Peripheral Neuropathy (SMQ)
! Tumour lysis (SMQ)
! Febrile Neutropenia (PT)
! Tumour Flare (PT)
To facilitate clinical study report writing, a summary table of TEAEs by PTs treatment arm will also be 
provided. 
In addition, the following listings will be provided as well:
! Listing of subjects who had treatment-emergent SAE by treatment arm, dose cohort, subject 
number, SOC, and PT;
! Listing of subjects who had TEAEs leading to permanent withdrawal of any study drug by 
treatment arm, dose cohort, subject number, SOC, and PT;
! Listings of subjects who had adverse events leading to study drug reduction or interruption 
! Listing of all subjects who died.
Individual subject listing of AEs will be presented as well. In addition, a listing of overdose will be 
provided. 
A summary table for the summary of deaths information will be presented.
11.1.2. 
Dose-limiting Toxicities (DLTs)
DLT is defined as a treatment-related AE(s) occurring in Cycle 1 (the first 28 days of treatment with CC-
122 and combination therapy) that meets one of the criteria defined in the Protocol Section 8.2.7. Subjects 
will be observed for early DLTs for 28 days following the initiation of CC-122 (for Arm A, Cycle 1 day 1 
through Cycle 1 Day 28; for Arm C, Cycle 1 day 9 through Cycle 2 day 8, and for Arm B, Cycle 2 Day 1 
through Cycle 2 Day 28) (DLT evaluation period).  
A summary table of DLTs during DLT evaluation period will be presented by dose cohort and treatment 
arm including number and percentage of subjects having a DLT. The percentage of subjects having a DLT 
is based on the number of subjects who are CC-122 evaluable for DLT Evaluable population. Listing of 
AEs which meet dose limiting toxicity will be provided. 
11.1.3. 
Adverse Events Subgroup Analysis
As per request of German EC, additional summary tables by SOC and PT will be provided for TEAE and 
SAE, grouping subjects by gender or age class (≤70 years, >70 years). 


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11.2. 
Clinical Laboratory Evaluations
Clinical laboratory tests include: 
! Amylase, Lipase, fasting lipid profile, Creatine Kinase, Thyroid-Stimulating Hormone (TSH), Free 
T4 (fT4), Immunoglobulins (IgG, IgM and IgA only), T-cell subsets. 
! Complete Blood Count (CBC): HGB, Hematocrit, Red Blood Cell (RBC) count with indices, WBC 
count with absolute differential and Platelet count.
! Serum chemistry: Albumin, Total Protein, Bicarbonate, Calcium, Phosphorus, Serum Creatinine, 
Serum Urea/Blood Urea Nitrogen (BUN), Glucose (fasting), Potassium, Sodium, Magnesium, 
Chloride, Total Bilirubin, ALP, AST/SGOT, ALT/SGPT, and LDH, Uric Acid, Troponin T and B-
type Natriuretic Peptide (BNP).
! Beta-2 Microglobulin
! C-Reactive Protein.
! Direct Antiglobulin test (local laboratory only).
! Coagulation tests: Prothrombin Time, INR and, PTT.
! Urinalysis: dipstick, with microscopy in event of positive (1+ or greater) blood or protein and 24-
hour collection for creatinine clearance and protein quantification in the event of 2+ or greater 
protein.
! Virus Serology: Hepatitis B surface Antigen (HBsAg), Hepatitis B core antibody (anti-HBc), and 
Hepatitis C Virus (HCV) RNA.
Clinical laboratory values will be graded, for applicable tests, according to NCI CTCAE version 4.03 or to 
IWCLL guidelines for the diagnosis and treatment of CLL (Section 17.8). The value from selected 
laboratory tests and the change from baseline value will be summarized using descriptive statistics by dose 
cohort/treatment arm for the timepoints when baseline, maximum or minimum values were observed. 
Bidirectional shift tables (low and high) demonstrating the change of NCI CTCAE grades from baseline to 
worst post-baseline during the treatment period will also be presented by, treatment arm and dose cohort.
In addition, frequency count of the worst post-baseline NCI CTCAE grades (low, high) during the treatment 
period will also be presented by treatment arm and dose cohort.
Summaries of laboratory values by treatment arm, dose cohort, cycle and maximum NCI CTCAE grade 
will be provided. 
Listings of clinical laboratory data, including cardiac laboratory data, with NCI CTCAE grades (if 
applicable) and abnormal flags (low or high) will be provided. 
For some key laboratory tests (HGB, Platelet, ANC,), spaghetti plots for each arm separately will be 
presented to show the pattern of the laboratory test percent change from baseline over time using the Safety 
population in dose escalation phase. All non-missing laboratory test values including assessments at 
scheduled, unscheduled, or EoT visits, will be presented. The X axis will be ticked at the study days, and 
the Y axis will be the percent change from baseline values. Valuesfor the EoT visit will be included in 
spaghetti plots but will be displayed for the nominal visit equal to or immediately after the EoT visit. 


