Clinical trial NCT02859324
Conditions: Carcinoma, Hepatocellular
Keywords: CC-122 Nivolumab Hepatocellular Carcinoma Phase 1/2 Safety
Sponsor: Celgene
Start date: 2016-09-20; Completion date: 2020-03-27
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
CC-122-HCC-002 is a Phase 1/2 dose escalation and expansion clinical study of CC-122 in combination with nivolumab in subjects with unresectable hepatocellular carcinoma (HCC) who have progressed after or were intolerant to no more than 2 previous systemic therapies for unresectable HCC, or are naïve to systemic therapy.

Detailed description:
Study population included subjects who had progressed after or were intolerant to no more than 2 previous systemic therapies for unresectable HCC, or are naïve to systemic therapy.

The dose escalation part of the study was designed to explore three dose levels of CC-122 to identify the recommended phase 2 dose (RP2D) to be used in the expansion phase. Approximately 20 subjects were to be enrolled in the dose escalation part of the study. Subjects could be treated for up to 2 years, or until progression of disease, unacceptable toxicity, subject/physician decision, withdrawal of consent, death. Safety follow up until 28 days after CC122 treatment and 90 days after nivolumab treatment. RECIST 1.1 criteria was used to determine response. Survival follow up until death, withdrawal of consent, or the study closes. Subjects were permitted to continue treatment beyond progression (TBP) if they continue to meet protocol criteria, had stable performance status, had clinical benefit, other treatment options were discussed. A separate ICF was signed to continue TBP.

During the dose escalation phase, CC-122 was administered orally 5 consecutive days out of 7 (5 days on/2 days off weekly) on Days 1 to 5, 8 to 12, 15 to 19 and 22 to 26 of each 28-day cycle. Once the RP2D for dosing of CC-122 in combination with nivolumab was defined, expansion (Phase 2) would start. A modified 3+3 dose escalation design was used to identify the initial toxicity of the combination. Up to six subjects were concurrently enrolled into a dose level. Decisions as to which dose level to enroll a new subject were based on the number of subjects enrolled and evaluable, the number of subjects experiencing DLTs, and the number of subjects enrolled but who are not yet evaluable for toxicity in the current cohort at the time of new subject entry. A Safety Review Committee (SRC) comprised of investigators participating in the study made dose escalation decisions based on these criteria.

After completion of the Dose Escalation Phase, the Dose Expansion Phase of the study did not proceed due to the changing landscape in the treatment of HCC. There were no additional safety concerns or safety signals identified in the dose escalation phase of the study.

Arms: arm 1: CC-122 orally 5/7 days with nivolumab Intravenously (IV) 3mg/kg every 2 weeks. Cohorts of up to 6 subjects per dose level until Recommended Phase 2 dose (RP2D).
Interventions: intervention 1: CC-122 intervention 2: Nivolumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
EDMS Doc. Number: 22132024 - 20879383
CC-122
Protocol CC-122-HCC-002
Celgene Corporation
Confidential and Proprietary
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CC-122-HCC-002 Amendment 2 Final: 29 Aug 2017
TITLE PAGE
A PHASE 1/2, MULTICENTER, OPEN-LABEL, DOSE 
FINDING STUDY TO ASSESS THE SAFETY, 
TOLERABILITY, AND PRELIMINARY EFFICACY OF 
CC-122 IN COMBINATION WITH NIVOLUMAB IN 
SUBJECTS WITH UNRESECTABLE
HEPATOCELLULAR CARCINOMA (HCC)
PROTOCOL NUMBER:
CC-122-HCC-002
DATE FINAL:
14 Mar 2016
DATE AMENDMENT 1 FINAL:
05 Jul 2016
DATE AMENDMENT 2 FINAL:
29 Aug 2017
EudraCT NUMBER:
2016-000112-15
IND NUMBER:
123487
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.


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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Alfredo Romano, MD, PhD
 
 


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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE


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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, International Conference on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.


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Protocol CC-122-HCC-002
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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: 22132024 - 20879383
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Protocol CC-122-HCC-002
Celgene Corporation
Confidential and Proprietary
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PROTOCOL SUMMARY
Study Title
A phase 1/2, multicenter, open-label, dose finding study to assess the safety, tolerability, and 
preliminary efficacy of CC-122 in combination with nivolumab in subjects with unresectable 
hepatocellular carcinoma (HCC).
Indication
Adult subjects who have progressed after or were intolerant to no more than 2 previous systemic 
therapies for unresectable HCC, or are naïve to systemic therapy. 
Objectives
The primary objective of the Phase 1 portion (dose finding) of the study is:

To determine the safety and tolerability of CC-122 when administered orally in 
combination with nivolumab and to define the recommended Phase 2 dose (RP2D)
The primary objective of the Phase 2 portion (dose expansion) of the study is:

To estimate the preliminary efficacy of CC-122 in combination with nivolumab based 
on overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors
Version 1.1 (RECIST 1.1)
The secondary objectives of the study are:

To evaluate the preliminary efficacy of CC-122 in combination with nivolumab based 
on various endpoints by RECIST 1.1

To evaluate the pharmacokinetics (PK) of CC-122 in subjects coadministered
multiple doses of CC-122 with nivolumab

To determine nivolumab PK when coadministered with CC-122
Study Design
CC-122-HCC-002 is a Phase 1/2 dose escalation and expansion clinical study of CC-122 in 
combination with nivolumab in subjects who have progressed after or were intolerant to no more 
than 2 previous systemic therapies for unresectable HCC, or are naïve to systemic therapy. The 
dose escalation part of the study will explore 1 or more dose levels of CC-122 in combination
with nivolumab using a modified dose escalation (3+3) design (Storer, 1989), followed by an 
expansion part once the RP2D is defined.
The study is designed to explore three dose levels, to identify the RP2D, and is not required to 
escalate to a nontolerated dose (NTD) or maximum tolerated dose (MTD). CC-122 will be 
administered orally 5 consecutive days out of 7 (5 days on/2 days off weekly) on Days 1 to 5, 8
to 12, 15 to 19 and 22 to 26 of each 28-day cycle. The starting daily dose of CC-122 will be 2.0 
mg, and two subsequent dose levels (3.0 and 4.0 mg) are planned to be evaluated based on
evaluation of pre-specified dose limiting toxicities (DLTs). The study intends to identify the 
RP2D at or below the 4.0 mg dose level, however intermediate dose levels, or a higher dose 
level, may be evaluated at the discretion of the Safety Review Committee (SRC).  Nivolumab 
will be administered intravenously (IV) at the fixed dose of 3.0 mg/kg every 2 weeks. 


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Up to six subjects will be concurrently enrolled into a dose level.  Decisions as to which dose 
level to enroll a new subject in will be based on the number of subjects enrolled and evaluable, 
the number of subjects experiencing DLTs and the number of subjects enrolled but who are not 
yet evaluable for toxicity in the current cohort at the time of new subject entry.
A dose is considered an NTD when 2 or more out of 6 evaluable subjects in a cohort experience 
a DLT in Cycle 1. During dose escalation, the decision to either evaluate a higher dose level, an 
intermediate dose level, declare an NTD, or define the RP2D will be determined by the SRC, 
based on their review of all available clinical data, PK, pharmacodynamic (PD) and laboratory 
safety data for a given dose cohort.  
Non-evaluable subjects will be replaced at the discretion of the SRC.
Following completion of the dose escalation part, up to 30 additional subjects will be enrolled in 
an expansion cohort of mixed HCC etiology – hepatitis B virus (HBV), hepatitis C virus (HCV)
and non-viral.  A futility analysis will be conducted as follows: in the first 14 subjects treated, if 
no responder is observed out of 14 subjects then enrollment for the expansion cohort will stop for 
futility.  Enrollment will continue during the evaluation of the 14 subjects.  If ≥ 1 subject out of 
14 responds (complete response [CR] or partial response [PR]), then approximately 30 total 
subjects will be enrolled in the expansion part.  The SRC will continue to review safety data 
regularly throughout the study and make recommendations about study continuation and dose 
modification, as appropriate.
The study will be conducted in compliance with International Conference on Harmonisation 
(ICH) Good Clinical Practices (GCPs).
Study Population 
Adult subjects with confirmed pathologic diagnosis of unresectable HCC, according to the 
American Association for the Study of Liver Diseases (AASLD) Guidelines (Bruix, 2005) who 
have progressed after or were intolerant to no more than 2 previous systemic therapies for 
unresectable HCC, or are naïve to systemic therapy. 
Subjects at screening must have a Child-Pugh score less than 7 (class A) and have an Eastern 
Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
Up to approximately 20 subjects will be enrolled in the dose escalation portion of the study 
(Phase 1), depending upon the number of cohorts opened.  Up to approximately 30 additional 
subjects will be evaluated for safety, PK, PD, and preliminary antitumor effects during the dose 
expansion portion (Phase 2).  Therefore up to approximately 50 total subjects may be enrolled 
into the study.
Length of Study
The screening period will last approximately up to 28 days. Subjects may remain on treatment 
for up to 2 years or until disease progression, unacceptable toxicity, subject or physician
decision, withdrawal of consent, or death. If treatment is discontinued for reasons other than 
disease progression, start of a new anticancer therapy, or withdrawal of consent, subjects will 
continue to be followed for tumor evaluation until progression. Subjects will be followed for 
survival status either until death, lost to follow-up, withdrawal of consent or until two years from 
enrollment, whichever event occurs first. The End of Trial is defined as either the date of the last 
visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last 


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data point from the last subject that is required for primary, secondary and/or exploratory
analysis, as pre-specified in the protocol, whichever is the later date. 
Study Treatments
All cohorts will receive different dose levels of CC-122 and a standard dose of nivolumab, 3.0
mg/kg IV every 2 weeks.  The duration of treatment will not exceed 2 years.  Study treatment 
may be discontinued if there is evidence of disease progression, unacceptable toxicity, or 
subject/physician decision to withdraw. 
Subjects may continue to receive study drugs beyond disease progression at the discretion of the 
Investigator, especially if required to confirm after 4 to 6 weeks the immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST) for tumor progression.
Overview of Key Efficacy Assessments
Tumor assessments will be performed at screening (up to 28 days before the Cycle 1 Day 1 
[C1D1] dose), every 8 weeks (±7 days) for the first 5 evaluations (10 months), and thereafter 
every 12 weeks (±7 days), regardless of treatment status. Tumor assessments should also be 
performed at any time, if clinically indicated.  Tumor assessments should continue at the defined 
schedule until radiologic disease progression or new anticancer therapy, beyond the end of 
treatment if necessary.
All subjects will be evaluated for tumor response and progression by the Investigator according 
to RECIST 1.1 guidelines using the same scanning modalities used at screening.
Tumor response will also be determined by the Investigator based on irRECIST (Bohnsack, 
2014) as an exploratory assessment. Other exploratory efficacy variables, such as ECOG PS, 
alpha-fetoprotein (AFP) reduction, etc, will be summarized as well. An independent review of 
the efficacy results may take place at any time during the study.
Following disease progression, survival status will be determined approximately every 3 months
thereafter until 2 years from enrollment, lost to follow-up, death or withdrawal of consent, 
whichever occurs sooner.
New anticancer therapies will also be collected at the same schedule. New anticancer therapy 
includes (but is not limited to) any systemic or locoregional medication, surgery, radiation, or 
any other therapy intended to treat the subject’s cancer.
Overview of Key Safety Assessments
All subjects will be monitored for adverse events (AEs), starting from the time the subject signs 
the informed consent form (ICF) until the end of treatment (EOT) visit, for 28 days after the last 
dose of CC-122 and for 90 days after the last dose of nivolumab, whichever occurs later. A 
thorough evaluation of medical conditions will be conducted during screening for eligibility. The 
safety variables for this study include AEs, safety clinical laboratory variables, 12-lead
electrocardiograms (ECGs), left ventricular ejection fraction (LVEF) assessments, physical 
examinations, ophthalmologic exams, vital signs, ECOG PS, exposure to investigational product 
(IP), assessment of concomitant medications, and pregnancy testing for females of child bearing 
potential (FCBP).


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Overview of Pharmacokinetic Assessments
Blood will be collected to estimate the PK of CC-122 when administered in combination with
nivolumab and the PK of nivolumab when administered in combination with CC-122.
For CC-122, during the dose escalation part, intensive PK sampling will be performed in all 
subjects at multiple time points on Cycle 1 Day 15. For nivolumab, sparse PK (at predose and at 
the end of infusion) will be performed in all subjects on Cycle 1 Days 1 and 15. No PK will be 
collected during the dose expansion part.
 
 
 
 
 
 
 
Statistical Methods
Statistical analyses will be performed by study part, dose level/dosing regimen and/or HCC 
etiology as needed or applicable. All analyses will be descriptive in nature.
All summaries of safety data will be conducted using subjects receiving at least one dose of 
either IP (the Treated Population).
The efficacy variables of primary interest include overall response rate (ORR), overall survival
(OS), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS) 
and time to progression (TTP). The primary assessment of tumor response will be according to 
RECIST 1.1 (Eisenhauer, 2009). Exploratory response assessment using irRECIST (Bohnsack, 
2014) will also be performed. Other preliminary efficacy variables such as AFP response will be 
summarized using frequency tabulations for categorical variables or descriptive statistics for 
continuous variables, and further analyses will be performed as appropriate. Efficacy analysis 
will be repeated for the Treated Population and Efficacy Evaluable Population (receiving at least 
50% of both assigned IP in the first 2 cycles, having a baseline tumor assessment and 1 on study 
tumor assessment), with the result using the Treated Population considered primary.
All biomarker-related data presentations will be based on treated subjects with at least one non-
missing biomarker assessment (the Biomarker Evaluable [BE] Population), unless specified 
otherwise. Descriptive statistics will be presented for baseline and change from baseline of 
continuous biomarker endpoints.
Exploration of PK, PD, safety and efficacy relationships will be assessed.


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During the dose escalation part, up to approximately 20 subjects will be enrolled. During the 
cohort expansion part, up to 30 subjects will be enrolled. At least 14 efficacy evaluable subjects 
will initially be accrued. If the response rate is 20% or more, there will be more than a 95% 
chance that 1 or more responders would be observed in the first 14 subjects (Gehan, 1961).  If 
no responder is observed out of 14 subjects, the enrollment for the expansion cohort will stop 
for futility. Otherwise, the expansion cohort will be expanded to up to approximately 30 
subjects if a responder is observed.  Enrollment will continue during the evaluation of the initial 
14 subjects.  With 30 subjects enrolled and assuming the observed ORR is 35%, the two-sided 
95% Wilson score confidence interval will exclude 20%, the estimated ORR for nivolumab 
monotherapy (El-Khoueiry, 2015).


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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................32
3.
OVERALL STUDY DESIGN ................................................................................35
3.1.
Study Design ..........................................................................................................35
3.2.
Study Duration for Subjects....................................................................................36
3.3.
End of Trial ............................................................................................................37
4.
STUDY POPULATION.........................................................................................38
4.1.
Number of Subjects ................................................................................................38
4.2.
Inclusion Criteria....................................................................................................38
4.3.
Exclusion Criteria...................................................................................................40
5.
TABLE OF EVENTS.............................................................................................42
6.
PROCEDURES......................................................................................................47
6.1.
Screening Period.....................................................................................................47
6.2.
Treatment Period ....................................................................................................49
6.3.
End of Treatment....................................................................................................50
6.4.
Follow-up Period....................................................................................................51


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6.4.1.
Safety Follow-up ....................................................................................................51
6.4.2.
Efficacy Follow-up.................................................................................................51
6.4.3.
Survival Follow-up.................................................................................................51
6.5.
Efficacy Assessments .............................................................................................51
6.5.1.
Assessment of Response According to RECIST 1.1................................................51
6.5.2.
Treatment Beyond Progression ...............................................................................52
6.5.3.
Other Assessments..................................................................................................52
6.5.4.
Assessment of Response According to Immune-Related Response Criteria 
(irRECIST).............................................................................................................53
6.6.
Pharmacokinetics....................................................................................................53
6.6.1.
Pharmacokinetics of CC-122 ..................................................................................53
6.6.2.
Pharmacokinetics of Nivolumab .............................................................................53
6.7.
12-lead Electrocardiograms ....................................................................................53
6.9.
CC-122 Risk Counseling Prior to Dosing................................................................56
7.
DESCRIPTION OF STUDY TREATMENTS........................................................57
7.1.
Description of Investigational Product(s)................................................................57
7.1.1.
CC-122...................................................................................................................57
7.1.2.
Nivolumab..............................................................................................................57
7.2.
Treatment Administration and Schedule .................................................................57
7.2.1.
Dose Levels............................................................................................................57
7.3.
Definition of a DLT Evaluable Subject ...................................................................58
7.4.
Definition of Non-tolerated Dose............................................................................58
7.5.
Definition of Maximum Tolerated Dose (MTD) .....................................................59
7.6.
Definition of Dose-Limiting Toxicity .....................................................................59
7.7.
Method of Treatment Assignment...........................................................................60
7.8.
Criteria for Dose Escalation....................................................................................60


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7.8.1.
Definition of Stopping Criteria for Dose Escalation ................................................61
7.9.
Permitted IP Adjustments .......................................................................................61
7.10.
Criteria for CC-122 Dose Reduction.......................................................................62
7.10.1.
Nivolumab Dose Delay/Interruption Criteria...........................................................66
7.10.2.
Nivolumab Dose Reductions...................................................................................67
7.10.3.
Nivolumab Dose Interruption / Discontinuation......................................................67
7.10.4.
Management of Expected AEs While Receiving CC-122........................................68
7.10.4.1.
Neutropenia, Thrombocytopenia, Anemia...............................................................68
7.10.4.2.
Infection .................................................................................................................68
7.10.4.3.
Pain ........................................................................................................................68
7.10.4.4.
Dose Modification and Management of Cardiac Laboratory Abnormalities ............68
7.10.4.5.
Dose Modification and Management of Pneumonitis ..............................................69
7.10.4.6.
Dose Modification and Management of Tumor Flare Reaction ...............................69
7.10.4.7.
Management and Follow-up of Liver Function Test Abnormalities Grade 3............70
7.10.4.8.
Management of Dermatological Toxicity................................................................70
7.10.5.
Management of Expected AEs While Receiving Nivolumab...................................70
7.11.
Definition of an Overdose.......................................................................................70
7.12.
Treatment Delay.....................................................................................................71
7.13.
Packaging and Labeling..........................................................................................71
7.14.
Investigational Product Accountability and Disposal ..............................................71
7.15.
Investigational Product Compliance........................................................................71
9.
STATISTICAL CONSIDERATIONS ....................................................................75
9.1.
Overview................................................................................................................75
9.2.
Study Population Definitions ..................................................................................75
9.3.
Sample Size and Power Considerations...................................................................75
9.4.
Background and Demographic Characteristics........................................................76
9.5.
Subject Disposition.................................................................................................76
9.6.
Efficacy Analysis....................................................................................................76
9.7.
Safety Analysis.......................................................................................................77


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9.8.
Interim Analysis .....................................................................................................77
9.9.
Other Topics...........................................................................................................78
9.9.1.
Assessment of Pharmacokinetics ............................................................................78
10.
ADVERSE EVENTS..............................................................................................80
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................80
10.2.
Evaluation of Adverse Events.................................................................................80
10.2.1.
Seriousness.............................................................................................................80
10.2.2.
Severity / Intensity..................................................................................................82
10.2.3.
Causality ................................................................................................................82
10.2.4.
Duration .................................................................................................................83
10.2.5.
Action Taken..........................................................................................................83
10.2.6.
Outcome.................................................................................................................83
10.3.
Abnormal Laboratory Values..................................................................................83
10.4.
Pregnancy...............................................................................................................83
10.4.1.
Females of Childbearing Potential ..........................................................................84
10.4.2.
Male Subjects.........................................................................................................84
10.5.
Reporting of Serious Adverse Events......................................................................85
10.5.1.
Safety Queries ........................................................................................................85
10.6.
Expedited Reporting of Adverse Events..................................................................85
11.
DISCONTINUATIONS .........................................................................................87
11.1.
Treatment Discontinuation......................................................................................87
11.2.
Study Discontinuation ............................................................................................87
12.
EMERGENCY PROCEDURES.............................................................................88
12.2.
Emergency Identification of Investigational Products .............................................88
13.
REGULATORY CONSIDERATIONS...................................................................89
13.1.
Good Clinical Practice............................................................................................89
13.2.
Investigator Responsibilities ...................................................................................89
13.3.
Subject Information and Informed Consent.............................................................90
13.4.
Confidentiality........................................................................................................90
13.5.
Protocol Amendments.............................................................................................90


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13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................90
13.7.
Ongoing Information for Institutional Review Board / Ethics Committee................91
13.8.
Termination of the Study ........................................................................................91
14.
DATA HANDLING AND RECORDKEEPING.....................................................92
14.1.
Data/Documents .....................................................................................................92
14.2.
Data Management...................................................................................................92
14.3.
Record Retention....................................................................................................92
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................94
15.1.
Study Monitoring and Source Data Verification......................................................94
15.2.
Audits and Inspections............................................................................................94
16.
PUBLICATIONS ...................................................................................................95
18.
APPENDICES......................................................................................................101
18.1.
Appendix A:  Table of Abbreviations ...................................................................101
 


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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................32
Table 2:
Study Endpoints .....................................................................................................33
Table 3:
Table of Events.......................................................................................................42
Table 4:
Dose Levels............................................................................................................57
Table 5:
Allowed Dose Reductions.......................................................................................61
Table 6:
Dose Adjustment Guidelines for CC-122 Related Non-hematologic 
Toxicities................................................................................................................62
Table 7:
Dose Adjustment Guidelines for CC-122 Related Hematologic Toxicities ..............65
Table 8:
Recommended Treatment Modification for Nivolumab ..........................................66
Table 9:
Confidence Interval for 20% and 35% Response Rate for Different Scenarios 
of Sample Size (Wilson Score Interval) ..................................................................76
Table 10:
Abbreviations and Specialist Terms......................................................................101
Table 11:
Time Point Response: Subjects With Target (± Non-target) Disease .....................108
Table 12:
Time Point Response: Subjects With Non-target Disease Only .............................109
Table 13:
Child-Pugh Classification .....................................................................................119


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LIST OF FIGURES
Figure 1:
Effect of CC-122 Combined with Nivolumab on IL-2 Secretion from SEB 
Stimulated PBMC...................................................................................................23
Figure 2:
Effects of CC-122 and Nivolumab in PBMC-mediated-Killing of JHH4 
Cells .......................................................................................................................24
Figure 3:
Overall Study Design..............................................................................................36
Figure 5:
BCLC Staging and Treatment Schedule................................................................118
Figure 6:
Diarrhea Management Guidelines.........................................................................137




























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2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the Phase 1 portion of the study is:

To determine the safety and tolerability of CC-122 when administered orally in 
combination with nivolumab and to define the recommended Phase 2 dose (RP2D)
The primary objective of the Phase 2 portion of the study is:

To estimate the preliminary efficacy of CC-122 in combination with nivolumab based 
on overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors
Version 1.1 (RECIST 1.1)
Secondary Objective(s)
The secondary objectives of the entire study are:

To evaluate the preliminary efficacy of CC-122 in combination with nivolumab based 
on various endpoints by RECIST 1.1

To evaluate the pharmacokinetics (PK) of CC-122 in subjects coadministered
multiple doses of CC-122 with nivolumab

To determine nivolumab PK when coadministered with CC-122
 
 
 
 
 
 
 


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Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary Phase 1
The incidence of dose 
limiting toxicities (DLTs) and 
the incidence and severity of 
treatment-emergent adverse 
events (TEAEs)
See Section 7.6 for the definition 
of DLTs
End of Phase 
1
Primary Phase 2
Preliminary efficacy as 
measured by overall response 
rate (ORR)
The combined incidence of 
complete response (CR) + partial 
response (PR), by investigator 
assessment of response by
Response Evaluation Criteria in 
Solid Tumors (RECIST) 1.1
End of Study
Secondary
Preliminary efficacy 
Disease control rate (DCR), 
duration of response (DoR), 
progression free survival (PFS), 
overall survival (OS), and time to 
progression (TTP) based on 
investigator assessment of 
response using RECIST 1.1 
guidelines
End of Study
Secondary
Plasma pharmacokinetic (PK)
parameters 
Including but not limited to 
maximum observed concentration 
(Cmax), area under the 
concentration time curve (AUC), 
time to maximum concentration 
(Tmax), terminal half-life (t1/2), 
apparent total body clearance 
(CL/F) and apparent volume of 
distribution (Vz/F) for CC-122 
and nivolumab after multiple dose 
administration
End of Phase 
1
 
 
 
 
 
 
 


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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.
OVERALL STUDY DESIGN
3.1.
Study Design
CC-122-HCC-002 is a Phase 1/2 dose escalation and expansion clinical study of CC-122 in 
combination with nivolumab in subjects with unresectable HCC who have progressed after or 
were intolerant to no more than 2 previous systemic therapies for unresectable HCC, or are naïve 
to systemic therapy. 
Subjects will have received either none or no more than 2 previous systemic therapies. The dose 
escalation part of the study will explore 1 or more dose levels of CC-122 in combination with 
nivolumab using a modified dose escalation (3+3) design (Storer, 1989), followed by an 
expansion part once the recommended Phase 2 dose (RP2D) is defined.
The study is designed to explore three dose levels, as described in Section 7.2.1, to identify the 
RP2D, and is not required to escalate to a nontolerated dose (NTD) or MTD.  CC-122 will 
initially be administered orally 5 consecutive days out of 7 (5 days on/2 days off weekly) on 
Days 1 to 5, 8 to 12, 15 to 19 and 22 to 26 of each 28-day cycle. The investigated starting daily 
dose of CC-122 will be 2.0 mg, and two subsequent dose levels (3.0 and 4.0 mg) are planned to
be evaluated based on evaluation of pre-specified DLTs. The study intends to identify the RP2D 
at or below the 4.0 mg dose level, however intermediate dose levels, or a higher dose level, may 
be evaluated at the discretion of the Safety Review Committee (SRC). Dose escalation to the 
intermediate or higher dose levels of CC-122 will not exceed 50% of the previously established 
tolerable dose level. Smaller dose increments based on toxicity, PK profile and PD findings may 
be evaluated, if necessary.  Nivolumab will be administered at the dose of 3.0 mg/kg 
intravenously (IV) every 2 weeks. Once the RP2D for dosing of CC-122 in combination with 
nivolumab is defined, expansion (Phase 2) will start.
A modified 3+3 dose escalation design will be used to identify the initial toxicity of the
combination.  Up to six subjects will be concurrently enrolled into a dose level.  Decisions as to 
which dose level to enroll a new subject will be based on the number of subjects enrolled and 
evaluable, the number of subjects experiencing DLTs, and the number of subjects enrolled but 
who are not yet evaluable for toxicity in the current cohort at the time of new subject entry.
A dose is considered an NTD if 2 or more out of up to 6 evaluable subjects in a cohort 
experience a DLT in Cycle 1.  During dose escalation, the decision to either evaluate a higher 
dose level, an intermediate dose level, or declare the RP2D dose (or if applicable, NTD) will be 
determined by the SRC, based on their review of all available clinical data, PK, PD and 
laboratory safety data for a given dose cohort.
The composition of the SRC will be defined in the SRC charter and will include at least all the 
Principal Investigators (PIs) of active sites and the Celgene medical monitors and safety 
physician.
Non-evaluable subjects will be replaced at the discretion of the SRC.
Following completion of the dose escalation part (Phase 1), up to 30 additional subjects will be 
enrolled in an expansion part (Phase 2).  A futility analysis will be conducted as follows.  In the 
first 14 subjects treated, if no responder is observed out of 14 subjects then enrollment for the 
expansion cohort will stop for futility.  Enrollment will continue during the evaluation of the 14 


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subjects.  If ≥ 1 subject out of 14 responds (CR or PR), then approximately 30 total subjects will 
be enrolled in the Phase 2 portion.  The SRC will continue to review safety data regularly 
throughout the study and make recommendations about study continuation and dose 
modification, as appropriate.
The study will be conducted in compliance with International Conference on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/ Good 
Clinical Practices (GCPs).
Figure 3:
Overall Study Design
HCC = hepatocellular carcinoma; IV = intravenous; RP2D = recommended Phase 2 dose.
3.2.
Study Duration for Subjects
The screening period will last approximately up to 28 days. Subjects may remain on treatment 
for up to 2 years or until disease progression, unacceptable toxicity, subject or physician
decision, withdrawal of consent, or death. If treatment is discontinued for reasons other than 
disease progression, start of a new anticancer therapy, or withdrawal of consent, subjects will 
continue to be followed for tumor evaluation until progression and/or initiation of new anticancer 
therapies. Subjects will be followed for survival status either until death, lost to follow-up, or 
until two years from enrollment, whichever event occurs first.


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3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol, 
whichever is the later date. 


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4.
STUDY POPULATION
4.1.
Number of Subjects 
The total number of subjects to be enrolled during dose escalation (Phase 1) is estimated to be up 
to approximately 20 depending on the number of cohorts and their sizes.  Up to approximately 
30 additional subjects will be evaluated for safety, PK, PD, and preliminary antitumor effects 
during the dose expansion part (Phase 2).
The study will be conducted in the US and European Union.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject has a confirmed pathologic diagnosis of HCC according to the American 
Association for the Study of Liver Diseases (AASLD) Guidelines (Bruix, 2005). Refer to
Appendix D in Section 18.4.  A biopsy performed at screening may serve as a diagnostic 
biopsy for subjects with radiographic diagnosis.
3. Subjects who have progressed after or were intolerant to no more than 2 previous 
systemic therapies for unresectable HCC, or are naïve to systemic therapy. 
4. Subject has unresectable Stages B (intermediate), or C (advanced) HCC according to the 
Barcelona Clinic Liver Cancer (BCLC) staging (Appendix E [Llovet, 2008]) in 
Section 18.5. Stage B subjects must have progressed after, or are not eligible for curative 
resection, transplantation, embolic, or ablative therapies.
5. Subject has at least one measurable lesion according to RECIST 1.1. Lesions previously 
treated with locoregional therapy may only be evaluated as target lesions if they are the 
only lesions available and have shown objective definite progression after prior 
treatment. 
6. Subject agrees to provide a tumor biopsy prior to starting Cycle 1 and during Cycle 2.
7. Subject has a life expectancy of ≥ 12 weeks.
8. Subject has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 
0 or 1.
9. Subject has a Child-Pugh score less than 7 with neither encephalopathy nor clinically 
significant ascites (ascites requiring paracentesis within 3 months of signing the ICF is 
excluded). Child-Pugh status is calculated based on clinical findings and laboratory 
results during the screening period. Please refer to Appendix F in Section 18.6 for Child-
Pugh classifications (Pugh, 1973).
10. Subject has the following laboratory parameters at screening:
Adequate hematologic function including:
a.
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
b. Platelets ≥ 60,000 x 106/L


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c.
Hemoglobin (Hgb) ≥ 9 g/dL
d. International normalized ratio (INR) ≤ 1.7
Adequate hepatic function including:
e.
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x 
upper limit of normal (ULN)
f.
Serum total bilirubin ≤ 2 x ULN
g. If serum total bilirubin is ≥ 1.5 and ≤ 2 x ULN then AST and ALT must be ≤ 3 x 
ULN
h. Serum albumin ≥ 2.8 g/dL
Note: The combined total of all laboratory values must still equal a Child-Pugh score < 7
Other laboratory parameters:
i.
Serum creatinine ≤ 1.5 x ULN
j.
Potassium within normal range or corrected with supplements
11. Subject is able to adhere to the study visit schedule and other protocol requirements.
12. Pregnancy Prevention Risk Management Plan (PPRMP) for CC-122 (Appendix G in 
Section 18.7):
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 PPRMP.

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 use barrier contraception 
(condoms) when engaging in sexual activity with FCBP as specified in PPRMP.
d. Males must agree not to donate semen or sperm for 3 months after last dose of CC-
122 and/or nivolumab.
e.
All subjects must:
-
Understand the information provided about pregnancy precautions and risks of 
fetal exposure after counseling and agree to follow the PPRMP (see PPRMP, 
Appendix G, Section 18.7)
-
Understand that CC-122 could have a potential teratogenic risk.
-
Agree not to share either IP with another person.
-
Agree that other than the subject, FCBP and males able to father a child should 
not handle CC-122 or touch the capsules, unless gloves are worn.
o
For nivolumab, agree to follow the pregnancy prevention plan described in 
the Summary of Product Characteristics (SmPC) or US Prescribing 
Information, specifically: females of childbearing potential must use 
effective contraception for at least 5 months following the last dose of 
nivolumab.


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13. Subject must understand and voluntarily sign an informed consent document prior to
conducting any study related assessments/procedures and be willing and able to adhere to 
the study visit schedule and other protocol requirements.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has received more than 2 previous systemic therapies for HCC. Prior treatment
with regorafenib is also excluded.
2. Subject has received previous treatment with any anti-PD-1 or anti-PD-L1 antibody.
3. Subject has received any systemic or local anticancer therapy ≤ 4 weeks prior to starting 
IP. Subject has undergone major surgery ≤ 4 weeks or minor surgery ≤ 2 weeks prior to 
signing the ICF or who has not recovered from surgery.
4. Subject has received an investigational drug or therapy for disease other than HCC within 
≤ 4 weeks or 5 half-lives, whichever is shorter, prior to starting study treatment on Cycle 
1 Day 1.
5. Subject has completed any radiation treatment < 2 weeks prior to starting study treatment.
6. Subject has received the last dose of α-interferon, ribavirin, sofosbuvir and/or other 
antiviral therapies for HCV < 4 weeks prior to starting study treatment.
7. Subject has any clinically significant bleeding, including bleeding from 
esophageal/gastric varices within ≤ 3 months of signing the ICF, which required 
transfusion, surgical procedure or hospitalization. Esophageal varices should be treated 
according to local standard practice (eg, ligation or banding and procedure completed ≤ 3 
months prior to signing the ICF).
8. Subject has histologic proof of fibrolamellar carcinoma, sarcomatoid HCC and combined 
hepatocellular-cholangiocarcinoma (cHCC-CC).
9. Subject has tumor invasion of stomach or duodenum or known symptomatic brain 
metastasis.
10. Subject has persistent diarrhea due to a malabsorptive syndrome (such as celiac sprue or 
inflammatory bowel disease) malabsorption ≥ National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE, Version 4.03) Grade 2, despite 
medical management, or any other significant gastrointestinal disorder that could affect 
the absorption of CC-122.
11. Subject has a concurrent second cancer requiring active, ongoing systemic treatment.
12. Subject has a known history of human immunodeficiency virus (HIV) seropositivity 
(HIV testing is not mandatory).
13. Subject has peripheral neuropathy ≥ NCI CTCAE Grade 2.
14. Subject has a history of persistent skin rash ≥ NCI CTCAE Grade 2.


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15. Subject has impaired cardiac function or clinically significant cardiac disease including 
any of the following:
a.
Left ventricular ejection fraction (LVEF) < 45% as determined by multi-gated 
acquisition (MUGA) scan or echocardiogram (ECHO)
b. Complete left bundle branch or bifascicular block
c.
Congenital long QT syndrome
d. Persistent or clinically meaningful ventricular arrhythmias
e.
QTcF > 460 msec on screening electrocardiogram (ECG)
f.
Unstable angina pectoris or myocardial infarction ≤ 6 months prior to starting either 
IP
g. Uncontrolled hypertension (blood pressure > 140/90 mmHg on at least 2 
measurements on sequential visits, despite blood pressure medication)
h. Troponin-T value > ULN or brain natriuretic peptide (BNP) > 300 pg/mL
a.
Subjects with baseline BNP > 100 pg/mL are eligible but must have a cardiologist 
evaluation prior to enrollment in the trial for baseline assessment and optimization 
of cardioprotective therapy.
16. Subject has acute or chronic active infectious disorders or uncontrolled nonmalignant 
illnesses whose control, in the opinion of the investigator, may be jeopardized by 
complications of this study therapy. Subjects with chronic HBV and HCV are excepted 
(ie, eligible for study).
17. Subject has undergone liver transplantation or other solid organ transplantation requiring 
ongoing immunosuppression.
18. Subject is receiving chronic treatment with systemic corticosteroids or other potentially
immunosuppressive agent.  Intermittent topical or local injection of corticosteroids and 
oral/IV aldosterone or other mineralocorticoids is allowed.
19. Subjects with history of non-healing wounds or ulcers, or bone fractures ≤ 3 months of a 
prior fracture.
20. Subject has active, known autoimmune disease.
21. Subject is a female who is pregnant or is breast feeding.
22. Subject is unwilling or unable to comply with the protocol, in the opinion of the 
investigator.
23. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study.
24. Subject has any condition that confounds the ability to interpret data from the study.
25. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study.


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5.
TABLE OF EVENTS
Table 3:
Table of Events
Screening 
Period
Treatment Period
Follow-
up 
Period
Follow-up Period
Screening
a
Cycle 1
Cycle 2
Subsequent 
Cycles
EOT
Day b
-28 to -1
1 c
8
15
22
1
8
15
18
22
1
15
28 day 
follow-up 
90 days 
follow-
up
Disease 
Progressio
n/ Survival/
Pregnancy
STUDY ENTRY
Informed consent 
X
Pregnancy prevention 
counseling
Pregnancy risk counseling and education prior to dispensing of IP
Demographics
X
Prior cancer history
X
Prior/post cancer therapies
X
At the same schedule as survival 
visits
Complete medical history
X
Prior/ concomitant 
medication evaluation
X
Continuous, until 28 days after treatment discontinuation
Prior/ concomitant 
procedures evaluation
X
Continuous, until 28 days after treatment discontinuation
Inclusion/exclusion criteria
X
SAFETY ASSESSMENTS
Adverse event collection
Continuous starting after informed consent signature, until 28 days after last dose of CC-122 and 90 days after the last dose of 
nivolumab or at any time afterwards if the PI feels the event is related to any IP
Physical examination 
(source documented only)
X
X
X
X
X
Ophthalmologic exam
X
As clinically indicated


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Table 3:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-
up 
Period
Follow-up Period
Screeninga
Cycle 1
Cycle 2
Subsequent 
Cycles
EOT
Day b
-28 to -1
1c
8
15
22
1
8
15
18
22
1
15
28 day 
follow-up 
90 days 
follow-
up
Disease
Progression/ 
Survival/ 
Pregnancy
Weight
X
X
X
X
X
Height
X
Vital signs
X
X
b
X
X
X
X
X
X
ECOG PS
X
Xa
X
X
X
CBC with differential
X
(-14 to -1)
Xa
X
X
X
X
X
X
X
X
X
X 
Cycles 
3-6 
only
X
Coagulation: PT, INR, 
PTT
X
(-14 to -1)
Xa
X
X
Troponin-T and BNP
X
Xa
X
X
X
X
X
X
Chemistry laboratory
(fasting, routine)
X
(-14 to -1)
Xa
X
X
X
X
X
X
X
X
X
Amylase, lipase, T3, CK, 
TSH, fT4, immuno-
globulins (IgG, IgM and 
IgA only) and T cell 
subsets (CD4+ and CD8+)
X
Xa
X
X
X
X
X
HBV and HCV serologies 
(HBsAg, HBeAg, HBsAb, 
HBeAb, HBcAb, HCVAb)
X
HCV viral load
X
HBV viral load
X
If HBsAg and/or HBcAb positive at screening, on day 1 of each cycle and at EOT


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Table 3:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-
up 
Period
Follow-up Period
Screeninga
Cycle 1
Cycle 2
Subsequent 
Cycles
EOT
Day b
-28 to -1
1 c
8
15
22
1
8
15
18
22
1
15
28 day 
follow-up 
90 days 
follow-
up
Disease 
Progression/ 
Survival/ 
Pregnancy
Urinalysis
X 
(-14 to -1)
X
X
Triplicate 12-lead 
electrocardiogram 
X
X
X
X
X
X
X
X
LVEF
X
X 
every 
3 
cycles
X
Serum and/or urine β-hCG 
(in females of childbearing 
potential [FCBP] only)
Xd
(-14 to -1)
Prior to first dose of study drug and as PPRMP indicated.
EFFICACY, PHARMACOKINETIC, AND PHARMACODYNAMIC ASSESSMENTS
 
 
 
 


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Table 3:
Table of Events (Continued)
Screening 
Period
Treatment Period
Follow-
up 
Period
Follow-up Period
Screeninga
Cycle 1
Cycle 2
Subsequent 
Cycles
EOT
Day b
-28 to -1
1 c
8
15
22
1
8
15
18
22
1
15
28 day 
follow-up 
90 days 
follow-
up
Disease 
Progression/ 
Survival/ 
Pregnancy
Fresh paired tumor biopsy 
Xf
D18 (+/- 7 
days, 
preferably 
after 3 
continuous 
days of CC-
122 adminis-
tration) g
Tumor evaluation
(CT or MRI)
X 
(-28 to -1)
RECIST 1.1 Every 8 weeks (±7 days) for the first 10 months, then every 12 weeks (±7 days), until 
death, lost to follow up, withdrawal of consent, progression or start of new anticancer therapy. See 
Section 6.5.1
irRECIST: At time of RECIST 1.1 progression if subject continues on treatment beyond progression. 
Additional evaluations should be performed at the time of rescan 4-6 weeks after RECIST 1.1 
progression, and then again per standard of care. See Sections 6.5.2 and 6.5.4
Alpha-fetoprotein
X
X
X
X
X
INVESTIGATIONAL PRODUCT
Administer CC-122
5/7 days continuously
Administer nivolumab
Q2W
CC-122 accountability
X
X
X
X
X
X
X
X
X
X
X
Nivolumab accountability
Q2W
Xh
Xh
FOLLOW-UP
Survival follow-up
Every 3 
months 
(+/- 7 days)


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Abbreviations: β-hCG = beta human chorionic gonadotropin; BNP = brain natriuretic peptide; CBC = complete blood count; CK = creatine kinase; CT = computed tomography; 
ECOG PS = Eastern Cooperative Oncology Group Performance Status; EOT = End of Treatment; FCBP = females of child bearing potential; FFPE = formalin-fixed, paraffin 
embedded; fT4 = free T4; HBV = hepatitis B virus; HBsAg = hepatitis B surface antigen; HBeAg = hepatitis B e antigen; HBsAb= hepatitis B surface antibody; HBeAb = 
hepatitis B e antibody; HBcAb = hepatitis B core antibody; HCVAb =  HCV antibody; HCV = hepatitis C virus; IG = immunoglobulin; INR = international normalized ratio; 
LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; PI = Principal Investigator; PK = pharmacokinetic; PPRMP = Pregnancy Prevention Risk 
Management Plan; PT = prothrombin time; PTT = partial thromboplastin time; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; TSH = thyroid 
stimulating hormone.
a All screening assessments must be performed prior to enrollment and subsequent treatment, however, these events may occur on the same calendar day as long as they are 
completed prior to enrollment.
b An administrative window of ± 3 days is permitted for all cycles except Cycle 1 Day 1 (C1D1).
c C1D1 assessment may be omitted if screening assessment performed within 72 hours of first dose with the exception of the pregnancy test, see footnote d.
d As per PPRMP, FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting CC-122. The first pregnancy test must be performed within 
10-14 days prior to the start of CC-122 and the second pregnancy test must be performed within 24 hours prior to the start of CC-122. The subject may not receive CC-122 until 
the study doctor has verified that the results of these pregnancy tests are negative.
e Pharmacodynamics biomarker sample to be collected with on-treatment tumor biopsy on Day 18 (± 7 days) at approximately 3 ± 1 hour post dose.
f Archival tumor tissue will be required only if fresh tissue is not evaluable at screening. See Sections 6.8.1 and 6.8.2.
g Sample may be collected on Day 18 ± 7 days of Cycle 2. The sample must be collected at 3 to 6 (±1) hours postdose. Due to the intermittent schedule of CC-122 administration, 
the sample should preferably be collected after at least 3 continuous days of administration.
h After discontinuation of nivolumab, females of childbearing potential must use effective contraception for at least 5 months.


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6.
PROCEDURES
6.1.
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 28 days prior to first dosing except as noted below and in
Table 3. All screening assessments must be performed prior to enrollment and subsequently 
treatment, however, these events may occur on the same calendar day as long as they are 
completed prior to enrollment.
Any questions regarding subject eligibility should be directed to the Celgene Medical Monitor or 
designee. Waivers to the protocol will not be granted during the conduct of this trial under any 
circumstances.
Unless otherwise specified, all assessments should be performed locally. Screening eligibility 
criteria laboratory values must demonstrate subject eligibility. Screening assessments may be 
repeated within the screening window if necessary, and the most recently obtained result should 
be used to demonstrate eligibility.
The following will be performed at screening as specified in the Table of Events (Table 3) after 
informed consent has been obtained:

Review of inclusion/ exclusion criteria

Commencement of pregnancy prevention counseling, per the PPRMP (Appendix G, 
Section 18.7)

Demographics

Prior cancer history (including specific information regarding diagnosis, staging, and 
histology)

Prior cancer therapies: includes surgery, radiation, systemic, locoregional, or any 
other therapy (eg, hormonal) for the subject’s cancer

Medical history (all relevant medical conditions occurring < 28 days before screening 
should be included)

Prior and concomitant medication evaluation (includes those taken ≤ 28 days before 
the screening visit, except those taken for cancer which are recorded as part of prior 
cancer therapy)

Prior and concomitant procedures (includes all procedures occurring ≤ 28 days before 
the screening visit)

Adverse event evaluation (begins when the subject signs the informed consent form 
[ICF])

Physical examination (source documented only), height, weight

Vital signs (including blood pressure, temperature and pulse)

Eastern Cooperative Oncology Group Performance Status 


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
Ophthalmologic exam to include visual acuity, slit-lamp exam with fluorescein for 
the anterior chamber, iris, and with pupillary dilatation (if required and not 
contraindicated) to assess the vitreous 

Complete blood count (CBC) with differential, including red blood cell (RBC) count, 
hemoglobin, hematocrit, white blood cell (WBC) count with absolute differentials 
(neutrophils, lymphocytes, monocytes, eosinophils and basophils), and platelet count 
(Days -14 to -1)

Coagulation panel: prothrombin time (PT), international normalized ratio (INR), 
partial thromboplastin time (PTT) (Days -14 to -1)

Chemistry laboratory (fasting, routine): including sodium, potassium, chloride, 
bicarbonate or carbon dioxide (CO2), glucose, calcium, magnesium, phosphorus, 
blood urea nitrogen (BUN), creatinine, albumin, total protein, alkaline phosphatase, 
bilirubin (total and direct), aspartate aminotransferase/ serum glutamic oxaloacetic 
transaminase (AST/SGOT), alanine aminotransferase/serum glutamic pyruvic 
transaminase (ALT/SGPT), lactate dehydrogenase (LDH) and uric acid (Days -14 
to -1)

Amylase, lipase, creatine kinase (CK), T3, thyroid stimulating hormone (TSH), fT4, 
immunoglobulins (IgG, IgM and IgA only) and T cell subsets (CD4+ and CD8+)

Alpha-fetoprotein

Hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies (hepatitis B surface 
antigen [HBsAg], hepatitis B e antigen [HBeAg], hepatitis B surface antibody 
[HBsAb], hepatitis B e antibody [HBeAb], hepatitis B core antibody [HBcAb], 
hepatitis C virus antibody [HCVAb])

Measurement of HBV viral load (HBV DNA quantitative by polymerase chain 
reaction (PCR) and HCV viral load (HCV ribonucleic acid [RNA] quantitative by 
PCR)

Confirmation of antiviral therapy with an appropriate antiviral agent for HBV is 
required in subjects with positive hepatitis B surface antigen, HBcAb IgM, and/or 
viral load - appropriate first line agents include entecavir, tenofovir, and 
lamivudine (note that lamivudine has higher resistance rates). Subjects with a 
detectable HBV and/or HCV viral load, HBcAb IgM, and/or HBsAg should be 
under the care of an expert hepatologist.

Urinalysis (Days -14 to -1)

12-lead ECG, central assessment; when an ECG time-point coincides with any other 
assessment, the ECG should always be collected first

Echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan for LVEF

Troponin-T and BNP, central assessment

Serum and/or urine beta human chorionic gonadotropin (β-hCG) (females of 
childbearing potential [FCBP] only) as per PPRMP


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
Mandatory paired tumor biopsies (formalin fixed paraffin embedded) collection. (See 
Section 6.8)

Pharmacogenomic blood sampling (see Section 6.8)

Blood samples for biomarker analyses (See Section 6.8)

Radiologic response assessment/tumor evaluation
6.2.
Treatment Period
The subject must start treatment within 28 days of signing the ICF. For all subsequent visits, an 
administrative window of ±3 days is permitted.
Treatment cycles are 28 days in duration. 
The following evaluations will be performed at the frequency specified in the Table of Events,
Table 3. The evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified:

Pregnancy prevention counseling (monthly), per the PPRMP (Appendix G, 
Section 18.7)

Adverse event evaluation (continuously)

Concomitant medications evaluation (including medications for best supportive care)

Concomitant procedures evaluation

Physical examination (source documented only) and weight

Vital signs (including blood pressure, temperature and pulse)

ECOG PS

Ophthalmologic exam (as clinically indicated)

Complete blood count (CBC) with differential and platelets

Coagulation panel: PT, INR, PTT

Troponin-T and BNP, central assessment

Chemistry laboratory (fasting, routine)

Amylase, lipase, CK, T3, TSH, fT4, immunoglobulins (IgG, IgM and IgA only) and 
T cell subsets (CD4+ and CD8+)

Alpha-fetoprotein

Hepatitis B virus viral load: Hepatitis B viral load performed only in subjects with 
positive hepatitis B viral load at baseline and/or positive HBsAg, HBcAb total, and/or 
HBcAb IgM. Laboratory test may be performed up to 48 hours before the visit.