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11.3. 
Vital Sign Measurements
Vital sign values and change from baseline will be summarized using descriptive statistics by treatment 
arm, dose cohort, and overall for the timepoints when baseline, maximum or minimum values were 
observed. 
Shift tables demonstrating the changes (low/normal/high) from baseline to worst post-baseline value will 
be displayed in cross-tabulations by arm and dose cohort for vital sign measurements. Normal ranges given 
in Table 6  will be used to determine the categories of low, normal, and high.  
Data collected for vital sign measurements will be listed.
Table 6: 
Normal Ranges of Vital Sign Measurements
Test 
Normal Range (Unit)
Diastolic Blood Pressure (DBP) 
[60, 90] (mmHg)
Systolic Blood Pressure (SBP) 
[100, 140] (mmHg)
Pulse 
[60, 100] (bpm)
Temperature 
[35, 38] (°C)
Respiration 
[12, 20] (BPM)
11.4. 
Electrocardiograms (ECG)
Shift from baseline to worst post-baseline in the overall ECG interpretation (‘Normal’ ‘Abnormal, not 
clinically significant’ and ‘Abnormal, clinically significant’ will be displayed in cross–tabulations by 
treatment arm and dose cohort.   
A listing of ECG by treatment and dose cohort will be provided.
11.5. 
Left Ventricular Ejection Fraction (LVEF) Assessment
LVEF assessment values by visit and change from baseline will be summarized using descriptive statistics. 
Similarly, maximum and minimum post-baseline values and corresponding change from baseline values 
will be summarized using descriptive statistics.
Shift from baseline to worst post-baseline in the overall LVEF interpretation (‘Normal’, ‘Abnormal, not 
clinically significant’ and ‘Abnormal, clinically significant’) will be displayed in cross–tabulations by 
treatment arm and dose cohort. 
A summary table of severity grade for LVEF will be provided using levels of “Ejection fraction decreased” 
from NIC CTCAE (Version 4.03):
! Grade 2 = Resting ejection fraction: 50 - 40%; 10 - 19% drop from baseline.
! Grade 3 = Resting ejection fraction: 39 - 20%; >20% drop from baseline.
! Grade 4 = Resting ejection fraction: <20%.
Moreover, descriptive summary statistics for baseline and worst post baseline LVEF will be provided by 
dose cohort, overall and treatment arm.
A listing of LVEF by treatment arm and dose cohort will be provided as well.


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11.6. 
Other Safety Assessments
Data collected for other safety assessments including pregnancy status, ophthalmologic examination, tumor 
lysis and tumor flare will be listed by treatment arm and dose cohort.
Spleen and liver physical examination assessments(‘Normal’ and ‘Abnormal’) for Safety population at 
each visit will be summarized using frequency count by dose cohort, overall and treatment arm. Data 
collected for physical exam for liver and spleen will be also listed.  