Urinalysis

12-lead ECG, central assessment; when an ECG time-point coincides with any other 
assessment, the ECG should always be collected first


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
Echocardiogram or MUGA scan for LVEF

Serum and/or urine β-hCG (weekly during Cycle 1, females of childbearing potential 
[FCBP] only) as per PPRMP 

Dispense and account for both IPs

Pharmacokinetic sampling (see Section 6.6)

Mandatory paired tumor biopsies (formalin fixed paraffin embedded) collection. (See 
Section 6.8)

Blood samples for biomarker analyses. see (Section 6.8)

Radiologic response assessment/tumor evaluation and assessment of disease 
progression (see Section 6.5)
6.3.
End of Treatment
An end of treatment (EOT) evaluation should be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made.
The following evaluations will be performed as specified in the Table of Events, Table 3:

Physical examination (source documented only) and weight

Vital signs

Concomitant medications evaluation

Concomitant procedures evaluation

ECOG PS

Ophthalmologic exam (as clinically indicated)

Complete blood count with differential and platelets

Troponin-T and BNP, central assessment

Chemistry laboratory (fasting, routine)

Amylase, lipase, CK,T3, TSH, fT4, immunoglobulins (IgG, IgM and IgA only) and T
cell subsets (CD4+ and CD8+)

Alpha-fetoprotein

Echocardiogram or MUGA scan for LVEF

12-lead ECG

Adverse event evaluation

Urine and/or serum β-hCG (for females of childbearing potential) as per PPRMP

Radiologic response assessment/tumor evaluation and assessment of disease 
progression


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
CC-122 and nivolumab accountability
6.4.
Follow-up Period
6.4.1.
Safety Follow-up
All subjects will be monitored for reporting of new or follow-up of existing concomitant 
medications, concomitant procedures and AEs for 28 days after the last dose of CC-122.
An additional safety follow-up is required after 90 days from the last dose of nivolumab. 
Pregnancy will be reported according to Section 10.4.1, females of childbearing potential will be 
monitored for the mandatory use of effective contraception for at least 5 months after the last 
dose of nivolumab.
6.4.2.
Efficacy Follow-up
All subjects who discontinue treatment for reasons other than disease progression, start of a new 
anticancer therapy, or withdrawal of consent from the entire study will be followed for response 
until confirmation of disease progression and/or initiation of new anticancer therapies.
6.4.3.
Survival Follow-up
After the EOT visit, all subjects will be followed for survival status either until death, lost to 
follow-up, or until two years from enrollment, whichever event occurs first. This evaluation 
should be conducted every 3 months (±7 days) thereafter.  New anticancer therapies will also be 
collected at the same schedule. New anticancer therapy includes (but is not limited to) any 
systemic or locoregional medication, surgery, radiation, or any other therapy intended to treat the 
subject’s cancer.
Survival follow-up may be conducted by record review (including public records) and/or 
telephone contact with the subject, family, or the subject’s treating physician.
6.5.
Efficacy Assessments
Tumor assessments will be performed at screening (up to 28 days before the start of study 
treatment), every 8 weeks (±7 days) for the first 5 evaluations (through Month 10), thereafter 
every 12 weeks (±7 days), regardless of treatment status. Tumor assessments should also be 
performed at any time, if clinically indicated.  Tumor assessments should continue at the defined 
schedule until radiologic disease progression or the start of new anticancer therapy, beyond the 
end of treatment if necessary.
Response will be assessed using RECIST 1.1 (investigator assessment), and irRECIST as an 
exploratory assessment.  An independent review of efficacy results may take place at any time at 
the discretion of the study Sponsor. Other exploratory efficacy variables, such as ECOG PS, AFP 
reduction, etc, will be summarized as well. 
6.5.1.
Assessment of Response According to RECIST 1.1
Response assessments include computed tomography (CT) scan or magnetic resonance imaging 
(MRI).  The regions to be imaged are the chest and abdomen/pelvis, as well as any other sites 


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required for tumor imaging. The same mode of imaging for lesion evaluation at screening must 
be used consistently throughout the study.
The CT imaging should include contrast unless medically contraindicated. Conventional CT 
should be performed with contiguous cuts of 5 mm or less in slice thickness. Spiral CT should be 
performed by use of a 5 mm contiguous reconstruction algorithm.
All subjects with evidence of objective tumor response (CR or PR) should have the response 
confirmed with repeat assessments at the next scheduled scan, but after no less than 4 weeks.  
Response assessments must have occurred ≥ 6 weeks from Cycle 1 Day 1 to be considered as 
stable disease (SD) for a best response.
Additional details and definitions of response are found in Appendix B in Section 18.2.
6.5.2.
Treatment Beyond Progression
Subjects will be permitted to continue treatment beyond initial RECIST 1.1 defined progressive 
disease as long as they meet the following criteria:

Continue to meet all other study protocol eligibility criteria

Investigator assessed clinical benefit and do not have rapid disease progression or 
clinical deterioration

Stable performance status

Tolerance to IP

Other treatment options, including no treatment and supportive care, have been 
discussed and subject has consented to continue IP
A follow-up scan should be performed within 4 to 6 weeks of the original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. Thereafter, response 
assessment should occur per standard of care. The assessment of clinical benefit should be 
balanced by clinical judgment as to whether the subject is clinically deteriorating and unlikely to 
receive any benefit from continued treatment. If the Investigator feels that the subject continues 
to achieve clinical benefit by continuing treatment, the subject may remain on study treatment.
The decision to continue treatment should be discussed with the Celgene Medical Monitor and 
documented in the study source documents.
Study therapy should be discontinued if further progression is documented. For the subjects who 
continue study therapy beyond progression, further progression is defined as an additional 10% 
increase in tumor burden from time of initial PD. This increase in tumor burden includes an 
increase in all target lesions and/or the development of new measurable lesions.
6.5.3.
Other Assessments
Additional scans, including brain scans, or nuclear medicine bone scan may be performed if 
clinically indicated (eg, symptoms of brain metastasis) at the discretion of the Investigator.


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6.5.4.
Assessment of Response According to Immune-Related Response Criteria 
(irRECIST)
Evaluation of response will also be performed using irRECIST guidelines as an exploratory, but 
not treatment-determining, assessment. Evaluation via irRECIST will begin if treatment is 
continued beyond RECIST 1.1 documented progression. Additional details and definitions of 
irRECIST are found in Appendix C in Section 18.3.
6.6.
Pharmacokinetics
Plasma/serum samples will be collected to assay plasma concentrations of CC-122 and 
nivolumab.
On PK sampling days, dosing and sample collection information including dosing date, dosing 
time (24 hour clock), and actual PK blood sampling time (24 hour clock) should be accurately 
documented on the appropriate electronic case report form (eCRF) pages.
6.6.1.
Pharmacokinetics of CC-122
Pharmacokinetic samples will be collected during the dose escalation part.  No PK will be 
collected during the dose expansion part.
Dose Escalation Part (all subjects): Cycle 1 Day 15: predose (-30 to -5 minutes prior to CC-
122 dose), 0.5 hour (± 5 minutes), 1 hour (± 10 minutes), 2 hours (± 10 minutes), 4 hours (± 10 
minutes), and 8 hours (± 60 minutes) after administration of CC-122.
On C1D15, subjects will be asked NOT to take CC-122 at home.  CC-122 will be administered 
to these subjects at the study center after the collection of the predose PK blood sample.  For 
convenience, on PK collection days CC-122 should be administered first, followed by 
nivolumab.
6.6.2.
Pharmacokinetics of Nivolumab
Pharmacokinetic samples will be collected during the dose escalation part.  No PK will be 
collected during the dose expansion part.
Dose Escalation Part (all subjects): Predose (-30 to -5 minutes prior to nivolumab dose) and 
end of infusion on C1D1 and C1D15.
6.7.
12-lead Electrocardiograms
Triplicate 12-lead ECGs will be recorded at the visits listed in Table 3 and assessed centrally.  
The 12-lead ECGs (12-lead at 25 mm/second reporting rhythm, ventricular rate, PR-interval, 
QRS complex, QT interval, and QTcF interval) will be performed after the subject has been in 
the supine position for at least 5 minutes.
Triplicate ECGs (3 recordings within 2±1 minute intervals) will be performed at the following 
time points:

Screening

Cycle 1, Day 1 - Predose (0 hour; within 90 minutes prior to CC-122 dosing)


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
Cycle 1, Day 8, 15, and 22 – Predose (0 hour; within 90 minutes prior to CC-122 
dosing), 1.5 (±15 minutes) and 3 hours (±15 minutes) postdose

Day 1 of Cycle 2 and subsequent cycles - Predose (0 hour; within 90 minutes prior to 
CC-122 dosing)
Subjects will be asked NOT to take CC-122 at home on ECG evaluation days.  CC-122 will be 
administered to these subjects at the study center after the predose ECG is conducted.  For 
convenience, on ECG evaluation days CC-122 should be administered first, followed by 
nivolumab.
 
 
 
 
 
 
 
 
 
 
 
 


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6.9.
CC-122 Risk Counseling Prior to Dosing
CC-122 Pregnancy Risk Minimization Plan for Celgene Clinical Trials (Appendix G, Section
18.7) applies to all subjects receiving CC-122 therapy.
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 fertile males, other than the subject, should not handle or 
administer CC-122 unless they are wearing gloves.


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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
7.1.1.
CC-122
CC-122 will be supplied by Celgene Corporation.  CC-122 is available as a 1.0 mg formulated 
capsule (equivalent to 1.13 HCl), 2.0 mg formulated capsule (equivalent to 2.254 HCl), 2.5 mg 
formulated capsule (equivalent to 2.818 HCl), 3.0 mg formulated capsule (equivalent to 3.38 
HCl), 3.5 mg formulated capsule (equivalent to 3.95 HCl), and 4.0 mg formulated capsule 
(equivalent to 4.51 mg HCl). Each formulated capsule is provided in reddish brown gelatin 
capsules, containing the following excipients: Avicel PH 102, spray dried mannitol, 
crospovidone, aerosil and stearic acid. 
7.1.2.
Nivolumab
Nivolumab 100 mg vials (10 mg/mL) will be supplied by Celgene Corporation and labeled 
appropriately as investigational material for this study. Nivolumab vials must be stored in the 
refrigerator at 2°C to 8°C, protected from light and freezing.
7.2.
Treatment Administration and Schedule
The study is designed to explore three dose levels of CC-122 to identify the RP2D, and is not 
required to escalate to a NTD or MTD.  CC-122 will initially be administered orally 5 
consecutive days out of 7 (5 days on/2 days off weekly) on Days 1 to 5, 8 to 12, 15 to 19 and 22
to 26 of each 28-day cycle. The investigated starting daily dose of CC-122 will be 2.0 mg, and 
two subsequent dose levels (3.0 and 4.0 mg) are planned to be evaluated as described in Table 4,
based on pre-specified DLTs.  Intermediate dose levels, or a higher dose level, may be evaluated 
at the discretion of the Safety Review Committee (SRC). Dose escalation to intermediate or 
higher dose levels of CC-122 will not exceed 50% of the previously established tolerable dose 
level. Smaller dose increments based on toxicity, PK profile and PD findings may be evaluated, 
if necessary. Nivolumab will be administered at the dose of 3.0 mg/kg IV every 2 weeks. Once 
the RP2D for dosing of CC-122 in combination with nivolumab is defined, expansion (Phase 2)
will start. Investigational products will be administered for up to 2 years.
7.2.1.
Dose Levels
Dose levels to be explored are shown in Table 4.
Table 4:
Dose Levels
Dose Level
CC-122 Dose 
(mg)
CC-122 Schedule
(days)
Nivolumab Dose 
(mg/kg)
Nivolumab 
Schedule
- 1
1.0
5/7
3.0
Every 2 weeks
1
2.0
5/7
3.0
Every 2 weeks
2
3.0
5/7
3.0
Every 2 weeks
3
4.0
5/7
3.0
Every 2 weeks


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Dosing will start at dose level 1.  Each dose level must be cleared by the SRC based on review of 
all available clinical, safety, PK, PD and laboratory data before initiating the next higher dose 
level.  The study intends to identify the RP2D at or below the 4.0 mg dose level, however 
intermediate or higher dose levels may be explored at the discretion of the SRC.
During dose escalation, the decision to either evaluate a higher dose level, an intermittent dose 
schedule, or declare the RP2D (or if applicable NTD) will be determined by the SRC, based on 
their review of all available clinical data, PK, PD and laboratory safety data for a given dose 
cohort.
Intra-subject dose escalation of CC-122 is not permitted during Cycle 1, but may be permitted in 
later cycles if approved by the SRC.
Dose reduction of CC-122 and temporary interruption of one or both IPs due to toxicity during 
Cycle 1 is allowed but may constitute a DLT, as outlined in Section 7.6 and 7.9.
Study treatment may be discontinued if there is evidence of clinically significant disease 
progression, unacceptable toxicity or subject/physician decision to withdraw.  Subjects may 
continue to receive CC-122 and nivolumab beyond disease progression at the discretion of the 
Investigator.
If any subject continues to experience unacceptable toxicity after permitted IP adjustments, one 
or both IPs will be discontinued permanently.
The estimated total number of subjects to be enrolled during dose escalation is approximately 20 
to 30, depending on cohort size.  Up to 30 additional subjects will be evaluated for safety, PK, 
PD, and preliminary anti-tumor effects in one or two expansion cohorts.
7.3.
Definition of a DLT Evaluable Subject
All subjects who receive at least one dose of either CC-122 or nivolumab will be evaluable for 
DLT.
In the dose escalation part, a subject evaluable for DLT is defined as one who:

Received at least 75% of the planned doses of CC-122 and of nivolumab during 
Cycle 1 without experiencing a DLT, having been followed for the entire DLT 
assessment period (see Section 7.6)
or

Experienced a DLT after receiving at least one dose of either IP.
Non-evaluable subjects will be replaced at the discretion of the SRC.  Additional subjects within 
any dose cohort may be enrolled at the discretion of the SRC.
7.4.
Definition of Non-tolerated Dose
An NTD is defined as a dose level at which 2 or more out of up to 6 evaluable subjects in any 
dose cohort experience a DLT in Cycle 1.  Escalation to an NTD is not required in this study, as 
described in Section 7.2


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7.5.
Definition of Maximum Tolerated Dose (MTD)
If an NTD is identified, dose escalation will be stopped.  The MTD is defined as the last dose 
level below the NTD with none or 1 out of 6 evaluable subjects experiencing DLT during Cycle 
1.  The RP2D may be a dose that meets the definition of MTD, however escalation to an MTD is 
not required in this study, as described in Section 7.2.1
7.6.
Definition of Dose-Limiting Toxicity
During dose escalation, the DLT assessment period is defined as Days 1 to 28 of Cycle 1 
including the predose assessments specified for Day 1 of Cycle 2.
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 4.03 are used as a guide for the grading of severity of adverse events.
A DLT is defined as any of the following toxicities occurring within the DLT assessment 
window unless the event can clearly be determined to be unrelated to the drug. Dose-limiting 
toxicities are described below:

Any toxicity that would lead to dose reduction or discontinuation of CC-122 or 
discontinuation of nivolumab during Cycle 1.

Any Grade 4 non-hematologic toxicity of any duration.

Any clinically relevant non-hematologic toxicity that is ≥ Grade 3 except for:

Grade 3 diarrhea or vomiting of not more than 5 days duration (with optimal 
medical management)

Grade 3 fatigue or asthenia of not more than 3 days duration with optimal medical 
management

Grade 3 infusion-related reaction controlled by interruption of the infusion and 
medical management Any liver enzymes elevation according to the definitions below:

AST or ALT ≥8 x ULN of > 7 days duration

Total bilirubin ≥5 x ULN of > 7 days duration

Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN

Hematological toxicities during Cycle 1 as follows:

Grade 4 neutropenia lasting > 7 days 

Febrile neutropenia

Grade 4 thrombocytopenia lasting > 48 hours

Grade 3 or 4 thrombocytopenia with clinically significant bleeding

Any ≥ Grade 2 uveitis or eye pain that does not respond to topical therapy and does 
not improve to Grade 1 severity within the re-treatment period (≤ 6 weeks and/or 
prior to next nivolumab dose), or requires systemic treatment.


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
Any ≥ Grade 2 pneumonitis or interstitial lung disease that does not resolve with dose 
delay and systemic steroids. The management algorithm for pneumonitis or 
pulmonary toxicity can be found in the current nivolumab SmPC and in Appendix H.
Repeat laboratory assessments are required to confirm the duration of time-bound DLT criteria.  
Isolated laboratory changes without associated clinical signs or symptoms (eg, hypomagnesemia, 
hypermagnesemia, hypoalbuminemia, hypophosphatemia, lymphocyte count increased or 
decreased) may not be included in this definition.  These findings will be discussed and reviewed 
by the SRC.
Events meeting the DLT definition occurring beyond the first cycle will be taken into account 
when determining the RP2D. Any AE with the potential to become a DLT based on the duration 
should be followed appropriately to accurately determine the duration of the event.
Subjects should delay/interrupt or discontinue treatment if they experience any adverse event, 
laboratory abnormality or intercurrent illness (regardless of causality) which, in the opinion of 
the investigator, presents a substantial clinical risk to the subject with continued dosing of any 
IP.  Such delay/interruption or discontinuation, however, will not be considered a DLT unless it 
meets at least one of the DLT criteria defined above or if deemed dose-limiting by the SRC.
7.7.
Method of Treatment Assignment
An integrated response technology (IRT) will be used to track subject assignments to the dose 
levels.
7.8.
Criteria for Dose Escalation
The SRC will make dose escalation decisions.  The decision criteria for dose escalation are:

If no DLT is observed in the first 3 evaluable subjects during the first cycle, dose 
escalation to the next higher dose level may occur.

If 1 out of 6 evaluable subjects experiences DLT during the first cycle, dose 
escalation to the next higher dose level may occur.  Additional subjects will be 
enrolled to expand the cohort to 6 evaluable subjects if less than 6 subjects are 
evaluable when the DLT is observed.

If 2 or more out of up to 6 evaluable subjects experience a DLT during the DLT 
assessment period in a cohort, any further recruitment into that cohort will cease and 
this dose will be defined as an NTD.

The SRC will determine if additional subjects will be enrolled in a parallel or at lower 
dose cohorts to have 6 evaluable subjects in order to define RP2D, or whether an 
intermediate dose level or an intermittent dosing schedule will be explored in up to 6 
newly enrolled subjects.  Additional subjects may be added at a given dose level to 
further assess the safety and/or PK.
Based on above criteria, if no DLT is observed in at least 3 evaluable subjects, the SRC may 
decide to escalate the dose to the next cohort.


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If one DLT occurs prior to a decision by the SRC to dose escalate, the cohort will be expanded to 
enroll 6 evaluable subjects in total. Subjects 4 to 6 may be enrolled concurrently with the first 3 
subjects if complete 28-day toxicity data are not yet available for the first 3 subjects.
If 1 subject out of 6 evaluable subjects experiences a DLT, the dose will be escalated in the next 
cohort, unless there are other safety considerations by the SRC.  The dose may also be declared 
the RP2D.
The number of cohorts depends on incidence of DLT.  A subject may experience more than 1 
DLT.  Dose escalation decisions are based on the number of subjects experiencing DLT events.
Intra-subject dose escalation beyond the dose initially assigned to a subject is not permitted in 
Cycle 1.  Those continuing to take IP beyond Cycle 1, following approval by the SRC, may have 
the dose level increased providing the alternative dose level has been shown to be well tolerated 
by at least one cohort of other subjects in this study.
7.8.1.
Definition of Stopping Criteria for Dose Escalation
Dose escalation stops when 2 or more out of up to 6 evaluable subjects at any dose level 
experience DLT, or when the RP2D is declared.
7.9.
Permitted IP Adjustments
CC-122 dose reductions are permitted in any cycle, including Cycle 1; however in Cycle 1 this
may constitute DLT. No dose reductions are allowed for nivolumab.

Any toxicity, unless the event can clearly be determined to be unrelated to the IPs, 
should be managed according to the following tables.

In the absence of clear alternative causes of liver enzyme abnormalities meeting DLT 
criteria, both IPs should be held and/or discontinued.

Any treatment-related toxicity that leads to dose reduction or discontinuation of CC-
122 or discontinuation of nivolumab that occurs in Cycle 1 during dose escalation 
will constitute DLT.

Subjects will be allowed to continue with CC-122 at a reduced dose.
Allowed dose reductions for CC-122 are described in Table 5.
For CC-122, dose reductions below 1.0 mg are not allowed. 
Table 5:
Allowed Dose Reductions
CC-122 Starting Dose
First Reduction
Second Reduction
1.0 mg (5/7)
NA
NA
2.0 mg (5/7)
1.0 mg (5/7)
NA
3.0 mg (5/7)
2.0 mg (5/7)
1.0 mg (5/7)
4.0 mg (5/7)
3.0 mg (5/7)
2.0 mg (5/7)
5/7 = 5 out of 7 days; NA = not applicable.


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
CC-122 may be dose reduced at the discretion of the investigator and based on 
guidelines in Section 7.10.

If any subject continues to experience unacceptable toxicity after the dose reductions 
described above one or both IPs will be discontinued permanently.

Once CC-122 dosage has been reduced, it can be escalated when toxicity reaches 
≤Grade 1.  If toxicity recurs at the higher dose, the dose will be reduced a second 
time, but no re-escalation is then permitted.
7.10.
Criteria for CC-122 Dose Reduction
Any IP-related toxicity meeting the definition of DLT will require dose reduction and/or 
interruption.  The criteria for dose reduction listed in Table 6 and Table 7 should be used for 
dose modifications.
Chronic Grade 2 toxicity may warrant dose reduction of CC-122. It is recommended that such 
cases be discussed with the Sponsor before changes are made.
Table 6:
Dose Adjustment Guidelines for CC-122 Related Non-hematologic Toxicities
Toxicity
Action
AST or ALT ≥8 x ULN, OR
Total bilirubin ≥5 x ULN, OR
Concurrent AST or ALT > 3 x ULN and 
total bilirubin > 2 x ULN

Hold CC-122 until laboratory values return to baseline 
and management with corticosteroids, if needed, is 
complete

Reintroduce CC-122 at the same or to the next lower 
dose level, if available, depending on whether toxicity 
meets DLT criteria (Section 7.6)
Grade 4 liver enzyme or bilirubin 
elevation or clinical liver failure 

Permanently discontinue CC-122
If recurrence of Grade 3 event after dose-
reduction

Reduce dose to the next lower dose level; if available.
If recurrence of Grade 4 event after dose 
reduction

Discontinue CC-122
Any non-hematological toxicity requiring 
interruption for > 4 weeks

Discontinue CC-122


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Table 6:
Dose Adjustment Guidelines for CC-122 Related Non-hematologic Toxicities 
(Continued)
Toxicity
Action
Troponin-T > ULN with associated 20% 
increase in BNP over baseline with an 
absolute value > 100 pg/mL (confirmed 
on repeated measurements) without 
associated cardiac symptoms or findings 

Hold CC-122

Cardiology evaluation, notify Sponsor

Follow troponin-T, BNP, and ECG at least every 7 
days

If troponin-T returns to normal levels in ≤ 7 days and 
there are no other significant cardiac findings, restart 
CC-122 at next lower dose level or same dose

If troponin-T elevation persists beyond 7 days or 
recurs upon rechallenge, permanently discontinue CC-
122
Troponin-T > ULN with cardiac 
symptoms or significant changes in ECG 
or LVEF

Discontinue CC-122, notify Sponsor
Rash Grade 1

Management with topical corticosteroid creams and/or 
oral antipruritic as clinically indicated.
Rash Grade 2

Continue therapy if involvement of < 30% of body 
surface area, are asymptomatic or toxicity can be 
managed with topical corticosteroid creams and 
antipruritics.

If rash does not meet the above criteria, hold CC-122
and initiate treatment with topical corticosteroids.
o
Consider systemic corticosteroids if rash 
does not improve to ≤Grade 1 in ≤ 7 
days.
Rash ≥ Grade 3

If Grade 3 hold CC-122 until recovery to Grade ≤ 1.

If AE resolution to Grade ≤ 1 occurs ≤ 8 days, 
reintroduce CC-122 at the same dose level

If AE resolution to Grade ≤ 2 or > 7 days, reintroduce 
CC-122 on lower level, if available

Discontinue CC-122 for 2nd occurrence of ≥ Grade 3 
rash

For desquamating (blistering) Grade 3 or any Grade 4 
rash, discontinue CC-122

For maculopapular, acneiform, or pustular rashes 
lasting ≤ 7 days medical management is warranted


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Table 6:
Dose Adjustment Guidelines for CC-122 Related Non-hematologic Toxicities 
(Continued)
Toxicity
Action
Peripheral neuropathy
(neuropathies which begin or worsen 
while on study)
≥ 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
Allergic reaction or hypersensitivity
≥ Grade 3

Discontinue CC-122 
Venous thrombosis / embolism
≥ Grade 3

Hold CC-122 and start anticoagulation; restart CC-122
at Investigator’s discretion (maintain dose level)
Pneumonitis 
Grade 2

Hold CC-122 and nivolumab (see Table 8), consider 
corticosteroids

Restart CC-122 at next lower dose level once 
completely resolved
Pneumonitis 
≥ Grade 3

Discontinue CC-122 and nivolumab (see Table 8)

Corticosteroids recommended until symptoms resolve
Tumor flare reaction (TFR)
Grades 1-2

Continue CC-122, maintain dose level

NSAIDs and/or narcotics may also be used as per 
investigator’s discretion 

Initiate therapy with corticosteroids at the 
Investigator’s discretion
Tumor flare reaction (TFR)
Grades 3-4 (severe – disabling)

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 CC-122 at Investigator’s discretion

When the toxicity resolves to ≤ Grade 2, restart CC-
122 at the same dose level or the next lower dose level 
at Investigator´s discretion
AE = adverse event; BNP = brain natriuretic peptide; ECG = electrocardiogram: IP =investigational product; LVEF 
= left ventricular ejection fraction; NSAID = nonsteroidal anti-inflammatory drug; ULN = upper limit of normal.


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Table 7:
Dose Adjustment Guidelines for CC-122 Related Hematologic Toxicities
Toxicity
Action
Grade 2 thrombocytopenia

No action
Grade 3 thrombocytopenia

Hold until resolution to Grade 1 or baseline

Follow complete blood count (CBC) at least every 7 
days

If resolution to Grade 1 or baseline occurs ≤ 8 days, 
reintroduce CC-122 at the same dose level

If AE resolution occurs > 8 days, or event occurs 
within the same cycle, reintroduce CC-122 at the 
lower dose level, if available
Grade 4 thrombocytopenia

Hold CC-122 until recovery to Grade 1 or baseline

Repeat CBC within 24 to 48 hours

Follow CBC at least every 7 days

Reintroduce CC-122 at the lower dose level, if 
available
Grade 3 neutropenia

Hold until resolution to Grade ≤ 1 

Follow CBC at least every 7 days

If AE resolution to Grade ≤ 1 occurs ≤ 8 days, 
reintroduce CC-122 at the same dose level

If AE resolution occurs > 8 days, or event occurs 
within the same cycle, reintroduce CC-122 at one 
dose level lower, if available
Grade 4 neutropenia

Grade 4: Hold CC-122 until recovery to Grade 1

Follow CBC at least every 5 days

Reintroduce CC-122 at the lower dose level, if 
available

Use of growth factors (G-CSF, GM-CSF) is permitted 
at the discretion of the Investigator
Febrile neutropenia

Hold further dosing until recovery to Grade ≤ 1 then 
resume dosing CC-122 at one dose level lower, if 
available

Use of growth factors (G-CSF, GM-CSF) is permitted 
at the discretion of the Investigator
Any hematological toxicity requiring 
interruption for > 3 weeks

Discontinue CC-122
AE = adverse event; CBC = complete blood count; G-CSF = granulocyte-colony stimulating factor; GM-CSF =
granulocyte-macrophage colony stimulating factor.


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7.10.1.
Nivolumab Dose Delay/Interruption Criteria
Nivolumab treatment-related interruptions > 6 weeks requires treatment discontinuation (refer to 
7.10.3).
Nivolumab administration should be delayed/interrupted according to Table 8:
Table 8:
Recommended Treatment Modification for Nivolumab
Immune-related AE
Severity
Treatment Modification
Immune-related 
pneumonitis
Grade 2 pneumonitis
Withhold nivolumab until symptoms resolve, 
radiographic abnormalities improve, and 
management with corticosteroids is complete
Grade 3 or 4 pneumonitis
Permanently discontinue nivolumab
Immune-related colitis
Grade 2 or 3 diarrhea or 
colitis
Withhold nivolumab until symptoms resolve 
and management with corticosteroids, if needed, 
is complete
Grade 4 diarrhea or colitis
Permanently discontinue nivolumab
Immune-related 
hepatitis
AST or ALT ≥8 x ULN, OR
Total bilirubin ≥5 x ULN,
OR
Concurrent AST or ALT > 3 
x ULN and total bilirubin > 
2 x ULN
Withhold nivolumab until laboratory values
return to baseline and management with 
corticosteroids, if needed, is complete
Grade 4 liver enzyme or 
bilirubin elevation or clinical 
liver failure
Permanently discontinue nivolumab
Immune-related 
nephritis and renal 
dysfunction
Grade 2 or 3 creatinine 
elevation
Withhold nivolumab until creatinine returns to 
baseline and management with corticosteroids is 
complete 
Grade 4 creatinine elevation
Permanently discontinue nivolumab
Immune-related 
endocrinopathies
Symptomatic
endocrinopathies (including
hypothyroidism, 
hyperthyroidism, 
hypophysitis, adrenal 
insufficiency and diabetes)
Withhold nivolumab until symptoms resolve 
and management with corticosteroids (if needed 
for symptoms of acute inflammation) is 
complete. Nivolumab should be continued in the 
presence of hormone replacement therapy as 
long as no symptoms are present
Immune-related rash
Grade 1 rash
Management with topical corticosteroid creams 
and/or oral antipruritic as clinically indicated.


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Table 8:
Recommended Treatment Modification for Nivolumab (Continued)
Immune-related AE
Severity
Treatment Modification
Grade 2 rash
Continue therapy if involvement of < 30% of 
body surface area, are asymptomatic or toxicity 
can be managed with topical corticosteroid 
creams and antipruritics.
If rash does not meet the above criteria, hold 
nivolumab and initiate treatment with topical 
corticosteroids.
Consider systemic corticosteroids if rash does 
not improve to ≤ Grade 1 in ≤ 7 days.
Grade 3 rash
Withhold dose until symptoms resolve and 
management with corticosteroids is complete
Grade 4 rash
Permanently discontinue nivolumab
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase. 
Nivolumab should also be permanently discontinued for Grade 2 or 3 immune-related AEs that 
persist despite treatment modification or for inability to reduce corticosteroid dose to 10 mg 
prednisone or equivalent per day.
Consider resuming nivolumab only in subjects whose adverse reactions recover to ≤ Grade 1 or 
baseline.
Please refer to the nivolumab SmPC for updated details.
7.10.2.
Nivolumab Dose Reductions
There will be no intra-subject dose reductions of nivolumab during the study. 
7.10.3.
Nivolumab Dose Interruption / Discontinuation

Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond 
to topical therapy and does not improve to Grade 1 severity within the re-treatment 
period (≤ 6 weeks and/or prior to next nivolumab dose) OR requires systemic 
treatment.

Any dosing delay/interruption lasting > 6 weeks with the following exceptions: 
Dosing delays/interruptions to manage drug-related AEs such as prolonged steroid 
tapers are allowed. Prior to re-initiating treatment in the subjects with dosing 
delays/interruptions lasting > 6 weeks, the Celgene Medical Monitor must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed/interrupted.

Dosing delays/interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Celgene Medical Monitor. Prior to re-initiating treatment 
for the subjects with a dosing delay/interruption lasting > 6 weeks, the Celgene 


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Medical Monitor must be consulted. Tumor assessment should continue as per 
protocol even if dosing is delayed/interrupted.

Any AE, laboratory abnormality or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued 
nivolumab dosing.
7.10.4.
Management of Expected AEs While Receiving CC-122
7.10.4.1.
Neutropenia, Thrombocytopenia, Anemia
Approximately 50% of subjects treated in Part B of CC-122-ST-001 experienced neutropenia
(preliminary data). Neutropenia and febrile neutropenia should be managed with CC-122 dose 
interruption and G-CSF administration. Hematopoietic growth factors or other hematologic 
support, such as erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), 
GM-CSF, RBC- or platelet- transfusions are allowed in the study with therapeutic intent.
Therapeutic use of G-CSF is allowed at any time for subjects experiencing Grade 4 neutropenia 
or any grade febrile neutropenia.  Prophylactic use of granulocyte (or granulocyte-macrophage) 
growth factors is not allowed during Cycle 1.
7.10.4.2.
Infection
In prior studies with CC-122 pyrexia and infections were observed in > 20% of subjects. 
Vigilance for the signs and symptoms of infection should be practiced and managed according to 
institutional standard medical practice.  Routine infectious disease prophylaxis is not 
recommended; however, antibiotic, antiviral, antipneumocystis, antifungal, or other prophylaxis 
may be implemented during the study at the discretion of the investigator and/or SRC.
7.10.4.3.
Pain
Tumor pain or treatment-induced pain can be controlled with opioid and opioid-related 
analgesics, such as codeine, meperidine, propoxyphene or morphine, administered at the 
clinician’s discretion, and as dictated by medical need. 
7.10.4.4.
Dose Modification and Management of Cardiac Laboratory Abnormalities
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, and 
other cardiac evaluations (such as an exercise stress test, additional evaluation of LVEF, or other 
cardiac tests or cardioprotective medications recommended by a cardiologist), and the addition 
of cardioprotective therapy (eg, beta blockers or calcium channel blockers) as appropriate.  
Laboratory evaluation to assess for assay interference may also be warranted. For any confirmed 
elevation of troponin-T > ULN associated with significant elevation of BNP (20% increase from 
baseline and an absolute value > 100 pg/mL), CC-122 dosing should be held and the Sponsor 
should be notified.  Additional cardiac monitoring should be performed as described in Table 6
and as medically indicated. CC-122 may be restarted at a reduced dose or the same dose, in 
consultation with the Sponsor, based on troponin-T/BNP guidelines in Table 6. For troponin-T 
elevations > ULN that either persist for > 7 days, recur with CC-122 rechallenge or are


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associated with cardiac symptoms or significant changes in ECG or LVEF, CC-122 should be 
permanently discontinued.
In addition to routine ECG monitoring, please refer to the nivolumab SmPC for additional 
information regarding potential cardiac toxicity with nivolumab.
7.10.4.5.
Dose Modification and Management of Pneumonitis
Pneumonitis has been observed in subjects 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 and nivolumab treatment should be interrupted and corticosteroids may be 
indicated. Once symptoms have resolved to Grade 0 or 1, CC-122 may be reintroduced at the 
next lower dose level. For drug-related Grades 3 or 4 pneumonitis, CC-122 and nivolumab must 
be permanently discontinued and corticosteroids are recommended until clinical symptoms have 
resolved.
Pneumonitis has been also observed in subjects taking nivolumab. Pneumonitis may be 
considered related to both IPs. Please refer to nivolumab SmPC (or Appendix H in Section 18.8)
for pneumonitis management guidelines in subjects receiving nivolumab. 
7.10.4.6.
Dose Modification and Management of Tumor Flare Reaction
Subjects in this study should be monitored for tumor flare.  Tumor flare reaction (TFR) is 
defined as a sudden and tender increase in the size of the disease-bearing sites, including the 
lymph nodes, spleen and/or the liver, often accompanied by low-grade fever, and non-pruritic 
diffuse rash.  Tumor flare usually occurs within the first cycle of treatment.  Tumor flare reaction 
may mimic progression of disease; however, the TFR will generally subside over time.  
Therefore, careful monitoring and evaluation is important prior to discontinuing a study subject 
for PD in the initial cycles of CC-122 therapy.
There are currently no laboratory or radiological tests that distinguish TFR from PD.  The 
distinction should be made on clinical grounds, incorporating observations such as associated 
physical findings, laboratory findings, and pace of disease before and after institution of 
treatment.  Tumor flare will be recorded as an AE (graded using the NCI CTCAE version 3.0 
criteria) and not as PD.
Treatment of the TFR is up to the discretion of the investigator depending on the severity and 
clinical situation.  In mild to moderate cases (Grades 1 to 2), it is suggested that CC-122 be 
continued along with symptomatic treatment such as nonsteroidal anti-inflammatory drugs
(NSAIDs) and/or narcotics. Corticosteroids can be administered at the investigator’s discretion.  
In more severe cases (Grade 3 to 4), CC-122 and/or nivolumab should be interrupted and therapy 
with corticosteroids should be initiated. NSAIDs and/or narcotics may also be used at the 
investigator’s discretion. When symptoms resolve to ≤ Grade 1, CC-122 and/or nivolumab can 
be restarted at the same dose level.


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7.10.4.7.
Management and Follow-up of Liver Function Test Abnormalities Grade 3
Subjects experiencing a Grade 3 liver function test (LFT) elevation should undergo the 
additional testing below until LFT abnormalities improve to Grade 1 or better:

Hepatitis A, B, and C acute infection serology testing

Once weekly HBV viral load (for subjects with known HBV infection)

Twice weekly check of AST, ALT, bilirubin, alkaline phosphatase, PT, PTT, INR
7.10.4.8.
Management of Dermatological Toxicity
Rash is a toxicity which has been previously observed with CC-122 therapy. Additionally, 
dermatological toxicity (rash and pruritis) is a documented immune related adverse event 
associated with checkpoint inhibitors. Initial treatment options may include topical corticosteroid 
creams and oral antipruritics. For Grade 3 rash, drug should be interrupted and treatment with 
oral corticosteroids may be warranted (Postow, 2015).
For Grade 2 toxicity, both drugs may be withheld and treatment with topical corticosteroids 
initiated with consideration for systemic corticosteroids if there is no improvement in symptoms 
within 1 week. Therapy may be continued if involvement of < 30% of body surface area, are 
asymptomatic, or toxicity can be managed with topical corticosteroid creams and antipruritics 
(Villadolid, 2015).
7.10.5.
Management of Expected AEs While Receiving Nivolumab
Please refer to nivolumab SmPC (or Appendix H in Section 18.8) for additional guidelines on
nivolumab toxicity management, or refer to the current local label.
7.11.
Definition of an Overdose
Overdose, as defined for this protocol, refers to CC-122 and nivolumab dosing.
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
doses of CC-122 and/or nivolumab assigned to a given subject, regardless of any associated 
adverse events or sequelae.

Orally (PO) any amount over the protocol-specified dose

Intravenously (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 rate specified in the 
local label. 
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 
10.1 for the reporting of AEs associated with overdose.


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7.12.
Treatment Delay
Treatment may be interrupted until treatment-related toxicity reaches either ≤ Grade 1 or 
baseline levels.  Treatment may restart either at the same, or a reduced, dose level, at the 
Investigator’s discretion as described in Section 7.10.
7.13.
Packaging and Labeling
The label(s) for CC-122 and nivolumab will include sponsor name, address and telephone
number, the protocol number, drug name, dosage form and strength (where applicable), amount 
of IP per container, lot number, expiry date (where applicable), medication identification/kit 
number, dosing instructions, storage conditions, and required caution statements and/or 
regulatory statements as applicable. Additional information may be included on the label as 
applicable per local regulations.
7.14.
Investigational Product Accountability and Disposal
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for IP return, disposal, and/or destruction including responsibilities for the site versus Celgene 
(or designee).
7.15.
Investigational Product Compliance
Only the pharmacist or the Investigator’s designee will dispense CC-122.  A record of the 
number of capsules dispensed to and taken by each subject must be maintained. The pharmacist 
or the investigator’s designee will document the dose dispensed in the appropriate study records.
Subjects will use weekly diary cards to record their daily self-administration of CC-122 at home.  
These will be reviewed by study staff each time the subject visits the clinic.  Entries will be 
clarified, as necessary, so that appropriate information can be captured on the eCRFs.  Study site 
personnel will perform a CC-122 administration compliance check and record this information 
on the subject’s source documentation and on the appropriate eCRF.
Accurate recording of nivolumab IV administration will be made in the appropriate section of the 
subject’s eCRF and source documents. The investigator or designee is responsible for accounting 
for all study-specific IPs both administered or in their custody during the course of the study.








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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
The primary objectives of this Phase 1/2, multicenter, open-label, dose finding study are to 
determine the safety and tolerability of CC-122 when administered orally in combination with 
nivolumab, to define the recommended Phase 2 dose (RP2D) and to determine the preliminary
efficacy of CC-122 in combination with nivolumab based on RECIST 1.1 (Eisenhauer, 2009).
Data summaries/statistical analyses will be performed by study part, dose level/dosing regimen 
and/or HCC etiology as needed or applicable.
9.2.
Study Population Definitions
The study population definitions are as follows:

Enrolled Population – All subjects who meet all the inclusion/exclusion criteria and 
are eligible for the study.

Treated Population – All subjects who enroll and take at least one dose of either IP 
(CC-122 or nivolumab).

Dose limiting toxicity evaluable population: defined in Section 7.3

Efficacy Evaluable (EE) Population – All subjects who enroll and meet eligibility 
criteria and receive at least 50% of both assigned IP in the first 2 cycles, have a 
baseline efficacy (tumor) assessment, and at least one post-baseline efficacy (tumor) 
assessment.

Pharmacokinetic (PK) Evaluable Population –All subjects who enroll and receive at 
least one dose of either IP and have at least one measurable concentration of CC-122
or nivolumab.

Biomarker Evaluable (BE) Population – all subjects who enroll and take at least one 
dose of either IP, and have at least 1 non-missing biomarker assessment, excluding 
the disqualified assessments.
9.3.
Sample Size and Power Considerations
During the dose escalation part (Phase 1) of the study, a modified 3+3 dose escalation design 
(Storer, 1989) will be used to identify initial toxicity of the combinations as described in 
Section 7.2 and up to approximately 20 subjects will be enrolled depending on the number and 
size of dose cohorts evaluated. 
During the dose expansion part (Phase 2), 30 additional subjects will be enrolled to an expansion 
cohorts of mixed HCC etiology (HBV, HCV and non-viral).  The sample size is not determined 
based on power calculation but rather on clinical, empirical and practical considerations 
traditionally used for exploratory studies of this kind.  If the response rate is 20% or more, there 
will be more than a 95% chance that one or more responders would be observed in the first 14 
subjects (Gehan, 1961).  If no responder is observed out of 14 subjects, the enrollment for the 
expansion cohort will stop for futility.  Otherwise, the cohort will be expanded to up to 
approximately 30 subjects.  Enrollment will continue during the evaluation of the initial 14 


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subjects.  The 2-sided 95% CI for 20% and 35% response rate is tabulated in Table 9 for 
different sample size scenarios.
With 30 subjects enrolled and assuming the observed overall response rate is 35%, the two-sided 
95% Wilson score CI will exclude 20%, the estimated overall response rate for nivolumab 
monotherapy (El-Khoueiry, 2015).
Table 9:
Confidence Interval for 20% and 35% Response Rate for Different Scenarios 
of Sample Size (Wilson Score Interval)
CI
Response Rate
Sample Size
14
20
30
40
0.95
0.2
(0.068 ,0.461)
(0.081 ,0.416)
(0.095 ,0.373)
(0.105 ,0.348)
0.95
0.35
(0.159 ,0.606)
(0.181 ,0.567)
(0.205 ,0.529)
(0.221 ,0.505)
CI = confidence interval.
9.4.
Background and Demographic Characteristics
Subjects’ age, weight, height and other continuous demographic and baseline variables will be 
summarized using descriptive statistics, while gender, race and other categorical variables will be 
summarized with frequency tabulations.  Medical history data will be summarized using 
frequency tabulations by the Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class (SOC) and preferred term (PT).  Prior therapies will be summarized by frequency 
tabulation, if available.  Supportive corresponding subject listings will also be provided.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, ongoing, discontinued from treatment and/or 
study, along with primary reason for discontinuation) will be summarized using frequency and 
percent.  A summary of subjects enrolled by site will be provided. Protocol violations will be 
summarized using frequency tabulations.  Supportive corresponding subject listings will also be 
provided.
9.6.
Efficacy Analysis
Efficacy analyses will be based on the Treated Population and certain efficacy analyses will also 
be performed on the EE Population.
The efficacy variables include ORR, DCR, duration of response (DoR), PFS, TTP and OS.  
Tumor response and progression will be determined by the Investigator based on RECIST 1.1
(Eisenhauer, 2009) as a primary guideline, and irRECIST (Bohnsack, 2014) as an exploratory 
assessment.
Tumor response will be summarized using frequency tabulation.  Two-sided 95% Clopper-
Pearson exact CIs of the response rate will be provided (Clopper, 1934).  A case-by-case 
description of all subjects who exhibited a complete or partial response will be provided.
The Kaplan-Meier estimate of the median of PFS, OS, DoR and TTP along with their 95% CI
will be provided as appropriate (Brookmeyer, 1982).  Progression free survival and OS rates at 


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selected time point(s) will be computed using the Kaplan-Meier estimates, along with standard 
errors of rate (
).
Other exploratory efficacy variables, such as AFP reduction, etc, will be summarized using 
frequency tabulations for categorical variables and/or descriptive statistics for continuous 
variables, as appropriate. Alpha-fetoprotein response rate will be provided with its 95% CI.  
Alpha-fetoprotein response is defined as normalization or > 50% decline from baseline. The AFP
response rate is the percentage of subjects with baseline elevation in AFP who meet AFP
response criteria.  A descriptive analysis for other evidence of antitumor activity will be provided 
based on clinical, radiographic, and biologic assessments of efficacy.
Listings and graphical displays will be provided where useful for the interpretation of results.
Full details on the efficacy analysis are described in the SAP.
9.7.
Safety Analysis
All summaries of safety data will be conducted using subjects receiving at least one dose of 
either IP (the Treated Population).
Adverse events observed will be classified using the Medical Dictionary for Regulatory 
Activities (MedDRA). The severity of the toxicities will be graded according to the NCI 
CTCAE (Version 4.03) whenever possible. The frequencies of adverse events will be tabulated 
by MedDRA (Version 17.1 or higher) SOC and PT.  In the by-subject analysis, a subject having 
the same AE more than once will be counted only once.  Adverse events will also be summarized 
by NCI CTCAE grade.  Investigational product-related AEs, AEs leading to dose 
reduction/interruption, or permanent discontinuation of study treatment, events classified as 
CTCAE Grade 3 or 4, deaths, and SAEs will be tabulated.  By-subject listings of all AEs, deaths, 
serious AEs (SAEs) and their attribution will be provided.
Clinical laboratory results will be summarized descriptively, which will include a display of 
change from baseline. Bidirectional shift tables (low and high) demonstrating the change of 
CTCAE grades from baseline to the worst post-baseline severity grade during the treatment 
period will also be presented for applicable tests.  Listings of abnormal clinical laboratory data 
according to NCI CTCAE severity grades (if applicable), abnormal flags (low or high) will be 
provided.  Graphical displays (eg, “spaghetti” plots or box plots) will be provided for key 
laboratory tests.
Descriptive statistics for ECG, vital sign and LVEF measurement, both observed values and 
changes from baseline, will be summarized.  Shift tables demonstrating the changes from 
baseline to the worst post-baseline qualitative assessment of abnormality will be displayed in 
cross-tabulations.  Post-baseline abnormal ECG and LVEF values will be summarized using 
frequency tabulations.  Electrocardiogram, vital sign and LVEF measurements will be listed by 
subject.  Graphical displays will be provided where useful to assist the interpretation of results.
9.8.
Interim Analysis
Not applicable.


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9.9.
Other Topics
9.9.1.
Assessment of Pharmacokinetics
Blood will be collected according to intensive and sparse sampling strategies to estimate the 
population PK of CC-122 when administered in combination with nivolumab.
Noncompartmental analyses will be performed using Phoenix WinNonlin Version 6.3 (Pharsight 
Corp., Mountain View, CA). The following PK measurements will be determined for CC-122 in 
subjects with intensive PK sampling:

Area under the plasma concentration time-curve (AUC).