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12.1. 
PK and Exposure Response Analyses
During the Dose Escalation phase, intensive PK sampling will be performed in a minimum of 3 subjects in
the first cycle in Arm A (Cycle 1, Days 1 and 15). PK parameters will be estimated based on the intensive 
PK population. Actual sampling times will be used in the calculations of PK parameters by using the non-
compartmental analysis (NCA) method.  Drug concentrations reported by the bioanalytical laboratory as 
Below the Quantification Limit (BQL) will be shown as BQL in the data listings. If >50% of results for a 
given timepoint and dose level, are reported as below the Low Limit of Quantification (LLoQ: 1.0 ng/mL), 
the mean, median and geometric mean are reported as LLoQ. In these scenarios, the other descriptive 
statistics are not calculated. Missing concentrations will be treated in PK calculations as if they were never 
drawn. If a concentration is missing (e.g., because no sample was taken, there was no valid result [including 
concentrations after dosing which are BQL], there was no detectable peak or the sample was lost), the 
concentration will not be imputed (i.e., it will remain missing). Every effort will be made to include all 
concentration data in the analysis. In the event that an actual sample collection time is missing for a certain 
time point, the planned time may be used for this time point instead.
Pharmacokinetic Plasma Concentrations:
CC-122 plasma concentrations from intensive sampling will be summarized by actual dose level, visit, and 
nominal time points. In general, geometric mean and the geometric CV (%) will be derived from non-zero 
concentration values. These results will be tabulated by dose cohort and treatment arms.
CV (%) is calculated as follows: 
(%)=
×100..
Geometric CV (%) is calculated as follows: CV(%) = 100 ×√(exp(σ)−1), where σ denotes the 
variance of the log-transformed values.
The following figures will be provided by dose cohort using intensive PK population:
! Individual subject’s concentration (linear scale and semi-logarithmic scale) over time spaghetti 
plot;
! Mean and ± Std Dev of concentration (linear scale and semi-logarithmic scale) over time plot;
Note: Mean of 1 ng/mL at timepoint 0 will be imputed when more than 50% of values are below LLOQ.
Summary for Ibrutinib plasma concentration will not be performed due to limit data collected. 
Pharmacokinetic Parameters:
For Arm A (CC-122 single agent), intensive PK samples collected are still very limited in time-points and 
limited in valid concentration values. For Arm B (CC-122 in combination with ibrutinib) and Arm C (CC-
122 in combination with obinutuzumab), only sparse PK samples were collected. Therefore, the analyses 
on the PK parameters stated in protocol (i.e. Cmax, T
max, AUC
t, etc.) will not be performed. Please see the 
details in Section 15 changes to the statistical analyses section of the protocol. 
Following by-subject listings will be provided for all Enrolled population:
! PK blood sampling 
! Individual CC-122 plasma concentration for scheduled timepoints
! Individual Ibrutinib plasma concentration for scheduled timepoints


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14. 
INTERIM ANALYSIS
As of Protocol Amendment 7, Phase 2 Expansion Phase will not proceed. The Interim analysis originally 
planned for the futility analysis of the expansion cohorts will not be conducted.


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15. 
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE PROTOCOL
! As of Protocol Amendment 7, Phase 2 Expansion Phase will not proceed. Any analysis on the 
endpoints related to expansion phase, as well as the futility analysis of the expansion cohorts and 
interim analysis, will not be conducted.
! As intensive PK samples collected are still very limited in timepoints and limited in valid 
concentration values, analyses on PK (pharmacokinetic) parameter will not be conducted. As a 
result, the outputs for secondary endpoint “CC-122 pharmacokinetic parameters when 
administered in combination with Ibrutinib” will not be included in the final CSR package. The 
analysis on secondary endpoint “Ibrutinib plasma concentrations and/or pharmacokinetic 
parameters when administered in combination with CC-122” will not be conducted either. 
However, a by-subject listing for Ibrutinib plasma concentrations for the subjects who received 
Ibrutinib will be provided. 
! In addition, analyses on biomarkers will not be performed and included in the final CSR package. 
Results might be reported separately. Similarly, the analysis on exploratory endpoint “Response 
rate, duration of response, and progression free survival in subtypes defined by biomarkers” will 
not be performed as well. 