Peak (maximum) plasma concentration (Cmax).

Terminal half-life (t1/2).

Time to maximum plasma concentration (Tmax).

Apparent total body clearance (CL/F).

Apparent volume of distribution (Vz/F).
Sparse serum concentrations of nivolumab will be evaluated after the first dose administration 
with nivolumab and at steady state.  Sparse concentrations of nivolumab will be summarized by 
descriptive statistics by cohort, visit and nominal time.  If warranted, the impact of CC-122 on 
target mediated disposition of nivolumab will be assessed by non-mixed effect modeling 
(NMEM) compartment approach.
Descriptive statistics (N, mean, standard deviation, coefficient of variation (CV%), geometric 
mean, geometric CV%, median, minimum, and maximum) for plasma concentration and PK 
parameters will be provided.  Correlations of drug exposure with safety, PD and clinical 
endpoints may also be analyzed as exploratory endpoints.  Results will be presented in tabular 
and graphic forms as appropriate.
 
 
 
 
 
 
 
 


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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, 
including laboratory test values (as specified by the criteria in Section 10.3), regardless of 
etiology. Any worsening (ie, any clinically significant adverse change in the frequency or 
intensity of a pre-existing condition) should be considered an AE.  A diagnosis or syndrome 
should be recorded on the AE page of the eCRF rather than the individual signs or symptoms of 
the diagnosis or syndrome.
Abuse, withdrawal, sensitivity or toxicity to an IP should be reported as an AE. Overdose, 
accidental or intentional, whether or not it is associated with an AE should be reported on the 
overdose eCRF. (See Section 7.11 for the definition of overdose.) Any sequela of an accidental 
or intentional overdose of an IP should be reported as an AE on the AE eCRF. If the sequela of 
an overdose is an SAE, then the sequela must be reported on an SAE report form and on the AE 
eCRF. The overdose resulting in the SAE should be identified as the cause of the event on the 
SAE report form and eCRF but should not be reported as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for CC-122 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 CC-122 and until 90 days after the last dose of nivolumab and 
those SAEs made known to the investigator at any time thereafter that are suspected of being 
related to CC-122 or nivolumab.  Adverse events and SAEs will be recorded on the AE page of 
the eCRF and in the subject’s source documents.  All SAEs must be reported to Celgene Drug 
Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, or other 
appropriate method, using the SAE Report Form, or approved equivalent form.
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to:
10.2.1.
Seriousness
A serious adverse event (SAE) is any AE occurring at any dose that:

Results in death;

Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);


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
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
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 that has no worsened from baseline.

Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the 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 CC-122 and nivolumab, action taken regarding both IPs, and outcome.


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10.2.2.
Severity / Intensity
For both AEs and SAEs, the Investigator must assess the severity / intensity of the event.
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the current active minor version of the NCI CTCAE (Version 4.03), whenever possible:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
AEs that are not defined in the NCI CTCAE, Version 4.03, (eg tumor flare reaction) should be 
evaluated for severity/intensity according to Version 3.0):
Otherwise, the following scale should be used:
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; no 
or minimal medical intervention/therapy required
Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible
Grade 4 = Life threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of CC-122 and 
nivolumab 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 
IPs 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.


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If an event is assessed as suspected of being related to a comparator, ancillary or additional IP
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with CC-122 and nivolumab as a result of an AE or 
SAE, as applicable (eg, discontinuation, interruption, or reduction of either IP, as appropriate) 
and report if concomitant and/or additional treatments were given for the event.
10.2.6.
Outcome
The investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered or death (due to the 
SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of either IP dose, or any other 
therapeutic intervention; or

is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as an SAE.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or female partner of a male subject are immediately reportable events.
In the event, of a pregnancy occurring in a female subject of childbearing potential or female 
partner of the male subject, Celgene Drug Safety will follow up with the clinical investigator 
each trimester of the pregnancy and for 1 year following the birth of the infant (if applicable). 


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Please reference the informed consent (permission) forms for data collection regarding the 
pregnancy of a female subject participating in a Celgene sponsored study, the pregnancy of a 
female partner of a male subject participating in a Celgene sponsored study and the pregnancy of 
a non-subject pregnant female.  In all scenarios, data collection will occur each trimester of the 
pregnancy and for 1 year after birth of infant (if applicable).  
The exposure of any non-subject pregnant female (eg, caregiver, pharmacist, study coordinator 
or monitor) to CC-122 is also an immediately reportable event.
10.4.1.
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated -βhCG and/or a positive pregnancy 
test in a female subject of childbearing potential regardless of disease state) occurring while the 
subject is on CC-122, or within 28 days of the subject’s last dose of CC-122, or within 5 months
of the last dose of nivolumab are considered immediately reportable events.  CC-122 and 
nivolumab are to be discontinued immediately. The subject will be instructed to return any 
unused CC-122 to the Investigator. 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 female 
subject should be referred to her 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.
In the event, of a pregnancy occurring in a female subject of childbearing potential, Celgene will 
follow up with the clinical investigator each trimester of the pregnancy and for 1 year following 
the birth of the infant (if applicable). Any follow-up information or outcome information must be 
reported to Celgene Drug Safety immediately. 
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 CC-122 or nivolumab 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.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant while the male subject is still 
receiving treatment or within 90 days of the male subject’s last dose of CC-122, the male subject 
taking CC-122 and nivolumab should notify the Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately.


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In the event, of a pregnancy occurring in a female partner of the male subject, Celgene will 
follow up with the clinical investigator each trimester of the pregnancy and for 1 year following 
the birth of the infant (if applicable). Any follow-up information or outcome information must be 
reported to Celgene Drug Safety immediately.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method, 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 CC-122 or nivolumab) that 
occur during the study (from the time the subject signs informed consent until 28 days after the 
last dose of CC-122 or until 90 days after the last dose of nivolumab) or any SAE made known 
to the Investigator at any time thereafter that are suspected of being related to either IP.  Serious 
adverse events occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board (IRB) /Ethics Committee (EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to CC-122 based on the Investigator Brochure. Celgene Drug 
Safety will determine the expectedness of events suspected of being related to nivolumab based 
on the SmPC.
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, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 


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presentation of adverse reaction reports arising from clinical studies on investigational products 
for human use (ENTR/CT3) and also in accordance with country-specific requirements.
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 CC-122 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 14.3 for record retention 
information.)
 


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11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the IP:

Adverse event

Progressive disease

Symptomatic deterioration (global deterioration of health status)

Physician decision

Withdrawal by subject

Death

Lost to follow-up

Protocol violation

Other (to be specified on the eCRF)
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.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Screen failure

Adverse event

Withdrawal by subject

Death

Lost to follow-up

Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.


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12.
EMERGENCY PROCEDURES
 
 
 
 
 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.


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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in (ICH) Guideline E6 and 
in accordance with the general ethical principles outlined in the Declaration of Helsinki. The 
study will receive approval from an IRB/EC prior to commencement. The Investigator will 
conduct all aspects of this study in accordance with applicable national, state, and local laws of 
the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for GCP and in the local 
regulations. Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an ICF 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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13.3.
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 ICF 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 ICF 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 ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor. Amendments will be submitted to the IRB/EC for written approval. 
Written approval must be obtained before implementation of the amended version occurs. The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
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 


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been received by Celgene or its authorized representative. This documentation must also include 
a list of the members of the IRB/EC and their occupation and qualifications. If the IRB/EC will 
not disclose the names, occupations and qualifications of the committee members, it should be 
asked to issue a statement confirming that the composition of the committee is in accordance 
with GCP. For example, the IRB General Assurance Number may be accepted as a substitute for 
this list. Formal approval by the IRB/EC should mention the protocol title, number, amendment 
number (if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the
IRB/EC prior to use.
13.7.
Ongoing Information for Institutional Review Board / Ethics
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected 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.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc.).
In 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;

Good clinical practice noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.


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14.
DATA HANDLING AND RECORDKEEPING
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the 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 case report forms (CRFs) or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team. Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions 
to these issues will be reflected in the database. An audit trail within the system will track all 
changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer.
Essential documents include, but are not limited to, the following:

Signed ICFs 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. 
Investigator or institutions should take measures to prevent accidental or premature destruction 
of these documents.


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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs. 
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigator’s 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.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a GCP 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 GCP guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, Food and Drug Administration 
(FDA), European Medicines Agency (EMA), Health Canada) and company authorized 
representatives. The Investigator should make every effort to be available for the audits and/or 
inspections. If the Investigator is contacted by any regulatory authority regarding an inspection, 
he/she should contact Celgene immediately.


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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications. Celgene protocol-
related information proposed for use in a publication, must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance. This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on several
considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.












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18.
APPENDICES
18.1.
Appendix A:  Table of Abbreviations
Table 10:
Abbreviations and Specialist Terms
Abbreviation or Specialist Term
Explanation
AASLD
American Association for the Study of Liver Diseases 
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse events
AFP
Alpha-fetoprotein 
AIC
Active ingredient in capsule
ALT/SGPT
Alanine aminotransferase/serum glutamic pyruvic transaminase
ANC
Absolute neutrophil count 
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase
AUC
Area under the concentration time curve
β-hCG
Beta human chorionic gonadotropin
BCLC
Barcelona Clinic Liver Cancer 
BE
Biomarker Evaluable
bFGF
Basic fibroblast growth factor
Β-hCG
Beta human chorionic gonadotropin
BNP
Brain natriuretic peptide
BUN
Blood urea nitrogen 
C
Cycle
CBC
Complete blood count
cHCC-CC
Combined hepatocellular cholangiocarcinoma
CI
Confidence interval
CK
Creatine kinase
CL/F
Apparent total body clearance 
Cmax
Maximum observed concentration
CO2
Carbon dioxide 
CP
Child-Pugh 
CR
Complete response
CRBN
Cereblon


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Table 10:
Abbreviations and Specialist Terms (Continued)
Abbreviation or Specialist Term
Explanation
CRF
Case report form
CT
Computed tomography 
CV%
Coefficient of variation
CYP
Cytochrome P450
D
Day
DCR
Disease control rate 
DLBCL
Diffuse large B cell lymphoma
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response 
EC
Ethics Committee 
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic case report form
EOT
End of treatment
EE
Efficacy Evaluable
EEA
European Economic Area
EMA
European Medicines Agency
FCBP
Females of child bearing potential 
FDA
Food and Drug Administration
FFPE
Formalin-fixed paraffin embedded 
GBM
Glioblastoma multiforme
GCP
Good Clinical Practices 
G-CSF
Granulocyte-colony stimulating factor 
GM-CSF
Granulocyte-macrophage colony stimulating factor 
HBcAb
Hepatitis B core antibody 
HBeAb
Hepatitis B e antibody
HBeAg
Hepatitis B e antigen 
HBsAb
Hepatitis B surface antibody 
HBsAg
Hepatitis B surface antigen


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Table 10:
Abbreviations and Specialist Terms (Continued)
Abbreviation or Specialist Term
Explanation
HBV
Hepatitis B virus 
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus 
HCVAb
Hepatitis C virus antibody 
Hgb
Hemoglobin
HIV
Human immunodeficiency virus 
HUVEC
Human umbilical vein endothelial cells
ICF
Informed consent form
ICH
International Conference on Harmonisation 
IFN-γ
Interferon-gamma 
Ig
Immunoglobulin
IGF
Insulin like growth factor 
IHC
Immunohistochemistry
IL
Interleukin
IMiD
A proprietary series of drugs with immunomodulatory and other 
properties
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board 
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors 
IRT
Integrated response technology
IV
Intravenously
LDH
Lactate dehydrogenase 
LFT
Liver function test
LVEF
Left ventricular ejection fraction 
mAb
Monoclonal antibody 
MedDRA
Medical Dictionary for Regulatory Activities 
MM
Multiple myeloma
MMPA
mouse Matrigel plug assay 
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose


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Table 10:
Abbreviations and Specialist Terms (Continued)
Abbreviation or Specialist Term
Explanation
MUGA
Multi-gated acquisition 
NASH
Non-alcoholic steatohepatitis (ie, non-alcoholic fatty liver disease) 
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NHL
Non-Hodgkin’s lymphoma 
NK
Natural killer (cells)
NMEM
Non-mixed effect modeling 
NSAIDS
Nonsteroidal anti-inflammatory drugs
NTD
Nontolerated dose
ORR
Overall response rate 
OS
Overall survival
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PD-1
Programmed death 1 
PD-L1
PD-1 ligand receptor 
PDGF
Platelet-derived growth factor
PDGFR
Platelet-derived growth factor receptor
PFS
Progression-free survival 
PI
Principal Investigator
PK
Pharmacokinetics
PO
Orally
PPRMP
Pregnancy Prevention Risk Management Plans
PR 
Partial response
PBMC
Peripheral blood mononuclear cells
PT
Prothrombin time 
PT
Preferred term
PTT
Partial thromboplastin time 
QD
Once a day
QTcF
QT interval corrected Fridericia
RANTES
Regulated upon activation, normal T cell expressed and secreted
RBC
Red blood cell 


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Table 10:
Abbreviations and Specialist Terms (Continued)
Abbreviation or Specialist Term
Explanation
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
RRMM
Relapsed or refractory multiple myeloma
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease
SEB
Staphylococcal enterotoxin B 
SEER
Surveillance, Epidemiology, and End Results 
SmPC
Summary of Product Characteristics
SOC
System organ class 
SOP
Standard operating procedure
SRC
Safety review committee
SUSARs
Suspected unexpected serious adverse reactions 
t1/2
Terminal half-life
TAA
Tumor-associated antigens
TCR
T cell diversity
TEAE
Treatment-emergent adverse events
TESAE
Treatment-emergent serious adverse event
TFR
Tumor flare reaction
TSH
Thyroid stimulating hormone
Tmax
Time to maximum concentration
TTP
Time to progression 
ULN
Upper limit of normal
US
United States
UV
Ultraviolet
VEGF
Vascular endothelial growth factor
VEGFR 1-3
Vascular endothelial growth factor receptor 1-3
Vz/F
Apparent volume of distribution
WBC
White blood cell 
WHO
World Health Organization




































































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Summary of Changes CC-122-HCC-002
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1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
1. Per Food and Drug Administration (FDA) request on Investigator Brochure (IB) Edition 
9, protocol was updated to include standard Cytochrome P450 (CYP) interaction 
language in alignment with all CC-122 studies.
Revised Sections:  8.2.
2. Updates to exclusion criteria. 
Exclusion criteria #1 was updated to exclude all subjects who have had prior treatment 
with regorafenib. This change is based on the recent FDA approval of regorafenib for 
hepatocellular carcinoma (HCC) in the second line setting in order to maintain the 
homogeneity of the patient population. 
Exclusion criteria #3 was updated to exclude any subjects with systemic therapy in the 4 
weeks prior to starting investigational product in order to allow for an appropriate wash 
out period for any prior therapies. 
Exclusion criteria #15h was changed from >100 pg/mL to >300 pg/mL to allow for 
inclusion of subjects with brain natriuretic peptide (BNP) between 100-300 pg/mL with 
cardiologist evaluation (specified under section 15.h.a). This change was made to allow 
subjects at low cardiac risk to be enrolled in the trial despite slightly elevated BNP. This 
language was updated in alignment with existing wording in other CC-122 protocols (eg,
CC-122-ST-001).
Revised Sections:  4.3.
3. Due to the incidence of rash (and subsequent dose limiting toxicities) observed during the 
dose escalation portion of the study, language was added to the protocol to provide 
guidelines on the management of Grade 1 and Grade 2 rash. Rash is known to be a
potential overlapping toxicity between CC-122 and nivolumab and these guidelines are 
being implemented to help mitigate the risk of these rashes reaching Grade 3 or higher.  
Revised Sections:  Table 6, Table 8, 7.10.4.8 (added).
4. Per Celgene protocol template and Informed Consent Form (ICF) template, updates to
pregnancy language as defined by Drug Safety for teratogenic compounds (including CC-
122). 
Revised Sections: 10.4, 10.4.1, 10.4.2.
Minor changes included in this amendment are summarized below:
Minor editorial changes throughout.
Revised Sections: Global
Addition of Celgene Therapeutic Area Head name and Title.
Revised Section: Celgene Therapeutic Area Head Signature Page


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Protocol Summary was updated to include withdrawal of consent as a reason why 
subjects would not be followed for tumor evaluation until progression. This update was 
made for consistency with section 3.2.
Revised Section: Protocol Summary (Length of Study)
Clarification of language surrounding when archival tumor biopsies may be accepted in 
lieu of fresh tumor biopsies.
 
Revised Sections: 4.3.
Clarification of wording surrounding pregnancy testing requirements to include serum 
and/or urine testing according to the Pregnancy Prevention Risk Management Plan 
(PPRMP). 
Revised Sections: Table 3, 6.1, 6.2, 6.3. 
Clarification of wording surrounding the timing of Immune-related Response Evaluation 
Criteria in Solid Tumors (irRECIST).
Revised Sections: Table 3, 6.5.4. 
Updated screening procedures to require hepatitis B virus (HBV) and hepatitis C virus 
(HCV) viral load at screening for all subjects to ensure consistency with table of events. 
Revised Sections: 6.1. 
Updated text of protocol for consistency with Protocol Summary to include that an 
independent review of efficacy results may take place at any time.
Revised Sections: 6.5. 
Added text to clarify that CC-122 should not be taken at home on days when predose 
assessments are scheduled for consistency with Section 6.6.1 Pharmacokinetics of CC-
122. 
Revised Sections: 6.7, 6.8.3. 
Updated text to reference the Summary of Product Characteristics (SmPC) for additional 
information regarding potential adverse events with nivolumab. 
Revised Sections: 7.10.4.4.
Additional references were added with revisions and/or new information: Flockhart,
Postow and Villadolid.
Revised Sections: 7.10.4.8, 8.2, 17
Changed text to clarify that a nivolumab overdose (on an infusion rate basis) is now 
defined as “any rate faster than the rate specified in the local label”. This was changed 
from “any rate faster than the protocol specified rate”.
Revised Sections: 7.11.

SAP_001.pdf: 
Official Title of Study: 
A PHASE 1/2, MULTICENTER, OPEN-LABEL, DOSE FINDING STUDY TO ASSESS THE SAFETY, 
TOLERABILITY, AND PRELIMINARY EFFICACY OF CC-122 IN COMBINATION WITH NIVOLUMAB 
IN SUBJECTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (HCC) 
NCT Number: NCT02859324 
Document Date (Date in which document was last revised): April 30, 2020 


CC-122
Statistical Analysis Plan. Protocol CC-122-HCC-002
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 1/2, MULTICENTER, OPEN-LABEL, DOSE FINDING STUDY TO ASSESS THE 
SAFETY, TOLERABILITY, AND PRELIMINARY EFFICACY OF CC-122 IN 
COMBINATION WITH NIVOLUMAB IN SUBJECTS WITH UNRESECTABLE 
HEPATOCELLULAR CARCINOMA (HCC)
STUDY DRUG:
CC-122
PROTOCOL NUMBER:
CC-122-HCC-002
DATE FINAL:
30APR2020
 
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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TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................7
1.
LIST OF ABBREVIATIONS...................................................................................9
3.
STUDY OBJECTIVES...........................................................................................14
3.1.
Primary Objective...................................................................................................14
3.2.
Secondary Objectives .............................................................................................14
4.
INVESTIGATIONAL PLAN .................................................................................15
4.1.
Overall Study Design and Plan ...............................................................................15
4.2.
Study Endpoints .....................................................................................................17
4.3.
Stratification, Randomization, and Blinding............................................................18
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................19
5.1.
Reporting Conventions ...........................................................................................19
5.1.1.
General Reporting Conventions ..............................................................................19
5.1.2.
General Definitions.................................................................................................20
5.2.
Analysis Populations ..............................................................................................20
5.2.1.
Efficacy Evaluable (EE) .........................................................................................20
5.2.2.
Enrolled..................................................................................................................20
5.2.3.
Safety.....................................................................................................................20
5.2.4.
Pharmacokinetics (PK) Evaluable...........................................................................20
5.2.6.
Reporting for Analysis Populations.........................................................................20
6.
SUBJECT DISPOSITION......................................................................................22
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................24
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................25
8.1.
Demographics.........................................................................................................25
8.2.
Baseline Characteristics..........................................................................................25
8.3.
Medical History......................................................................................................26
8.4.
Prior Therapies for This Disease.............................................................................26
 


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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................28
9.1.
Treatment Duration.................................................................................................28
9.2.
Number of Days Dosed...........................................................................................28
9.3.
Number of Cycles...................................................................................................29
9.4.
Average Length of Cycle........................................................................................29
9.5.
Average Number of Days Dosed per Cycle.............................................................29
9.6.
Cumulative Actual Dose.........................................................................................29
9.7.
Average Daily Dose................................................................................................30
9.8.
Actual Dose Intensity .............................................................................................30
9.9.
Relative Dose Intensity...........................................................................................30
9.10.
Dose Reduction/Interruption/Delay.........................................................................31
10.
EFFICACY ANALYSIS ........................................................................................33
10.1.
Response Criteria....................................................................................................34
10.2.
Best Overall Response (BOR).................................................................................36
10.3.
Duration of Response (DoR) and duration of SD ....................................................38
10.4.
Time to Best Overall Response...............................................................................39
10.5.
Progression-Free Survival (PFS) and Time to Progression (TTP)............................39
10.5.1.
Progression-Free Survival (PFS).............................................................................39
10.5.2.
Time to Progression (TTP) .....................................................................................40
10.6.
Overall Survival (OS).............................................................................................41
10.7.1.
Eastern Cooperative Oncology Group Performance Status (ECOG PS)...................41
10.7.2.
Alpha-fetoprotein (AFP) Reduction and HBV Viral Load.......................................41
11.
SAFETY ANALYSIS ............................................................................................42
11.1.
Adverse Events.......................................................................................................42
11.1.1.
Summary of Adverse Events...................................................................................42
11.1.2.
Dose-limiting Toxicities (DLTs).............................................................................44
11.2.
Clinical Laboratory Evaluations..............................................................................45
11.3.
Vital Sign Measurements........................................................................................45


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11.4.
Electrocardiograms (ECG)......................................................................................46
11.5.
Left Ventricular Ejection Fraction (LVEF) Assessment ..........................................46
11.6.
Ophthalmologic Exam............................................................................................47
12.
PK AND BIOMARKER ANALYSES....................................................................48
12.1.
PK and Exposure Response Analyses .....................................................................48
12.1.1.
PK Parameters........................................................................................................48
12.1.2.
Exposure vs. Dose ..................................................................................................49
12.1.3.
Exposure vs. Efficacy and/or Safety Parameters......................................................49
12.3.
Adjustment of Multiplicity......................................................................................51
13.
QUALITY OF LIFE ANALYSIS...........................................................................52
14.
INTERIM ANALYSIS...........................................................................................53
15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................54
17.
APPENDICES........................................................................................................57
17.1.
Dose Escalation Rules ............................................................................................57
17.2.
Handling of Dates...................................................................................................58
17.2.1.
Calculation Using Dates .........................................................................................59
17.2.2.
Calculation of Cycles..............................................................................................59
17.3.
Baseline, Repeated Measurements, and End of Trial...............................................59
17.4.
Date Imputation Guideline......................................................................................60
17.4.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications.......................60
17.5.
Laboratory Data Handling Rules.............................................................................62
17.6.
PK Data Handling...................................................................................................62


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17.8.
Study Procedures....................................................................................................65
17.9.
Guideline for Tumor Response Evaluation..............................................................70
17.9.1.
Solid Tumor ...........................................................................................................70
17.9.2.
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) ...........70


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LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................9
Table 2:
Study Endpoints .....................................................................................................17
Table 3:
Confidence Interval for 20% and 35% Response Rate for Different Scenarios 
of Sample Size (Wilson Score Interval) ..................................................................18
Table 4:
Time Point Overall Tumor Response Definitions by RECIST 1.1 and 
irRECIST ...............................................................................................................34
Table 5:
RECIST 1.1 Best Overall Response When Confirmation of CR and PR is 
Required.................................................................................................................35
Table 6:
ORR and DCR Derivation rules..............................................................................37
Table 7:
DoR and Duration of SD Derivation Rules .............................................................38
Table 8:
Progression and Censoring Rules for PFS Analysis.................................................40
Table 9:
Normal Ranges of Vital Sign Measurements...........................................................46
Table 10:
Decision Rules for Rolling 6 Dose Escalation Design.............................................57
Table 11:
Data Handling Conventions for Laboratory Parameters...........................................62
  
Table 14:
Table of Events.......................................................................................................65
LIST OF FIGURES
Figure 1:
Overall Study Design.............................................................................................16






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1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
AE
Adverse events
AFP
Alpha-fetoprotein 
ATC
Anatomical Therapeutic Chemical
AUC
Area under the concentration-time curve
BCLC
Barcelona Clinic Liver Cancer 
BE
Biomarkers evaluable
BLQ
Below the limit of quantification
BMI
Body mass index
BNP
Brain natriuretic peptide
BOR
Best overall response
BPM
Breathes per minute
bpm
Beats per minute
CBC
Complete blood count
CI
Confidence interval
CL/F
Apparent clearance of drug from plasma after extravascular administration
Cmax
Maximum observed concentration
CR
Complete response
CRBN
Cereblon
CSR
Clinical study report
CT
Computed tomography 
CV%
Coefficient of variation
DBP
Diastolic blood pressure
DCR
Disease control rate 
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response 
ECGs
Electrocardiograms
ECHO
Echocardiogram


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Abbreviation or 
Specialist Term
Explanation
ECOG PS
Eastern Cooperative Oncology Group Performance Status
EE
Efficacy evaluable
EOT
End of treatment
FCBP
Females of child bearing potential 
FDA
Food and Drug Administration
FFPE
Formalin-fixed paraffin embedded 
GCP
Good Clinical Practice 
GM-CSF
Granulocyte-macrophage colony stimulating factor 
HBcAb
Hepatitis B core antibody 
HBeAb
Hepatitis B e antibody
HBeAg
Hepatitis B e antigen 
HBsAb
Hepatitis B surface antibody 
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus 
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus 
HCVAb
Hepatitis C virus antibody 
ICH
International Conference on Harmonisation 
IFN-γ
Interferon-gamma 
IHC
Immunohistochemistry  
IL
Interleukin
IP
Investigational product
irBOR
irRECIST best overall response
irDCR
irRECIST disease control rate
irNN
irRECIST irNon-CR/Non-PD
irORR
irRECIST objective response rate
irPD
irRECIST progressive disease
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors 
IV
Intravenously
LLOQ
Lower limit of quantification
LoD
Limit of detection


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Abbreviation or 
Specialist Term
Explanation
LVEF
Left ventricular ejection fraction 
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities 
MEFL
Molecules of equivalent fluorescent label
Min
Minimum
MTD
Maximum tolerated dose
MUGA
Multi-gated acquisition 
NCA
Non-compartmental analysis
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
ND
Not done
NE
Not evaluable
NTD
Non-tolerated dose
ORR
Objective response rate 
OS
Overall survival
PBMC
peripheral blood mononuclear cells 
PD
Progressive disease
PFS
Progression free survival 
PI
Principal investigator
PK
Pharmacokinetics
PPRMP
Pregnancy Prevention Risk Management Plans
PR 
Partial response
PT
Preferred Term
PTT
Partial thromboplastin time 
QNS
Quantity not sufficient
RECIST
Response Evaluation Criteria in Solid Tumors 
RP2D
Recommended Phase 2 Dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SD
Stable disease


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Abbreviation or 
Specialist Term
Explanation
SMQ
Standardized MedDRA Queries
SOC
System organ class 
SRC
Safety Review Committee
t1/2
Terminal half-life
TCR
T cell receptor
TEAE
Treatment-emergent adverse events
Tmax
Time to maximum concentration
TMTB
total measured tumor burden
TNF-α
Tumor necrosis factor alpha
TTP
Time to progression 
ULN
Upper limit of normal
ULOQ
Upper limit of quantification
Vz/F
Apparent volume of distribution  
WBC
White blood cell 
WHO
World Health Organization
WHODrug
World Health Organization Drug Dictionary


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3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective of the Phase 1 portion (dose finding) of the study is:

To evaluate the safety and tolerability of CC-122 when administered orally in 
combination with Nivolumab and to define the RP2D
The primary objective of the Phase 2 portion (dose expansion) of the study is:
3.2.
Secondary Objectives
The secondary objectives of the entire study are:

To evaluate the preliminary efficacy of CC-122 in combination with Nivolumab
based on various endpoints by RECIST 1.1

To evaluate the pharmacokinetics (PK) of CC-122 in subjects coadministered 
multiple doses of CC-122 with Nivolumab

To determine Nivolumab PK when coadministered with CC-122
 
 
 
 
 


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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
CC-122-HCC-002 is a Phase 1/2 dose escalation and expansion clinical study of CC-122 in 
combination with Nivolumab in subjects with unresectable HCC who have progressed after or 
were intolerant to no more than 2 previous systemic therapies for unresectable HCC or are naïve 
to systemic therapy. 
The dose escalation part of the study will explore 1 or more dose levels of CC-122 in 
combination with Nivolumab using a modified dose escalation (3+3) design (Storer,1989), 
followed by an expansion part once the RP2D is defined.
The study is designed to explore three dose levels, to identify the RP2D, and is not required to 
escalate to a nontolerated dose (NTD) or maximum tolerated dose (MTD). CC-122 will initially 
be administered orally 5 consecutive days out of 7 (5 days on/2 days off weekly) on Days 1 to 5, 
8 to 12, 15 to 19 and 22 to 26 of each 28-day cycle. The investigated starting daily dose of CC-
122 will be 2.0 mg, and two subsequent dose levels (3.0 and 4.0 mg) are planned to be evaluated 
based on evaluation of pre-specified dose limiting toxicities (DLTs). The study intends to 
identify the RP2D at or below the 4.0 mg dose level, however intermediate dose levels, or a 
higher dose level, may be evaluated at the discretion of the Safety Review Committee (SRC).
Dose escalation to the intermediate or higher dose levels of CC-122 will not exceed 50% of the 
previously established tolerable dose level. Smaller dose increments based on toxicity, PK 
profile and pharmacodynamic findings may be evaluated, if necessary. Nivolumab will be 
administered at the dose of 3.0 mg/kg intravenously (IV) every 2 weeks. Once the RP2D for 
dosing of CC-122 in combination with Nivolumab is defined, expansion (Phase 2) will start.
A modified 3+3 dose escalation design will be used to identify the initial toxicity of the
combination. Up to six subjects will be concurrently enrolled onto a dose level. Decisions as to 
which dose level to enroll a new subject will be based on the number of subjects enrolled and 
evaluable, the number of subjects experiencing DLTs, and the number of subjects enrolled but 
who are not yet evaluable for toxicity in the current cohort at the time of new subject entry. 
A dose is considered an NTD if 2 or more out of up to 6 evaluable subjects in a cohort 
experience a DLT in Cycle 1. During dose escalation, the decision to either evaluate a higher 
dose level, an intermediate dose level, or declare the RP2D dose (or if applicable, NTD) will be
determined by the SRC, based on their review of all available clinical data, PK, 
pharmacodynamic and laboratory safety data for a given dose cohort.
Non-evaluable subjects will be replaced at the discretion of the SRC.
Following completion of the dose escalation part (Phase 1), up to 30 additional subjects will be 
enrolled in an expansion part (Phase 2). A futility analysis will be conducted as follows. In the 
first 14 subjects treated, if no responder is observed out of 14 subjects then enrollment for the 
expansion cohort will stop for futility. Enrollment will continue during the evaluation of the 14 
subjects. If ≥ 1 subject out of 14 responds (Complete Response [CR] or Partial Response [PR]), 
then approximately 30 total subjects will be enrolled in the Phase 2 portion. The SRC will 


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continue to review safety data regularly throughout the study and make recommendations about 
study continuation and dose modification, as appropriate.
The study will be conducted in compliance with International Conference on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/ Good 
Clinical Practices (GCPs).
Figure 1:
Overall Study Design
HCC = hepatocellular carcinoma; IV = intravenous; RP2D = Recommended Phase 2 Dose.


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4.2.
Study Endpoints
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary Phase 1
The incidence of DLTs and the 
incidence and severity of 
treatment-emergent adverse events 
(TEAEs)
See Section 7.6 of protocol for the
definition of DLTs
Dose Escalation 
Phase 
Primary Phase 2
Preliminary efficacy as measured 
by ORR
The combined incidence of CR + PR, 
by investigator assessment of 
response by RECIST 1.1
Dose Escalation 
and Dose 
expansion Phase
Secondary
Preliminary efficacy 
Disease control rate (DCR), duration 
of response (DoR), progression free 
survival (PFS), overall survival (OS), 
and time to progression (TTP) based 
on investigator assessment of 
response using RECIST 1.1 
guidelines
Dose Escalation 
and Dose 
expansion Phase
Secondary
Plasma PK parameters
Including but not limited to maximum 
observed concentration (Cmax), area 
under the concentration time curve 
(AUC), time to maximum 
concentration (Tmax), terminal half-
life (t1/2), apparent total body
clearance (CL/F) and apparent
volume of distribution (Vz/F) for CC-
122 and Nivolumab after multiple 
dose administration
Dose Escalation 
Phase
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
4.3.
Stratification, Randomization, and Blinding
This study is an open-label study. Treatment assignment does not require randomization, 
blinding or stratification.
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
5.1.1.
General Reporting Conventions
General reporting conventions for this study are: 

By default, descriptive statistics include: n (the corresponding sample size), Mean, 
Median, Standard Deviation, Minimum (Min), and Maximum (Max). Unless 
specified in the actual table shells, the mean, median, and the upper and lower limits 
of a 2-sided 95% confidence interval (CI) should be displayed to one more decimal 
place than the original data (derived analysis data). Standard deviation and standard 
error should be formatted to two more decimal places than the measured value. The 
minimum and maximum should be displayed to the same number of decimal places 
as the original data.

P-values will be presented with 4 decimal places.

Summary tables, listings, and any supportive SAS output will include a “footer” of 
explanatory notes that will indicate, at a minimum, the following: 
o
Program and data source (e.g., SAS program, including the path that generates 
the output). 
o
Data extraction date (e.g., the database lock date, run date). The purpose of 
showing the data extraction date is to link the output to a final database, either 
active or archived, that is write-protected for replication and future reference.
o
Output date (appearing on each output page). The output date will indicate the 
date the output was generated by the analysis program.

Individual subject listings will display all data supporting corresponding tables and 
figures.

If the end of treatment (EOT) visit is performed on a date different from the date of 
any nominal visit, the nominal visit immediately after the EOT will be used for 
plotting. The data from the EOT visit will not be included for any parameter mean-
over-time plot.
Other general conventions include:
For the dose escalation part, subjects will be grouped according to their initially assigned dose 
cohort. In dose expansion part, the subjects may be categorized into different subgroups, such as 
HCC etiology. In addition, subjects in the same subgroup at the same dose level from both study 
parts will be combined for analysis as appropriate. All analyses specified in this SAP will be 
summarized by dose cohorts in the dose escalation part by selected subgroups in the dose 
expansion part, by selected subgroup at the expanded dose with subjects and by study overall in 
the dose expansion part, unless specified otherwise.


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5.1.2.
General Definitions 
General definitions for this study are:

Where study drug or study treatment is referenced, this refers to Investigational 
Product (IP): CC-122 or Nivolumab, unless otherwise stated;

The first dose date refers to the earliest dose of study drug and the last dose date 
refers to the latest dose of study drug. 
5.2.
Analysis Populations
5.2.1.
Efficacy Evaluable (EE)
EE Population – All subjects who enroll, meet eligibility criteria, take at least 50% of both 
assigned IP in the first 2 cycles, have a baseline efficacy (tumor) assessment, and at least one 
post-baseline efficacy (tumor) assessment.
5.2.2.
Enrolled
Enrolled Population – All subjects who are enrolled, i.e., all subjects who are assigned to study.
5.2.3.
Safety
Safety Population – All subjects who enroll and take at least one dose of either IP i.e. have 
received at least one dose of CC-122 or Nivolumab. 
5.2.4.
Pharmacokinetics (PK) Evaluable
PK Evaluable Population – All subjects who enroll and receive at least one dose of either IP and 
have at least one measurable concentration of CC-122 or Nivolumab.
 
.
5.2.6.
Reporting for Analysis Populations
In general,

The Enrolled and Safety Populations will be used for the subject disposition.

The demographic and baseline characteristics will be summarized on all Populations 
defined above.

Drug exposure and all safety analyses (except for PK and biomarker) will be based on 
the Safety Population.

Efficacy analyses (including Eastern Cooperative Oncology Group Performance 
Status [ECOG PS], except for PK or biomarker related endpoints) will be based on 
the Safety Population. Key Efficacy analyses [summary of ORR, DCR, DoR, PFS,
OS and TTP] will be based on both the Safety Population and the EE Population.  PK 
analyses will be based on the PK Population.


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
 

All listings will use the Enrolled Population unless otherwise stated.


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6.
SUBJECT DISPOSITION
The total number of screen failures with the reasons for failure will be summarized overall.
A summary of subject disposition will be presented by dose cohorts in dose escalation part by 
selected subgroups in dose expansion part, by selected subgroup at the expanded dose with
subjects from both parts, and for the following analysis populations:

Enrolled Population 

Safety Population
A tabulated summary of all analysis populations in Section 5.2 will be presented together with 
the subject disposition. A listing of whether a subject is excluded from those populations will be 
provided.  A summary of subjects enrolled by site will be presented. A listing of subject 
enrollment (protocol version and date, informed consent date, and study phase assignment) will 
be provided.
Reasons for treatment discontinuation will be summarized separately for CC-122 and Nivolumab
with the following categories:

Adverse event

Progressive disease

Symptomatic deterioration 

Physician decision

Withdrawal by subject

Death

Lost to follow-up

Protocol violation

Pregnancy

Other 
Reasons for discontinuation from the study will be summarized with the following categories:

Adverse event

Screen failure

Withdrawal by subject

Death 

Pregnancy

Lost to follow-up

Other


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The following by-subject listing of subjects with demographic information attached will be 
provided:

Subject listing of discontinuation

Subject listing of screen failures

Subject listing of visit completion

Subject listing of previous participation


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7.
PROTOCOL DEVIATIONS/VIOLATIONS
The protocol violations and deviations will be identified and assessed by the clinical research 
physician or designee following company standard operational procedure. Protocol violations 
and protocol deviations will be summarized for the Enrolled Population.
A by-subject listings of subjects with protocol violations and deviations in the Enrolled 
Population will be provided.


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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The demographics and baseline characteristics will be summarized by dose cohorts in the dose
escalation part by selected subgroups in dose expansion part, by selected subgroups at the 
expanded dose with subjects from both parts, and by study overall for all populations defined in 
Section 5.2. Individual subject listings for the Enrolled Population will be provided to support 
the summary tables.
8.1.
Demographics
Age (years), height (cm), weight (kg) and Body Mass Index (BMI kg/m2) will be summarized 
using descriptive statistics (e.g., n, mean, standard deviation, median, minimum, and maximum). 
Age is calculated based on the date of birth and the date of informed consent (if date of birth is 
not collected due to country specific regulations, the age recorded in the database will be used, 
see Section 17.2). Age category (≤65 versus >65 years), BMI category (< 20, ≥20 to <25, ≥25 to 
<30 and ≥30), sex, race, ethnicity and reproductive status (female of child bearing potential, 
female of non-childbearing potential) will be summarized with frequency tabulations.
BMI = Weight (kg) / (Height (m) x Height (m)).
8.2.
Baseline Characteristics
Baseline clinical characteristics include the following parameters:

Temperature (°C), 

Systolic Blood Pressure (SBP, mmHg),

Diastolic Blood Pressure (DBP, mmHg), 

Pulse Rate (beats per minute [bpm]),

ECOG PS

Evidence of HCC diagnosis (Histological, Clinical and/or Radiologic),

Barcelona Clinic Liver Cancer (BCLC) staging (B or C), 

Cirrhosis (Yes/No),

HCC Risk Factor (alcohol, HBV, HCV, non-alcoholic steatohepatitis, unknown or 
other),

Child-Pugh score (0-6), 

Baseline AFP level, 

Baseline HBV viral load, 

Baseline HCV viral load, 

Macroscopic Vascular Invasion (Yes/No), 

Extrahepatic Disease (Yes/No), and


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
Hepatitis serology (Hepatitis B surface Antigen [HBsAg], Hepatitis B e Antigen
[HBeAg], Hepatitis B surface Antibody [HBsAb], Hepatitis B e Antibody [HBeAb], 
Hepatitis B core Antibody [HBcAb] and/or Hepatitis C Virus Antibody [HCVAb]).
Categorical baseline variables will be summarized using frequency counts and percentage.
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 the Enrolled Population.
8.3.
Medical History
A summary table of medical history with frequency counts and percentage will be presented 
using Medical Dictionary for Regulatory Affairs® (MedDRA) system and system organ class 
(SOC) and preferred term (PT) for the Safety Population.  Listings will be presented for the
Enrolled Population.
8.4.
Prior Therapies for This Disease
The number of prior therapies/surgeries will be summarized for prior radiation therapies, prior 
cancer surgeries, prior systemic anti-cancer therapies, prior hormonal anti-cancer therapies, prior 
stem cell transplants and prior locoregional therapy for this disease separately and overall by 
frequency tabulations for the Safety Population. The therapies/surgeries with the same 
sequence/regimen number are counted as one prior therapy/surgery. Listings of therapies for this 
disease will also be presented by categories (prior, concomitant, and follow-up) for the Enrolled 
Population. Prior therapies are the therapies that were started before the first dose of study drug. 
Concomitant therapies are the therapies that were started on or after the first dose of study drug, 
but on or before the last dose of study drug.  Therapies in the follow-up are the therapies that 
were started after the last dose of study drug.
 
 
 
 
 
 
 
 
 
 


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.  


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9.
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 days dosed, 
average length of cycle, average number of days dosed per cycle, number of cycles, number of 
subjects who entered each cycle, actual cumulative dose, average daily dose, actual dose 
intensity, and relative dose intensity and number of subjects who overdose by dose cohorts in the 
dose escalation part by selected subgroups in dose expansion part, by selected subgroup at the 
expanded dose with subjects from both parts, and by study overall. 
9.1.
Treatment Duration
For each subject and for each study drug, the treatment duration is defined as the length of time 
elapsed between the first and last non-zero and non-missing study drug dose date and including 
the duration between planned administration (i.e. rest period for CC-122 and time between last 
infusion and subsequent planned infusion for Nivolumab). The treatment duration is derived in 
days which are converted in weeks (by dividing the treatment duration by 7) for the summary.
The first study drug dose date is defined as the earliest date where study drug has been
administered (i.e. the drug was administered and the actual dose is not null or zero).
The last study drug dose date is defined as the latest date where study drug has been 
administered (i.e. the drug was administered and the actual dose is not null or zero).
CC-122 (5/7-day schedule):
CC-122 treatment duration (days) = 
(Last dose date of CC-122 in the study) – (First dose date of study drug in the study) + 
number of days in drug rest period +1. 
The number of days in rest period to be added is 2 days for 5-days on 2-days off intermittent
dose schedule. 
Nivolumab:
Nivolumab treatment duration (days) = 
(Last infusion start date of Nivolumab in the study) – (first dose date of study drug in the 
study) + days covered by last infusion + 1
The days covered by last infusion are 13 days with Nivolumab being administered every 2 weeks 
(Days 1 and 15).
9.2.
Number of Days Dosed
For each subject and for each study drug, the number of days dosed is defined as the total 
number of days the subjects received a non-zero and non-missing dose.  
CC-122 (5/7-day schedule):
CC-122 number of days dosed = 



dose
zero
non
122
-
CC
and
missing
non
122
-
CC
 with 
days


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Nivolumab:
Nivolumab number of infusions =



dose
zero
non
nivolumab
and
missing
non
nivolumab
 with 
days
9.3.
Number of Cycles
For each subject and for CC-122, the number of cycles where CC-12 was administered will be 
summarized.
The number of cycles initiated will be equal to the last cycle number as recorded in the CRF. The 
number of cycles treated will be equal to the number of cycles dosed.
The detailed calculation of a cycle is described in Section 17.2.2.
9.4.
Average Length of Cycle
For each subject and for CC-122, the average length of cycle is defined as the treatment duration 
in days divided by the number of cycles for each subject.  
CC-122:
CC-122 average length of cycle (days) =
dosed
cycles
122
CC
of
Number 
(days)
duration 
 treatment
122
CC


9.5.
Average Number of Days Dosed per Cycle
For each subject and for CC-122, the average number of days dosed per cycle is defined as the 
number of days dosed divided by the number of cycles for each subject; therefore it corresponds
to the average number of days the subject was dosed in a cycle.  
CC-122:
CC-122 average dose exposure per cycle (mg/cycle) = 
cycles
122
-
CC
of
Number 
dosed
days
of
number 
122
-
CC
9.6.
Cumulative Actual Dose
For each subject and for each study drug, the cumulative actual dose is defined as the sum of all 
doses (actual) taken across the treatment period (i.e. across all cycles).
CC-122:
CC-122 cumulative actual dose (mg) =

doses
122
-
CC


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Nivolumab
Nivolumab cumulative actual dose (mg/kg) =

doses
nivolumab
9.7.
Average Daily Dose
For each subject and for CC-122, the average daily dose is defined as the cumulative actual dose 
divided by the number of days dosed.
CC-122:
CC-122 average daily dose (mg/day) =
dosed
days
of
number 
122
-
CC
dose
actual
cumulative
122
-
CC
9.8.
Actual Dose Intensity
For each subject and for each study drug, the actual dose intensity is defined as the cumulative 
actual dose divided by the treatment duration (weeks).
CC-122:
CC-122 actual dose intensity (mg/week)=
(weeks)
duration 
 treatment
122
-
CC
dose
actual
cumulative
122
-
CC
Nivolumab:
Nivolumab actual dose intensity (mg/kg/week) =
(weeks)
duration 
 treatment
Nivolumab
dose
actual
cumulative
Nivolumab
9.9.
Relative Dose Intensity
For each subject and for each study drug, the relative dose intensity is defined as actual dose 
intensity (dose/weeks) divided by expected dose intensity (dose/weeks) and expressed as a 
percentage. Relative dose intensity will be used for the measurement of study drug compliance.
CC-122:
As per the protocol, the expected dose intensity (dose/week) for each cohort is: 

For dose level -1: 5 mg/week,

For dose level 1: 10 mg/week,

For dose level 2: 15mg/week,

For dose level 3: 20 mg/week.
CC-122 relative dose intensity (%)


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100
(mg/week)
intensity 
dose
expected
122
-
CC
(mg/week)
intensity 
dose
actual
122
-
CC

Nivolumab
As per the protocol, the expected dose intensity (dose/week) for Nivolumab is fixed at 1.5 
mg/kg/week. 
Nivolumab relative dose intensity (%)
100
k)
(mg/kg/wee
intensity 
dose
expected
Nivolumab
k)
(mg/kg/wee
intensity 
dose
actual
Nivolumab

9.10.
Dose Reduction/Interruption/Delay
For CC-122, dose reduction is defined as a decrease in dose (non-zero) between current and the 
immediately previous non-missing assigned dose (planned cohort dose level if the first dose) or 
between assigned dose and actual dose. Total days of dose reduction due to AE include all the 
days from the start of assigned dose decrease due to AE until either the assigned dose is changed 
(excluding missing values) or a new (non-missing) reason for assigned dose adjustment is 
entered, including the days with dose not administered, as well as those days when the actual 
dose administered is less than the assigned dose due to AE (count only once if redundant with 
the previous interval. Dose interruption occurs if the dose is not administered except as pre-
specified by the protocol (i.e. rest period). If an interruption happens at the start of a cycle and 
causes a cycle to be postponed, it is also called dose delay. Consecutive doses not administered 
(including those separated by protocol planned rest period) with the same reason are counted as 
one interruption.  The rest period between two consecutive dose interruptions due to AE will be 
included in the total days for that dose interruption.
For Nivolumab, a skipped infusion is defined as an infusion that is not administered at all before 
the subject discontinue from Nivolumab treatment.  An incomplete infusion is defined as an 
infusion for which the actual dose administered is less than the dose assigned.
Dose reduction and interruption will be summarized and summaries will include:
For CC-122

Frequency count of number of dose reductions; 

Frequency count of number of dose interruptions;

Reason for dose reduction (including the reason for assigned dose adjustment and the 
reason for actual dose that is different from assigned dose);

Reason for dose interruptions;

Descriptive statistics of time to the first dose reduction (from the first dose);

Descriptive statistics of time to the first dose reduction (from the first dose) due to an 
adverse event (AE) for those who have at least one dose reduction due to an AE;

Descriptive statistics of time to the first dose interruption (from the first dose);


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
Descriptive statistics of time to the first dose interruption (from the first dose) due to 
an AE for those who have at least one dose interruption due to an AE;

Number and percentage of subjects who have ≥7 days of dose interruption due to an 
AE; 

Descriptive statistics of total days of dose reduction due to an AE for those who have 
at least one dose reduction due to an AE; 

Descriptive statistics of total days of dose interruption due to an AE for those who 
have at least one dose interruption due to an AE.
For Nivolumab

Number of incomplete infusions; 

Number of skipped infusions;

Reason for incomplete infusion;

Reason for skipped infusion;

Descriptive statistics of time to the first incomplete infusion (from the first dose);

Descriptive statistics of time to the first incomplete infusion (from the first dose) due 
to an adverse event (AE) for those who have at least one dose reduction due to an AE;

Descriptive statistics of time to the first skipped infusion (from the first dose);

Descriptive statistics of time to the first skipped infusion (from the first dose) due to 
an AE for those who have at least one dose interruption due to an AE.