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17. 
APPENDICES 
17.1. 
Dose Escalation Rules
Table 8: 
Intrasubject Dose Escalation and Fixed-Doses Cohort Escalation Rules
Arm
No. of subjects recruited
Number of subjects that meet 
the criteria for DLT
NTD 
Arm A[a]
20
> 20 %
Arm B[b]
3+3
≥2
Yes
Arm C[b]
3+3
≥2
Yes
Notes: 
[a]Intrasubject escalation.
[b]Fixed-doses cohort escalation.
17.2. 
Handling of Dates 
Dates will be stored as numeric variables in the SAS analysis files and reported in DDMMMYYYY format 
(i.e., the Date9. datetime format in SAS).  Dates in the clinical database are classified into the categories of 
procedure dates, log dates, milestone dates, outcome dates, and special dates.
! Procedure Datesare the dates on which given protocol-specified procedure are performed.  They 
include the dates of laboratory testing, physical examinations, tumor scans, etc.  They should be 
present whenever data for a protocol-specified procedure are present and should only be missing 
when a procedure are marked as NOT DONE in the database.  Procedure dates will not be imputed.
! Log Datesare dates recorded in CRF data logs.  Specifically, they are the start and end dates for 
AEs and concomitant medications/procedures.  They should not be missing unless an event or 
medication is marked as ongoing in the database.  Otherwise, incomplete log dates will be imputed 
according to the rules in Appendix 17.4. However, in listings, log dates will be shown as recorded 
without imputation.
! Milestone Dates are dates of protocol milestones such as randomization, study drug start date, 
study drug termination date, study closure date, etc.  They should not be missing if the milestone 
occurs for a subject.  They will not be imputed.
! Outcome Datesare dates corresponding to study endpoints such as survival, progression, etc.  In 
most cases they are derived either from a milestone (e.g., the survival date is derived from the death 
date), or a procedure date (e.g., the progression date is derived from the date of the tumor scan that 
was used to determine progression).  They may be subject to endpoint-specific censoring rules if 
the outcome did not occur but are not otherwise subject to imputation.
! Special Datescannot be classified in any of the above categories and they include the date of birth.  
They may be subject to variable-specific censoring and imputation rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
17.2.1. 
Calculation Using Dates
Calculations using dates (e.g., subject’s age or relative day after the first dose of any study drug) will adhere 
to the following conventions.


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Study days after the start day of study drug (referred as DSTART) will be calculated as the difference 
between the date of interest and the first date of dosing of study drug plus 1 day. The generalized calculation 
algorithm for relative day is the following: 
If TARGET DATE ≥ DSTART then STUDY DAY = (TARGET DATE – DSTART) + 1; 
Else use STUDY DAY = TARGET DATE – DSTART.
Note that Study Day 1 is the first day of treatment of study drug (i.e. the earliest date between CC-122, 
ibrutinib and obinutuzumab). Negative study days are reflective of observations obtained during the 
baseline/screening period.  Note: Partial dates for the first study drug are not imputed in general. All effort 
should be made to avoid incomplete study drug start dates. 
Age (expressed in days) is calculated: AGE = CONSENT – DATE of BIRTH + 1.  In practice, age will be 
transformed into years by dividing the difference by 365.25 days, then truncating. Preference is for using 
calculated age from clinical database. When not available, calculated age from CRF or Interactive Voice 
Response System (IVRS) may be used.
Partial birth date: impute missing day as 15thof the month; impute missing month as July; set missing age 
for missing year.
Intervals that are presented in weeks will be transformed from days to weeks by using (without truncation) 
the following conversion formula: WEEKS = DAYS /7
Intervals that are presented in months will be transformed from days to months by using (without 
truncation) the following conversion formula: MONTHS = DAYS /30.4375
17.2.2. 
Calculation of Cycles 
Study Treatment Cycles 
The start date of each cycle is defined as the first day when the subject receives CC-122, ibrutinib or 
obinutuzumab (non-zero dose) in that cycle. After the start dates are determined, the end date of each cycle 
is defined as (start date of subsequent cycle-1). The end date of the last cycle will be the last dose date for 
any study drug, the last dose date of CC-122+2 days or the Day 28 from the start of the last cycle, whichever 
is later. Any doses of study drug with start/stop dates on or after Day 1 of Cycle 1 but before Day 1 of Cycle 
2 will be counted as taken in the Cycle 1. Any doses of study drug taken on or after Day 1 of Cycle 2 but 
before Day 1 of Cycle 3 will be counted as taken in the Cycle 2, and so forth. Any doses of study drug taken 
on or after the first day of the last cycle will be counted as taken in the last cycle.
After last cycle in treatment phase, cycles might be defined with 28-days intervals as necessary.
CC-122 Cycles 
CC-122 cycle is also defined: CC-122 cycle starts after first CC-122 dose (C1D1 for Arm A, C2D1 for Arm 
B and C1D9 for Arm C) and each CC-122 cycle lasts 28 days. 
17.3. 
Baseline, Repeated Measurements, and End of Trial
The general conventions for handling baseline, repeated measurements, and End of Trial (EOT) are 
provided below:
! Baseline for any clinical laboratory test, efficacy endpoints and vital sign is defined as the last value 
of a specific endpoint measured before the first dose of the IP. 


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! Baseline values for biomarkers will be the average of non-missing values collected at screening 
and the last value before first dose of the IP, if both samples are collected. Otherwise, either the 
values collected at screening or the last value of a specific endpoint measured before the first dose 
of the IP, whichever is collected, will be used as the baseline. Other pre-dose samples from on-
treatment visits after the first dose of the IP will not be used to impute baseline value. 
! Central laboratory values will be used; local laboratories will be used only if there is not any central 
laboratory by first dose date. When there are multiple values for any laboratory test (clinical and 
biomarker) or vital sign collected at the same visit, the one with last/latest assessment time stamp 
will be used for data analysis. 
! End of trial assessment for a particular endpoint is defined as the last non-missing post-baseline 
assessment during the study period. 
! Adequate efficacy assessment encompasses protocol defined assessments of tumor lesions (lymph 
nodes, spleen, and liver), peripheral blood test, bone marrow assessment when indicated, and 
clinical assessment.
17.4. 
Date Imputation Guideline
This subsection gives guideline on imputation of complete or partial missing AEs, or Concomitant 
medications start and/or stop dates.
Incomplete Start Date:
Missing day and month
! If the year is the same as the year of the first dosing date, then the day and month of the first dosing 
date will be assigned to the missing fields.
! If the year is prior to the year of first dosing date, then December 31 will be assigned to the missing 
fields.
! If the year is after the year of first dosing, then January 1 will be assigned to the missing fields.
Missing day only 
! If the month and year are the same as the year and month of first dosing date, then the first dosing 
date will be assigned to the missing day.
! If either the year of the partial date is before the year of the first dosing date or the years of the 
partial date and the first dosing date are the same but the month of partial date is before the month 
of the first dosing date, then the last day of the month will be assigned to the missing day.
! If either the year of the partial date is after the year of the first dosing date or the years of the partial 
date and the first dose date are the same but the month of partial date is after the month of the first 
dosing date, then the first day of the month will be assigned to the missing day.
! If the stop date is not missing, and the imputed start date is after the stop date, the start date will be 
imputed by the stop date. 
Missing day, month, and year
! No imputation is needed, the corresponding AE will be included as TEAE. 


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Incomplete Stop Date:If the imputed stop date is before the start date, then the imputed stop date will be 
equal to the start date.
Missing day and month
! If the year of the incomplete stop date is the same as the year of the last dosing date, then the day 
and month of the last dosing date will be assigned to the missing fields. 
! If the year of the incomplete stop date is prior to the year of the last dosing date or prior to the year 
of the first dosing date, then December 31 will be assigned to the missing fields. 
! If the year of the incomplete stop date is prior to the year of the last dosing date but is the same as 
the year of the first dosing date, then the first dosing date will be assigned to the missing date. 
! If the year of the incomplete stop date is after the year of the last dosing date, then January 1 will 
be assigned to the missing fields.
Missing day only 
! If the month and year of the incomplete stop date are the same as the month and year of the last 
dosing date, then the day of the last dosing date will be assigned to the missing day. 
! If either the year of the partial date is not equal to the year of the last dosing date or the years of the 
partial date and the last dosing date are the same but the month of partial date is not equal to the 
month of the last dosing date, then the last day of the month will be assigned to the missing day.  
 
 
 


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17.6. 
Laboratory Data Handling
For absolute and percent values of basophils, eosinophils, lymphocytes, monocytes, and neutrophils, the 
missing absolute values will be imputed by (corresponding non-missing percent values × WBC counts), 
while the missing percent values will be imputed by (corresponding non-missing absolute values ÷ WBC 
counts) ×100. If both absolute and percent values are missing, no imputation will be performed.
The following data handling rules for laboratory parameters are for data analysis purpose (Tables and 
Figures).  All original data will be presented as is in the data listings.
Table 11: 
Data Handling Conventions for Laboratory Parameters
Case
Convention
Example Data
values recorded as “<xx” Set the numerical value to 
one tenth less in the next 
digit/decimal point
Immunoglobulin M (Serum) recorded 
as “<0.20” (g/l), set the numerical value 
to 0.199
values recorded as “>xx” Set the numerical value to 
one tenth more in the next 
digit/decimal point
Creatinine clearance recorded as “> 60” 
(ml/min), set the numerical value to 
60.1
17.7. 
Study Procedures
Please refer to Protocol Section 5 – Table of Events


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17.8. 
Laboratory Abnormalities Toxicity Grading as Recommended by IWCLL Guidelines
Subjects will be evaluated for laboratory abnormalities as recommended by the IWCLL guidelines for the 
diagnosis and treatment of chronic lymphocytic leukemia
 as listed below:
Table 13: 
Grading Scale for Hematologic Toxicity in Chronic Lymphocytic Leukemia 
Studies 
Grade[a]
Decrease in Platelets[b]or HGB[c](nadir) From 
Pre-treatment Value (%)
Absolute Neutrophil Count[d](mm
3) (nadir)
0 
No change to 10%
≥ 2,000
1 
11% - 24%
≥ 1,500 and < 2,000
2 
25% - 49%
≥ 1,000 and < 1,500
3 
50% - 74%
≥ 500 and < 1,000
4
≥ 75%
< 500
Notes:
[a]Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal.  Death occurring as a result of toxicity at any level of decrease from 
pre-treatment will be recorded as Grade 5.
[b]Platelet counts must be below normal levels for Grades 1-4.  If, at any level of decrease the platelet count is < 20,000/mm3, this will be 
considered Grade 4 toxicity, unless a severe or life-threatening decrease in the initial platelet count (e.g., 20,000/ mm3) was present 
pre-treatment, in which case the subject is not evaluable for toxicity referable to platelet counts.
[c]Hemoglobin (HGB) levels must be below normal levels for Grades 1-4.  Baseline and subsequent HGB determinations must be 
performed before any given transfusions.  The use of erythropoietin is irrelevant for the grading of toxicity but should be documented.
[d]If the absolute neutrophil count (ANC) reaches less than 1,000/ mm3, it should be judged to be Grade 3 toxicity
.  Other decreases in 
white blood cell count, or in circulating granulocytes, are not to be considered, since a decrease in white blood cell count is a desired 
therapeutic end point.  A gradual decrease in granulocytes is not a reliable index in CLL for stepwise grading of toxicity.  The use of 
granulocyte colony-stimulating factor (G-CSF) is irrelevant for the grading toxicity but should be documented.


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17.9. 
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing chronic comorbid 
conditions, classified by 14 organ systems. Please specify the name of the conditions within an organ system. 
If there are two or more illnesses/impairments in one organ system, the illness/impairment with the highest 
severity will be evaluated. Please take into account that CLL-induced discomfort, symptoms, or disability 
should not be considered. If additional explanation would be helpful, text comments may be inserted. The sum 
of all individual organ scores should be calculated.
Table 14: 
Cumulative Illness Rating Scale 
Please insert the appropriate grade of illness/impairment (0-4):
Organ System
If illness/Impairment Present, please specify: 
Score (0-4)
Cardiac
Vascular
Hematological/Immunological
Respiratory
Ophthalmological/Otolaryngological
Upper Gastrointestinal
Lower Gastrointestinal
Hepatic/Pancreatic
Renal
Gynecological/Urological
Dermatological/Musculoskeletal
Neurological
Endocrine/Metabolic
Psychiatric
Total Score:
For the severity rating, please use the scoring guidelines shown in the table below, considering the magnitude 
of symptoms, how manageable the condition is, and the extent of intervention required. A score of 0 is given if 
organ system is not compromised (i.e. no problem).


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Table 15: 
CIRS Rating Scale
Score 
Severity 
Findings
1 
Mild
!
Mild discomfort, symptoms or disability
!
Easy
 to control
!
Requiring either no therapy/medication or only as needed
2 
Moderate
!
Moderate discomfort, symptoms or disability
!
Manageable
!
Requiring daily treatment or first-line therapy
3 
Severe
!
Severe discomfort, symptoms or disability
!
Hard to control
!
Requiring second-line therapy or multiple medications
4 
Extremely 
severe
!
Life threatening, permanently disabling disability, causing organ failure
!
Poorly manageable
!
Requiring urgent intervention or resistant to therapy
Abbreviation: CIRS=Cumulative Illness Rating Scale