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10.
EFFICACY ANALYSIS
The efficacy endpoints of this study include ORR, DCR, DoR, PFS, TTP and OS. Tumor 
response and progression will be determined by the Investigator based on RECIST 1.1
) as a primary guideline, and irRECIST (
 as an exploratory
assessment.
Tumor assessments will be performed at screening (up to 28 days before the Cycle 1 Day 1 
[C1D1] dose), every 8 weeks (± 7 days) for the first 5 evaluations (10 months) and thereafter 
every 12 weeks (±7 days), regardless of treatment status. Tumor assessments should also be 
performed at any time, if clinically indicated. Tumor assessments should continue at the defined 
schedule until radiologic disease progression or new anticancer therapy, beyond the end of 
treatment if necessary.
Following disease progression, survival status will be determined approximately every 3 months 
thereafter until 2 years from enrollment, lost to follow-up, death or withdrawal of consent,
whichever occurs sooner.
Survival follow-up may be conducted by record review (including public records) and/or 
telephone contact with the subject, family, or the subject’s treating physician.
All summaries, analyses and figures of efficacy data will be presented as applicable by dose 
cohorts in dose escalation part, by selected subgroups in dose expansion part, by selected 
subgroup at the expanded dose with subjects from both parts, unless otherwise specified.
Individual listings of tumor assessment and derived endpoints will be provided, which include:

For RECIST 1.1 and irRECIST, listing for total measured tumor burden (TMTB), 
including change (in mm and percentage) from baseline and change from nadir for 
each visit; the TMTB is calculated separately for target and new measurable lesions 
as the sums of the respective diameters of target and new measurable lesions; nadir is 
the smallest TMTB of all assessments since study treatment starts before the current 
assessment.

Listing for non-target lesions (RECIST 1.1) and new non-measurable lesions 
(irRECIST);

Listing of overall response by visit unconfirmed and confirmed best overall response
(BOR) using RECIST 1.1;

Listing of unconfirmed BOR using irRECIST;

Listing of DoR, duration of Stable Disease (SD) and time to BOR (using RECIST 
1.1);

Listing of PFS, TTP (using RECIST 1.1) and OS with flags for the censored data;

Listing of DoR, duration of Stable Disease (SD) and time to BOR (using irRECIST);

Listing of PFS and TTP (using irRECIST) with flags for the censored data;
The detailed rules for using dates are described in Section 17.2.1.


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10.1.
Response Criteria
Investigators will use RECIST 1.1 and irRECIST to assess tumor response for subjects treated 
with CC-122 in combination with Nivolumab (see Table 4).
Table 4:
Time Point Overall Tumor Response Definitions by RECIST 1.1 and 
irRECIST
Overall 
Response
RECIST 1.1
RECIST 1.1[1]
Overall 
Response
irRECIST
irRECIST[2]
CR
Disappearance of all target lesions, 
disappearance of all non-target 
lesions and normalisation of tumor 
marker level. All lymph nodes 
must be non-pathological in size
(<10mm short axis).
irCR
Complete disappearance of all 
measurable and non-measurable 
lesions. Lymph nodes must decrease 
to < 10 mm in short axis. 
Confirmation of response is not 
mandatory.
PR
At least a 30% decrease in the sum 
of diameters of target lesions, 
taking as reference the baseline 
sum diameters, no unequivocal
progression of non-target lesions 
and no new lesion(s), but the 
criteria for CR are not met
irPR
Decrease of ≥ 30% in TMTB relative 
to baseline, non-target lesions are 
irNN, and no unequivocal progression 
of new non-measurable lesions.
SD
Neither sufficient shrinkage in the 
sum of diameters of target lesions 
to qualify for PR nor sufficient 
increase to qualify for PD, taking 
as reference the smallest sum 
diameters while on study, no 
unequivocal progression of non-
target lesions and no new lesion(s).
irSD
Failure to meet criteria for irCR or 
irPR in the absence of irPD.
PD
At least a 20% increase in the sum 
of diameters of target lesions from
nadir. In addition, the sum must 
also demonstrate an absolute 
increase of at least 5 mm, or 
unequivocal progression of non-
target lesions, or appearance of 
new lesion(s).
irPD
At least 20% increase and minimum 5 
mm absolute increase in TMTB 
compared to nadir, or irPD for non-
target or new non-measurable lesions. 
Confirmation of progression is 
recommended minimum 4 weeks 
after the first irPD assessment.
Abbreviations: CR = Complete Response; PR = Partial Response; SD = Stable Disease; PD = Progressive Disease; ir=immune-related; irNN = 
irNon-CR/Non-PD, TMTB = total measured tumor burden,
[1] RECIST 1.1 overall response is based on the sum of diameters of the target lesions.
[2] irRECIST overall response is based on TMTB for target and new measurable lesions.


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Table 5:
RECIST 1.1 Best Overall Response When Confirmation of CR and PR is 
Required
Overall Response First 
Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR 
CR
CR
CR 
PR
SD, PD or PR[1]
CR 
SD
SD provided minimum criteria for SD 
duration met, otherwise, PD
CR 
PD
SD provided minimum criteria for SD 
duration met, otherwise, PD
CR 
NE
SD provided minimum criteria for SD 
duration met, otherwise NE
PR 
CR
PR
PR 
PR
PR
PR 
SD
SD
PR 
PD
SD provided minimum criteria for SD 
duration met, otherwise, PD
PR 
NE
SD provided minimum criteria for SD 
duration met, otherwise NE
NE 
NE
NE
Abbreviations: CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = 
non evaluable.
[1] If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not 
CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR.
Note: All responses after first PD will not be considered as a response.


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10.2.
Best Overall Response (BOR)
Confirmed and unconfirmed BOR (or irBOR) will be summarized using frequency tabulation for 
the Safety Population and EE Population, separately.
Confirmed BOR will only be used to summarize ORR by RECIST1.1, with unconfirmed BOR 
used in the derivation of ORR, DCR, sustained DCR, DoR, duration of SD, PFS and TTP. 
Unconfirmed BOR will be used for graphs.
Figures of tumor assessment will be provided, which include:

Waterfall plots: Each subject’s best percent change as defined below will be 
represented by a bar, with a pattern specific to the dose cohort to which they were 
initially assigned to (in the dose escalation part) and designated subgroup (in dose 
expansion part), and with their overall relative dose intensity annotated below/above 
each bar. For each study phase, a separate graph on the next page will be produced.
o
For RECIST 1.1, a waterfall plot of best percentage change from baseline in 
the sum of diameters (longest for non-nodal lesions, short axis for nodal 
lesions) of target lesions for all subjects with non-missing target lesion. 
o
For irRECIST, waterfall plot for best percent change from baseline in TMTB, 
for all subjects with non-missing TMTB.

Spider plots: Each subject’s percent change from baseline as defined below, will be 
represented by lines with a colour specific to the dose cohort to which they were 
initially assigned to (in the dose escalation part) and designated subgroup (in dose 
expansion part). For each phase, a separate graph on the next page will be produced. 
o
For RECIST 1.1, a spider plot of percent change from baseline in target 
lesions by time from first dose.
o
For irRECIST, a spider plot of percent change from baseline in TMTB by 
time from first dose
Unconfirmed BOR - RECIST 1.1 
Unconfirmed BOR is the best of overall response across all time points evaluated by investigator 
using RECIST 1.1 criteria as defined in Table 4. The order in which responses are rated are CR, 
PR, SD, Progressive Disease (PD), not evaluable (NE). BOR is derived from post-baseline 
responses up until the date of progression or data cut-off date if progression has not occurred 
prior to the cut-off date.  For example, if a subject has overall responses of PR, SD and PD, the 
unconfirmed BOR would be PR.
Duration of SD must meet minimum duration for at least 6 weeks if the BOR is SD. If the 
minimum time for a best response of SD is not met, the subject’s best response depends on the 
subsequent assessments.
For example:

A subject who has SD at the first assessment, PD at the second but does not meet 
minimum duration for SD, will have a best response of PD. PD assessment does not 


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required to be confirmed. A subject who has SD at the first assessment and is then 
lost to follow-up would be considered not evaluable.
Confirmed BOR – RECIST 1.1
Confirmed BOR is derived using Table 5 to confirm the best response. Confirmation of response 
requires repeat assessment of response (CR or PR) at the next scheduled scan more than 4 weeks 
following the first assessment meeting response criteria. If best overall response is SD, it must 
meet the minimum duration of 6 weeks. If the minimum time for a best response of SD is not 
met, the subject’s best response depends on the subsequent assessments. 
irBOR – irRECIST
In irRECIST , the determination of the adaptation of the immune-related unconfirmed best 
overall response (irBOR) is the single best immune-related response of overall response across 
all time points (post-baseline) evaluated by investigator using irRECIST criteria defined in
Table 4 . The order in which responses are rated are irCR, irPR, irSD, irPD, irNE. For example if 
a subject has overall responses of irPR, irSD and irCR, the unconfirmed irBOR would be irCR.  
The same minimum duration of SD required in RECIST 1.1 must be met if the best overall 
response is irSD.
Objective Response Rate (ORR) and Disease Control Rate (DCR)
Unconfirmed ORR, confirmed ORR, DCR and sustained DCR will be derived separately for 
investigator RECIST 1.1 and irRECIST assessment 
 
Table 6:
ORR and DCR Derivation rules
Endpoint
Confirmed
Criteria 
Derivation
ORR
Yes
RECIST 
1.1
Confirmed BOR of CR or PR
No
RECIST 
1.1
Unconfirmed BOR of CR or PR
No
irRECIST
Unconfirmed irBOR of CR or PR
DCR
No
RECIST 
1.1
Unconfirmed BOR of CR, PR or SD
No
irRECIST
Unconfirmed irBOR of CR, PR or SD
Sustained 
DCR
No
RECIST 
1.1
Unconfirmed BOR of CR, PR or SD (duration of SD ≥ 16 
weeks)
No
irRECIST
Unconfirmed irBOR of CR, PR or SD (duration of SD ≥ 16 
weeks)
Abbreviations: BOR = best overall response; CR = complete response, SD = stable disease, PR = partial response,
ir = immune related
Note: the immune-related endpoints will be referred to as irORR, irDCR and sustained irDCR respectively.


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Frequency count and percentage of subjects meeting the criteria of each of the endpoints defined 
in 
will be provided. In addition, two-sided 95% Clopper-
Pearson (
) exact CIs will be provided for each endpoint. The 
summaries and inferential statistics will be provided for the Safety Population and EE
Population.
In dose expansion phase, a figure (similar to a forest plot) of the estimate and associated two-
sided Clopper-Pearson (
) 95% CI will be provided for each
endpoint defined in
using the Safety Population for 
selected subgroups. The figures will also be provided for the EE Population.
10.3.
Duration of Response (DoR) and duration of SD
DoR and duration of SD are derived for RECIST 1.1 and irRECIST separately and are defined as 
per the rules in Table 7.
Table 7:
DoR and Duration of SD Derivation Rules
Endpoint
Derivation
Common Censoring Rules
DoR
For subjects with an unconfirmed 
BOR of PR or CR:
DoR is measured from the date the 
criterion is first met for CR/PR 
(whichever is first recorded) until the 
first date when PD is documented or 
death occurred.
If the subject is still alive and did not experience PD at 
the date of cutoff, DoR and duration of SD will be 
censored at the date of last adequate1 post-baseline 
tumor assessment prior to the cutoff date.
If a subject progresses or dies after an extended lost-
to-follow up time (two or more missed assessments),
DoR and duration of SD will be censored on the date 
of last adequate tumor assessment.
Duration 
of SD
For subjects with an unconfirmed 
BOR of SD:
Duration of SD is measured from the 
first dose date (i.e. the first dose of CC-
122 or Nivolumab whichever occurred 
first) until the first date when PD is 
documented or death occurred. 
Abbreviations: BOR = best overall response; CR = complete response, SD = stable disease, PD = progressive 
disease, PR = partial response.
1 Adequate tumor assessment is defined as the latest tumor assessment which is not missing or recorded as “not 
done” or “not all evaluable”.
The Kaplan-Meier estimate of median DoR and SD for both RECIST 1.1 and irRECIST along 
with a 2-sided 95% CI (
) will be provided by using Safety and
EE Populations. The Kaplan-Meier estimate will only be provided for the phase and dose 
cohort/subgroup where the following conditions are met:

DoR (RECIST 1.1): at least 3 subjects have unconfirmed DCR;

DoR (irRECIST): at least 3 subjects have unconfirmed irDCR;

Duration of SD (RECIST 1.1): at least 3 subjects with BOR of SD;


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
Duration of SD (irRECIST): at least 3 subjects with irBOR of SD.
10.4.
Time to Best Overall Response
Time to unconfirmed BOR is derived for RECIST 1.1 and irRECIST separately. The Kaplan-
Meier estimate of median time to BOR for both RECIST 1.1 and irRECIST along with a 2-sided 
95% CI
) will be provided in a table using Safety and EE
Populations. 
Time to the BOR is measured from first dose date to the earliest of unconfirmed BOR (or 
irBOR) (CR or PR) based on RECIST 1.1 (irRECIST respectively). A subject whose BOR has 
never reached the level of CR or PR will be censored on the date of his or her last adequate 
tumor assessment. Subjects without valid baseline or post baseline tumor assessments will be 
censored on the study discontinuation date. Any valid overall post-baseline tumor assessment 
(not missing or not recorded as “not done” or “not all evaluable”) are considered adequate tumor 
assessments in this case.
10.5.
Progression-Free Survival (PFS) and Time to Progression (TTP)
10.5.1.
Progression-Free Survival (PFS)
PFS is defined as the time from the first dose date until tumor progression or death, whichever 
occurs first. 
Based on Food and Drug Administration (FDA) Guidance (
) a subject who has
neither progressed nor died or who progresses or dies after an extended lost-to-follow up time 
(two or more missed assessments) will be censored on the date of last adequate tumor 
assessment. Subjects without valid baseline or post-baseline tumor assessments will be censored 
on their first dose date (i.e. the first dose of CC-122 or Nivolumab whichever occurred first).
Censoring rules are defined in Table 8.
For PFS by irRECIST, the date of progression is the first date of PD as defined under irRECIST.
Analysis of PFS will be provided for RECIST and irRECIST separately and be presented for the 
Safety and EE Populations. Median of PFS times will be calculated using the Kaplan-Meier 
method and the corresponding 95% CIs will be presented. The number of events, subjects 
censored, and the Kaplan-Meier estimates of PFS rates at the time points of 3 months (90 days)
and 6 months (180 days), along with standard errors of rate estimates (Greenwood’s formula, 
) will also be provided.


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Table 8:
Progression and Censoring Rules for PFS Analysis
Situation
Date of Progression or Censoring 
Outcome
No baseline assessment 
Date of first dose of study drug
Censored 
No progression 
Date of last visit with adequate assessment 
Censored
Treatment discontinuation for toxicity or 
other reason without progression
Date of last visit with adequate assessment 
Censored 
New anticancer treatment started with no 
claim of progression
Date of last visit with adequate assessment 
Censored 
Death before first PD assessment 
Date of death 
Progressed
Death between adequate assessment visits 
or after patient misses one assessment visit 
Date of death 
Progressed
Death or progression after an extended lost-
to-follow up time (two or more missed 
assessments)
Last visit with adequate assessment 
Censored
In dose expansion phase, for the Safety and EE Populations, Kaplan-Meier survival curves of 
PFS will be presented for RECIST 1.1 and irRECIST separately; subgroup will be presented in 
the same figure using different lines colour/symbol.
10.5.2.
Time to Progression (TTP)
TTP is defined as the time from the first dose date (i.e. the first dose of CC-122 or Nivolumab
whichever occurred first) until tumor progression; TTP does not include death. The censoring 
rules for TTP are the same as described for PFS, except deaths without progression are censored 
at the time of the date of last adequate tumor assessment.
For TTP by RECIST 1.1, a subject who has not progressed will be censored on the date of last 
adequate tumor assessment. Subjects without valid baseline or post-baseline tumor assessments 
will be censored on their first dose dates. Any valid overall post-baseline tumor assessment (not
recorded as “not done” or “not all evaluable”) are considered adequate tumor assessments in this 
case.
For TTP by irRECIST, the date of progression is the first date of PD as defined under irRECIST.
A subject who has not progressed or who progresses or dies after an extended lost-to-follow up 
time (two or more missed assessments) will be censored on the date of his or her last adequate 
tumor assessment. Subjects without valid baseline or post-baseline tumor assessments will be 
censored on their first dose dates (i.e. the first dose of CC-122 or Nivolumab whichever occurred 
first).
Analysis of TTP will be provided for RECIST and irRECIST separately and presented for the
Safety and EE Populations. Median of TTP will be calculated using the Kaplan-Meier method 
and the corresponding 95% CIs will be presented.


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10.6.
Overall Survival (OS)
OS is measured as the time from the first dose to death from any cause. All deaths, regardless of 
the cause of death, will be included. Subjects who have no death reported (known to be still alive 
or lost to follow-up) will be censored at the last contact date the subject is known to be alive or 
the clinical cut-off date whichever is earlier. OS will be analyzed similarly to PFS but the OS 
rates at 6 months (180 days) and 12 months (360 days) will be provided (instead of the rates at 3 
and 6 months) by phase, dose cohort and overall for the Safety and EE Populations. A Kaplan-
Meier curve will be provided for the dose expansion phase similarly to the PFS figure.
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 result of the study. All summaries of safety data will be conducted using the Safety
Population and will be presented by dose cohorts in the dose escalation part by selected 
subgroups in the dose expansion part, and by selected subgroup at the expanded dose with 
subjects from both parts. Safety measurements will include AEs, clinical laboratory information 
(including troponin-T and Brain natriuretic peptide [BNP]), vital sign measurements, 12-lead 
electrocardiograms (ECGs), left ventricular ejection fraction (LVEF) assessments, 
ophthalmological exam, and pregnancy status. Individual subject listings 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 will also be included in plots for parameters of individual subjects over time.
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 start between the date of first dose of study drug and 28 days after the last dose 
of CC-122 or 90 days after the last dose of Nivolumab, whichever is later. All AEs will be coded
using the MedDRA® dictionary Version 21.0 or higher.
The incidence of TEAEs will be summarized by MedDRA SOC and PT. The intensity of AEs 
will be graded 1 to 5 according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (NCI CTCAE) Version 4.03 or higher if possible. AEs that are not 
defined in the NCI CTCAE Version 4.03 or higher should be evaluated for severity/intensity 
according to Version 3.0. For all other AEs not described in the NCI CTCAE criteria, the 
intensity will be assessed by the investigator as mild (grade 1), moderate (grade 2), severe (grade 
3), life-threatening (grade 4) or death (grade 5).
If a subject experiences the same AE more than once with a different grade, then the event with 
the highest grade will be tabulated in “by grade” tables. If a subject experiences multiple AEs 
under the PT (SOC), then the subject will be counted only once for that PT (SOC). In addition, 
AEs with a missing grade will be presented in the summary table as a grade category of 
“Missing” and will not be imputed. 
A summary table of the subject incidence rate in each of the following categories will be 
provided. In addition, a table for each of the following categories will be produced where the 
incidence rate will be tabulated by SOC and PT and provided.

TEAEs;

TEAEs related to CC-122, Nivolumab and study drugs (CC-122 and/or Nivolumab); 

TEAEs of NCI CTCAE grade 3 or 4 by maximum NCI CTCAE grade; 


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
TEAEs related to CC-122, Nivolumab and study drugs (CC-122 and/or Nivolumab) 
with NCI CTCAE grade 3 or 4 by maximum NCI CTCAE grade;

Grade 5 TEAEs with death outcome;

Grade 5 TEAEs with death outcome related to CC-122, Nivolumab and study drugs
(CC-122 and/or Nivolumab);

Serious TEAEs;

Serious TEAEs related to CC-122, Nivolumab and study drugs (CC-122 and/or 
Nivolumab);

TEAEs leading to discontinuation of CC-122, Nivolumab and both study drugs (CC-
122 and Nivolumab);

TEAEs related to CC-122 leading to discontinuation of CC-122 and both study drugs
(CC-122 and Nivolumab);

TEAEs related to Nivolumab leading to discontinuation of Nivolumab and both study 
drugs (CC-122 and Nivolumab);

TEAEs related to study drugs (CC-122 and/or Nivolumab) leading to discontinuation 
of CC-122, Nivolumab, and both study drugs (CC-122 and Nivolumab);

TEAEs leading to dose reduction of CC-122;

TEAEs related to CC-122 leading to dose reduction of CC-122;

TEAEs related to study drugs (CC-122 and/or Nivolumab) leading to dose reduction 
of CC-122;

TEAEs leading to dose interruption of CC-122, Nivolumab and both study drugs 
(CC-122 and Nivolumab);

TEAEs related to CC-122 leading to dose interruption of CC-122 and both study 
drugs (CC-122 and Nivolumab);

TEAEs related to Nivolumab leading to dose interruption of Nivolumab and both 
study drugs (CC-122 and Nivolumab);

TEAEs related to study drugs (CC-122 and/or Nivolumab) leading to dose 
interruption of CC-122, Nivolumab and both study drugs (CC-122 and Nivolumab);
As well as

TEAEs by cycle of onset; 

TEAEs related to CC-122, Nivolumab and study drugs (CC-122 and/or Nivolumab) 
by cycle of onset;

TEAEs by maximum NCI CTCAE grade;

TEAEs related to CC-122, Nivolumab and study drugs (CC-122 and/or Nivolumab)
by maximum NCI CTCAE grade;

Common (≥10%) TEAEs; 


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
Common (≥10%) TEAEs related to CC-122, Nivolumab and study drugs (CC-122 
and/or Nivolumab); 

The selected TEAEs of interest  
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 cohort and grade or as 
needed. Standardized MedDRA queries (SMQs) will be used in the search strategy for some of 
the selected AEs of interest, intending to aid in case identification. The groupings of selected 
AEs, described by one phrase or topic term will be determined by clinicians based on SMQ or 
relevant search terms and provided to the statistical team, prior to database lock. To facilitate 
clinical study report (CSR) writing, a summary table of selected TEAEs of interest by PTs will 
also be provided. 
The following tabulated lists will be provided together with AE tables,

List of subjects who died by phase, dose cohort/disease subtype, subject number, 
SOC, and PT.

List of SAEs by phase, dose cohort/disease subtype, subject number, SOC and PT;

List of TEAEs leading to permanent withdrawal of study drug by phase, dose
cohort/disease subtype, subject number, SOC, and PT;
Individual subject listings of AEs and AESIs will be presented.  In addition, following tabulated 
lists will be provided as well,

List of TEAEs that fulfill any of the DLT (see section 11.1.2) criteria by phase, dose 
cohort, subject number, DLT term, SOC, and PT

List of TEAEs with NCI CTCAE grade 3 or 4 by phase, dose cohort/disease subtype, 
subject number, SOC, and PT

List of TEAEs leading to dose reduction and dose interruption of study drug by 
phase, dose cohort/disease subtype, subject number, SOC, and PT.
11.1.2.
Dose-limiting Toxicities (DLTs)
DLT is defined as a treatment-related AE(s) occurring in Cycle 1 (including pre-dose 
assessments on Cycle 2 Day 1) that meets one of the criteria defined in the protocol. A summary 
table of DLTs will be presented for the dose escalation phase only by dose cohort including 
number and percentage of subjects having a DLT. The percentage of subjects having a DLT is 
based on the number of subjects in the DLT evaluable Population. DLT flag will be added to the
listing of AEs.
In the dose escalation phase, a subject evaluable for DLT is defined as one who:

Received at least 75% of the planned doses of CC-122 and of Nivolumab during
Cycle 1 without experiencing a DLT, having been followed for the entire DLT 
assessment period (Days 1 to 28 of Cycle 1 including the pre-dose assessments 
specified for Day 1 of Cycle 2)
or


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
Experienced a DLT after receiving at least one dose of either IP.
Non-evaluable subjects will be replaced at the discretion of the SRC. Additional subjects within 
any dose cohort may be enrolled at the discretion of the SRC.
11.2.
Clinical Laboratory Evaluations
Clinical laboratory results of interest include: chemistry (including troponin T and BNP), 
hematology (including PT/INR/PTT), immunology, thyroid functions and urinalysis. Clinical 
laboratory values will be graded according to NCI CTCAE version 4.03 or higher for applicable 
tests. Book or literature normal ranges will be used to determine the categories of High, Low, 
and Normal. 
Lab results and change from baseline will be summarized by visit using descriptive statistics for 
continuous variables. Similarly, maximum and minimum post-baseline values and corresponding 
change from baseline values (including unscheduled visits) will be summarized using descriptive 
statistics.
Shift tables demonstrating the changes (low/normal/high) from baseline to worst post-baseline 
value will be displayed in cross-tabulations for categorical variables. 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. These will be presented in separate 
tables for low and high NCI CTCAE grades. Summaries of worst NCI CTCAE grade by cycle
(up to and including cycle 6) and worst post-baseline NCI CTCAE grade will be provided. 
Listings of clinical laboratory data with NCI CTCAE grades (if applicable) and abnormal flags 
(low or high) will be provided.
Listing of pregnancy status will be also provided. 
For some key lab tests, spaghetti plots for individual subjects will be presented to show the 
pattern of the lab test values over time using the Safety Population. All non-missing lab test 
values including assessments at scheduled and unscheduled visits will be presented. The x-axis 
will be the scheduled visits, and the y-axis will be the exact values (unscheduled results will be 
associated with the scheduled visit they relate to). Value for 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. The mean plot lab test values for each dose cohort in the dose escalation part and for each 
subgroup in dose expansion part will also be provided. 
11.3.
Vital Sign Measurements
Vital sign values and change from baseline will be summarized using descriptive statistics for 
each visit. Similarly, maximum and minimum post-baseline values and corresponding change
from baseline values (including unscheduled visits) will be summarized using descriptive 
statistics.
Shift tables demonstrating the changes (low/normal/high) from baseline to worst post-baseline 
value will be displayed in cross-tabulations. Normal ranges in Table 9 will be used to determine 
the categories of low, normal and high. A listing of vital sign results will be provided.


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Table 9:
Normal Ranges of Vital Sign Measurements
Test
Normal Range (Unit)
DBP 
[60, 90] (mmHg)
SBP 
[100, 140] (mmHg)
Pulse 
[60, 100] (bpm)
Temperature
[35, 38] (°C)
11.4.
Electrocardiograms (ECG)
ECG parameters (from central review) and change from baseline with two-sided 95% CI will be 
summarized for each timepoint using descriptive statistics. Similarly, maximum and minimum 
post-baseline values (including unscheduled visits) and corresponding change from baseline 
values will be summarized using descriptive statistics.
Post-baseline abnormal QTc (both QTcF and QTcB) values will be summarized using frequency 
tabulations for the following 5 categories separately: QTc >450 msec; QTc >480 msec; QTc 
>500 msec; QTc increase from baseline >30 msec; QTc increase from baseline >60 msec.
Shift from baseline to worst post-baseline in the overall ECG interpretation (‘Normal’
‘Abnormal, not clinically significant’ and ‘Abnormal, clinically significant’ by investigator 
review or ‘Normal’ and ‘Abnormal’ by central review) by visit will be displayed in cross-
tabulations.
The mean change from baseline for each cohort along with the t-test 2-sided 95% CI, and the raw 
values for each individual subject will be plotted against scheduled/unscheduled visit to show the
trend. Listings of ECG by investigator and central review will be provided.
11.5.
Left Ventricular Ejection Fraction (LVEF) Assessment
LVEF assessment values and change from baseline will be summarized for each visit using 
descriptive statistics. Similarly, maximum and minimum post-baseline values (including 
unscheduled visits) 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. A summary table of abnormal LVEF will be provided. The following 
categories will be used in the summary: 

≥20% absolute drop from baseline in LVEF (%);

≤45% in LVEF (%) at any post-baseline assessment;

≥20% absolute drop from baseline in LVEF (%) or ≤45% in LVEF (%) at any post-
baseline assessment.
A listing of LVEF will be provided as well.


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11.6.
Ophthalmologic Exam
Data collected for ophthalmologic exam will be listed.


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12.
PK AND BIOMARKER ANALYSES
12.1.
PK and Exposure Response Analyses
12.1.1.
PK Parameters
PK parameters will be estimated based on the PK Population. Actual sampling times will be used 
in the calculations of PK parameters by using non-compartmental analysis (NCA). The following 
plasma PK parameters will be summarized for CC-122 and Nivolumab.
Cmax
Peak (maximum) plasma drug concentration
Tmax
Time to peak (maximum) plasma concentration at steady state
AUCt
Area under the concentration-time curve calculated to the last observable 
concentration at time t
AUCinf
Area under the concentration-time curve calculated from time zero to infinity.
Vz/F
Apparent volume of distribution during the terminal (λz) phase after extravascular 
administration
CL/F
Apparent clearance of drug from plasma after extravascular administration
t1/2
Terminal elimination half-life
The following PK parameters will be also calculated for diagnostic purposes and listed but not be 
summarized.


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z
Terminal elimination rate constant (first-order)
z lower
Lower limit of time (h) included in the calculation of z. 
z N
Number of data points used in the calculation of z.
z upper
Upper limit of time (h) included in the calculation of z.
Rsq adjusted
Adjusted regression coefficient for calculation of z.
AUC %Extrap
Percentage of AUC∞due to extrapolation from the time of the last 
measurable concentration to infinity.
12.1.2.
Exposure vs. Dose
CC-122 and Nivolumab plasma concentrations will be summarized by phase, actual dose level
(CC-122), visit, and nominal time points. Plasma PK parameters will be summarized by phase, 
actual dose level (CC-122) using descriptive statistics (N, mean, standard deviation, coefficient 
of variation [CV%], geometric mean, geometric CV%, median, min, and max). In general, 
geometric mean and the geometric CV (%) will be derived from non-zero concentration values.
Coefficient of variation CV (%) is calculated as follows: 100×(standard deviation/mean).
Geometric CV (%) is calculated as follows: CV (%)=100×
, where 
denotes the 
variance of the log-transformed values. 
The following figures will be provided by actual CC-122 dose levels:

Individual subject’s concentration (linear scale) over time spaghetti plot;

Individual subject’s concentration (semi-logarithmic scale) over time spaghetti plot;

Mean and ± standard deviation of concentration (linear scale) over time plot;

Mean and ± standard deviation of concentration (semi-logarithmic scale) over time 
plot.
In addition, scatter plots of log transformed AUCt, AUC∞, and Cmax versus CC-122 dose will be 
presented.
12.1.3.
Exposure vs. Efficacy and/or Safety Parameters
Analyses will be performed to assess the exposure-response relationship of CC-122 plasma 
exposure (e.g. Cmax, and AUC) with key efficacy parameters (tumor burden reduction and tumor 
shrinkage). Graphical analyses of the data will be conducted to visualize potential trends between 
drug exposure and response.
 
 


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12.3.
Adjustment of Multiplicity
Not applicable for this study.


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13.
QUALITY OF LIFE ANALYSIS
Not applicable for this study.


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14.
INTERIM ANALYSIS
No formal interim analysis is planned.


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15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
1.
The protocol defines “enrolled population” as “All subjects who meet all the 
inclusion/exclusion criterion and are eligible for the study.” As written, this definition 
excludes those subjects who were enrolled into the study and later discovered to have not 
met an inclusion/ or met an exclusion criteria. In order to accurately reflect ALL subjects 
who were enrolled into the study, the definition of enrolled population is expanded to 
remove the inclusion/exclusion criteria caveat which include all subjects who were 
assigned an enrollment number. The enrolled subjects who did not meet 
inclusion/exclusion criteria will be captured as protocol violators, which will be reported 
separately in a listing of protocol violations. 
2. Per study HODC (Hematology and Oncology Development Committee) decision, this 
study will not be moving into expansion phase, thus the analyses described in the 
protocol for expansion phase as well as the exploratory efficacy analyses limited by the 
data will not be performed.
3.
The following exploratory objectives, originally described in the study protocol, are not 
considered in this SAP and will be described in separate reports, if applicable.

To determine the relationship between baseline gene expression profiling, 
deoxyribonucleic acid (DNA) mutations, T cell clonality and protein biomarker 
expression with clinical endpoints including tumor response, response duration and 
progression free survival (PFS)

To determine the relationship of CC-122 and Nivolumab pharmacodynamics (PD)
biomarkers in peripheral blood and changes in immune markers in tumor to clinical 
endpoints including tumor response, response duration and PFS

To determine the relationship between the plasma concentrations of CC-122 and 
Nivolumab and 
s, safety, and clinical endpoints
Therefore, the corresponding analyses including the analysis 
 
described in Section 9.9 of the protocol are not considered in this SAP.
4.
Futility analysis is no longer planned in this study.
5. Shift tables for vital signs and LVRF are no longer needed in this study.
6. Treated Population has been changed to Safety Population. This change was made 
because regulatory guidance provides a definition for Safety Population (all patients who 
took at least 1 dose of study medication; 
), which represents the same subject 
population in the CC-122-HCC-002 protocol named as the “Treated Population” (ie, all 
subjects who enroll and take at least one dose of either IP [CC-122 or nivolumab]). Food 


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and Drug Administration (FDA). Guidance for industry:  Submitting Select Clinical Trial 
Data Sets for Drugs Intended To Treat Human Immunodeficiency Virus-1 Infection. Mar 
2018.
7. Correlation analyses will no longer be performed.
8. A listing of AESIs will now be created along with the listing of AEs
9. Summary of number of subjects who overdose is added to section 9.


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17.
APPENDICES
17.1.
Dose Escalation Rules
Table 10:
Decision Rules for Rolling 6 Dose Escalation Design
Current Cohort Information
Enrolling Dose Level*
No. Enrolled
No. with 
DLTs
No. Without 
DLT
No. Pending
MTD Not 
Exceeded
MTD 
Exceeded
2
0,1
Any
Any
n
2
2
0
0
n-1
3
0
0,1,2
3,2,1
n
3
0
3
0
n+1
3
1
0,1
2,1
n
3
1
2
0
n
3
≥2
Any
Any
n-1
4
0
0,1,2
4,3,2
n
n
4
0
3
1
n
n
4
0
4
0
n+1
n
4
1
0,1
3,2
n
n
4
1
2
1
n
n
4
1
3
0
n
n
4
≥2
Any
Any
n-1
n-1
5
0
0,1,2
5,4,3
n
n
5
0
3,4
2,1
n
n
5
0
5
0
n+1
n
5
1
0,1
4,3
n
n
5
1
2
2
n
n
5
1
3,4
1,0
n
n
5
≥2
Any
Any
n-1
n-1
6
0
0,1,2
6,5,4
Suspend
Suspend
6
0
3,4
3,2
Suspend
Suspend
6
0
5,6
1,0
n+1
MTD**
6
1
0,1
5,4
Suspend
Suspend
6
1
2
3
Suspend
Suspend


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Current Cohort Information
Enrolling Dose Level*
No. Enrolled
No. with 
DLTs
No. Without 
DLT
No. Pending
MTD Not 
Exceeded
MTD 
Exceeded
6
1
3,4
2,1
Suspend
Suspend
6
1
5
0
n+1
MTD
6
≥2
Any
Any
n-1
n-1
* n is the current dose level of subjects enrolled; n+1 and n-1 represent dose level escalation and de-
escalation, respectively. Enrollment will be suspended at where it is indicated.
** MTD is claimed only when there are 6 evaluable subjects. 
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 Dates are the dates on which given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, tumor 
scans, etc. They should be present whenever data for a protocol-specified procedure 
are present and should only be missing when a procedure are marked as NOT DONE 
in the database. Procedure dates will not be imputed.

Log Dates are dates recorded in 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 Dates are 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 Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 


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17.2.1.
Calculation Using Dates
Calculations using dates (e.g., PFS, subject’s age or relative day after the first dose of study 
drug) will adhere to the following conventions: 

Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study drug plus 1 day. The 
generalized calculation algorithm for relative day is the following: 
o
If TARGET DATE ≥DSTART then STUDY DAY = (TARGET DATE –
DSTART) + 1; 
o
Else use STUDY DAY = TARGET DATE – DSTART.
Note that Study Day 1 is the first day of treatment of CC-122. 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 to years by dividing the difference by 365.25 days, 
then truncating.
o
Preference is for using calculated age from clinical database. When not 
available, calculated age from CRF or IVRS may be used
o
Partial birth date: impute missing day as 15th of 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 /30.4167
17.2.2.
Calculation of Cycles
The start date of each cycle is defined as the date when the subject receives CC-122 if they 
receive CC-122; otherwise the first date they received Nivo will be the start date 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 dose start date of last cycle + 27.
17.3.
Baseline, Repeated Measurements, and End of Trial
The general conventions for handling baseline, repeated measurements, and EOT are provided 
below:

Baseline for any clinical laboratory test, vital sign and ECOG performance status is 
defined as the last value of a specific endpoint measured before first dose of the 
earliest of CC-122 or Nivolumab;


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
Baseline values for biomarkers in the study is defined as the average of all qualified 
values (as specified in Table 12 and Table 13) collected at screening and before first
dose of the earliest of CC-122 or Nivolumab, including values from Cycle 1 Day 1 
pre-dose (0 hr) and qualified unscheduled visits. Other pre-dose samples from on-
treatment visits after the first dose of the IP will not be used to impute the study 
baseline value.  In addition, for those biomarkers with measurements at multiple 
timepoints within a visit, the qualified pre-dose (0 hr) value will be used to calculate 
the change from pre-dose, percent of pre-dose and/or percent change from pre-dose
for the post-dose time points from the same visit.

When there are multiple values for any laboratory test (clinical) or vital sign collected 
at the same visit, the one with last/latest assessment time stamp will be used for data 
analysis.

When there are multiple values for biomarker data collected at the same visit, the 
average will be used for data analysis.

Baseline of ECG triplicate measurement is defined as the mean of the ECGs recorded 
prior to initiation of therapy. Hence the baseline ECG endpoint value is obtained by 
averaging the last 3 ECGs or whatever number is available before the first dose of 
study treatment (earliest of CC-122 or Nivolumab). If the ECG overall interpretation 
is different in the triplicate, the best value (i.e. the lowest one) at baseline and the 
worst value (i.e. the highest one) at post-baseline visits will be used in the shift tables. 
The overall interpretation is classified as (from lowest to highest) normal, abnormal 
not clinically significant and abnormal clinically significant.

For repeat ECGs at a particular post-baseline visit, derive RR, QTcB, QTcF first for 
each measurement and then derive the average of heart rate, RR, PR, QRS, QT, 
QTcB, QTcF measurements from all repeat ECGs. The average will be used to 
compute the descriptive statistics for that visit and the worst value at that visit will be 
used in the shift tables.

EOT assessment for a particular endpoint is defined as the last non-missing post-
baseline assessment during the study period.
17.4.
Date Imputation Guideline
This subsection gives guideline on imputation of complete or partial missing AEs start and/or 
stop dates.
17.4.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications 
Incomplete Start Date:
Missing day and month

If the year is the same as the year of the first dosing date (earliest of CC-122 or 
Nivolumab), then the day and month of the first doing date will be assigned to the 
missing fields.


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
If the year is prior to the year of first dosing date (earliest of CC-122 or Nivolumab), 
then December 31 will be assigned to the missing fields.

If the year is after the year of first dosing (earliest of CC-122 or Nivolumab), 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 (earliest 
of CC-122 or Nivolumab), then the first doing date will be assigned to the missing 
day.

If either the year of the partial date is before the year of the first dosing date (earliest 
of CC-122 or Nivolumab) 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 (earliest of 
CC-122 or Nivolumab) 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. 
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
(latest of CC-122 or Nivolumab), 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
(latest of CC-122 or Nivolumab), 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 
(latest of CC-122 or Nivolumab), but is the same as the year of the first dosing date
(earliest of CC-122 or Nivolumab), 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 (latest 
of CC-122 or Nivolumab), then January 1 will be assigned to the missing fields.
Missing day only 


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
If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date (latest of CC-122 or Nivolumab), 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
(latest of CC-122 or Nivolumab) 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. 
17.5.
Laboratory Data Handling Rules
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
17.6.
PK Data Handling
Values Below the Limit of Quantification or Missing
Pre-dose concentrations that are below the limit of quantification (BLQ) or missing will be 
assigned a numerical value of zero. A BLQ value that occurs between pre-dose and the first 
quantifiable concentration point will be assigned a numerical value of zero. A BLQ value that 
occurs between quantifiable concentration points will be treated as missing. If BLQ values occur 
at the end of the collection interval, they will be assigned a numerical value of zero, unless 
otherwise warranted by the concentration-time profile. A concentration of zero occurring after 
quantifiable concentrations will be considered as missing for the calculation of PK parameters.
Concentrations assigned a value of missing will be omitted from the calculation of descriptive 
statistics. A concentration value of zero will be included for the computation of arithmetic mean, 
and a post-dosing zero concentration will be substituted with a 50% value of the low limit of 
quantification (LLOQ), for the computation of geometric mean. If 50% or more of the values are 
BLQ at one timepoint, the arithmetic mean, median, and geometric mean will be reported as 
BLQ, and other descriptive statistics will not be calculated.


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17.8.
Study Procedures
Table 14:
Table of Events
Screening 
Period
Treatment Period
Follow-
up
Period
Follow-up Period
Screening
a
Cycle 1
Cycle 2
Subsequent 
Cycles
EOT
Day b
-28 to -1
1 c
8
15
22
1
8
15
18
22
1
15
28 day 
follow-up 
90 days 
follow-
up
Disease 
Progressio
n/ Survival/ 
Pregnancy 
STUDY ENTRY
Informed consent 
X
Pregnancy prevention 
counseling
Pregnancy risk counseling and education prior to dispensing of IP
Demographics
X
Prior cancer history
X
Prior/post cancer therapies
X
At the same schedule as survival 
visits
Complete medical history
X
Inclusion/exclusion criteria
X
SAFETY ASSESSMENTS
Adverse event collection
Continuous starting after informed consent signature, until 28 days after last dose of CC-122 and 90 days after the last dose of 
Nivolumab or at any time afterwards if the PI feels the event is related to any IP
Physical examination 
(source documented only)
X
X
X
X
X


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Screening 
Period
Treatment Period
Follow-
up
Period
Follow-up Period
Screening
a
Cycle 1
Cycle 2
Subsequent 
Cycles
EOT
Day b
-28 to -1
1 c
8
15
22
1
8
15
18
22
1
15
28 day 
follow-up 
90 days 
follow-
up
Disease 
Progressio
n/ Survival/ 
Pregnancy 
Ophthalmologic exam
X
As clinically indicated
Weight
X
X
X
X
X
Height
X
Vital signs
X
X
b
X
X
X
X
X
X
ECOG PS
X
Xa
X
X
X
CBC with differential
X
(-14 to -1)
Xa
X
X
X
X
X
X
X
X
X
X 
Cycles 
3-6 
only
X
Coagulation: PT, INR, 
PTT
X
(-14 to -1)
Xa
X
X
Troponin-T and BNP
X
Xa
X
X
X
X
X
X
Chemistry laboratory
(fasting, routine)
X
(-14 to -1)
Xa
X
X
X
X
X
X
X
X
X
Amylase, lipase, T3, CK, 
TSH, fT4, immuno-
globulins (IgG, IgM and 
IgA only) and T cell 
subsets (CD4+ and CD8+)
X
Xa
X
X
X
X
X
HBV and HCV serologies 
(HBsAg, HBeAg, HBsAb, 
HBeAb, HBcAb, HCVAb)
X
HCV viral load
X
HBV viral load
X
If HBsAg and/or HBcAb positive at screening, on day 1 of each cycle and at EOT


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Screening 
Period
Treatment Period
Follow-
up 
Period
Follow-up Period
Screeninga
Cycle 1
Cycle 2
Subsequent 
Cycles
EOT
Day b
-28 to -1
1 c
8
15
22
1
8
15
18
22
1
15
28 day 
follow-up 
90 days 
follow-
up
Disease 
Progression/ 
Survival/ 
Pregnancy
Urinalysis
X 
(-14 to -1)
X
X
Triplicate 12-lead 
electrocardiogram 
X
X
X
X
X
X
X
X
LVEF
X
X 
every 
3 
cycles
X
Serum β-hCG (in FCBP)
X
(-14 to -1)
As PPRMP indicated – to be updated according to PPRMP
Urine β-hCG (females of 
childbearing potential 
[FCBP] only)
Xd
(-14 to -1)
As PPRMP indicated – to be updated according to PPRMP
EFFICACY ASSESSMENTS
PK samples (Intensive or 
sparse, multiple time 
points)
X
X
 
 
 


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Screening 
Period
Treatment Period
Follow-
up 
Period
Follow-up Period
Screeninga
Cycle 1
Cycle 2
Subsequent 
Cycles
EOT
Day b
-28 to -1
1 c
8
15
22
1
8
15
18
22
1
15
28 day 
follow-up 
90 days 
follow-
up
Disease 
Progression/ 
Survival/ 
Pregnancy
Fresh paired tumor biopsy 
Xf
D18 (+/- 7 
days, 
preferably 
after 3 
continuous 
days of CC-
122 adminis-
tration)
c
g
Tumor evaluation 
(CT or MRI)
X 
(-28 to -1)
RECIST 1.1 and irRECIST algorithm: Every 8 weeks (±7 days) for the first 10 months, then every 12 
weeks (±7 days), until death, lost to follow up, progression or start of new anticancer therapy. See 
Sections 6.5.1 and 6.5.2 in the protocol
Alpha-fetoprotein
X
X
X
X
X
INVESTIGATIONAL PRODUCT
Administer CC-122
5/7 days continuously
Administer Nivolumab
Q2W
CC-122 accountability
X
X
X
X
X
X
X
X
X
X
X
Nivolumab accountability
Q2W
Xh
Xh
FOLLOW-UP
Survival follow-up
Every 3 
months 
(+/- 7 days)
Abbreviations: β-hCG = beta human chorionic gonadotropin; BNP = brain natriuretic peptide; CBC = complete blood count; CK = creatine kinase; CT = computed tomography; 
ECOG PS = Eastern Cooperative Oncology Group Performance Status; EOT = End of Treatment; FCBP = females of child bearing potential; FFPE = formalin-fixed, paraffin 
embedded; fT4 = free T4; HBV = hepatitis B virus; HBsAg = hepatitis B surface antigen; HBeAg = hepatitis B e antigen; HBsAb= hepatitis B surface antibody; HBeAb = 
hepatitis B e antibody; HBcAb = hepatitis B core antibody; HCVAb =  HCV antibody; HCV = hepatitis C virus; IG = immunoglobulin; INR = international normalized ratio; 


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LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging;; PI = Primary Investigator; PK = pharmacokinetic; PPRMP = Pregnancy Prevention Risk 
Management Plan; PT = prothrombin time; PTT = partial thromboplastin time; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; TSH = thyroid 
stimulating hormone.
a All screening assessments must be performed prior to enrollment and subsequently treatment, however, these events may occur on the same calendar day as they are completed 
prior to enrollment.
b An administrative window of ± 3 days is permitted for all cycles except Cycle 1 Day 1 (C1D1).
c C1D1 assessment may be omitted if screening assessment performed within 72 hours of first dose with the exception of the pregnancy test, see footnote d.
d As per PPRMP, FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting CC-122. The first pregnancy test must be performed within 
10-14 days prior to the start of CC-122 and the second pregnancy test must be performed within 24 hours prior to the start of CC-122. The subject may not receive CC-122 until 
the study doctor has verified that the results of these pregnancy tests are negative.
f Archival tumor tissue will be required only if fresh tissue is not evaluable at screening. See Sections 6.8.1 and 6.8.2 in the protocol.
g Sample may be collected on Day 18 ± 7 days of Cycle 2. The sample must be collected at 3 to 6 (±1) hours postdose. Due to the intermittent schedule of CC-122 administration, 
the sample should preferably be collected after at least 3 continuous days of administration.
h After discontinuation of Nivolumab, females of childbearing potential must use effective contraception for at least 5 months.


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17.9.
Guideline for Tumor Response Evaluation
17.9.1.
Solid Tumor
Guidelines for the New Response Evaluation Criteria in Solid Tumors (RECIST 1.1) can be 
accessed online at the following address: 
17.9.2.
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Adaptation of the 
Immune Related Response Criteria can be accessed online at the following address: