Conditions: Neoplasms
Keywords: CC-90011 Nivolumab Advanced Cancers Small cell lung cancer Squamous non-small cell lung cancer LSD1 inhibitor
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 92
Healthy volunteers: no

Brief summary:
This is a Phase 2, multicenter, open-label, multi-cohort study to assess safety and efficacy of CC-90011 in combination with nivolumab in subjects with small cell lung cancer or squamous non-small cell lung cancer who have progressed after 1 or 2 lines of therapies.

The primary objectives of the study are to evaluate the overall response rate of subjects treated with CC-90011 in combination with nivolumab in three cohorts:

* Cohort A: SCLC in ICI naïve subjects
* Cohort B: SCLC in ICI progressor subjects
* Cohort C: sqNSCLC in ICI progressor subjects Overall response rate is defined as the proportion of subjects in the treated population who had complete response (CR) or partial response (PR) as assessed by Investigator review per RECIST v1.1.

In Cohort A, expected ORR for nivolumab monotherapy is 14% while target ORR is 30%. To achieve at least 80% power with one-sided type 1 error 0.1, 39 subjects will be enrolled according to a 2-stage group sequential design based on a binomial test. In stage 1, 12 subjects will be enrolled and treated with CC-90011 in combination with nivolumab. If there are 2 or more subjects responding, Cohort A will continue to enroll an additional 27 subjects. If 1 or less subjects respond in stage 1, Cohort A will stop for futility.

In Cohort B and C, expected ORR for nivolumab monotherapy is 5% while target ORR is 15%. To achieve at least 80% power with one-sided type 1 error 0.1, 48 subjects will be enrolled according to a 2-stage group sequential design based on a binomial test. In stage 1, 14 subjects will be enrolled and treated with CC-90011 in combination with nivolumab. If there are 1 or more subjects responding, Cohort B and C will continue to enroll an additional 34 subjects each. If 0 subjects respond in stage 1, Cohort B and C will stop for futility.

Detailed description:

Arms:
arm 1: CC-90011 will be given orally (PO) at a dose of 40 mg on a once weekly basis in a continuous 28-day cycle.

Nivolumab will be administered intravenously at a dose of 480 mg every 4 weeks per local practice as a 30 minute or a 60-minute infusion as per local practice. arm 2: CC-90011 will be given orally (PO) at a dose of 40 mg on a once weekly basis in a continuous 28-day cycle.

Nivolumab will be administered intravenously at a dose of 480 mg every 4 weeks per local practice as a 30 minute or a 60-minute infusion as per local practice. arm 3: CC-90011 will be given orally (PO) at a dose of 40 mg on a once weekly basis in a continuous 28-day cycle.

Nivolumab will be administered intravenously at a dose of 480 mg every 4 weeks per local practice as a 30 minute or a 60-minute infusion as per local practice.

Interventions: intervention 1: CC-90011 intervention 2: Nivolumab
Intervention descriptions: intervention 1: CC-90011 intervention 2: Nivolumab

Protocol document:
Prot_SAP_000.pdf: 
Official Title of Study: 
A Phase 2, Multicenter, Open-label, Multi-cohort Study to Assess Safety and Efficacy of CC-90011 in 
Combination with Nivolumab in Subjects with Advanced Cancers 
 
NCT Number: NCT04350463 
Document Date (Date in which document was last revised): 30 April 2022 
 
 
 


CC-90011
Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
1
A PHASE 2, MULTICENTER, OPEN-LABEL, MULTI-COHORT STUDY TO ASSESS 
SAFETY AND EFFICACY OF CC-90011 IN COMBINATION WITH NIVOLUMAB IN 
SUBJECTS WITH ADVANCED CANCERS
PROTOCOL NUMBER:
CC-90011-ST-002
COMPOUND NUMBER:
CC-90011 (BMS-986363)
DATE FINAL:
06 Dec 2019
DATE AMENDMENT 1 FINAL:
21 Sep 2020
DATE AMENDMENT 2 FINAL:
02 Mar 2021
AMENDMENT 3 FINAL:
30 Apr 2022
EudraCT NUMBER:
2019-004194-95
IND NUMBER:
139229
SPONSOR NAME/ ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
 
 
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Celgene Corporation
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Final: 30 Apr 2022
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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Phone:
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
 
 
 
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
See appended electronic signature page
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
 
 
 
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study site 
and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Celgene representatives, the Declaration of Helsinki, International Council for
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations governing 
the conduct of clinical studies.
 
 
 
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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.
 
 
 
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 3.0:
This Protocol Amendment is to reduce the duration of survival follow-up period. As of this 
amendment, 92 patients have been enrolled across the 3 cohorts, with 41 patients in Cohort A (4 
confirmed responses), 15 patients in Cohort B (0 confirmed responses), and 36 patients in Cohort 
C (2 confirmed responses). With the limited number of enrolled patients, overall survival (OS) 
may not provide meaningful interpretative data. As a result, OS is being moved to an exploratory 
objective and endpoint. The survival follow-up period is being modified by removing the up to 2-
year duration and adding in that survival follow-up will stop after the 100-day safety follow-up 
visit of the last subject on study treatment.
The Protocol Summary has also been updated in accordance with changes made in the body of the 
protocol. 
The revisions in this Protocol Amendment apply to all participants who are on the study.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 3.0
Section Number & 
Title
Description of Change
Brief Rationale
Title Page;
Protocol Summary;
Section 1.1.2.1: 
Current Treatment 
for First Line 
Extensive-stage 
Small Cell Lung 
Cancer
Added the Bristol-Myers 
Squibb Company (BMS)
compound number.
For clarification purposes.
Protocol Summary 
(Objectives, 
Statistical Methods); 
Section 2: Study 
Objectives and 
Endpoints, Table 4 
(Study Objectives), 
Table 5 (Study 
Endpoints); Section 
9.6.2: Secondary 
Endpoint
Removed overall survival
from secondary objective 
and endpoint and added to 
exploratory objective and 
endpoint.
Moved to exploratory given limited data 
availability due to shortened duration of 
survival follow-up.
Section 1.4: 
Risk/Benefit 
Assessment
New section added referring 
to the newly added 
appendix.
As the stand-alone risk benefit 
assessment document is now 
incorporated into the protocol.
Section 2: Study 
Objectives and 
Added “in combination with 
nivolumab” to the 
For clarification purpose.
 
 
 
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 3.0
Section Number & 
Title
Description of Change
Brief Rationale
Endpoints, Table 5 
(Study Endpoints)
phamacokinetic endpoint
description.
Figure 3: Overall 
Study Design; 
Section 3.2: Study 
Duration for 
Subjects; Section 
6.3.3: Survival 
Follow-up
Removed the up to 2-year 
duration and added in that 
survival follow-up will stop 
after the 100-day safety 
follow-up visit of the last 
subject on study treatment.
To reduce the duration of survival 
follow-up collection due to the limited 
number of enrolled patients.
Section 5: Table of 
Events, Table 6 
(Table of Events)
Added the “X” at the 
100-day safety follow-up 
timepoint.
To align with the updated survival 
follow-up period.
Appendix G: Risk 
Benefit Assessment
New appendix was added.
To incorporate the stand-alone risk 
benefit assessment document into the 
protocol.
All
Minor formatting and 
typographical corrections.
Minor, therefore have not been 
summarized.
 
 
 
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PROTOCOL SUMMARY
Study Title
A Phase 2, multicenter, open-label, multi-cohort study to assess safety and efficacy of CC-90011 
in combination with nivolumab in subjects with advanced cancers. 
Indication
This trial will enroll subjects with small cell lung cancer (SCLC) and squamous non-small cell 
lung cancer (sqNSCLC) who have progressed after 1 or 2 lines of therapy. 
Based on safety/tolerability and preliminary efficacy data, the combination of CC-90011 (also 
known as BMS-986363) and nivolumab could be expanded to add cohorts of subjects with other 
tumor types and the Sponsor may consider amending the study design to investigate the efficacy 
of the combination versus the current standard of care in one or more tumor types. 
Objectives
Primary Objective
The primary objective is to evaluate in each individual cohort the:

Overall response rate (ORR) in subjects with SCLC or sqNSCLC treated with CC-90011 in 
combination with nivolumab
Secondary Objective(s)
The secondary objectives are to
evaluate in each individual cohort the following 
endpoints/outcomes in subjects with SCLC or sqNSCLC receiving CC-90011 in combination with 
nivolumab:

Safety and tolerability

Duration of response (DOR)

Time to response (TTR)

Progression-free survival (PFS) assessed by the Investigator using Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1

Time to first subsequent therapy (TFST)
Exploratory Objectives(s)
The exploratory objectives in each individual cohort are to:

Evaluate overall survival (OS)
 
 
 
 
 
 
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
Explore the relationship between pharmacokinetics (PK), pharmacodynamic (PD) biomarkers 
and/or clinical outcomes of CC-90011 in combination with nivolumab

Evaluate the disease control rate

Assess the pharmacokinetics and immunogenicity of nivolumab in small cell lung cancer and 
squamous non-small cell lung cancer cohort subjects

Assess the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
serologic status on subjects and to support health authority requests
Study Design
This is a Phase 2, multicenter, open-label, multi-cohort study designed to assess the safety and 
efficacy of CC-90011 in combination with nivolumab in subjects with small cell lung cancer or 
squamous non-small cell lung cancer who have progressed after 1 or 2 lines of therapy.
For the purpose of this protocol, immune checkpoint inhibitor (ICI) means anti-PD-1 or anti-PD-
L1 treatments.
Approximately 135 subjects total globally will be enrolled into one of the following cohorts in 2 
stages:

Cohort A: SCLC in ICI naïve subjects 

Cohort B: SCLC in ICI progressor subjects 

Cohort C: sqNSCLC in ICI progressor subjects
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
Adult subjects 18 years and older with SCLC or sqNSCLC who have progressed after 1 or 2 lines 
of therapy.
Length of Study
The Screening Period will last up to 28 days. Treatment must begin within 3 days of enrollment. 
Subjects will be treated until death, progressive disease, unacceptable toxicity, withdrawal of 
consent from treatment, physician decision, or for up to 2 years. In the event of discontinuation of 
the study treatments, subjects will be followed in survival follow-up until death, withdrawal of 
consent from the entire study, lost to follow-up, the 100-day safety follow-up visit of the last 
subject on study treatment, or end of study.
 
 
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Enrollment is expected to take approximately 18 months. The total study duration is estimated to 
be approximately 36 months from the enrollment of the first subject to last subject last visit.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment survival follow-up, or the date of receipt of the last data point from the last subject 
that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
Study Treatments
Celgene Corporation (Celgene) will supply the investigational product, CC-90011, and nivolumab 
for administration, labeled appropriately for investigational use as per the regulations of the 
relevant country’s health authority.
All cohorts will receive CC-90011 at a dose of 40 mg unless otherwise determined during the 
ongoing safety evaluation (Section 7.3.1.1) given orally (PO) once weekly in a continuous 28-day 
cycle, and nivolumab at a dose of 480 mg intravenously (IV) every four weeks. Subjects will be 
treated until death, progressive disease, unacceptable toxicity, withdrawal of consent from 
treatment, physician decision, or for up to 2 years. For subjects who progress with only brain 
metastasis, treatment with investigational product (IP) will be stopped, but may be continued after 
completion of, and recovery from local radiation treatment per the Investigator’s judgement. 
Subjects may continue to receive investigational product beyond disease progression at the 
discretion of the Investigator.
Overview of Key Efficacy Assessments
All subjects will be evaluated for tumor response and progression by Investigator assessment 
according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines, at 
screening, every 6 weeks (± 7 days) post Cycle 1 Day 1 (C1D1) for the first 24 weeks and then 
every 8 weeks (± 7 days) until documented disease progression, start of new anticancer therapy, 
withdrawal of consent from the entire study, or death. Tumor assessments should also be 
performed at any time, if clinically indicated. 
Response assessments will include computed tomography (CT) scan or magnetic resonance 
imaging (MRI).
After the end of treatment visit, survival status will be followed every 2 months (± 14 days) until 
death, withdrawal by subject from the entire study, lost-to-follow-up, or the 100-day safety follow-
up visit of the last subject on study treatment, whichever occurs first, or the End of Trial.
New anticancer therapies should 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
A thorough evaluation of medical conditions will be conducted during screening. Documented 
physical examination, vital signs, laboratory assessments (eg, serum chemistry, hematology), 12-
lead electrocardiogram (ECG), and Eastern Cooperative Oncology Group (ECOG) performance 
 
 
 
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status will be monitored regularly. Preventative measures will be taken to avoid pregnancy in study 
subjects or their partners, and females of childbearing potential will have pregnancy testing 
performed at screening and then throughout the study. The full schedule of assessments is 
described in Table 6.
All subjects will be monitored for adverse events starting from the time the subject signs the 
informed consent form (ICF) until 28 days after the last dose of CC-90011 or 100 days after the 
last dose of nivolumab, whichever is later, as well as those serious adverse events (SAEs) made 
known to the Investigator at any time thereafter that are suspected of being related to study 
treatment. Toxicity severity will be graded according to the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
Concomitant medications and procedures are collected from 28 days prior to enrollment and until 
28 days after the last dose of CC-90011 and until 100 days after the last dose of nivolumab.
Statistical Methods
The primary objective of the statistical analysis is to evaluate the overall response rate of subjects 
treated with CC-90011 in combination with nivolumab in 3 cohorts:

Cohort A: SCLC in ICI naïve subjects 

Cohort B: SCLC in ICI progressor subjects 

Cohort C: sqNSCLC in ICI progressor subjects
The overall response rate is defined as the proportion of subjects in the treated population who had 
confirmed complete response (CR) or confirmed partial response (PR) as assessed by Investigator 
review per RECIST v1.1. The point estimate of ORR will be summarized along with a 95% 
confidence interval (CI) using exact binomial method proposed by Clopper and Pearson (Clopper, 
1934).
In Cohort A, expected ORR for nivolumab monotherapy is 14% while target ORR is 30%. To 
achieve at least 80% power with one-sided type 1 error 0.1, 39 subjects will be enrolled according 
to a 2-stage group sequential design based on a binomial test. In Stage 1, 12 subjects will be 
enrolled and treated with CC-90011 in combination with nivolumab. If there are 2 or more subjects 
responding, Cohort A will continue to enroll an additional 27 subjects. If 1 or less subjects respond 
in Stage 1, Cohort A will stop for futility. 
In Cohort B and C, the expected ORR for nivolumab monotherapy is 5% while the target ORR for 
the combination is 15%. To achieve at least 80% power with one-sided type 1 error 0.1, 48 subjects 
will be enrolled according to a 2-stage group sequential design based on a binomial test. In Stage
1, 14 subjects will be enrolled and treated with CC-90011 in combination with nivolumab. If there 
are 1 or more subjects responding, Cohort B and C will continue to enroll an additional 34 subjects 
each. If 0 subjects respond in Stage 1, Cohort B and C will stop for futility.
The secondary efficacy endpoint includes safety and tolerability, duration of response, time to 
response, progression-free survival, and time to first subsequent therapy. The DOR is defined as 
 
 
 
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the time from the first occurrence of a confirmed documented response to the time of first 
documented tumor progression, as determined by Investigator review per RECIST v1.1, or death 
from any cause, whichever comes first. The DOR will be summarized based on the Kaplan-Meier 
method. The time to response is defined as the time from the first dose of study drug to the date of 
the first confirmed documented response (CR or PR), as assessed by Investigator per RECIST 
v1.1. Time to response will be summarized for responders (confirmed CR or PR) using descriptive 
statistics.
Progression-free survival is defined as the time from the first dose of the study drug to the date of 
the first objectively documented tumor progression or death from any cause, whichever occurs 
first. Progression-free survival will be summarized based on the Kaplan-Meier method. The time 
to first subsequent therapy will be defined as the time in days from the date of first dose of study 
drug to the date of the next cancer therapy or death. Time to first subsequent therapy will be 
analyzed similarly to PFS.  All efficacy analyses will be primarily performed in the treated 
population, which is defined as subjects receiving at least 1 dose of CC-90011 or nivolumab.  
All safety analyses will be performed on the treated population. Adverse events (AE) will be 
summarized by the Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
and preferred term. Treatment-emergent AEs (TEAE) leading to death, TEAEs leading to 
discontinuation from treatment, NCI CTCAE Grade 3 or Grade 4 TEAEs, TEAEs any NCI 
CTCAE grade, TEAEs related to study treatment and serious TEAEs will be summarized 
separately. Clinical laboratory results will be summarized descriptively, which will also include a 
display of change from baseline.
 
 
 
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TABLE OF CONTENTS 
 
 
TITLE PAGE ................................................................................................................ 
 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 3.0: ........................... 
 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 3.0 ............... 
 
PROTOCOL SUMMARY ............................................................................................ 
 
TABLE OF CONTENTS .............................................................................................. 
 
LIST OF TABLES ........................................................................................................ 
 
LIST OF FIGURES ...................................................................................................... 
 
1 INTRODUCTION ..................................................................................................... 
 
1.1 Disease Background.......................................................................................... 
 
1.1.1 Lung Cancers ........................................................................................... 
 
1.1.2 Small-Cell Lung Cancer .......................................................................... 
 
1.1.2.1 Current Treatment for First Line Extensive-stage Small Cell Lung 
Cancer ................................................................................................... 
 
1.1.2.2 Current Treatment for Second and Third Line Extensive-stage 
Small Cell Lung Cancer ........................................................................ 
 
1.1.3 Squamous Non-Small Cell Lung Cancer ................................................. 
 
1.1.3.1 Current Treatment for First-Line Squamous Non-Small Cell Lung 
Cancer ................................................................................................... 
 
1.1.3.2 Current Treatment for Second-Line Squamous Non-Small Cell Lung 
Cancer ................................................................................................... 
 
1.2 Compound Background .................................................................................... 
 
1.2.1 Lysine-specific Histone Demethylase 1A ................................................. 
 
1.2.2 Overview of CC-90011 Mechanism of Action and In Vitro and In Vivo 
Nonclinical Pharmacology ......................................................................... 
 
 
 
1.2.4 Overview of Nonclinical Toxicology ........................................................ 
 
1.2.5 Prior Clinical Experience of CC-90011 .................................................. 
 
1.2.5.1 Overview of Clinical Safety and Efficacy ....................................... 
 
1.2.5.2 Overview of Clinical Pharmacology ............................................... 
 
1.2.5.3 Overview of Clinical Pharmacodynamics ...................................... 
 
1.2.6 Nivolumab ................................................................................................ 
 
1.2.6.1 Duration of Treatment with Nivolumab: ......................................... 
 
1.3 Rationale ........................................................................................................... 
 
1.3.1 Study Rationale and Purpose ................................................................... 
 
1.3.2 Rationale for the Study Design ................................................................ 
 
1.3.2.1 Combination of CC-90011 with Immune Checkpoint Inhibitors .... 
 
1.3.2.2 Direct Anti-Tumor Action of CC-90011 Mediated via SOX2 ......... 
 
1.3.2.3 Immunomodulatory Activities of CC-90011 ................................... 
 
 
 
 
 
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1.3.4 Benefit/Risk Assessment Due to SARS-COV-2/COVID-19 Infection ....... 
 
1.4 Risk/Benefit Assessment .................................................................................. 
 
2 STUDY OBJECTIVES AND ENDPOINTS ............................................................. 
 
3 OVERALL STUDY DESIGN ................................................................................... 
 
3.1 Study Design ..................................................................................................... 
 
3.2 Study Duration for Subjects .............................................................................. 
 
3.3 End of Trial ....................................................................................................... 
 
4 STUDY POPULATION ............................................................................................ 
 
4.1 Number of Subjects ........................................................................................... 
 
4.2 Inclusion Criteria .............................................................................................. 
 
4.3 Exclusion Criteria ............................................................................................. 
 
5 TABLE OF EVENTS ................................................................................................ 
 
6 PROCEDURES.......................................................................................................... 
 
6.1 Screening Period ............................................................................................... 
 
6.1.1 Retesting During Screening Period ......................................................... 
 
6.2 Treatment Period ............................................................................................... 
 
6.2.1 End of Treatment...................................................................................... 
 
6.3 Follow-up Period .............................................................................................. 
 
6.3.1 Safety Follow-up ...................................................................................... 
 
6.3.2 Efficacy Follow-up ................................................................................... 
 
6.3.3 Survival Follow-up................................................................................... 
 
6.4 Efficacy Assessment ......................................................................................... 
 
6.4.1 Treatment Beyond Progression ................................................................ 
 
6.5 Pharmacokinetics .............................................................................................. 
 
6.5.1 Collection of Blood Samples for Nivolumab Pharmacokinetics and 
Immunogenicity ........................................................................................... 
 
6.6 12-lead Electrocardiograms .............................................................................. 
 
6.7 Biomarkers, Pharmacodynamics, Pharmacogenomics ..................................... 
 
6.7.1 Other Assessment ..................................................................................... 
 
6.8 Additional and Optional Research .................................................................... 
 
6.8.1 Additional Research ................................................................................. 
 
6.8.2 Optional Research ................................................................................... 
 
6.9 Subject Reported Outcomes .............................................................................. 
 
7 DESCRIPTION OF STUDY TREATMENTS .......................................................... 
 
7.1 Description of Investigational Product(s) ......................................................... 
 
7.1.1 CC-90011 ................................................................................................. 
 
7.1.2 Nivolumab ................................................................................................ 
 
7.2 Treatment Administration and Schedule .......................................................... 
 
7.2.1 CC-90011 ................................................................................................. 
 
7.2.2 Nivolumab ................................................................................................ 
 
7.2.3 Missed Doses ........................................................................................... 
 
7.2.4 Definition of an Overdose ........................................................................ 
 
7.3 Safety Evaluation .............................................................................................. 
 
7.3.1 Initial Safety Evaluation .......................................................................... 
 
7.3.1.1 Safety Evaluation for CC-90011 Starting Dose of 40 mg ............... 
 
7.3.2 Definition of Stopping Criteria ................................................................ 
 
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Final: 30 Apr 2022
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7.4 Dose Adjustment of Study Treatments ............................................................. 
 
7.4.1 Permitted Dose Reduction for CC-90011 ................................................ 
 
7.4.2 Criteria for CC-90011 Dose Adjustment ................................................. 
 
7.4.2.1 Recommended Dose Adjustment Guidelines for CC-90011 ........... 
 
7.4.3 Criteria for Nivolumab Dose Management ............................................. 
 
7.4.4 Treatment of Related Infusion Reactions due to Nivolumab ................... 
 
7.4.5 Dose Delay and Criteria to Resume in Case of SARS-CoV-2 Infection .. 
 
7.5 Method of Treatment Assignment .................................................................... 
 
7.6 Packaging and Labeling .................................................................................... 
 
7.7 Investigational Product Accountability and Disposal ....................................... 
 
7.8 Investigational Product Compliance ................................................................. 
 
8 CONCOMITANT MEDICATIONS AND PROCEDURES ..................................... 
 
8.1 Permitted Concomitant Medications and Procedures ....................................... 
 
8.2 Prohibited Concomitant Medications and Procedures ...................................... 
 
8.2.1 Medications to be used with Caution ....................................................... 
 
8.3 Required Concomitant Medications and Procedures ........................................ 
 
9 STATISTICAL CONSIDERATIONS....................................................................... 
 
9.1 Overview ........................................................................................................... 
 
9.2 Study Population Definitions ............................................................................ 
 
9.2.1 Enrolled Population ................................................................................. 
 
9.2.2 Treated Population .................................................................................. 
 
9.2.3 Per Protocol Population .......................................................................... 
 
9.3 Sample Size and Power Considerations ............................................................ 
 
9.4 Background and Demographic Characteristics ................................................. 
 
9.5 Subject Disposition ........................................................................................... 
 
9.6 Efficacy Analysis .............................................................................................. 
 
9.6.1 Primary Endpoint..................................................................................... 
 
9.6.2 Secondary Endpoint ................................................................................. 
 
9.7 Safety Analysis ................................................................................................. 
 
9.8 Interim Analysis ................................................................................................ 
 
9.9 Other Topics...................................................................................................... 
 
9.9.1 Steering Committee .................................................................................. 
 
9.9.2 Safety Evaluation ..................................................................................... 
 
9.9.3 Exploratory Analysis ................................................................................ 
 
9.9.3.1 Subgroup Analysis .......................................................................... 
 
9.9.4 Pharmacokinetic Analysis ........................................................................ 
 
10 ADVERSE EVENTS ............................................................................................... 
 
10.1 Monitoring, Recording and Reporting of Adverse Events ............................. 
 
10.1.1 Immune-Mediated Adverse-Events ........................................................ 
 
10.2 Evaluation of Adverse Events ......................................................................... 
 
10.2.1 Seriousness ............................................................................................. 
 
10.2.2 Severity/Intensity .................................................................................... 
 
10.2.3 Causality ................................................................................................ 
 
10.2.4 Duration ................................................................................................. 
 
10.2.5 Action Taken .......................................................................................... 
 
10.2.6 Outcome ................................................................................................. 
 
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Final: 30 Apr 2022
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10.2.7 Detecting Immune-Mediated Adverse-Events ........................................ 
 
10.3 Abnormal Laboratory Values ......................................................................... 
 
10.4 Pregnancy ........................................................................................................ 
 
10.4.1 Females of Childbearing Potential ........................................................ 
 
10.4.2 Male Subjects ......................................................................................... 
 
10.5 Reporting of Serious Adverse Events ............................................................. 
 
10.6 Expedited Reporting of Adverse Events ......................................................... 
 
11 DISCONTINUATIONS .......................................................................................... 
 
11.1 Treatment Discontinuation .............................................................................. 
 
11.2 Study Discontinuation ..................................................................................... 
 
12 EMERGENCY PROCEDURES .............................................................................. 
 
12.1 Emergency Contact ......................................................................................... 
 
12.2 Emergency Identification of Investigational Products .................................... 
 
13 REGULATORY CONSIDERATIONS ................................................................... 
 
13.1 Good Clinical Practice .................................................................................... 
 
13.2 Investigator Responsibilities ........................................................................... 
 
13.3 Subject Information and Informed Consent .................................................... 
 
13.4 Confidentiality ................................................................................................ 
 
13.5 Protocol Amendments ..................................................................................... 
 
13.6 Institutional Review Board/Independent Ethics Committee Review and 
Approval ........................................................................................................... 
 
13.7 Ongoing Information for Institutional Review Board/ Ethics Committee ...... 
 
13.8 Termination of the Study ................................................................................ 
 
14 DATA HANDLING AND RECORDKEEPING .................................................... 
 
14.1 Data/Documents .............................................................................................. 
 
14.2 Data Management ........................................................................................... 
 
14.3 Record Retention ............................................................................................ 
 
15 QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 
 
15.1 Study Monitoring and Source Data Verification ............................................ 
 
15.2 Audits and Inspections .................................................................................... 
 
15.3 Product Quality Complaint ............................................................................. 
 
16 PUBLICATIONS ..................................................................................................... 
 
17 REFERENCES ........................................................................................................ 
 
18 APPENDICES ......................................................................................................... 
 
APPENDIX A TABLE OF ABBREVIATIONS .......................................................... 
 
APPENDIX B VETERANS AFFAIRS LUNG STUDY ............................................. 
 
APPENDIX C PERFORMANCE STATUS CRITERIA ............................................. 
 
APPENDIX D CALCULATED CREATININE CLEARANCE (COCKCROFT AND 
GAULT, 1976) ........................................................................................................ 
 
APPENDIX E THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 .............................................................. 
 
APPENDIX F NIVOLUMAB ADVERSE EVENT MANAGEMENT ALGORITHMS
................................................................................................................................. 
 
APPENDIX G RISK BENEFIT ASSESSMENT ......................................................... 
 
 
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Protocol CC-90011-ST-002
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Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
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LIST OF TABLES 
 
 
Table 1: Studies with Anti-PD-1 or Anti-PD-L1 Inhibitors for the Treatment of SCLC
................................................................................................................................. 
 
Table 2: Studies with Anti-PD-1 or Anti-PD-L1 Inhibitors for the Treatment of NSCLC
................................................................................................................................. 
 
................................................................................................................................. 
 
Table 4: Study Objectives ............................................................................................. 
 
Table 5: Study Endpoints .............................................................................................. 
 
Table 6: Table of Events ............................................................................................... 
 
Table 7: Schedule of Pharmacokinetic Blood Sample and Triplicate Time-matched 
ECG Collection ....................................................................................................... 
 
Table 8: Schedule of Electrocardiogram Collection ..................................................... 
 
 ............. 
 
Table 10: SARS-CoV-2 Samples Schedule .................................................................. 
 
Table 11: Permitted Dose Reduction for CC-90011 ..................................................... 
 
Table 12: Recommended Dose Adjustment Guidelines for CC-90011 Related 
Hematologic Toxicities ........................................................................................... 
 
Table 13: Recommended Dose Adjustment Guidelines for CC-90011 Related to Non-
hematologic Toxicities ............................................................................................ 
 
Table 14: Recommended Treatment Modifications for Nivolumab ............................. 
 
Table 15: Abbreviations and Specialist Terms ............................................................. 
 
Table 16: Veterans Affairs Lung Study Group Staging ................................................ 
 
Table 17: Eastern Cooperative Oncology Group Performance Status .......................... 
 
Table 18: Time Point Response: Subjects with Target (± Non-target) Disease ........... 
 
Table 19: Time Point Response: Subjects with Non-target Disease Only.................... 
 
 
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Protocol CC-90011-ST-002
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Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
18
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1.0
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LIST OF FIGURES 
 
 
 
 
Figure 2: Changes in Chromogranin A (A) and Monocyte to Macrophage 
Differentiation-associated (B) Over Time in Subjects Treated with CC-90011 ..... 
 
Figure 3: Overall Study Design .................................................................................... 
 
Figure 4: Cohort A - Study Power Under Various True Response Rates and Sample 
Sizes ........................................................................................................................ 
 
Figure 5: Cohorts B and C – Study Power Under Various True Response Rates and 
Sample Sizes ........................................................................................................... 
 
 
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Protocol CC-90011-ST-002
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Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
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C C - 9 0 0 1 1
Pr ot oc ol C C -9 0 0 1 1 -S T - 0 0 2
Cel ge ne C or p orati o n
Pr ot oc ol C C -9 0 0 1 1 -S T - 0 0 2 A me n d me nt 3 . 0
Fi nal : 3 0 A pr 2 0 2 2
2 0
1
I N T R O D U C TI O N 
1. 1
Di s e a s e B a c k gr o u n d 
1. 1. 1
L u n g C a n c er s
L u n g ca ncer is t he m ost c o m m o n ca ncer w orl d wi de wit h a p pr o xi matel y 1. 8 milli o n ne w dia g n oses 
a n d 1. 5 9 millio n  deat hs i n 2 0 1 2, w hi c h c orres p o n ds t o t he t hird hi g hest i nci de nce a m o n g ca ncers 
a n d t he m o st c o m m o n ca ncer -r elate d m o rtality ( F erl a y, 2 0 1 5 ). T he W o rld Heal t h Or ga nizati on 
( W H O) di vi des l u n g ca ncer i nt o 2 maj o r classes base d o n its bi o l og y , t hera p y, a n d pr o g n osis: s mall 
cell l u n g ca ncer ( S C L C) a n d n o n-s mall cell l u n g ca ncer ( N S C L C).
S m all c ell lu n g ca ncer acc o u nts f or u p t o 1 3 % t o 1 5 % of all  lu n g ca ncer di a g n oses, wit h 2 5 0, 0 0 0 
cases dia g n ose d a n n uall y w orl d wi de. It is the si xt h m ost -c o m m o n ca use of ca ncer -r elate d m o rtality
(G o vi n da n, 2 0 0 6 ;  Je mal, 2 0 0 7;  L oza n o, 2 0 1 2 ). N o n-s mall cell l u n g ca ncer acc o u nts f or 8 0 % t o 
9 0 % of  lu n g ca ncers a n d i ncl u des 2 maj o r t ypes: ( 1) n o n- s q ua m o us carci n o ma (incl u di n g 
a de n ocarci n o ma, lar ge-cell carci n o ma, ot her cell t ypes); a n d ( 2) s qu a m o us cell (e pi der moi d) 
carci n o ma. S q ua m o us hist ol o g y  acc o u nt f or a p pr o xi matel y 2 0 %
t o 3 0 % a n d is ass ociate d wi t h 
s h orter s ur vi val t ha n n o n- s q ua m o us hist ol o g y (C he n g, 2 0 1 6 ;  L ortet -Ti e ule nt, 2 0 1 4 ;  S ol dera, 
2 0 1 7 ).
As l un g ca ncer ca n be as y m pt o mat ic at earl y sta ges, m o st patie nts are dia g n ose d at a n a d va nce d 
sta ge w hic h is n ot c ura ble b y s ur ger y (Ya n g, 2 0 1 7 ), a n d t hus ha ve p o or pr o g n oses. S cree ni n g 
pr o gra ms f or l un g ca ncer ha ve allo we d f or earlier di a g n oses b ut t he ma j orit y of patie nts are still 
di a g n ose d wi t h ad va nce d disease. M ost s oli d t um o rs, i ncl u di n g t hose wit h rece nt a d va nces i n 
tar gete d a n d i m m u ne me diate d t hera p y s uc h as a nti-pr o gra m me d cell deat h 1 ( P D 1 )/pr o gra m me d 
deat h -li ga n d 1 (P D -L 1 ), still ha ve patient s w h o d o n ot ac hie ve l o n g ter m disease c o ntr ol.
I n S C L C, c yt ot oxic c he m ot hera p y re mai ns a n i m p orta nt disease c o ntr ol m o dalit y i n b ot h first - a n d 
sec o n d-li ne tr e at me nt, t ho u g h l on g -t er m disease c o ntr ol is li mite d, a n d t here is m o dest  
i m pr o ve me nt wit h a nt i-P D 1/ P D -L 1 t hera pies. Alt h o u g h c he mot h era p y, tar gete d t hera p y, a nd/ or 
a nt i-P D -1/ P D -L 1 t hera pies pr o vi de l o n g ter m be nefit t o N S C L C patie nts, t he ma j orit y of N S C L C 
pati e nts will ul ti matel y pr o gress d ue t o resi sta nce mec ha nis ms a n d s ucc u m b d ue t o t he disease.
1. 1. 2
S m all -C ell L u n g C a n c er 
S m all cell l un g ca ncer is a n a g gressi ve hi g h -gra de ne ur oe n d ocri ne t u mor ass o ci ate d wit h a s h ort 
d o u bli n g ti me, a hi g h gr o wt h fracti o n, a n d earl y de vel o p me nt of  wi des prea d metastases, w hic h 
c o ntri b ute t o t he e xtre mel y p o or disease pr o g n osis (Sa bari, 2 0 1 7 ). T hese as pects of S C L C, as well 
as t he li mite d s uccess of  curre nt treat me nts, per ha ps d ue t o ca ncer ste m cells ( C S Cs) ( disc usse d 
bel o w), hi g hli g ht t he u n met me dical nee d f or t he de vel o p me nt of  ne w t hera pe ut ics f or S C L C, 
parti c ularl y i n rela pse d disease. 
Hi st oricall y, S C L C is sta ge d b y t he Vetera ns’
Affairs A d mi nistrati o n L u n g Ca ncer St u d y Gr o u p 
classificat i on ( Kale m keria n, 2 0 1 2 ) (0 ). At ti me of di a g n osis, a p pr o xi matel y 7 0 % of  p atie nts ha ve 
e xte nsi ve sta ge ( E S) S C L C, mea ni n g t hat t he t u m or has s prea d o utsi de of  the he mit h ora x, wit h 
prese nce of metastases (Al vara d o -L u na, 2 0 1 6 ;  Gas par, 2 0 1 2 ).
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
21
1.1.2.1
Current Treatment for First Line Extensive-stage Small Cell Lung 
Cancer
Standard first-line treatment for ES SCLC consists of platinum-based chemotherapy, mainly 4 to 
6 cycles of cisplatin or carboplatin plus etoposide (Fruh, 2013;  Kalemkerian, 2018). Treatment 
beyond 6 cycles is not recommended based on several trials suggesting the increased risk of 
cumulative toxicity with no benefits in overall survival (OS) (Fruh, 2013). In patients with ES 
SCLC, response rates of 60% to 70% can be achieved with combination chemotherapy alone. 
Despite the initial chemosensitivity, almost all patients relapse and have limited or no response to 
subsequent therapy. The median progression-free survival (mPFS) is from 4 to 7 months
(Alvarado-Luna, 2016;  Foster, 2011;  Nicholson, 2016) and the median overall survival (mOS) is 
approximately 10 months (Farago, 2018), with a 5-year overall survival of 1% to 5% (Nicholson, 
2016) in front line treatment.
Many strategies have been evaluated to improve the treatment regimen for ES SCLC, including 
the addition of a third agent. The addition of ifosfamide to carboplatin and etoposide yielded a 
modest survival benefit, however the addition of an alkylating agent significantly increased the 
hematologic toxicity (Miyamoto, 1992). More recent trials have further confirmed the lack of 
survival improvement with 3-drug chemotherapy regimens (Berghmans, 2017;  Jalal, 2017). 
Similarly, paclitaxel added to platinum-based chemotherapy did not improve survival and was 
associated with unacceptable toxicity in a Phase 3 study (Niell, 2005).
While the exploratory use of other chemotherapy regimens has not yielded significant survival 
improvement in patients with extensive disease, the introduction of immune checkpoint inhibitors 
(ICI) has provided an important advancement in the treatment of ES SCLC. On 18-Mar-2019, the 
United States Food and Drug Administration (FDA), and on 06-Sep-2019, the European Medicines 
Agency (EMA), approved atezolizumab, an anti-PD-L1, in combination with carboplatin plus 
etoposide, followed by maintenance atezolizumab as first-line treatment for ES SCLC. The 
addition of an anti-PD-L1 to chemotherapy resulted in 0.9 months improvement in mPFS, from 
4.3 to 5.2 months (hazard ratio [HR] for disease progression or death, 0.77; 95% confidence 
interval [CI], 0.62 to 0.96; p = 0.02), and a 2-month benefit in mOS, from 10.3 to 12.3 months 
(HR for death, 0.70; 95% CI, 0.54 to 0.91; p = 0.007). However, the confirmed overall response 
rate (ORR) was similar in both groups, 60.2% versus 64.4%, with 5 patients (2.5%) having a 
completed response (CR) in the atezolizumab group and 2 patients (1%) with a CR in the 
chemotherapy alone group (Horn, 2018).  
Similar results from a clinical trial of durvalumab (anti-PD-L1) in addition to the standard 
chemotherapy, cisplatin, or carboplatin plus etoposide in first line ES SCLC were recently 
presented. Overall survival increased from 10.3 months with chemotherapy, to 13 months with the 
addition of durvalumab (HR for death, 0.73; 95% CI, 0.591 to 0.909; p = 0.0047; mPFS was similar 
in both arms with 5.4 months for chemotherapy and 5.1 months for the durvalumab arm (HR for 
disease progression or death, 0.78; 95% CI, 0.645 to 0.936) (Paz-Ares, 2019). 
The safety profile of atezolizumab or durvalumab added to platinum-based chemotherapy was 
consistent with the previously reported safety profile of the individual agents. The increase of 
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
22
toxicities related to the addition of an ICI to platinum-based chemotherapy are minimal compared 
to platinum-based chemotherapy alone (Horn, 2018;  Paz-Ares, 2019). The addition of durvalumab 
to platinum-based chemotherapy had similar profiles between both arms: the incidences of Grade
3/4 adverse events (AEs) was 61.5% versus 62.4% and AEs leading to discontinuation was 9.4% 
for each arm; the incidence of hematological toxicities was numerically higher in the platinum-
based chemotherapy arm (Paz-Ares, 2019).
Despite the recent approval of atezolizumab as first-line treatment for ES SCLC, and the positive 
but still modest results with the addition of durvalumab, overall attempts to improve long-term 
survival rates have failed to yield significant advantages. The progression-free survival (PFS) at 
one year is still low at 17.5% with the addition of durvalumab (Paz-Ares, 2019) and below 20% 
with the addition of atezolizumab (Horn, 2018). Given the efficacy of immunotherapy in SCLC is 
observed in a minority of subjects, a predictive biomarker study is warranted for finding patients 
most likely to benefit (Ahn, 2019). Biomarker such as PD-L1 expression was not predictive of 
response to nivolumab or nivolumab and ipilimumab (Antonia, 2016) and tumor mutation burden 
did not differentiate benefit of atezolizumab (Horn, 2018).
Despite the rationale to combine chemotherapy with ICI, based on immunogenic cell death 
induction and immunogenicity of tumor cells modulation by chemotherapy, the benefits observed 
are modest (Ahn, 2019). Explanation of this resistance could be found in the nature the SCLC 
tumor with characteristics of a “cold tumor”: limited PD-L1 expression, decreased major 
histocompatibility complex 1 (MHC1) expression, activation or accumulation of suppressors cells, 
myeloid derived suppressor cells, regulatory lymphocytes, ineffective priming or activation of 
dendritic cells and lymphocytes T-cells, and finally low rate of immune cell infiltration (Hamilton, 
2019). Modifying one of these characteristics by using CC-90011 (also known as BMS-986363)
would have the potential to enhance ICI activity (see Section 1.3).
Most patients relapse despite the initial chemosensitivity indicating the inability to eradicate 
residual tumor cells and suggesting the existence of CSC that are resistant to radiation and 
cytotoxic therapy. The CSC theory is a key component of cancer cell biology and is hypothesized 
to be associated with aggressive cancer spread and metastatic progression, as well as resistance to 
therapy (Codony-Servat, 2016). After relapse, these patients have a median survival of only 4 to 5 
months when treated with further systemic therapy (Owonikoko, 2012). Therefore, exploring 
treatment strategies that target CSC and address this mechanism of resistance appears to be 
essential (Nunes, 2018).
1.1.2.2
Current Treatment for Second and Third Line Extensive-stage Small 
Cell Lung Cancer
Subsequent systemic therapy provides significant palliation in many patients; however, the 
likelihood of response is highly dependent on the time from initial therapy to relapse. This interval 
of time is also referred to as platinum sensitivity (Owonikoko, 2012). If the interval to relapse is 
less than 3 months (platinum refractory disease), response to most agents or regimens is poor 
(≤10%). If more than 3 months have elapsed (sensitive disease), expected response rates are 
approximately 25% (Fruh, 2013;  Kalemkerian, 2018). If subjects relapse more than 6 months after 
 
 
 
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Protocol CC-90011-ST-002
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Final: 30 Apr 2022
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first-line treatment, then treatment with their original platinum-based regimen is recommended
(Owonikoko, 2012;  Postmus, 1987). For refractory subjects or subjects with early relapse (< 6 
weeks), participation in a clinical trial or best supportive care is recommended (Fruh, 2013).
While there are numerous systemic therapy options for patients who have relapsed 6 months or 
less after initial therapy, the likelihood of response is low, and duration of response is very limited. 
Recommended subsequent systemic therapies for these patients include topotecan, irinotecan, 
paclitaxel, docetaxel, temozolomide, vinorelbine, oral etoposide, gemcitabine, cyclophosphamide, 
doxorubicin and vincristine (CAV), and bendamustine (Cheng, 2007;  Kalemkerian, 2018). Single-
agent topotecan is approved by the FDA as second-line therapy, after it was shown to have better 
symptom control including slower time to quality-of-life deterioration and improved survival 
compared with best supportive care in a study in which half of the subjects had resistant disease. 
The median overall survival increased from 13.9 weeks to 25.9 weeks with topotecan (O'Brien, 
2006). 
In CheckMate-331, the overall survival in subjects with SCLC who relapsed after a first-line 
platinum-based chemotherapy was not statistically improved significantly with nivolumab versus 
chemotherapy (7.5 months versus 8.4 months). There was an initial OS advantage with 
chemotherapy; however, OS curves showed late but sustained separation favoring nivolumab 
beyond 10 to 11 months. Although ORR was numerically higher and PFS longer with 
chemotherapy, 16.5% and 3.8 months, compared to 13.7% and 1.4 months with nivolumab, a trend 
towards longer duration of response (DOR) with nivolumab (8.3 months) versus chemotherapy 
(4.5 months) was observed. Subgroup analyses suggest a trend towards OS benefit for nivolumab 
in some select groups of subjects, including platinum-resistant subjects (7.0 months with 
nivolumab versus 5.7 months with chemotherapy) (Reck, 2018).
In third-line treatment, both nivolumab and pembrolizumab were approved by FDA for subjects 
with ES SCLC with disease progression on or after platinum-based chemotherapy and at least one 
other prior line of therapy. Pembrolizumab has shown an ORR of 18.7%, a DoR ≥ 9 months for 
77% of the responders, mPFS of 2 months and mOS of 9 months (Chung, 2018). In another study 
in which only enrolled patients expressing PD-L1 either in the tumor or in the immune cells, 
pembrolizumab has shown ORR of 33.3%, DoR of 19.4 months, mPFS of 1.9 months and OS of 
9.7 months (Ott, 2017). Nivolumab has demonstrated an ORR of 12%. Responses were durable 
for 6 months or longer in 77%, 12 months or longer in 62%, and 18 months or longer in 39% of 
the 13 responding patients (Antonia, 2016).
Activity of ICIs after progression on platinum-based chemotherapy is modest with low response 
rates and low progression-free and overall survival rates, thus prompting the testing of combination 
therapy as a potential modality to enhance ICI efficacy and improve outcomes in SCLC patients. 
However, the durable DoR observed is supporting the use of ICIs in second-line but understanding 
how to enhance efficacy and enrich subject selection are key.
A summary of studies with anti-PD-1 and anti-PD-L1 inhibitors for the treatment of SCLC can be 
found in Table 1.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
24
Table 1:
Studies with Anti-PD-1 or Anti-PD-L1 Inhibitors for the 
Treatment of SCLC
First-line Treatment
Second-line Treatment
Study
IMpower 133 (Horn, 2018)
CASPIAN (Paz-Ares, 2019)
CHECKMATE-331 (Reck, 2018)
Subjects
N = 403
N = 805a
N = 569
Treatment
Atezolizumab 
+ carboplatin + 
etoposide 
(n=201)
Carboplatin + 
etoposide 
(n=202)
Durvalumab + 
platinum + 
etoposide 
(n=268)
Platinum + 
etoposide 
(n=269)
Nivolumab 
(n=284)
Chemotherapy 
(n=285)
mOS 
(months)
12.3 (10.8 –
15.9)
10.3 (9.3 – 11.3)
13.0 (11.5 – 14.8)
10.3 (9.3 –
11.2)
7.5 (5.7 – 9.2)
8.4 (7.0 – 10.0)
HR (95% 
CI)
0.70 (0.54 – 0.91; p = 0.007)
0.73 (0.59 – 0.91; p = 0.0047)
0.86 (0.72 – 1.04; p = 0.11)
mPFS 
(months)
5.2 (4.4 – 5.6)
4.3 (4.2 – 4.5)
5.1 (4.7 – 6.2)
5.4 
(4.8 –
6.2)
1.4 (1.4 – 1.5)
3.8 (3.0 – 4.2)
HR (95% 
CI)
0.77 (0.62 – 0.96; p = 0.02)
0.78 (0.65 to 0.94)
1.41 (1.18 – 1.69)
ORR (%)
60.2 (53.1 –
67.0)
64.4 (57.3 –
71.0)
68
58
14
16
p-value
NA
NA
NA
NA
NA
NA
TEAE > 
Grade 3/4 
(%)
57
56
62
62
14
73
Abbreviations: CI = confidence interval; HR = hazard ratio; mPFS = median progression-free survival; NA = not 
available; ORR = overall response rate; mOS = median overall survival; TEAE = treatment emergent adverse event.
a Study includes another treatment arm of durvalumab + tremelimumab + platinum + etoposide, which has not met 
predefined statistical significance threshold at time of interim analysis.
1.1.3
Squamous Non-Small Cell Lung Cancer
Advanced squamous non-small cell lung cancer (sqNSCLC) remains a recalcitrant disease. While 
non-squamous NSCLC has benefited from advances in chemotherapy doublets (pemetrexed and 
platinum), VEGF targeted therapy (bevacizumab) and tumor profiling with actionable mutations 
for therapeutic interventions (ie, EGFRmut, ALK, BRAF, ROS1), the same has not occurred in 
the setting of sqNSCLC. Together, these factors make sqNSCLC an especially challenging disease 
to manage (Socinski, 2016) such that new therapies, especially ICI and combinations, could have 
a large impact.
1.1.3.1
Current Treatment for First-Line Squamous Non-Small Cell Lung 
Cancer
Platinum-based doublet chemotherapy (cisplatin or carboplatin) has been the standard first-line 
treatment for sqNSCLC for decades. Taxanes (including paclitaxel, albumin-bound paclitaxel 
[nab®]-paclitaxel or docetaxel) or gemcitabine commonly complete the standard chemotherapy 
 
 
 
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backbone as the initial systemic therapy for patients with advanced sqNSCLC without major 
comorbidities and with a performance status of 0 to 2 (Scarpace, 2015).
More recently, the introduction of ICIs in combination with first-line platinum doublets has 
resulted in improvements in ORR, PFS and OS. This has resulted in the FDA approval of 
pembrolizumab and atezolizumab.
Pembrolizumab, an anti-PD-1, in combination with platinum-based chemotherapy and paclitaxel 
or nab-paclitaxel, is approved and recommended for patients with any PD-1 expression and 
without any contraindication to ICIs (Ettinger, 2018;  Paz-Ares, 2018;  Planchard, 2019). In 
KEYNOTE-407, the combination of pembrolizumab plus chemotherapy was associated with 
improved ORR (57.9% versus 38.4%) and improved mOS of 15.9 versus 11.3 months (HR for 
death, 0.56; 95% CI; 0.49 to 0.85, P < 0.001) (Paz-Ares, 2018). In the IMpower131 study, 
atezolizumab plus carboplatin and nab-paclitaxel improved PFS compared with carboplatin plus 
nab-paclitaxel (mPFS 6.5 versus 5.6 months, HR 0.75; 95% CI; 0.64 to 0.88), but no improvement 
in OS (mOS 14.2 versus 13.5 months, HR 0.88; 95% CI, 0.73 to 1.05, P = 0.16) was observed at 
the first interim analysis (Cappuzzo, 2019). However, atezolizumab with carboplatin and nab-
paclitaxel is also an option in first-line therapy (Planchard, 2019).
Despite several limitations, expression of PD-L1 has been recognized as a predictive marker of 
ICI agents’ sensitivity in NSCLC. For patients with tumor PD-L1 expression ≥ 50%, ESMO and 
National Comprehensive Cancer Network (NCCN) guidelines recommend pembrolizumab alone 
as first-line therapy (Langer, 2016;  Planchard, 2019;  Reck, 2016). For subjects with a high tumor 
mutation burden (≥ 10 mutations), a combination of nivolumab and ipilimumab is an option 
regardless of PD-L1 status (European Society of Medical Oncology [ESMO]). For patients with 
tumor PD-L1 expression < 50%, ICI combinations with platinum-based chemotherapy is 
recommended for good performance status patients (Planchard, 2019).
1.1.3.2
Current Treatment for Second-Line Squamous Non-Small Cell Lung 
Cancer
Three anti-PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, and atezolizumab) have been 
approved by the FDA and the EMA as second-line treatment based on Phase 3 studies 
demonstrating improved survival rates, longer duration of response, and fewer adverse events in 
comparison to docetaxel. However, these therapies were evaluated in immunotherapy-naïve 
patients, prior to approval of ICIs in the first line setting. 
There is a general trend in the Phase 3 studies in second-line (nivolumab, pembrolizumab and 
atezolizumab versus docetaxel) for enriched efficacy of anti-PD-1/PD-L1 agents in subjects with 
higher PD-L1 expression compared with those with no/less PD-L1 expression. However, 
unselected subjects may still have improved survival and tolerability with anti-PD-1/PD-L1 agents 
compared with docetaxel. Nivolumab, pembrolizumab and atezolizumab are the treatment of 
choice for most subjects with advanced, previously treated, anti-PD1/anti-PD-L1-naive NSCLC, 
irrespective of PD-L1 expression. Compared to docetaxel, nivolumab showed an mOS of 9.2 
months (95%, CI, 7.3 to 13.3) versus 6 months (95% CI, 5.1 to 7.3), an ORR of 20% versus 9% 
 
 
 
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(P = 0.008), and a mPFS of 3.5 months versus 2.8 months (HR for death or disease progression, 
0.62; 95% CI, 0.47 to 0.81; P < 0.001) (Brahmer, 2015).
Treatment options are limited for sqNSCLC patients who are intolerant to immunotherapy or for 
patients whose disease has progressed on anti-PD-1/PD-L1 therapy. In this case, retreatment with 
platinum-based doublet chemotherapy, docetaxel (with or without ramucirumab), or gemcitabine 
is recommended (Planchard, 2019).
As switching to another PD-l/PD-L1 inhibitor is not routinely recommended after a patient 
progresses on PD-1/PD-L1 inhibitor (Ettinger, 2018), there are several combinations involving 
ICIs that are being investigated in patients who progressed during or after an ICI therapy. 
A summary of studies with anti-PD-1 and anti-PD-L1 inhibitors for the treatment of advanced or 
metastatic NSCLC can be found in Table 2.
 
 
 
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Table 2:
Studies with Anti-PD-1 or Anti-PD-L1 Inhibitors for the Treatment of NSCLC
First-line Treatment
Second-line Treatment
Study
KEYNOTE 407 (Paz-Ares, 
2018)a
KEYNOTE 10 (Herbst, 2016)a,b
CHECKMATE 017 
(Brahmer, 2015)
OAK (Rittmeyer, 2017)a
Subjects
N = 559
N = 1034
N = 272
N = 1225
Treatment
Pembrolizumab 
200 mg + ChT 
(n=278)
Carboplatin + 
(nab) paclitaxel 
[ChT] (n=281)
Pembrolizumab 
2 mg/kg 
(n=344)
Pembrolizumab 
10 mg/kg 
(n=346)
Docetaxel 
(n=343)
Nivolumab 
(n=131)
Docetaxel 
(n=129)
Atezolizumab 
(n=425)
Docetaxel 
(n=425)
OS (months)
15.9 (13.2 - NR)
11.3 (9.5 - 14.8)
10.4 (9.4 – 11.9)
12.7 (10.0 –
17.3)
8.5 (7.5 – 9.8)
9.2
6
13.8 (11.8 -
15.7)
9.6 (8.6 -
11.2)
HR (95% CI)
0.64 (0.49 - 0.85; p<0.001)
0.71 (0.58 –
0.88; p = 
0.0008)
0.61 (0.49 –
0.75; p = 
0.0001)
NA
0.59, (0.44 - 0.79; p<0.001)
0.73 (0.62 - 0.87; p=0003)
mPFS 
(months)
6.4 (6.2 - 8.3)
4.8 (4.3 - 5.7)
3.9 (3.1 – 4.1)
4.0 (2.7 – 4.3)
4.0 (3.1 – 4.2)
3.5
2.8
2.8 (2.6 - 3.0)
4.0 (3.3 - 4.2)
HR (95% CI)
0.56 (0.45 to 0.70; p<0.001)
0.88, (0.74 –
1.05; p=0.068)
0.79, (0.66 –
0.94; p=0.004)
NA
0.62, (0.47 – 0.81; 
p<0.001)
0.95 (0.82 - 1.10)
ORR (%)
57.9 (51.9 -
63.8)
38.4 (32.7 -
44.4)
18 (14 – 23)
18 (15 – 23)
9 (7-13)
20
9
14
13
p-value
NA
NA
P<0.001
P<0.001
NA
P=0.008
NA
NA
NA
TEAE > Grade 
3 (%)
69.8
68.2
13
16
35
7
55
15
43
Abbreviations: CI = confidence interval; FDA =Food and Drug Administration; HR = hazard ratio; mPFS = median progression-free survival; NA = not available; 
NSCLC = non-small cell lung cancer; ORR = overall response rate; OS = overall survival; TEAE = treatment emergent adverse event.
a Included squamous and non-squamous NSCLC.
b FDA accelerated approval was granted for pembrolizumab in the metastatic NSCLC population with PD-L1 ≥ 1%.
 
 
 
 
 
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1.2
Compound Background 
Please refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational product (IP).
1.2.1
Lysine-specific Histone Demethylase 1A
The epigenetic code influences when, and where specific genes are expressed. It is a dynamic and 
reversible process, during which histone modifications are written, erased, and read by families of 
enzymes. Initiation and progression of cancer has increasingly been linked to misreading, 
miswriting or miserasing of histone modifications (Chi, 2010).
Lysine-specific histone demethylase 1A (LSD1) is an eraser of the epigenetic code, thereby 
regulating the expression of many genes important in cancer progression and cell proliferation
(Hoffmann, 2012;  Lynch, 2012;  Scoumanne, 2007). LSD1 over-expression promotes 
proliferation, migration, and tumor invasion (Lv, 2012) and has been documented in many human 
solid tumors including bladder, breast, colorectal, prostate and SCLC (Hayami, 2011;  Kahl, 2006;  
Kauffman, 2011;  Serce, 2012). Moreover, LSD1 over-expression has been correlated with poor 
prognosis in hepatocellular carcinoma, neuroblastoma, prostate cancer, non-small cell lung cancer, 
and estrogen receptor negative breast cancer (Chen, 2015;  Kahl, 2006;  Lim, 2010;  Lv, 2012;  
Schulte, 2009;  Zhao, 2012).
LSD1 is required for normal differentiation in adult as well as embryonic cells (Wang, 2007). It 
controls the balance between histone H3 lysine 4 (H3K4) and histone H3 lysine 27 (H3K27)
methylation, thereby regulating differentiation-associated genes (Adamo, 2011). It is required for 
normal hematopoiesis through interaction and modulation of growth factor independence 1b 
(GFI1b) transcriptional programs, and loss of LSD1 impairs hematopoiesis through a block in 
differentiation (Saleque, 2007;  Sprussel, 2012). 
The importance of LSD1 in normal differentiation suggests that aberrant gene expression resulting 
from dysregulation of LSD1 may result in alterations in pathways associated with a stem-cell like 
phenotype. Moreover, LSD1 plays a part in stem cell maintenance, regulation of epithelial-to-
mesenchymal transition (Adamo, 2011;  McDonald, 2011), and has been shown to be an essential 
regulator of leukemia stem cell potential (Harris, 2012). LSD1 is a master regulator of normal stem 
cell phenotype, which is required for regulation of pluripotency genes, such as the transcription 
factor SRY (sex determining region Y)-box 2 (SOX2) and NANOG (Whyte, 2012), and which 
represses expression of lineage commitment genes (Adamo, 2011). In mouse embryonic stem cell 
lines, 2 experiments, ribonucleic acid (RNA) interference–mediated knockdown of LSD1 
expression and treatment by small molecule LSD1 inhibitor, have demonstrated inhibition of the 
proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and 
seminoma or embryonic stem cells that express the stem cell markers OCT4 and SOX2, while 
displaying minimum growth-inhibitory effects on non- pluripotent cancer or normal somatic cells
(Wang, 2011). Short hairpin RNA (shRNA) knockdown experiments in human embryonic stem 
cell lines show that decreased LSD1 activity lessens the proliferation and self-renewal ability of 
embryonic stem cells while promoting differentiation.
 
 
 
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1.2.2
Overview of CC-90011 Mechanism of Action and In Vitro and In Vivo 
Nonclinical Pharmacology
Lysine-specific histone demethylase 1A was the first lysine demethylase to be discovered and, 
unlike the Jumonji class of demethylases, belongs to the broad family of monoamine oxidases that 
uses flavin adenine dinucleotide (FAD) as a cofactor in its enzymatic demethylase activity 
(unpublished data, current version of the IB).
The importance of LSD1 in development is exemplified by the embryonic lethality seen in 
knockout mice (Wang, 2007). The shRNA knockdown experiments in human embryonic stem cell 
lines show that suppression of LSD1 activity decreases the proliferation and self-renewal ability 
of ES cells while promoting differentiation towards endoderm and mesoderm lineages 
(unpublished data, current version of the IB). In the adult setting, LSD1 is necessary for normal 
hematopoiesis through interaction and modulation of GFI1b transcriptional programs and loss of 
LSD1 results in impaired hematopoiesis through a block in differentiation (Mohammad, 2015). 
The importance of LSD1 in normal differentiation suggests that aberrant gene expression resulting 
from dysregulation of LSD1 may result in alterations in pathways associated with a stem-cell like 
phenotype. 
In prior studies, proliferation screens of cell lines representing a number of tumor types indicated 
that SCLC is sensitive to LSD1 inhibition (Mohammad, 2015). In SCLC, LSD1 and H3K4 
methylation are associated with regions of chromatin that are implicated in the regulation of cell 
state. Inhibition of LSD1 increases methylation and LSD1 enrichment at these sites.  While 
differentiation of SCLC is not well understood, LSD1 positioning at genes associated with 
neuronal differentiation and transcriptional regulation may suggest that inhibition of LSD1 will 
promote alterations in expression programs associated with differentiation of this tumor type
(Mohammad, 2015).
 
 
 
 
 
 
 
 
 
 
 
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1.2.4
Overview of Nonclinical Toxicology
Exploratory and Good Laboratory Practice (GLP)-compliant repeated-dose toxicity studies of oral 
CC-90011 for up to 3 months in mice and dogs following several weekly dosing schedules (mouse 
= once daily [QD], QDx5/week, and every other day [QOD]x3/week; dog = once weekly [QW], 
twice a week [BIW], and once every 2 weeks [Q2W]) were conducted to 1) assess the systemic 
exposure and toxicities over a range of dose levels and dose schedules, 2) to aid in dose and dose 
schedule selection for clinical trials, and 3) to further characterize CC-90011-related toxicity.
In 4-week studies, treatment-related mortality was observed at 45 mg base/kg/dose in mice 
following a QDx5/week dose schedule; and at ≥0.375 mg base/kg/dose in dogs following a QW 
dose schedule. The cause of mortality in mice was not determined; the moribund condition of dogs 
was due to CC-90011-related gastrointestinal (GI) toxicity and ensuing septicemia. 
In mice dosed at up to 45 mg base/kg/dose for 4 weeks, there was dose-proportional marrow 
toxicity, evidenced by a myeloid shift and/or marrow hypocellularity. The marrow space was 
replaced by fibrosis in the sternum and/or femur, with hyperostosis of endosteal, periosteal, and 
trabecular bone surfaces of affected sternebrae. Collectively, these changes persisted through a 
 
 
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recovery period at the highest dose only. Some increase in marrow megakaryocytes (without 
peripheral correlate) was noted at all doses, also persisting at the highest dose. Marrow toxicity 
occurred in concert with declines in peripheral red cell mass (red blood cell [RBC] count, 
hemoglobin, and hematocrit), and declines in platelet, reticulocyte and/or leukocyte counts along 
with significant increases in splenic extramedullary hematopoiesis at all doses (a reactive change 
to which mice are particularly sensitive). Depletion of splenic marginal zone lymphocytes was 
observed in all but the lowest dose groups but did not persist through a recovery period.  
In dogs dosed for 4 weeks, findings were more clearly inflammatory in nature. The predominant 
finding centered on GI inflammation which in some instances was ulcerative and associated with 
secondary septicemia and mortality at higher doses. Changes in the bone marrow reflected 
peripheral demand, with myeloid hypercellularity and variable evidence of marrow toxicity 
reflected in the peripheral blood as either a decrease or increase in peripheral leukocyte numbers; 
unlike mice, no reactive bone alterations were noted.
In one 4-week dog study, there was mortality at ≥ 0.375 mg base/kg/dose, with morbidity generally 
attributed to gastric inflammation and/or ulceration. Slight to marked, acute to subacute 
inflammation was observed variably in the esophagus, stomach, small and/or large intestines, 
and/or rectum of dogs dying early. Findings that correlated with these microscopic changes 
included dehydration, abnormal feces (liquid, red), red vomitus, decreased food consumption and 
body weight, hypoactivity, fever, and/or GI tract discomfort. Related clinical pathology findings 
included decreased albumin, albumin:globulin ratio, calcium, and inorganic phosphorous; increased 
monocytes, large unstained cells, and neutrophils; and decreased red cell mass, platelets, 
reticulocytes, and eosinophils. Other findings in these animals were attributed to generalized 
inflammation and/or septicemia secondary to mucosal ulceration in the GI tract (inflammation in 
multiple lymph nodes, subcutaneous edema, acute inflammation in the heart or liver), and/or 
physiologic stress, including extramedullary hematopoiesis in the spleen and an increased 
myeloid:erythroid ratio in the sternal marrow. In surviving animals, only minimal to moderate 
acute inflammation of the intestines and/or rectum was observed at ≤ 0.75 mg/kg/dose, with 
complete recoverability following a 4-week non-dosing interval. 
In a 4-week study at lower doses (0.125 or 0.25 mg base/kg/dose QW or 0.5 mg/kg/dose Q2W), 
there was no mortality, and findings were of lower severity, with acute inflammation in the cecum, 
ileum, and/or gut-associated lymphoid tissue of dogs from the highest dose-groups from each 
dosing-interval. Changes were minimal when dosed Q2W, becoming marked when dosed QW. 
Other findings included minimal extramedullary hematopoiesis in animals from the highest dose 
groups of either dosing regimen.
All CC-90011-related findings in mice and dogs treated for 4 weeks demonstrated evidence of 
partial to complete reversibility following a 4-week treatment-free period.
In mice dosed daily for up to 3 months at up to 10 mg/kg/dose, further evidence of CC-90011-
related systemic inflammation was observed. Inflammation affected multiple tissues, with 
instances of mortality (10 mg/kg/dose level) being associated with more severe inflammatory foci. 
Specifically, scattered neutrophilic inflammatory cell infiltrates occurred at 10 mg/kg/day in the 
 
 
 
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heart valve, epididymides, eye sclera, and/or periocular tissue. Some instances of periocular 
inflammation were clearly an extension of peripheral glandular inflammation and, in general, the 
interior of the eye was unaffected. At 3 mg/kg/day, such infiltrates became minimal and were 
restricted to the periocular tissues; no such findings were seen at the 1 mg/kg/day. At the non-
tolerated dose level, ophthalmology examination revealed hyporeflection and reduced pallor in the 
fundus of the eye. Also, at 10 mg/kg/day, mortality was associated with focal abscessation in the 
Harderian glands and/or skin/subcutis. Reactive alterations in affected doses groups included 
increased (myeloid) marrow cellularity, and extramedullary hematopoiesis in the liver (with some 
necrosis at the highest dose), spleen and/or adrenal glands.
In dogs dosed once weekly for 3 months, CC-90011 was well tolerated up to 0.25 mg/kg/dose, the 
highest dose level administered, with no signs of toxicity.
Safety pharmacology evaluations were performed to determine the potential cardiovascular and 
respiratory effects of CC-90011 in conscious Beagle dogs as part of a GLP 4-week repeat dose 
toxicity study. There were no CC-90011-related effects on electrocardiograms (ECGs), heart rate 
(HR), or respiratory rate up to 0.75 mg base/kg/dose on a QW schedule and 0.375 mg base/kg/dose 
on a twice weekly schedule (the highest doses with cardiovascular and respiratory endpoints 
evaluated). The effects of CC-90011 on hemodynamic and ECG parameters were also examined 
in anesthetized male Dunkin Hartley guinea pigs administered CC-90011 at doses of 0, 5, 10, 15, 
and 20 mg base/kg via a 10-minute infusion into the jugular vein. At 20 mg base/kg, CC-90011 
caused a slight decrease in HR with a maximum suppression of 19% observed at 9 minutes into 
the 10-minute infusion period, as compared to vehicle. Heart rate remained decreased by 18% at 
the end of the monitoring period. A dose-dependent increase in QT and QT corrected based on 
Bazett’s equation (QTcB) intervals was observed at 10, 15, and 20 mg base/kg; a maximum 
increase of QTcB interval by approximately 9%, 13%, and 16% at 10 to 18 minutes after infusion 
initiation was observed at 10, 15, and 20 mg base/kg respectively, as compared to time-matched 
vehicle. The QTcB interval remained increased by 10% at the end of the monitoring period. There 
were no remarkable CC-90011 related effects on arterial pressure, PR interval, QRS duration, or 
qualitative ECG parameters. Based on these results, the NOAEL for hemodynamic and ECG 
endpoints was 10 mg base/kg following intravenous administration. An in vitro human ether-à-go-
go-related gene study was also performed and identified an IC50 of 3.4 μM.
CC-90011 was not mutagenic based on the results obtained from the in vitro mutagenicity (Ames)
assays.
Overall, CC-90011 exhibits an acceptable safety profile in preclinical species for a clinical drug 
candidate in an advanced oncology setting and the toxicology program for CC-90011 adequately 
supports the conduct of clinical trials in oncology subjects.
1.2.5
Prior Clinical Experience of CC-90011
Clinical experience with CC-90011 in humans is based on 2 ongoing clinical Phase 1 studies, CC-
90011-ST-001 (monotherapy) and CC-90011-SCLC-001 (combination therapy). 
Study CC-90011-ST-001 is an open-label, Phase 1, multicenter, dose escalation (Part A) and 
expansion (Part B), first-in-human (FIH) clinical study (national clinical trial identifier: 
 
 
 
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NCT02875223) to assess the safety (including an assessment of maximum tolerated dose [MTD]), 
PK, and preliminary efficacy of oral CC-90011 in adult subjects with relapsed and/or refractory 
(R/R) advanced solid tumors and R/R advanced non-Hodgkin lymphomas. 
Study CC-90011-SCLC-001 is an open-label, Phase 1b, multicenter, dose-finding study to assess 
the safety, tolerability, PK, PD, and preliminary efficacy of CC-90011 given in combination with 
cisplatin or carboplatin and etoposide, defined as Chemotherapy, followed by CC-90011 single 
agent in maintenance, and CC-90011 given in combination with Chemotherapy plus nivolumab 
followed by CC-90011 plus nivolumab in maintenance, to adult subjects with first line, extensive 
stage (ES) SCLC. The study consists of a dose-finding Chemotherapy Treatment Period, where 
increasing oral doses of CC-90011 are given in combination with standard dose of Chemotherapy 
with or without nivolumab and a Maintenance Treatment Period, following completion of the 
chemotherapy regimen, where CC-90011 at 60 mg is administered as a single agent or with 
nivolumab for responding subjects.
The most current summary of clinical data is available in the most current version of the IB and 
an overview of these data is described below.
1.2.5.1
Overview of Clinical Safety and Efficacy
1.2.5.1.1
Study CC-90011-ST-001
As of 11-Sep-2020, 50 subjects were enrolled in Part A of the study and received escalating oral 
doses of CC-90011 QW at 9 dose levels from 1.25 mg to 120 mg/dose and 16 subjects (14 subjects 
with low/intermediate-grade lung neuroendocrine tumors [NETs] [typical and atypical carcinoid] 
and 2 subjects with 
 neuroendocrine carcinomas [NECs] were enrolled in Part B of the 
study and received oral CC-90011 QW at 60 mg. The Part A of the study has been completed and 
the primary objectives were met. Seven out of the 47 evaluable subjects experienced a dose-
limiting toxicity (DLT) and all DLTs were Grade 3 or 4 thrombocytopenia. Thrombocytopenia, an 
on-target effect, occurred at and beyond 60 mg QW and were successfully managed with dose 
interruption and/or dose reductions. The NTD was established at 120 mg QW with all 4 treated 
subjects experiencing Grade 3 (N = 2) or Grade 4 (N = 2) thrombocytopenia (requiring platelet 
transfusion). The MTD has been identified at 80 mg QW since the expanded cohort to 10 subjects 
identified 2 subjects with DLT, ie, one Grade 3 and one Grade 4 thrombocytopenia (requiring 
platelet transfusion). One subject at 60 mg QW experienced a Grade 4 thrombocytopenia requiring 
transfusion.
In Part A of the study (N = 50), the most frequently reported treatment-emergent adverse events 
(TEAEs) (in at least 10% of subjects) were thrombocytopenia (46.0%), vomiting and anemia
(28.0% each), fatigue (26.0%), nausea, constipation and asthenia (22.0% each), diarrhea, pyrexia, 
and decreased appetite (20.0% each), musculoskeletal pain (16.0%), back pain (14.0%), 
neutropenia, abdominal pain, increased alanine aminotransferase (ALT), increased aspartate 
aminotransferase (AST), and cough (12.0% each), and tumor pain, headache, and dyspnea (10.0% 
each). Overall, 24 (48.0%) subjects experienced at least one Grade 3 or 4 TEAE and the most 
frequently reported Grade 3 or 4 TEAEs (in at least 2 subjects) were thrombocytopenia (24.0%), 
neutropenia (8.0%), anemia (6.0%), and general physical health deterioration, increased ALT, 
 
 
 
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increased blood bilirubin, increased lipase, and hypophosphatemia (4.0% each). Grade 3 or 4 
thrombocytopenia occurred from the dose level of 40 mg and Grade 3 or 4 neutropenia occurred 
from the dose level of 80 mg and only after clinically significant thrombocytopenia. Three (6.0%) 
subjects experienced at least one TEAE leading to discontinuation of study treatment (1 subject at 
2.5 mg had Grade 3 portal acute vein thrombosis assessed as not related to study drug and 2 
subjects at 120 mg had Grade 3 thrombocytopenia, assessed as related to study treatment). Overall, 
33 (66.0%) subjects died during Part A mainly due to progression of malignant disease in this 
heavily treated population. No death due to drug-related toxicity occurred during the study.
CC-90011 demonstrated preliminary evidence of antitumor activity in this difficult-to-treat patient 
population with very few treatment options. Among 27 neuroendocrine neoplasm (NEN) subjects, 
7 subjects have demonstrated prolonged stabilization of disease (stable disease [SD] > 4 months). 
Notably, 3 subjects with bronchial NEN had prolonged SD of > 6 months and 2 subjects with 
 NEN stayed over 6 months under study drug treatment due to clinical benefit. The R/R 
non-Hodgkin’s lymphoma subject (transformed marginal zone lymphoma) experienced a 
complete metabolic response.
In Part B of the study (N = 17), the most frequently reported TEAEs (in at least 10% of subjects) 
were thrombocytopenia (70.6%), asthenia (41.2%), anemia (35.3%), constipation, diarrhea, and 
nausea (29.4% each), neutropenia and dysgeusia (23.5% each), decreased appetite, arthralgia, 
musculoskeletal pain, cough and epistaxis (17.6% each), and leucopenia, stomatitis, vomiting, 
fatigue, hepatic pain, bronchitis, lipase increased, hypokalemia, bone pain, neck pain, dizziness, 
peripheral sensory neuropathy, sciatica, confusional state, dyspnea, and pruritus (11.8% each). 
Overall, 13 (76.5.0%) subjects experienced at least one Grade 3 or 4 TEAE and the most frequently 
reported Grade 3 or 4 TEAEs (in at least 2 subjects) were thrombocytopenia (35.3%), neutropenia 
(17.6%), and asthenia (11.8%). No subject experienced TEAE leading to discontinuation of study 
treatment. Overall, 9 (52.9%) subjects died during Part B due to progression of malignant disease 
(N = 6), occurrence of an adverse event (AE) (N = 2), and unknown cause (N = 1). No death due 
to drug-related toxicity occurred during the study.
In the 14 subjects with low/intermediate-grade lung NET, a best response of SD was observed in 
10 (71.4%) subjects, including 7 subjects with SD ≥ 4 months. The 2 subjects with 
 NEC 
progressed.
1.2.5.1.2
Study CC-90011-SCLC-001
As of 11-Sep-2020, safety and efficacy data are available for 19 enrolled subjects with first-line 
ES SCLC, who received escalating doses of oral CC-90011 at 20 mg (Cohort 1; N = 8) and 40 mg 
(Cohort 2; N = 7), and 60 mg (Cohort 3; N = 4), in combination with etoposide plus cisplatin (EP). 
One subject, who received CC-90011 20 mg, and 2 subjects, who received CC-90011 60 mg plus 
EP experienced a DLT during Chemotherapy Treatment Period. No DLT was observed in the 
6 evaluable subjects treated at the dose of 40 mg. The NTD was determined to be 60 mg and the 
CC-90011 recommended Phase 2 dose (RP2D) was 40 mg on Days 1 and 8 of each 21-day 
chemotherapy cycle.
 
 
 
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During the Chemotherapy Treatment Period (N = 19), the most frequently reported TEAEs (in at 
least 20% of subjects) were anemia (78.9%), thrombocytopenia and neutropenia (68.4% each), 
asthenia (52.6%), nausea (42.1%), constipation (31.6%), blood alkaline phosphatase (ALP) 
increased (26.3%), and mucosal inflammation, pyrexia, diarrhea, decreased appetite, 
hyponatremia, dyspnea, and alopecia (21.1% each). Overall, 16 (84.2%) subjects experienced at 
least one Grade 3 or 4 TEAE and the most frequently reported Grade 3 or 4 TEAEs (in at least 2 
subjects) were neutropenia (63.2%), thrombocytopenia (42.1%), febrile neutropenia (15.8%), and 
anemia (10.5%).
As of 11-Sep-2020, the best objective response of PR was observed in 16 of the 19 treated subjects.
1.2.5.2.3
Study CC-90011-ST-002
Two SAEs of Grade 4 thrombocytopenia which were reported in the first 2 subjects participating 
in this ongoing study. On Cycle 1 Day 1 (C1D1), both subjects received their first dose of CC-
90011 60 mg and nivolumab 480 mg, and on C1D8, they received their second dose of CC-90011 
60 mg. Both subjects were treated with prior chemotherapy, and followed a similar course, with 
normal platelet count at baseline and a decrease in platelet count (within normal protocol limits) 
at C1D8. On C1D15, both subjects were diagnosed with Grade 4 thrombocytopenia for which they 
were hospitalized and recovered within a week. Both subjects received platelet transfusions and 
demonstrated an increase in platelet count over the course of a week. The events were assessed by 
the Investigator as related to CC-90011. Per protocol, study treatment was resumed upon resolution 
of the events with a dose reduction of CC-90011 to 40 mg.
On 14-Aug-2020, the Sponsor reviewed the 2 SAEs in the first 2 subjects with the treating 
Investigator and the Steering Committee. Thrombocytopenia occurred in both subjects around 
C1D15 and were consistent with observations from the early CC-90011 monotherapy studies. As 
a result of the first 2 subjects developing Grade 4 thrombocytopenia, which both followed a similar 
course, Celgene in agreement with the Steering Committee concluded that new subjects enrolled 
in Study CC-90011-ST-002 will receive CC-90011 at a reduced starting dose of 40 mg, unless 
otherwise determined during the ongoing safety evaluation in Section 7.3.1.1. The dose of 
nivolumab will remain at 480 mg.
1.2.5.2
Overview of Clinical Pharmacology
Pharmacokinetic results are available for 50 treated subjects from Part A of Study CC-90011-ST-
001. 
Median time to peak concentrations ranged from 2 to 4 hours post-dose across treatment groups. 
Drug accumulation was limited (range: 0% to 59% for area under the plasma concentration time 
curve from 0 to 24 hours [AUC0-24] and maximum observed plasma concentration [Cmax]) upon 
repeated QW dosing. Terminal half-life was estimated to be approximately 71 hours. Increase in 
CC-90011 plasma exposure (AUC0-24 and Cmax) on Day 1 and Day 22 was approximately 
proportional to dose across the ~ 100-fold dose-range. Additional summary of PK data, by each 
dose group, is provided in the current version of the IB.
 
 
 
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1.2.5.3
Overview of Clinical Pharmacodynamics
Preliminary PD analysis from CC-90011-ST-001 Clinical Trial revealed a decrease in 
chromogranin A (CgA) levels in response to CC-90011 at doses as low as 2.5 mg QW in subjects 
with NENs (Figure 2).
Additionally, CC-90011 decreased expression of monocyte to macrophage differentiation-
associated (MMD) RNA by ≥ 50% in subject blood samples at doses ≥ 60 mg QW (Figure 2). 
These preliminary findings indicate that downregulation of MMD is a potential marker for 
pharmacodynamics by CC-90011 in the clinical setting.
Figure 2:
Changes in Chromogranin A (A) and Monocyte to Macrophage 
Differentiation-associated (B) Over Time in Subjects Treated with 
CC-90011
Abbreviations: C1D1 = Cycle 1 Day 1; MMD = monocyte to macrophage differentiation-associated; QW = once 
weekly; RP2D = recommended phase 2 dose.
1.2.6
Nivolumab
Please refer to the Investigator’s Brochure (IB), summary of product characteristics (SmPC), 
package insert, for detailed information concerning the available pharmacology, toxicology, drug 
metabolism, clinical studies, and adverse event profile of nivolumab.
A
B
 
 
 
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1.2.6.1
Duration of Treatment with Nivolumab:
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumors types in the nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 2 to 4 
months, and emerging data suggests that benefit can be maintained in the absence of continued 
treatment. A recent analysis in a melanoma study suggests the majority of patients who discontinue 
nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of further 
treatment (Schadendorf, 2017). Furthermore, a limited duration of ipilimumab, including only 4 
induction doses, resulted in long term survival in patients with metastatic melanoma, with a 
sustained plateau in survival starting around 2 years after the start of treatment (Schadendorf, 
2015).
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 subjects with NSCLC), specified a maximum treatment duration of 2 years. Among 
16 subjects with non-small cell lung cancer (NSCLC) who discontinued nivolumab after 
completing 2 years of treatment, 12 subjects were alive > 5 years and remained progression-free 
without any subsequent therapy. In the CA209003 NSCLC cohort, the overall survival curve 
begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years (Gettinger, 
2018). These survival outcomes are similar to Phase 3 studies in previously treated NSCLC, in 
which nivolumab treatment was continued until progression or unacceptable toxicity (2 year OS 
rates of 23% and 29%, and 3 year OS rates of 16% to 18% for squamous and non-squamous 
NSCLC respectively) (Felip, 2017).
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 2 
years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; HR = 0.42 (95% CI, 
0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (ie, 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years (Spigel, 2017).
 
 
 
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Collectively, these data suggest that there is minimal if any benefit derived from continuing 
immunotherapy treatment beyond two years in advanced tumors. Even though immunotherapy is 
well tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, 
in this study, treatment will be given for a maximum of 2 years from the start of study treatment.
1.3
Rationale
1.3.1
Study Rationale and Purpose
The use of ICIs in the treatment for lung cancer has proven efficacy as demonstrated by the
increasing OS, PFS, ORR and longer DoR compared to chemotherapy alone. However, only 
limited number of subjects have long term benefit with ICI treatment.
The LSD-1 inhibition sequentially or in combination with cytoreductive therapy could improve 
disease-free survival by preventing the emergence of resistant clones through treatment of 
tumorigenic stem cells. This mechanism of action is applicable to many earlier stages of solid 
tumors where existing standard of care does not result in long term disease control for all patients.
The LSD-1 could prove to have a role in treating tumors resistant to current immune check-point 
blockade, an area of high unmet need for multiple solid tumors where ICIs are either not effective, 
or where ICIs are currently employed.
CC-90011 has the potential to mitigate primary and acquired resistance to ICI, due to its expected 
reversal of the CSC phenotype and T cell exclusion in SCLC and sqNSCLC. 
In addition, recognizing the multiple mechanisms of resistance, this study will examine biomarkers 
in blood and tissue that could be used to identify responsive patients and improve outcomes. SCLC 
and sqNSCLC have high expression of potential predictive biomarkers for CC-90011 (eg, SOX-2 
and an LSD1-associated molecular signature), which will be evaluated for potential future use for 
patient enrichment.
This multi-cohort lung cancer study will evaluate the ability of CC-90011 to increase response 
rates in 3 different lung cancer populations: PD-1 inhibitor naïve (Cohort A, SCLC) and a PD-1 
inhibitor “experienced” (Cohort B, SCLC; and Cohort C, sqNSCLC) when given in combination 
with nivolumab. Cohort A tests the hypothesis that CC-90011 could enhance nivolumab responses 
in SCLC “cold tumor” phenotype. In this cohort, the proportion of enrolled subjects who respond 
to treatment is expected to increase by the action of CC-90011. Tumors with higher expression of 
an LSD1-associated molecular signature and low TILs may have the best response to the 
combination of ICI with CC-90011, based on CC-90011 hypothesized mechanism of action of 
increasing T cell infiltration into tumors. Cohorts B and C tests whether CC-90011 can mitigate 
acquired resistance to ICI in SCLC as well as sqNSCLC. For these cohorts, the trial will be 
enrolling subjects who have an initial response or stable disease to ICI, but progress within the 
first 9 months after completion of the chemotherapy treatment. 
For the purpose of this protocol, ICI means anti-PD-1 or anti-PD-L1 treatments.
 
 
 
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1.3.2
Rationale for the Study Design
1.3.2.1
Combination of CC-90011 with Immune Checkpoint Inhibitors
The effectiveness of ICIs is grounded on a pre-existent anti-tumoral cellular immune response, 
which is usually recognized by the presence of tumor T-lymphocytic infiltrates that are, however, 
most often ineffective because of expression of co-inhibitory (or checkpoint) receptors such as 
PD-1, CTLA-4, and others. Blocking these checkpoint receptors or their ligands restores T cell 
function and leads to clinical responses.
PD-1 is expressed on activated CD8+ T cells, as well as B cells and natural killer cells, in the 
setting of chronic antigen exposure. PD-1 ligand (PD-L1) expression is induced by localized 
inflammatory stimuli, such as interferons released by the infiltrating T cells. Although PD-1 and 
PD-L1 checkpoint blockade can result in dramatic therapeutic responses, this therapy is effective 
only in a subset of subjects, and many of them are only partial responders to therapy (Nowicki, 
2017). Subjects who do not respond to initial therapy with PD-1/PD-L1 blockade are referred to 
as having “primary resistance” to therapy (Sharma, 2017). Furthermore, a growing subset of 
subjects show robust initial response to therapy, but later have progressive disease. This 
phenomenon, in which the disease is either refractory to resumption of therapy or develops despite 
continuation of therapy, is known as “acquired resistance” to PD-1/PD-L1 blockade 
immunotherapy (O'Donnell, 2016). In all, almost four-fifths of patients either do not respond or 
lose their responsiveness to ICI. These limitations have made it necessary to explore combination 
treatment methods which are generally aimed at enhancing or activating antitumor immunity.
The tumor microenvironment can encompass multiple immunosuppressive mechanisms including 
dysfunctional T cells and lack of T cell infiltration or recognition by T cells, which prevent subjects 
to respond to anti-PD-1/PD-L1 therapy (Sharma, 2017;  Zou, 2016). These mechanisms provide a 
basis for selecting appropriate combinations to complement the anti-PD-1/PD-L1 action. For 
example, the presence of T cytotoxic tumor infiltrates (defining the so-called “hot tumors”) 
justifies targeting other checkpoint inhibitors and enhance anti-tumor immune response. With 
modest and immunosuppressed infiltrates, new therapy should be aimed at inhibitory mediators 
(such as TGF-β, IL-10, etc), immune suppressive cells (such as myeloid derived suppressor cells, 
regulatory lymphocyte T cells), or immune ignored cancer stem cells. Also, when T cells are 
excluded from the tumor bed and accumulate at the tumor border, then potentially effective 
combinations might be aimed at reactivating or supplanting T cell recruiting signals (eg,
chemokines). Finally, when T cells are absent (“cold tumors”), then various modalities to increase 
tumor immunogenicity and restart antigen-presentation or T cell priming might prove useful.
Based on current understanding, CC-90011, 
 
(unpublished data, current version of the Investigator Brochure), can be a combination partner for 
ICIs due to (1) its direct effects on tumor cells, 
 
 
and (2) due to its potential immunomodulatory effects via 
its abilities to impact lymphocytic infiltrates and immunogenicity of tumors (see below). In 
addition, we have found that tumors which lack T cell infiltration (cold tumors) have higher mRNA 
 
 
 
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expression of LSD1 and an LSD1-associated molecule, which could be used to identify patients 
susceptible to the action of CC-90011 with ICI.
Preclinical data provide strong mechanistic rationale for the combination of CC-90011 and an ICI 
in SCLC. Although checkpoint inhibitors have demonstrated some efficacy in SCLC, the 
magnitude of benefit has been relatively modest, and only a subset of patients respond. These 
clinical results may be related to the low abundance of T cells in SCLC tumors. CC-90011 is 
expected to reverse this phenotype, allowing T cells to infiltrate the tumor.
Preclinical data in the literature and from Celgene, including survival data in mice with tumors, 
suggest that CC-90011 could induce pro-inflammatory and T cell permissive changes in the tumor 
microenvironment and, thus, enhance efficacy of checkpoint inhibitors, such as nivolumab.
Mouse tumor models have known limitations especially for evaluating immune oncology (IO) 
agents. Testing potential therapies in animal models of human disease is a key part of drug 
development, despite well-known limitations of such models (Ben-David, 2019;  Day, 2015;  
Ochoa de Olza, 2018). A few main types of mouse models are used for IO studies, with advantages 
and disadvantages to each (Buque, 2018;  Ochoa de Olza, 2018). Of these, syngeneic tumor models 
are often used because of the relative ease with which molecules can be tested.  Variations in tumor 
response to immunotherapies, such as nivolumab, even in controlled laboratory studies with inbred 
mice, may be related to the gut microbiome (Gopalakrishnan, 2018;  Matson, 2018;  Ochoa de 
Olza, 2018;  Pitt, 2016;  Routy, 2018;  Vetizou, 2015).
 
 
 
 
1.3.2.2
Direct Anti-Tumor Action of CC-90011 Mediated via SOX2
LSD1 appears to play a significant role in the development and progression of malignancies with 
stem cell features. Accumulating evidence suggests that transcription factor SOX2 drives cancer 
stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug 
resistance mechanisms like epithelial-to-mesenchymal transition, adenosine triphosphate (ATP)-
binding cassette drug transporters, anti-apoptotic or pro-survival signaling, lineage plasticity, and 
evasion of immune surveillance (Mamun, 2018). Cancer stem cells, which are quiescent and 
express drug efflux pumps, may avoid killing by cytotoxic agents. Cancer stem cells are believed 
to be immune privileged, at least in part by expression of immune-modulatory factors (Bruttel, 
2014). By driving differentiation of stem cells, LSD1 inhibition may re-sensitize these cells. 
Inhibition or genetic silencing of LSD1 has been shown to promote differentiation and reduce 
proliferation, migration, and invasion in vitro (Augert, 2019;  Lv, 2012) and to reduce tumor 
growth in preclinical models (Augert, 2019;  Mohammad, 2015)
 
 
 
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The SOX2 is the most frequently altered gene in human squamous cell carcinoma (skin, lung and 
esophageal carcinomas) (Mamun, 2018). The SOX2 gene expression is amplified in more than 
20% of tumors, including 27% of SCLC tumors, and is associated with stemness and an un-
differentiated state (Hayami, 2011;  Rudin, 2012). The SOX2 protein expression is overexpressed 
in 60% to 90% of tumors, including gliomas, breast, lung, head and neck carcinoma, sarcoma, 
pancreatic ductal carcinoma, ovarian cancer, colorectal cancer, melanoma, gastric cancers, and 
medulloblastoma (Mamun, 2018). The SOX2 is frequently amplified and/or over-expressed in 
SCLC and is involved in the induction of pluripotent stem cells (Takahashi, 2006). 
 
 
 
 
CC-90011 may induce differentiation of CSCs. CSCs can be resistant to treatments, including 
checkpoint inhibitors (Bruttel, 2014). The LSD1 is key regulator of stemness (Zhang, 2018). SOX2 
is over-expressed in some SCLC tumors and is a driver of SCLC cell growth (Rudin, 2012;  Sholl, 
2010;  Zhang, 2018). LSD1 inhibitors can decrease SOX2 mRNA expression (Zhang, 2013). LSD1 
prevents SETD7-Driven proteolysis of SOX2 (Zhang, 2018), providing another mechanism by 
which LSD1 inhibitors would decrease SOX2 protein levels.
Therefore, 
 CC-90011 may be a useful therapeutic approach for tumors with 
CSC involvement such as SCLC and sqNSCLC, which are known to have high expression of 
SOX2 (Karachaliou, 2013;  Wuebben, 2017;  Ying, 2016). Overexpression of LSD1 is associated 
with poor prognosis in NSCLC, and promotes tumor cell proliferation, migration and invasion in 
NSCLC (Lv, 2012). Inhibition of LSD1 inhibits SCLC cell proliferation (Takagi, 2017). 
1.3.2.3
Immunomodulatory Activities of CC-90011
CC-90011 may increase the number of tumor T infiltrating lymphocytes (TIL). This could be 
related to the observation that LSD1 ablation can lead to activation of type 1 interferon and 
stimulate anti-tumor T cell immunity (Sheng, 2018); and it can also result in enhanced tumor 
immunogenicity and T cell infiltration in poorly immunogenic tumors. LSD1 inhibition can also 
result in re-expression of effector T cell-attracting chemokines (CCL5, CXCL9, and CXCL10)
(Qin, 2019). 
In addition, CC-90011 may inhibit CSC self-renewal and induce their differentiation. The CSCs
are known to be resistant to chemotherapy and at least in part by their expression of immune-
inhibitory factors to immunotherapy as well (Bruttel, 2014). A tumor without a CSC compartment 
would remain sensitive to killing by cytoreductive agents or immune regulators. This impact on 
CSC suggests that CC-90011 could also help mitigate acquired resistance (eg, responders that 
relapse after a period of response). However, given potential mechanisms of acquired resistance, 
such as loss of T cell function, lack of T cell recognition by downregulation of tumor antigen 
presentation, and development of escape mutation variants in the cancer (Sharma, 2017), it is 
expected that the other immune activities of CC-90011, increasing TIL, stimulating 
 
 
 
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immunogenicity and anti-tumor T cell immunity (Sheng, 2018), would also contribute to CC-
90011 activity in relapsed subjects.
One of the best predictors of response to immunotherapy is the number and activity of tumor 
infiltrating CD8+ cytotoxic T lymphocytes recruited to the tumor site (Qin, 2019). Consistent with 
their biological role, tumor infiltrated lymphocytes have been associated with improved outcome 
in several tumor types, including melanoma, colorectal and breast cancer (Fridman, 2013). Tumor 
CD8+ T cell infiltration has been linked to antitumor activity of immune checkpoint inhibitors 
(ICI) in subjects with advanced melanoma or NSCLC (Sharma, 2017;  Thomas, 2019)
High levels of tumor infiltrating immune cells are associated with improved overall survival in 
SCLC, irrespective of tumor stage, subject performance status, or type of treatment received
(Wang, 2013). In SCLC, tumor responses were observed in all cases where pretreatment tumors 
were T cell inflamed. In extended or relapsed SCLC, pre-existing CD8+ T cell response may be 
predictive of benefit from ICI-based therapies (Thomas, 2019).
As an LSD1 inhibitor, CC-90011 may switch cold tumors (lacking T cells) into hot tumors (T cell 
infiltrated). Internal analyses of tumor data in The Cancer Genome Atlas (TCGA) identified > 100 
genes which negatively correlate with T cell infiltration. Expression of LSD1 and an LSD1-
associated molecule anti-correlated with T cells in tumors. The LSD1 complex regulates 
embryonic stem cells property and substitutes for SOX2 in reprogramming somatic cells to 
pluripotency (Yang, 2011). Approximately 50% of SCLC and approximately 33% of sqNSCLC 
had a gene expression pattern which may predict for LSD1 activity and thus response to CC-90011, 
when combined with anti-PD1 or anti-PD-L1.
CC-90011 may enhance tumor immunity in “cold” tumors. LSD1 expression is inversely 
associated with that of cytotoxic T cell-attracting chemokines and PDL1 (Qin, 2019). LSD1 knock-
down increases inflammatory gene expression (Hanzu, 2013;  Qin, 2019). LSD1 KO or inhibition 
increases T cell trafficking into tumors and check-point inhibitor efficacy in preclinical 
models (Qin, 2019;  Sheng, 2018). LSD1 inhibitors upregulate PDL1 expression in cell lines (Qin, 
2019).  
Subsequently, LSD1 knockdown was shown to enhance efficacy of anti-PD1, as evidenced by 
decreased tumor size and increased mouse survival in syngeneic tumor models (Sheng, 2018). In 
a separate study, LSD1 inhibition plus an anti-PD-1 antibody significantly suppressed tumor 
growth and pulmonary metastasis and augmented CD8+ T cell infiltration into xenograft tumors 
of triple negative breast cancer (Qin, 2019). Thus, CC-90011 is expected to enhance response to 
ICI, such as anti-PD1, when used in combination.
 
 
 
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1.3.4
Benefit/Risk Assessment Due to SARS-COV-2/COVID-19 Infection
In 2019, a new coronavirus was identified as the cause of a widespread disease outbreak. The virus 
is now known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and causes 
the disease called coronavirus disease 2019 (COVID-19), which can lead to severe disease 
including substantial mortality. 
At this time, the risk of COVID-19 in subjects receiving CC-90011 is unknown. Current available 
clinical data from the ongoing CC-90011-ST-002 study suggest an overall favorable safety profile 
and no specific evidence of elevated risk of infection. However, since at least a theoretical risk of 
increased infection rates cannot be ruled out, clinical studies of CC-90011 have been further 
designed to minimize the overall risk to subjects; additional measures to mitigate risk associated 
specifically with COVID-19 will include the following:
 
 
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
Continuous safety assessments will be utilized by the Investigators and Sponsor to determine 
whether additional safety measures are required. In addition, AEs and SAEs associated with 
confirmed or suspected SARS-CoV-2 infection will be collected from the date the subject signs 
informed consent until 100 days following discontinuation of study treatment. The event will 
be followed until resolution, the condition stabilizes, the event is otherwise explained, the event 
is deemed irreversible, the subject is lost to follow-up), or for suspected cases, until SARS-
CoV-2 infection is ruled-out. Adverse events and SAEs will be reviewed on an ongoing basis 
by the Medical Monitor (or designee) and Global Pharmacovigilance and Epidemiology 
representatives to monitor for any safety signals or trends. There will be prompt surveillance 
of SARS-CoV-2/COVID-19 infections in study subjects to ensure that the investigational 
study treatment do not pose an increased risk of SARS-CoV-2/COVID-19.

The testing capability for SARS-CoV-2 to provide prompt results is not uniformly available. 
Due to these challenges, testing for SARS-CoV-2 will be deferred to local or regional policies. 
However, study subjects who test positive for SARS-CoV-2 during screening may be 
rescreened after meeting criteria in Section 6.1.1.

Subjects with previous SARS-CoV-2 infection either suspected or confirmed within 4 weeks 
prior to screening are excluded until symptoms have completely resolved and based on 
investigator assessment in consultation with the Medical Monitor, there are no sequelae that 
would place the subject at a higher risk of receiving investigational treatment.

Subjects currently in other interventional trials for COVID-19 may not participate in the study. 
If a study participant has received an investigational COVID-19 vaccine prior to screening, 
enrollment must be delayed until the biologic impact of the vaccine is stabilized, as determined 
by discussion between the Investigator and the Medical Monitor. It is also advised to avoid 
overlap of study treatment and vaccine administration, if possible (for example, at least 2 days, 
preferably 7 days apart), given that adverse events related to vaccine administration may 
confound potential study treatment infusion reactions.

SARS-CoV-2 may have short- and long-term impact on the study population, which may affect 
the safety profile and outcome of investigational products. Thus, serologic testing will be 
implemented at screening, during study treatment, after a documented or suspected SARS-
CoV-2 infection, and at follow-up for potential future measurements of anti-SARS-CoV-2 
serology.

Dose delay and criteria to resume study treatment in cases when a subject develops confirmed 
or suspected SARS-CoV-2 is included in Section 7.4.5.
It is important to acknowledge the widespread impact of SARS-CoV-2 and the potential risks 
SARS-CoV-2 may have on this study population. However, there are limited treatment options 
available to individuals with advanced lung cancer who have a poor prognosis and few, if any, 
curative options. The absence of other available treatments supports the urgent need to develop 
therapeutic options for these serious diseases while not negating the implementation of mitigation 
measures to protect the safety of the study population.
The potential for direct benefit described within Section 1.3 warrants evaluating CC-90011 in 
combination with nivolumab in this Phase 2 clinical study with the risk mitigation described above.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
48
1.4
Risk/Benefit Assessment
Please see Appendix G for the Risk Benefit Assessment document.
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
49
2
STUDY OBJECTIVES AND ENDPOINTS
Table 4:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate in each individual cohort the overall response rate in 
subjects with SCLC or sqNSCLC treated with CC-90011 in combination with nivolumab.
Secondary Objective(s)
The secondary objectives are to evaluate in each individual cohort the following endpoints/outcomes in 
subjects with SCLC or sqNSCLC receiving CC-90011 in combination with nivolumab:

Evaluate the safety and tolerability

Evaluate the duration of response

Evaluate the time to response

Evaluate the Investigator-assessed progression-free survival

Evaluate the time to first subsequent therapy
Exploratory Objective(s)
The exploratory objectives for each individual cohort are to:

Evaluate the overall survival

Explore the relationship between PK, PD biomarkers and/or clinical outcomes of CC-90011 in 
combination with nivolumab

Evaluate the disease control rate

Assess the pharmacokinetics and immunogenicity of nivolumab in small cell lung cancer and squamous 
non-small cell lung cancer cohort subjects

Assess the impact of SARS-CoV-2 serologic status on subjects and to support health authority requests
Abbreviations: LSD1 = lysine-specific histone demethylase 1 A; PD = pharmacodynamic; PK = pharmacokinetic; 
; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; sqNSCLC 
= squamous non-small cell lung cancer; SCLC = small cell lung cancer; 
.
 
 
 
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Final: 30 Apr 2022
50
Table 5:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary
Overall response rate
The proportion of subjects in the treated 
population who had confirmed complete 
response (CR) or confirmed partial 
response (PR) as assessed by Investigator 
review per RECIST v1.1
Every 6 weeks post C1D1 
for the first 24 weeks and 
then every 8 weeks until 
disease progression, new 
anticancer therapy, death 
or withdrawal by subject.
Secondary
Safety and tolerability
Safety and tolerability will be assessed 
from adverse events (using NCI CTCAE 
v5.0), laboratory tests, vital signs, ECOG 
performance status, concomitant 
medications, and dose modifications.
Signature of informed 
consent through 28 days 
after the last dose of CC-
90011 and 100 days after 
the last dose of nivolumab.
Duration of response 
The time from the first occurrence of a 
confirmed documented response to the 
time of the first documented tumor 
progression, as determined by 
Investigator review per RECIST v1.1, or 
death from any cause, whichever comes 
first.
Every 6 weeks post C1D1 
for the first 24 weeks and 
then every 8 weeks until 
disease progression, new 
anticancer therapy, death 
or withdrawal by subject.
Time to response
The time from the first dose of the study 
drug to the date of the first confirmed 
documented response (CR or PR), as 
assessed by Investigator review per 
RECIST v1.1. 
Every 6 weeks post C1D1 
for the first 24 weeks and 
then every 8 weeks until 
disease progression, new 
anticancer therapy, death 
or withdrawal by subject.
Progression-free 
survival 
The time from first dose of study 
treatment to the date of the first 
objectively documented tumor 
progression as assessed by Investigator 
review per RECIST v1.1 or death from 
any cause, whichever occurs first.
Every 6 weeks post C1D1 
for the first 24 weeks and 
then every 8 weeks until 
disease progression, new 
anticancer therapy, death 
or withdrawal by subject.
Time to first 
subsequent therapy
The time from the first dose of the study 
drug to the date of the next cancer 
therapy or death. 
From the first dose of 
study drug to the date of 
next cancer therapy or 
death due to any cause.
Exploratory
Overall survival 
The time from first dose of the study drug 
to the date of death due to any cause.
From the first dose of the 
study drug to the date of 
death due to any cause.
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
51
Table 5:
Study Endpoints
Endpoint
Name
Description
Timeframe
Pharmacodynamics/
Biomarkers
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics
Assess the relationship between PK/PD 
biomarkers and clinical outcomes of CC-
90011 in combination with nivolumab.
Cycle 1 and subsequent 
Cycles at specified 
timepoints.
Disease control rate
The proportion of subjects in the treated 
population who had confirmed CR, 
confirmed PR, or stable disease (SD) for 
the minimum interval of 12 weeks as 
assessed by Investigator review per 
RECIST v1.1
Every 6 weeks post C1D1 
for the first 24 weeks and 
then every 8 weeks until 
disease progression, new 
anticancer therapy, death 
or withdrawal by subject.
Nivolumab 
Pharmacokinetics and 
Immunogenicity
Assess anti-nivolumab antibodies and 
explore relationship between
pharmacokinetics, immunogenicity and 
selected efficacy and safety endpoints 
Prespecified timepoints in 
treatment period
SARS-CoV-2 serology
Exploratory measurements of SARS-
CoV-2 serology (anti-SARS-CoV-2 total 
or IgG) and the potential association 
between these measurements and selected 
endpoints related to safety, efficacy, 
and/or biomarkers
Baseline, every 6 months 
post C1D1, and at follow-
up.
Abbreviations: 
; ECOG = Eastern Cooperative Oncology Group; IgG = immunoglobulin G; 
; NCI CTCAE = National Cancer Institute Common Terminology 
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
52
Criteria for Adverse Events; ORR = overall response rate; 
; PK = pharmacokinetic; 
; RECIST = Response Evaluation Criteria in Solid Tumors; SARS-CoV-2 = 
severe acute respiratory syndrome coronavirus 2.
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3.0
Final: 30 Apr 2022
53
3
OVERALL STUDY DESIGN
3.1
Study Design
This is a Phase 2, multicenter, open-label, multi-cohort study to assess safety and efficacy of CC-
90011 in combination with nivolumab in subjects with small cell lung cancer or squamous non-
small cell lung cancer who have progressed after 1 or 2 lines of therapies.
Approximately 135 subjects total globally will be enrolled into one of the following cohorts in 2 
stages:

Cohort A: SCLC in ICI naïve subjects 

Cohort B: SCLC in ICI progressor subjects 

Cohort C: sqNSCLC in ICI progressor subjects
For the purpose of this protocol, ICI means anti-PD-1 or anti-PD-L1 treatments.
During Stage 1 of each cohort, a Data Review Team (DRT) will review all safety and preliminary 
efficacy data and will be responsible for conducting a futility review for go/no-go decision for 
Stage 2. The DRT will consist of the Celgene Medical Monitors, Celgene lead safety physician, 
Celgene biostatistician, other Celgene functional area representatives, as appropriate, and site 
investigator(s) and/or designees who have enrolled subjects in the Stage(s) 1 of the study. Data 
Review Team meetings will be held to review the data, monitor safety and make expansion 
decisions.
The primary endpoint is investigator assessed ORR.
Based on safety/tolerability and preliminary efficacy data, the combination of CC-90011 and 
nivolumab could be expanded to add cohorts of subjects within other tumor types and the Sponsor 
may consider amending the Study design to investigate the efficacy of the combination versus the 
current standard of care in one or more tumor types.
All subjects will receive CC-90011 40 mg, unless otherwise determined during the ongoing safety 
evaluation (Section 7.3.1.1) PO weekly on Days 1, 8, 15, and 22 of every 28-day cycle and 
nivolumab 480 mg IV every 4 weeks. The decision to discontinue a subject, which will not be 
delayed or refused by the Sponsor, remains the responsibility of the treating physician. However, 
prior to discontinuing a subject, the Investigator may contact the Medical Monitor and forward 
appropriate supporting documents for review and discussion.
The study conduct will be overseen by a Steering Committee (SC) composed of selected 
Investigators who are taking part in the study. The SC will serve in an advisory capacity to the 
Sponsor.  
The study will be conducted in compliance with the International Council on Harmonisation (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice (GCP) and applicable regulatory requirements.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
Figure 3:
Overall Study Design
End of Treatment
Until evidence of progression, death, 
unacceptable toxicity, 
subject/physician decision, lost to 
follow-up, withdrawal of consent from 
treatment, or up to 2 years.
STAGE 1
STAGE 2
Cohort A: SCLC in 
subjects with no 
prior ICI
N=12
Cohort A: SCLC in 
subjects with no prior 
ICI
N=27 (39 total)
SCREENING
Eligibility Check
If ≥ 2 confirmed 
response(s)
If ≥ 1 confirmed response(s) 
If ≥ 1 confirmed 
response(s) 
Cohort B: SCLC in 
subjects with prior 
ICI
N=14
Follow-Up 
Safety follow-up
Response evaluation until progression, new 
anticancer therapy, lost to follow-up or death, 
whichever is earlier. 
Survival follow-up until death, lost to follow-
up, withdrawal of consent from study, the 
100-day safety follow-up visit of the last 
subject on study treatment, or study closure.
Cohort B: SCLC in 
subjects with prior ICI
N=34 (48 total)
Cohort C: 
sqNSCLC in 
subjects with prior 
ICI
N=14
Cohort C: sqNSCLC in 
subjects with prior ICI
N=34 (48 total)
 
 
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
3.2
Study Duration for Subjects 
Subjects may begin screening up to 28 days before first dose of study treatment. Treatment must 
begin within 3 days of enrollment. Subjects will be treated until death, progressive disease, 
unacceptable toxicity, withdrawal of consent from treatment, physician decision, or for up to 2 
years. For subjects who progress with only brain metastasis, treatment with IP will be stopped, but 
may be continued after completion of, and recovery from local radiation treatment per the 
Investigator’s judgement. 
In the event of discontinuation of the study treatments, subjects will be followed in survival follow-
up until death, withdrawal of consent from the entire study, lost to follow-up, the 100-day safety 
follow-up visit of the last subject on study treatment, or end of study.
Enrollment is expected to take approximately 18 months. The total study duration is estimated to 
be approximately 36 months from the enrollment of the first subject to the last subject last visit.
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 survival follow-up, or the date of receipt of the last data point from the last subject 
that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
 
 
 
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CC-90011
Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
4
STUDY POPULATION
4.1
Number of Subjects 
Approximately 135 subjects with SCLC or sqNSCLC will be enrolled globally. The total number 
of subjects to be enrolled in Stage 1 across all cohorts is approximately 40 subjects. In Stage 2, 
approximately 95 additional subjects will be enrolled across all cohorts. 
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 with histological or cytological confirmation of extensive stage SCLC (ES SCLC) or 
Stage IIIb or IV sqNSCLC.
3) Subject has received 1 or 2 prior lines of therapies, defined as:
a) Cohort A (SCLC, ICI naïve): 

At least 1 prior treatment including a platinum-based chemotherapy doublet 

A minimum of 3 cycles of platinum-based chemotherapy in first line treatment, unless 
stopped at 2 cycles due to treatment-related toxicity
b) Cohort B (SCLC, ICI progressors): 

At least 1 prior first or second line treatment includes an ICI

If treatment includes an ICI as maintenance therapy, at least 1 cycle of ICI in 
maintenance should have been completed

At least 1 prior treatment including a platinum-based chemotherapy doublet

A minimum of 3 cycles of platinum-based chemotherapy, with or without ICI, in first 
line treatment, unless stopped at 2 cycles due to treatment-related toxicity

Subject must have progressed during ICI therapy, defined as unequivocal progression 
on or within 3 months of the last dose of ICI therapy (if no subsequent therapy)
c) Cohort C (sqNSCLC, ICI progressors): 

At least 1 prior first or second line treatment includes an ICI

If treatment includes an ICI as maintenance therapy, at least 1 cycle of ICI in 
maintenance should have been completed

At least 1 prior treatment including a platinum-based chemotherapy doublet 

A minimum of 3 cycles of platinum-based chemotherapy, with or without an ICI, in 
first line treatment, unless stopped at 2 cycles due to treatment-related toxicity

Subject must have progressed during ICI therapy, defined as unequivocal progression 
on or within 3 months of the last dose of ICI therapy (if no subsequent therapy)
4) Subject has progressed at the last line of therapy.
5) Subject has a measurable disease defined by RECIST v1.1.
6) Subject agrees to provide a tumor biopsy from primary or metastatic site prior to first dose and 
at a pre-specified timepoint during treatment. Core biopsy is required however, in the event a 
core biopsy may not otherwise be feasible in the opinion of the treating physician, an 
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
endobronchial ultrasound-guided fine needle aspirate [EBUS-FNA]) biopsy, using the largest 
gauge needle, may be performed instead. 
7) Subject has ECOG Performance Status of 0 to 1 (APPENDIX C).
8) Subject is able to swallow medication.
9) Subject must have the following laboratory values: 
a) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
b) Hemoglobin (Hgb) ≥ 9 g/dL (one-time blood transfusion is allowed)
c) Platelet (Plt) Count ≥150 x 109/L
d) White blood cells (WBC) ≥ 2 x 109L
e) Serum AST/serum glutamic oxaloacetic transaminase (SGOT) or ALT/serum glutamic 
pyruvic transaminase (SGPT) ≤ 3 x upper limit of normal (ULN) or ≤ 5 x ULN if presence 
of liver metastases
f)
Total serum bilirubin ≤ 1.5 x ULN (≤ 3 x ULN, if Gilbert’s syndrome or if indirect bilirubin 
concentrations are suggestive of extrahepatic source of the elevation)
g) Creatinine clearance (CrCl) ≥ 60 mL/minute based on Cockcroft-Gault (APPENDIX D) or 
modification of diet in renal disease (MDRD) or ≥ 60 mL/min/1.73 m2 
10) A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some 
point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been 
naturally postmenopausal (amenorrhea following cancer therapy or other medical condition 
does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses 
at any time in the preceding 24 consecutive months) and must:
a) Have 2 negative pregnancy tests as verified by the Investigator prior to starting study 
treatments:  

Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at Screening

Have a negative serum or urine pregnancy test within 72 hours prior to Cycle 1 Day 1 
of study treatment. A urine pregnancy test must have a sensitivity of at least 
25 mIU/mL.
b) Either commit to true abstinence* from heterosexual contact (which must be reviewed on 
a monthly basis and source documented) or agree to use, and be able to comply with 1 
highly effective contraceptive method plus 1 barrier method during the following time 
periods related to this study: 1) from signing of ICF; 2) while taking study treatment; 3) 
during dose interruptions; and 4) for at least 45 days after the subject’s last dose of 
CC-90011 or 5 months after the last dose of nivolumab, whichever is later. 

Highly effective contraceptive methods are combined (containing estrogen and 
progestogen) or progestogen-only hormonal contraception associated with inhibition 
of ovulation (oral, injectable, intravaginal, patch or implantable) bilateral tubal 
ligation; intra-uterine device; intrauterine hormone-releasing system, or vasectomized 
partner sterilization (note that vasectomized partner is a highly effective birth control 
method provided that partners is the sole sexual partner of the FCBP trial participant 
                                                       
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception].
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
and that the vasectomized partner has received medical assessment of the surgical 
success). Barrier methods are male or female latex or synthetic condom, diaphragm, 
cervical cap or sponge with spermicide.  
c) Avoid conceiving or donating ova while on treatment and for 45 days after the last dose of 
CC-90011 or 5 months after the last dose of nivolumab, whichever is later.  
d) Agree to ongoing pregnancy testing during the course of the study. This applies even if the 
subject practices true abstinence* from heterosexual contact.
11) Males must practice true abstinence* from heterosexual intercourse (which must be reviewed 
on a monthly basis) or agree to use a condom (a latex or non-latex synthetic condom is 
recommended) during sexual contact with a pregnant female or a FCBP while participating in 
the study, during dose interruptions, and for at least 105 days after the subject’s last dose of 
CC-90011, even if he has undergone a successful vasectomy. Males must agree not to donate 
semen or sperm while on treatment and for at least 105 days following the last dose of CC-
90011, whichever is later.
12) Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
13) Subject is 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 any significant medical condition, including active or uncontrolled infection, or 
the presence of laboratory abnormalities, or psychiatric illness which places the subject at 
unacceptable risk if he/she were to participate in the study.
2) Subject has any condition that confounds the ability to interpret data from the study.
3) Subject has not recovered to Grade 2 or lower clinically significant toxicities related to the 
prior therapy (alopecia excluded).
4) Subject has received prior LSD1 therapies.
5) Subject has a history of severe hypersensitivity reactions to other monoclonal antibodies.
6) Subject with symptomatic and untreated or unstable central nervous system (CNS) metastases.
a) Subject has recently been treated with whole brain radiation or stereotactic radiosurgery 
for CNS metastases must have completed therapy at least 2 weeks prior to Cycle 1 Day 1 
and has a follow-up brain computed tomography (CT) or magnetic resonance imaging 
(MRI) demonstrating either stable or improving metastases 2 or more weeks after 
completion of radiotherapy.
b) Subject must be asymptomatic and off steroids or on stable dose of steroids for at least 2 
weeks (≤ 10 mg daily prednisone or equivalent) prior to first dose.
7) Subject has persistent diarrhea due to a malabsorptive syndrome (such as celiac sprue or 
inflammatory bowel disease) ≥ NCI CTCAE Grade 2, despite medical management), or any 
                                                       
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception].
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
other significant gastrointestinal (GI) disorder that could affect the absorption of the study 
treatments.
8) Subject with symptomatic or uncontrolled ulcers (gastric or duodenal), particularly those with 
a history of and/or risk of perforation and GI tract hemorrhages.
9) Subject with any hemorrhage/bleeding event > NCI CTCAE Grade 2 or haemoptysis > 1 
teaspoon within 4 weeks prior to the first dose.
10) Subject has any of the following cardiovascular criteria: 
a) Evidence of acute or ongoing cardiac ischemia 
b) Current symptomatic pulmonary embolism 
c) Unstable angina pectoris or myocardial infarction ≤ 6 months prior to enrollment 
d) Heart failure of New York Heart Association Classification III or IV ≤ 6 months prior to 
enrollment 
e) Persistent or clinically meaningful ventricular arrhythmias prior to enrollment 
f)
Cerebral vascular accident or transient ischemic attack ≤ 6 months prior to enrollment 
g) QT corrected based on Fridericia’s equation (QTcF) ≥ 450 milliseconds (msec) on 
Screening ECG, a baseline prolongation of QTcF interval ≥ 450 msec (NCI CTCAE Grade 
≥ 2)
h) A history of additional risk factors for Torsades de pointes (TdP) (eg, heart failure, 
hypokalemia, family history of Long QT Syndrome)
i)
Uncontrolled hypertension (blood pressure ≥ 160/95 mm Hg)
11) Subject has known human immunodeficiency virus (HIV) infection. 
12) Subject has known chronic active hepatitis B or C virus (HBV, HCV) infection.
a) Subject who is seropositive due to HBV vaccination is eligible.
b) Subject who has no active viral infection and is under adequate prophylaxis against HBV 
reactivation is eligible.
13) Subject has any other malignancy within 2 years prior to enrollment, with the exception of 
adequately treated in-situ bladder cancer, in-situ carcinoma of the cervix, uteri, non-
melanomatous skin cancer, ductal in situ breast carcinoma, thyroid cancer, or early stage 
prostate cancer (all treatment of which should have been completed 6 months prior to 
enrollment).
14) Enrollment in any other clinical protocol or investigational study with an interventional agent 
or assessments that may interfere with study procedures.
15) Subject has medical conditions requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days 
of enrollment.  
a) A brief (≤ 7 days) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of nonautoimmune conditions (eg, delayed-type hypersensitivity reaction caused
by contact allergen) is permitted. 
b) Adrenal replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in 
the absence of active autoimmune disease. 
c) Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption) are permitted. 
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
16) Subject has active autoimmune diseases or history of autoimmune diseases that may relapse.  
Subjects with the following diseases are allowed to be enrolled after further screening: type I 
diabetes, hypothyroidism managed with hormone replacement therapy only, skin diseases not 
requiring systemic treatment (such as vitiligo, psoriasis, or alopecia), or diseases not expected 
to recur in the absence of external triggering factors.
17) Subject is pregnant or nursing.
18) Subject has a history of persistent skin rash ≥ NCI CTCAE Grade 2 related to prior ICI therapy.
19) Subject has organ transplant history, including allogeneic stem cell transplant.
20) Subject has interstitial lung disease history.
21) Subject has received a live/attenuated vaccine within 30 days of first dose.
22) Subject who is currently in other interventional trials, including those for COVID-19, may not 
participate in Bristol Myers Squibb (BMS) or Celgene Corporation clinical trials until the 
protocol specific washout period is achieved. If a study subject has received an investigational 
COVID-19 vaccine or other investigational product designed to treat or prevent COVID-19 
prior to screening, enrollment must be delayed until the biologic impact of the vaccine or 
investigational product is stabilized, as determined by discussion between the Investigator and 
the Medical Monitor.
23) Subject has previous SARS-CoV-2 infection either suspected or confirmed within 4 weeks 
prior to screening.
a) Acute symptoms must have resolved and based on Investigator assessment in consultation 
with the Medical Monitor, there are no sequelae that would place the subject at a higher 
risk of receiving investigational treatment.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
61
5
TABLE OF EVENTS
Table 6:
Table of Events
Events
Screening 
Perioda
Treatment Period
Follow-up Period
Cycle 1
Cycle 2
Subsequent 
Cycles
EOTc
Safety
Survival
-28 to 1
Day 1b
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
28 
days
100 
days
Q2 
months
Window (days)
± 1
± 1
± 1
± 1
± 1
± 7
± 1
+ 7
+ 7
± 14
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed consent
form
X
-
-
-
-
-
-
-
-
-
-
-
Optional informed 
consent form to 
continue IP and 
research
X
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusio
n criteria
X
-
-
-
-
-
-
-
-
-
-
-
IRT Registration 
X
X
-
-
-
X
-
X
X
-
-
-
Complete medical 
history
X
-
-
-
-
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
-
-
-
Prior disease 
history
X
-
-
-
-
-
-
-
-
-
-
-
Prior disease 
therapies
a
X
-
-
-
-
-
-
-
-
-
-
-
Histological or 
cytological 
confirmation
X
-
-
-
-
-
-
-
-
-
-
-
 
 
 
 
 
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Final: 30 Apr 2022
62
Table 6:
Table of Events
Events
Screening 
Perioda
Treatment Period
Follow-up Period
Cycle 1
Cycle 2
Subsequent 
Cycles
EOTc
Safety
Survival
-28 to 1
Day 1b
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
28 
days
100 
days
Q2 
months
Window (days)
± 1
± 1
± 1
± 1
± 1
± 7
± 1
+ 7
+ 7
± 14
Prior/ concomitant 
medication 
evaluation
X
Continuous, until 28 days after CC-90011 discontinuation or 100 days for nivolumab or EOT Visit, whichever 
occurs later
-
Prior/ concomitant 
procedures 
evaluation
X 
Continuous, until 28 days after CC-90011 discontinuation or 100 days for nivolumab or EOT Visit, whichever 
occurs later
-
SAFETY ASSESSMENTS
Adverse event 
evaluation
Continuous for all AEs (SAEs or non-serious AEs), including those associated with SARs-CoV-2 infection, starting after 
informed consent signature, until 28 days after CC-90011 discontinuation or 100 days for nivolumab or EOT Visit, 
whichever occurs later. All AEs (SAEs or non-serious AEs) associated with confirmed or suspected SARS-CoV-2 infection 
will be followed until resolution, the condition stabilizes, the event it otherwise explained, the event is deemed irreversible, 
the subject is lost to follow-up, or for suspected cases, until SARS-CoV-2 infection is ruled out.
-
Physical 
examination 
X
X
-
-
-
X
-
X
X
X
-
-
Vital signs
X
X
X
X
X
X
X
X
X
X
X
-
Weight
X
X
-
-
-
X
-
X
X
X
X
-
Performance status 
(ECOG)
X
X
-
-
-
X
-
X
X
X
-
-
Height
X
-
-
-
-
-
-
-
-
-
-
-
12-lead ECGd
X
Xd
X
-
-
X
-
Cycle 3
-
-
-
-
Hematology 
laboratorye
X
X
X
X
X
X
X
X
X
X
X
-
 
 
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
63
Table 6:
Table of Events
Events
Screening 
Perioda
Treatment Period
Follow-up Period
Cycle 1
Cycle 2
Subsequent 
Cycles
EOTc
Safety
Survival
-28 to 1
Day 1b
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
28 
days
100 
days
Q2 
months
Window (days)
± 1
± 1
± 1
± 1
± 1
± 7
± 1
+ 7
+ 7
± 14
Chemistry 
laboratoryf
X
X
X
X
X
X
X
X
X
X
X
-
Thyroid function
X
X
-
-
-
-
-
Every 8 
weeks
X
X
X
-
Coagulation 
laboratory
X
As clinically indicated
-
Serum β- hCG for 
FCBP
X
As clinically indicated
-
Urine β- hCG for 
FCBPg
-
X
-
-
-
X
-
X
X
X
X
-
Fertility 
counselingh
X
-
-
-
-
-
-
-
-
-
-
-
Contraceptive 
counseling for 
FCBP and males
X
X
-
-
-
-
-
-
X
X
X
-
EFFICACY AND OTHER ASSESSMENTS
Efficacy 
assessments: CT 
scan/ MRI (chest, 
abdomen, pelvis)i
X
Every 6 weeks (± 7 days) for the first 24 weeks and then every 8 weeks (± 7 days) until disease progression, 
start of a new anticancer therapy, or withdrawal of consent by subject from the entire study.
-
 
 
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
64
Table 6:
Table of Events
Events
Screening 
Perioda
Treatment Period
Follow-up Period
Cycle 1
Cycle 2
Subsequent 
Cycles
EOTc
Safety
Survival
-28 to 1
Day 1b
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
28 
days
100 
days
Q2 
months
Window (days)
± 1
± 1
± 1
± 1
± 1
± 7
± 1
+ 7
+ 7
± 14
CT scan, with 
contrast, of the 
head or brain MRI 
with contrastj
X
As clinically indicated
CC-90011 
Pharmacokinetics 
(Refer to Table 7) 
-
X
X
-
-
X
-
Cycle 3
-
-
-
-
Nivolumab 
Pharmacokinetics 
and 
Immunogenicity 
(Refer to
Section 6.5.1) 
-
X
-
-
-
X
-
Cycle 3 and
then every 
4th Cycle 
thereafter
-
-
-
-
SARS-CoV-2 
Serologyo (Refer to 
Table 10)
X
Every 6 months during study treatment and approximately 4 weeks after 
a documented or suspected SARS-CoV-2 infectiono
-
X
-
-
 
 
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
65
Table 6:
Table of Events
Events
Screening 
Perioda
Treatment Period
Follow-up Period
Cycle 1
Cycle 2
Subsequent 
Cycles
EOTc
Safety
Survival
-28 to 1
Day 1b
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
28 
days
100 
days
Q2 
months
Window (days)
± 1
± 1
± 1
± 1
± 1
± 7
± 1
+ 7
+ 7
± 14
INVESTIGATIONAL PRODUCT (IP)
Administer CC-
90011 
-
Weekly administration on Days 1, 8, 15, 22 of each cycle
-
-
-
-
Dispense CC-
90011
-
X
-
-
-
X
-
X
-
-
-
-
Administer 
nivolumabn
-
X
-
-
-
X
-
X
-
-
-
-
Provide, collect, 
and/or review 
medication diary 
for CC-90011m
-
X
X
X
X
X
X
X
X
-
-
-
Accountability of 
CC-90011
-
X
-
-
-
X
-
X
X
-
-
-
Accountability of 
nivolumab
-
X
-
-
-
X
-
X
X
-
-
-
FOLLOW-UP
Survival follow-up
-
-
-
-
-
-
-
-
-
-
X
X
Disease therapy 
since IP 
discontinuation
-
-
-
-
-
-
-
-
-
X
X
X
Abbreviations: AE = adverse event; β- hCG = beta human chorionic gonadotropin; CT = computed tomography; 
; 
 
; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FCBP = female of child bearing 
 
 
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
66
potential; IRT = Interactive Response Technology; MRI = magnetic resonance imaging; 
; 
; Q2 = every 
two; Q4W = every 4 weeks; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
a All screening assessments to be done within 28 days before enrollment. If screening assessments are performed within 72 hours of Day 1, safety, laboratory and 
physical examinations need not be repeated at Cycle 1 Day 1.
b Subjects should have first dosing initiated within 3 days of enrollment.
c End of treatment visit to be completed as soon as possible after IP discontinuation decision, within 28 days.
d ECG assessed locally per Investigator for immediate clinical decision. Triplicate ECGs to be collected on Cycle 1 Day 1 only at timepoints specified in Table 7
and Table 8. Single ECGs to be collected at screening, pre-dose on Cycle 1 Day 8, Cycle 2 Day 1, Cycle 3 Day 1, and as clinically indicated.
e Hematology tests will be performed pre-dose. All hematology tests will be performed locally and can be performed the day before next study treatment 
administration. Unscheduled hematology tests can be planned between each study visit. 
f Chemistry tests will be performed pre-dose. All chemistry tests will be performed locally and can be performed the day before next study treatment 
administration. Unscheduled chemistry tests can be planned between each study visit.
g Urine (or serum) pregnancy test will be performed to assess subject eligibility within 72 hours prior to the first administration of IP, if the initial serum pregnancy 
test did not already occur with 72 hours of dosing (negative results required for IP administration).
h Fertility counseling including sperm banking for males, if appropriate.
i
Imaging of pelvis if per local practice. Modality used at screening is to be used throughout the study if possible.
j
For subjects who received prophylactic cranial irradiation (PCI), the brain imaging performed prior to initiation of PCI, must occur within 56 days prior to 
enrollment. For subjects who did not receive PCI, brain imaging must occur within 28 days prior to enrollment. Refer to Section 6.1 and Section 6.4.
Medication diary for CC-90011 should be provided at every Day 1 of every cycle. However, medication diary should be reviewed at each study visit, including 
Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, and Cycle 2 Day 15.
n Nivolumab Q4W dosing may be dosed within ± 3-day window but no less than 25 days from the previous dose.
o If a documented or suspected SARS-CoV-2 infection occurs within 4 weeks of the 6 month sampling time point, a single serum sample will be collected to 
satisfy the requirements for both every 6 month and approximately 4 week after infection time points.
 
 
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
6
PROCEDURES
Any questions regarding the protocol should be directed to the Sponsor’s study physician or 
designee. The procedures conducted for each subject enrolled in the study are outlined in the Table 
of Events.
6.1
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 28 days of first dosing unless noted otherwise below.
Safety laboratory analyses and all assessments will be performed locally. Screening laboratory 
values must demonstrate subject eligibility, but may be repeated within the screening window, if 
necessary.
Any questions regarding subject eligibility should be directed to the Sponsor or other Sponsor 
nominated representatives or designees for approval. Waivers to the protocol will not be granted 
during the conduct of this trial, under any circumstances.
The baseline tumor assessment on chest, abdomen, and pelvis (pelvis if per local practice) is to be 
performed within 28 days prior to enrollment. For subjects who received prophylactic cranial 
irradiation (PCI), the brain imaging performed prior to initiation of PCI, must occur within 56 days 
prior to enrollment. For subjects who did not receive PCI, brain imaging must occur within 28 
days prior to enrollment.
The following will be performed at screening as specified in the Table of Events, after informed 
consent has been obtained:

Informed consent: Written informed consent must be obtained before performing any study 
specific tests or procedures. Results of standard of care tests or examinations performed prior 
to obtaining informed consent and within 28 days prior to enrollment (or 56 days for the brain 
imaging performed prior to initiation of PCI as per practice for subjects treated with PCI) may 
be used for screening assessments rather than repeating such tests. Subject may be rescreened
beyond the screening window and the subject will sign a new ICF at the time of rescreening.

Optional informed consent for continuing IP beyond initial progression

Inclusion/exclusion criteria assessment

Interactive response technology (IRT) registration

Demographics (initials, date of birth, sex, race, and ethnicity-if allowed by local regulations)

Prior disease history (including but not limited to specific information regarding diagnosis, 
staging, histological or cytological confirmation of SCLC or sqNSCLC)

Prior disease therapies: includes surgery, radiation, systemic or any other therapy for the 
subject’s disease

Complete medical history (all relevant medical conditions diagnosed/ occurring prior to 
screening should also be included)

Prior and concomitant procedures (including all procedures occurring ≤ 28 days before 
screening)
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022

Prior and concomitant medication evaluation (including those taken ≤ 28 days before 
screening, except for those taken for disease)

Physical examination (can be source documented only)

Height and weight

Vital signs (including blood pressure, temperature, and heart rate)

ECOG Performance status

Single 12-lead ECG, assessed locally for immediate clinical decision (see Table 8) 

Hematology panel including complete blood count (CBC) with differential, including RBC 
count, hemoglobin, hematocrit, white blood cell (WBC) count (with differential), and platelet 
count

Chemistry panel including sodium, potassium, calcium, chloride, blood urea nitrogen (BUN), 
creatinine, glucose, albumin, total protein, alkaline phosphatase, bilirubin (total and direct), 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine 
aminotransferase (ALT/SGPT), lactate dehydrogenase (LDH)

Thyroid function (thyroid-stimulating hormone [TSH], free triiodothyronine [T3], free 
thyroxine [T4])

Coagulation tests including, prothrombin time (PT), partial thromboplastin time (PTT), 
international normalized ratio (INR)
 

SARS-CoV-2 serology as listed in Table 10

Efficacy assessments/tumor evaluation (see Section 6.4)
 
 

Pregnancy test is required for all female subjects of childbearing potential.  Serum beta human 
chorionic gonadotropin (β-hCG) pregnancy test will be performed at screening. Urine (or 
serum) pregnancy test will be performed to assess subject eligibility within 72 hours prior to 
the first administration of IP, if the initial serum pregnancy test did not already occur with 72 
hours of dosing (negative results required for IP administration)

Contraceptive counseling: Explain to females of childbearing potential and male subjects the 
need for contraception

Fertility counseling for men: Subjects will be informed that the effects of CC-90011 on
spermatogenesis are unknown and they will be encouraged to collect and bank sperm if
appropriate, prior to taking IP

Adverse event assessment begins when the subject signs the ICF
6.1.1
Retesting During Screening Period
Subjects who become screen failures can be rescreened, as necessary, if it is reasonable to believe 
they will meet eligibility criteria during rescreening. If screening assessments are not within the 
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
allowed Screening Period, the rescreened subject must reconsent to participation in the study by 
signing a new and current informed consent form.
Testing for asymptomatic SARS-CoV-2 infection, for example by reverse transcription-
polymerase chain reaction (RT-PCR) or viral antigen is not required. However, some subjects may 
develop suspected or confirmed symptomatic SARS-CoV-2 infection or be discovered to have 
asymptomatic SARS-CoV-2 infection during the screening period.  In such cases, subjects may be 
considered eligible for the study after meeting all inclusion/exclusion criteria related to active 
infection, and after meeting the following criteria:

At least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive RT-PCR or viral antigen test result, and

At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and

Acute symptoms (eg, cough, shortness of breath) have resolved and

In the opinion of the Investigator, there are no COVID-19-related sequelae that may place the 
participant at a higher risk of receiving investigational treatment, and 

Negative follow-up SARS-CoV-2 RT-PCR or viral antigen test based on institutional, local or 
regional guidelines
6.2
Treatment Period
The subject may be enrolled once all inclusion/exclusion criteria are verified and the subject is 
deemed to be eligible. The subject must start treatment within 3 days of enrollment. If screening 
assessments are performed within 72 hours of Day 1, safety, laboratory and physical examinations 
need not be repeated at Cycle 1 Day 1.
For all subsequent visits until Cycle 3, an administrative window of ± 1 days is permitted. For all 
visits starting with Cycle 3, an administrative window of ± 7 days is permitted. Study visits to the 
clinic will occur on Cycle 1 Days 1, 8, 15, 22, Cycle 2 Day 1, Cycle 2 Day 15, and Day 1 of all 
subsequent cycles. At each study visit, IP is to be administered in the clinic. 
If the Investigator suspects a drug-related toxicity, an unscheduled visit with additional laboratory 
tests may be performed. Any assessments can be performed as clinically indicated.
Treatment cycles are 28 days in duration and will occur as described in 7.2. 
The following evaluations will be performed at the frequency specified in the Table of Events,
Table 6. The evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified.  

IRT registration for subject enrollment and IP assignment

Concomitant medications evaluation

Concomitant procedures evaluation

Physical examination (source documented only)
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022

Vital signs (blood pressure, temperature, and heart rate): on-treatment vital sign measurements 
will be source documented and collected in the electronic case report form (eCRF).  If an 
abnormal (out of range) value is reported at any given visit and is considered clinically 
significant, that parameter should also be collected in the eCRF as an adverse event (AE) if 
appropriate

Weight 

Hematology panel including CBC with differential, including RBC count, hemoglobin, 
hematocrit, WBC count (with differential), and platelet count

Chemistry panel including sodium, potassium, calcium, chloride, BUN, creatinine, glucose, 
albumin, total protein, alkaline phosphatase, bilirubin (total and direct), AST/SGOT or 
ALT/SGPT, LDH

Thyroid function (TSH, free T3, free T4)

ECOG performance status 

Paired triplicate 12-lead ECGs and blood samples for plasma concentrations collected at 
selected timepoints on Cycle 1 Day 1 as listed in Table 7. Single 12-lead ECG on Cycle 1 Day 
8, Cycle 2 Day 1, Cycle 3 Day 1, and as clinically indicated in Table 8. ECGs assessed locally 
for immediate clinical decision.

Adverse event evaluation (continuously)

Efficacy assessment (see Section 6.4)

Blood PK and immunogenicity collection as listed in Table 7 and Section 6.5.1
 

SARS-CoV-2 serology as listed in Table 10
 
 

Contraceptive counseling on Cycle 1 Day 1: Explain to females of childbearing potential and 
male subjects the need for contraception and the potential risks of fetal exposure. Reinforce 
importance of adherence to contraception and reevaluate abstinence and contraception 
methods used. 

Urine β-hCG for FCBP. Reinforce urine (or serum) pregnancy test requirement.

CC-90011 and nivolumab administration 

Provide, collect, and/or review medication diary collection and review

CC-90011 and nivolumab accountability on Cycle 3 Day 1 and every cycle thereafter on Day 1 
6.2.1
End of Treatment
An end of treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible (within 7 days if feasible) after the decision to 
permanently discontinue treatment has been made. 
The following evaluations will be performed as specified in the Table of Events:
 
 
 
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v


CC-90011
Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022

IRT registration for subject treatment discontinuation

Physical examination (source documented only)

Vital signs (blood pressure, temperature, and heart rate)

Weight

Concomitant medications evaluation

Concomitant procedures evaluation

ECOG performance status

Adverse event evaluation (monitored through 28 days after the last dose of IP)

Hematology panel including CBC with differential, including RBC count, hemoglobin, 
hematocrit, WBC count (with differential), and platelet count

Chemistry panel including sodium, potassium, calcium, chloride, BUN, creatinine, glucose, 
albumin, total protein, alkaline phosphatase, bilirubin (total and direct), AST/SGOT or 
ALT/SGPT, LDH

Thyroid function (TSH, free T3, free T4)

Urine β-hCG (for females of childbearing potential)

Efficacy assessment will be continued according to the schedule defined in the Table of Events, 
and does not need to be performed specifically for the EOT visit except as specified in Section
6.4
 
 
 

Contraceptive counseling: Explain to females of childbearing potential and male subjects the 
need for contraception and the potential risks of fetal exposure. Reinforce importance of 
adherence to contraception and reevaluate abstinence and contraception methods used. 

Collection and review medication diary 

CC-90011 and nivolumab accountability
6.3
Follow-up Period 
6.3.1
Safety Follow-up
All subjects will be followed for 28 days after the last dose of CC-90011 for AE reporting, as well 
as serious adverse events (SAEs) made known to the Investigator at any time thereafter that are 
suspected of being related to IP, as described in Section 10.1. An additional safety follow-up is 
required after 100 days from the last dose of nivolumab.
The following evaluations will be performed at the 28-day follow-up as specified in the Table of 
Events:

Adverse event evaluation (monitored through 28 days after the last dose of CC-90011)
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022

Concomitant medications evaluation

Concomitant procedures evaluation

Physical examination (source documented only)

Vital signs (blood pressure, temperature, and heart rate)

Weight

ECOG performance status

Urine β-hCG (for females of childbearing potential)

Hematology panel including CBC with differential, including RBC count, haemoglobin, 
haematocrit, WBC count with differential, and platelet count

Chemistry panel including but not limited to sodium, potassium, calcium, chloride, BUN, 
creatinine, glucose, albumin, total protein, alkaline phosphatase, bilirubin (total and direct), 
AST/SGOT or ALT/SGPT, LDH

Thyroid function (TSH, free T3, free T4)
 

SARS-CoV-2 serology as listed in Table 10

Contraceptive counseling: Explain to females of childbearing potential and male subjects the 
need for contraception and the potential risks of fetal exposure. Reinforce importance of 
adherence to contraception and re-evaluate abstinence and contraception methods used. 

Follow-up disease anticancer therapies
The following evaluations will be performed at the 100-day follow-up as specified in the Table of 
Events:

Adverse event evaluation (monitored through 100 days after the last dose of nivolumab). Every 
adverse event must be assessed by the Investigator regarding whether it is considered immune-
mediated. For events which are potentially immune-mediated, additional information will be 
collected on the eCRF.

Concomitant medications evaluation

Concomitant procedures evaluation

Vital signs (blood pressure, temperature, and heart rate)

Weight

Urine β-hCG (for females of childbearing potential)

Hematology panel including CBC with differential, including RBC count, haemoglobin, 
haematocrit, WBC count with differential, and platelet count

Chemistry panel including but not limited to sodium, potassium, calcium, chloride, BUN, 
creatinine, glucose, albumin, total protein, alkaline phosphatase, bilirubin (total and direct), 
AST/SGOT or ALT/SGPT, LDH

Thyroid function (TSH, free T3, free T4)
 
 
 
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CC-90011
Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022

Contraceptive counseling: Explain to females of childbearing potential and male subjects the 
need for contraception and the potential risks of fetal exposure. Reinforce importance of 
adherence to contraception and re-evaluate abstinence and contraception methods used. 

Follow-up disease anticancer therapies
6.3.2
Efficacy Follow-up
All subjects who discontinue treatment for reasons other than disease progression, start of a new 
disease therapy, or withdrawal of consent from the entire study, will be followed for efficacy 
response assessments and new disease therapies as specified in Section 6.4.
6.3.3
Survival Follow-up
After the end of treatment visit, all subjects will be followed every 2 months (± 14 days) for 
survival/long-term follow-up until death, lost to follow-up, withdrawal by subject from entire 
study, the 100-day safety follow-up visit of the last subject on study treatment, or the End of Trial,
whichever occurs first. Subsequent anticancer therapies should be collected at the same time 
schedule. Subsequent new anticancer therapy includes, but is not limited to, any systemic or local 
medication, surgery, radiation, or any other therapy intended to treat the subject’s disease.
Survival/long-term 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.
Sponsor may request that survival data be collected on all treated subjects outside of the protocol 
defined window (refer to Section 5 and Section 6). At the time of this request, each subject will be 
contacted to determine their survival status unless the subject has withdrawn consent for all 
contacts or is lost to follow-up.
6.4
Efficacy Assessment
Tumor assessments by CT scan or MRI of the chest, abdomen, and pelvis (pelvis if per local 
practice) should be performed at screening within 28 days prior to enrollment, and at every 6 weeks 
(± 7 days) post Cycle 1 Day 1 for the first 24 weeks and every 8 weeks (± 7 days) thereafter, until 
disease progression, start of new anticancer therapy, or withdrawal of consent by the subject from 
the entire study.
Brain imaging by CT scan with contrast or MRI should be performed at screening and as clinically 
indicated. For subjects who received PCI, the brain imaging performed prior to initiation of PCI, 
must occur within 56 days prior to enrollment. For subjects who did not receive PCI, brain imaging 
must occur within 28 days prior to enrollment.
To ensure sufficient ability to assess tumor response, the same imaging procedure should be used 
throughout the study for each subject, and these imaging studies must include all lesions assessed 
at baseline. Tumor assessments by CT scan or MRI should also be performed at any time if 
clinically indicated. Subjects who did not receive PCI treatment and with historical tumor scans 
evaluable per RECIST v1.1 performed within 28 days before enrollment need not repeat scans for 
the purposes of screening. Evaluation of response for therapeutic decisions should be performed 
using RECIST v1.1 guidelines by Investigator assessment.
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
All subjects with evidence of tumor response (CR or PR) should have their response confirmed 
with repeat assessments at the next scheduled scan, but no less than 4 weeks after initial response.
At the sponsor’s discretion, scans may be collected for review.
Additional details and definitions of response for RECIST v1.1 are found in APPENDIX E.
6.4.1
Treatment Beyond Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD (Spigel, 2017).
Subjects will be permitted to continue study treatment beyond initial RECIST v1.1 defined 
progressive disease, up to a maximum of 24 months, 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 of study treatment

Other treatment options, including no treatment and supportive care, have been discussed and 
subject has consented on the optional ICF to continue study treatment
A follow-up scan should be performed within 6 to 8 weeks of the original PD to determine whether 
there has been a decrease in the tumor size, or continued PD. 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 and continue to receive monitoring according to Table 6. The decision to continue 
treatment should be discussed with the Celgene Medical Monitor and documented in the study 
source documents.  
For the subjects who continue study treatment beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum 5 mm absolute increase from time 
of initial PD. This includes an increase in the sum of diameters of all target lesions and/or the 
diameters of new measurable lesions compared to the time of the initial PD. Study treatment should 
be discontinued permanently upon documentation of further progression, unless the clinical 
judgement of the investigator is that continuing treatment is in the subject’s best interest and the 
Medical Monitor is in agreement upon discussion.
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 15 
mm). Any new lesion considered non-measurable at the time of initial progression may become 
measurable and, therefore, included in the tumor burden if the longest diameter increases to at least 
10 mm (except for pathological lymph nodes which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to inclusion of 
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
new lesions which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm.
6.5
Pharmacokinetics
For evaluation of the PK of CC-90011 in plasma, blood samples will be collected from all subjects 
at the timepoints listed in Table 7. An exploratory analysis of CC-90011 metabolites in plasma 
may be performed utilizing the plasma samples collected for PK evaluation. Time-matched 
triplicate ECGs will also be collected on Cycle 1 Day 1 at time points listed in Table 7. 
The blood PK samples collected after CC-90011 administration should be collected from the arm 
contralateral to the arm used for nivolumab administration. If a peripheral IV catheter is used for 
nivolumab IV administration, the PK samples should be obtained from the opposite arm. In 
general, blood for PK samples should not be drawn from a central line. If a peripheral line is not 
accessible, blood for PK samples drawn from a central line must be collected after the lumen is 
flushed with saline, and the non-dosing lumen of a dual/triple lumen catheter should be used. 
All pre-dose samples should be collected before administration of CC-90011 (preferably within 
30 minutes). If it is known that a CC-90011 dose is going to be delayed, then the pre-dose sample 
should be collected just prior to the delayed CC-90011 dose. 
Detailed information regarding the collection, handling, and shipment of blood for the assessment 
of pharmacokinetics is provided in the study Laboratory Manual.
Table 7:
Schedule of Pharmacokinetic Blood Sample and Triplicate Time-
matched ECG Collection
Time in Hours 
Relative to CC-
90011 Dosea
Collection 
Window
Cycle 1
Cycle 2 and 
Cycle 3
Day 1
Day 8
Day 1
PK
Triplicate 
ECGsa
PK
PK
0 (pre-dose)
Within 30 
minutes prior to 
dosing
X
X
X
X
1
±10 minutes
X
-
-
-
2
±15 minutes
X
X
-
-
3
±20 minutes
X
X
-
-
4
±20 minutes
X
X
-
-
Abbreviations: ECG = electrocardiogram; PK = pharmacokinetics.
a Triplicate ECGs to be collected on Cycle 1 Day 1 only.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
6.5.1
Collection of Blood Samples for Nivolumab Pharmacokinetics and
Immunogenicity
Subjects enrolled in all 3 cohorts will have blood samples collected to measure PK and anti-
nivolumab antibodies (ADA). Blood samples for the analysis of ADA should be drawn from the 
arm not used for infusion of study drug. Detailed instructions for the collection, processing, 
handling, labeling, storage, and shipment of PK and ADA samples will be provided in the 
laboratory manual. All samples will be collected pre-dose (approximately within 30 minutes prior 
to infusion) on the following visits, for up to 2 years:

Cycle 1 Day 1: pre-dose

Cycle 2 Day 1: pre-dose

Cycle 3 Day 1: pre-dose

Every 4th cycle after Cycle 3 (i.e. Cycle 7, Cycle 11, Cycle 15 etc) Day 1: pre-dose
6.6
12-lead Electrocardiograms
12-lead ECGs will be recorded at the visits as outlined in Table 8. The 12-lead ECGs (12-lead at 
25 mm/sec reporting rhythm, ventricular rate, PR interval, QRS complex, QT interval, and QT 
corrected based on Fridericia’s equation [QTcF] interval) should be performed before any other 
blood is drawn and after the subject has been in the supine position for at least 5 minutes. 
Investigators will make immediate clinical decisions based on their interpretation of the ECG 
results and provide their overall assessment of the ECG in the eCRF. Clinically significant changes 
from baseline will be recorded in the AE section of the eCRF.
The ECG outputs will also be uploaded to the central ECG laboratory for the Sponsor’s definitive 
analysis and interpretation.
Table 8:
Schedule of Electrocardiogram Collection
Time in 
Hours 
Relative to 
Study Dose
Screening
Cycle 1 Day 1
Cycle 1 Day 8
Cycle 2 Day 1
Cycle 3 Day 1
Single ECG
Triplicate ECGa
Single ECG
Single ECG
Single ECG
0 (pre-dose)
X
X
X
X
X
2
-
X
-
-
-
3
-
X
-
-
-
4
-
X
-
-
-
Abbreviation: ECG = electrocardiogram.
a Timepoints matched with blood PK collection. Three ECGs within 2 minutes at each nominal time point should be 
collected.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
6.7
Biomarkers, Pharmacodynamics, Pharmacogenomics 
6.7.1
Other Assessment
Serum will be collected for potential future measurements of anti-SARS-CoV-2 antibodies by 
serology (anti-SARS-CoV-2 total or immunoglobulin G [IgG]) to explore potential association 
with safety, efficacy, and/or immune biomarkers (Table 10).
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
Table 10:
SARS-CoV-2 Samples Schedule
Visits
SARS-CoV-2 serology
Screening
X
Every 6 months during study treatment
X
Approximately 4 weeks after a documented or suspected 
SARS-CoV-2 infectiona
Xa
28-day Safety Follow-up
X
a If a documented or suspected SARS-CoV-2 infection occurs within 4 weeks of the 6 month sampling time point, a 
single serum sample will be collected to satisfy the requirements for both every 6 month and approximately 4 week 
after infection time points.
6.8
Additional and Optional Research
Additional and optional research as described below may be performed using left-over samples 
originally collected for another test required in this study or using samples collected specifically 
for biomarker testing. The research may involve genetic tests using deoxyribonucleic acid (DNA)
or RNA and may lead to the development of new diagnostic tests.
6.8.1
Additional Research
Additional research related to the study drug and/or disease may be performed. The results of this 
additional research could help to improve the diagnosis and/or the treatment of this disease in the 
future. 
6.8.2
Optional Research
Optional research not related to the study drug or the subject’s disease may be performed. The 
subject’s decision to participate in this optional research will not impact their ability to participate 
in the main study. 
6.9
Subject Reported Outcomes
Not Applicable. 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
7
DESCRIPTION OF STUDY TREATMENTS
Study treatment is CC-90011 in combination with nivolumab and is referred as the investigational 
product (IP) or as investigational medicinal product (IMP).
Celgene Corporation (Celgene) will supply CC-90011 and nivolumab for administration and 
labeled appropriately as investigational product for this study.
Additional information may be included on the label as needed or applicable.  Label(s) for IP will 
contain information as required per local health authority.
7.1
Description of Investigational Product(s)
7.1.1
CC-90011
The study Sponsor will supply the CC-90011 capsules for oral administration. The capsules will 
be supplied in high-density polyethylene bottles with child-resistant caps, labeled appropriately 
for investigational use as per the regulations of the relevant country health authority.
CC-90011 is stored in room temperature (below 25°C [77°F]) and must be used within the 
individually assigned expiry date on the label. Subjects should not extensively handle CC-90011 
capsules and should maintain storage in the packaging until ingestion.
Refer to the Pharmacy Manual for details regarding oral administration, accountability, storage 
and disposal. Please also refer to the IB for other details regarding CC-90011.
7.1.2
Nivolumab
The study sponsor will provide nivolumab 100 mg vials in cartons, labeled appropriately for 
investigational use as per the regulations of the relevant country health authority.
Refer to the Pharmacy Manual for details regarding administration, accountability, storage and 
disposal. Please also refer to the IB for other details regarding nivolumab.
For details regarding product storage, preparation, and administration, please refer to supply labels, 
current Investigator Brochure, Pharmacy Manual or Summary of Product Characteristics 
(SmPC)/United States Package Insert.
7.2
Treatment Administration and Schedule
CC-90011 should be administered first, before nivolumab administration, if possible.
No pre-medication is required. Supportive care per the institution’s normal standard of care 
including concomitant medications can be provided at the investigator’s discretion.
7.2.1
CC-90011
CC-90011 will be given orally (PO) at a dose of 40 mg, unless otherwise determined during the 
ongoing safety evaluation (Section 7.3.1.1), on a once weekly basis in a continuous 28-day cycle.
CC-90011 will be administered with at least 240 mL of water. Subjects should fast for a minimum 
of 4 hours prior CC-90011 administration and refrain from any food intake for up to 1 hour after 
dosing. Subjects should abstain from food or other medication intake for at least 1 hour after each 
dose. Grapefruit juice should be avoided during study treatment.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
CC-90011 will be administered at home except on the following study visits: Cycle 1 Day 1, Cycle 
1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 15, and Day 1 of all 
subsequent cycles.
7.2.2
Nivolumab
Nivolumab will be administered intravenously at a dose of 480 mg every 4 weeks per local practice
as a 30 minute or a 60-minute infusion as per local practice.
There will be no dose escalations or reductions of nivolumab allowed. For Q4W dosing cycles, 
subjects may be dosed within a ± 3-day window, but no less than 25 days from the previous dose. 
Premedications are not recommended for the first dose of nivolumab.
Subjects should be carefully monitored for infusion reactions during nivolumab administration. If 
an acute infusion reaction is noted, subjects should be managed according to Section 7.
Doses of study drug(s) may be interrupted, delayed, or discontinued depending on how well the 
subject tolerates the treatment. Dosing visits are not skipped, only delayed.
Please refer to the current Investigator Brochure and/or Pharmacy Manual for further details 
regarding storage, preparation, and administration of nivolumab.  
Care must be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent. 
No premedication is required. Supportive care per the institution’s normal standard of care 
including concomitant medications can be provided at the Investigator’s discretion.
7.2.3
Missed Doses
All efforts should be made to administer study treatment on all the scheduled days of each 
treatment cycle. Any missed doses during that period should not be taken after the last scheduled 
day of administration but should be returned by the subject for IP accountability.
If a subject vomits within 1 hour of taking a dose of CC-90011 and the whole unbroken capsule is 
visible in the vomit, the subject can take a replacement dose within 1 hour of vomiting. However, 
if the subject vomits more than 1 hour after taking a dose of CC-90011, or the whole unbroken 
capsule is not visible in the vomit, the subject should not take a replacement dose.
If a subject miss or forgets to take the scheduled dose of CC-90011, the subject can take the dose 
should it be less than 24 hours than the scheduled dose. If more than 24 hours since the scheduled 
dose, the dose should be skipped, and administration resumed at the next planned date.
7.2.4
Definition of an Overdose
Overdose, as defined for this protocol, refers to CC-90011 and nivolumab dosing. On a per dose 
basis, an overdose is defined as the following amount over the protocol-specified dose of CC-
90011 and/or nivolumab assigned to a given subject, regardless of any associated adverse events 
or sequelae:

PO any amount over the protocol-specified dose
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022

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 eCRF. Refer to Section 10.1 for 
the reporting of adverse events associated with overdose.
7.3
Safety Evaluation 
7.3.1
Initial Safety Evaluation
A safety evaluation will be conducted to assess the safety of CC-90011 with nivolumab after 6 
subjects (without distinction of cohorts) have completed at least 2 Cycles. A Bayesian method will 
be used to monitor for the rate of thrombocytopenia Grade 4 and neutropenia Grade 3 to 4 events.
The expected rate of thrombocytopenia Grade 4 is 20% and the expected rate of neutropenia Grade 
3 to 4 is 12% from CC-90011 alone. No serious overlapping toxicities are expected for the 
combination of CC-90011 with nivolumab. No immune-related adverse events (irAEs) have been 
observed in the first-in-human study with CC-90011.  
After the enrollment of 6 successive subjects completing 2 cycles, or sooner per Section 7.3.2, the 
following stopping criteria based on the posterior distributions of the rate of thrombocytopenia 
Grade 4 and neutropenia Grade 3 to 4 events with a noninformative Jeffreys prior distribution of 
Beta (1/2, 1/2) will be evaluated:
1) Probability (rate of thrombocytopenia Grade 4 > 0.2|data from 6 subjects) > 0.95 or
2) Probability (rate of neutropenia Grade 3 to 4 > 0.12|data from 6 subjects) > 0.95
If any of these stopping criteria are met, the starting dose of CC-90011 will be reduced to the next 
lower dose level 40 mg. The first criterion is equivalent to observing 3 or more thrombocytopenia 
events Grade 4 out of 6 and the second criterion is equivalent to observing 3 or more neutropenia
events Grade 3 to 4. Enrollment will not be paused during this evaluation.
Once the starting dose is reduced to 40 mg, the same rule will be applied. If any of these stopping 
criteria are met for the 6 subjects treated at 40 mg, the starting dose of CC-90011 will be reduced 
to the next lower dose level 20 mg.
Once the initial 6 subjects at a given dose level do not trigger the dose reduction rule, subjects’ 
safety data will be closely monitored on an ongoing basis and individual dose delays and/or 
reduction recommendations will be followed. In case the starting dose is reduced to a lower dose 
level, it will be ensured that the sample size at the selected dose meets the planned number of 
subjects.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
7.3.1.1
Safety Evaluation for CC-90011 Starting Dose of 40 mg
As of 14 Aug 2020, the Sponsor, in agreement with the Steering Committee made the decision to 
reduce the starting dose of CC-90011 to 40 mg, as per Section 7.3.2. Implementation of this dose 
reduction was not considered an urgent safety measure. The same stopping criteria as specified in 
Sections 7.3.1 and 7.3.2 will be applied to the reduced starting dose of 40 mg.
To further evaluate if the RP2D of 60 mg that was established in the first-in-human study can be 
safely administered in this study and in order to maximize the potential efficacy of CC-90011 and 
level of target engagement (see FIH data, Figure 2), re-escalation to 60 mg may be considered after 
review of the overall data and AEs/SAEs by the Sponsor in agreement with the Steering 
Committee. Specifically, if in the first 2 cycles, there are no reports of Grade 4 thrombocytopenia 
or Grade 3 or 4 neutropenia, in any of the 6 subsequent subjects (without distinction of cohorts) 
who received 40 mg, then re-escalation of the starting dose to 60 mg for subsequent subjects may 
be considered. 
If the starting dose is re-escalated to 60 mg, an additional 4 subjects (without distinction of cohorts) 
will be treated so that 6 subjects in total (including the 2 subjects in which Grade 4 
thrombocytopenia [n=2] and Grade 3 neutropenia [n=1] was reported) will have received 60 mg. 
There will be staggered dosing, where the second subject to receive 60 mg will not be dosed until 
at least 15 days after the first subject has been treated and safety has been reviewed. This sentinel 
dosing scheme may or may not be continued for the rest of the 60 mg subjects, depending on the 
findings in the first subject and the overall safety profile to date.  
The stopping criteria in Sections 7.3.1 and 7.3.2 will be applied to these 6 subjects. Therefore, if 
in the first 2 cycles, there are no reports of Grade 4 thrombocytopenia and 1 or less reports of 
Grade 3 or 4 neutropenia, in any of the 4 subsequent subjects who received 60 mg, then 60 mg 
will be declared as the starting dose of CC-90011 and the dose to continue with in this study. If in 
the first 2 cycles, there is at least 1 report of Grade 4 thrombocytopenia or at least 2 reports of 
Grade 3 or 4 neutropenia, in any of the 4 subsequent subjects who received 60 mg, then 40 mg 
will be declared as the starting dose of CC-90011 and the dose to continue with in the study.
7.3.2
Definition of Stopping Criteria
If any of these stopping criteria described in Section 7.3.1 are met for the 6 subjects treated at 20
mg, the trial will be stopped. 
Events to be monitored with special interest and which may trigger the above stopping criteria 
include but are not limited to: 

Serious adverse events (SAEs) related to IPs of the same nature or organ system

Clinically significant SAEs related to IPs of the same nature or organ system which would 
prevent further dosing of an individual subject
Review of the AEs and SAEs, and any decision to pause enrollment, or modify the dose and/or 
schedule of the cohorts, will be determined by the Sponsor in agreement with Steering Committee. 
Decisions to pause enrollment or stop cohorts or modify the dose and/or schedule of the cohorts 
of the study will be communicated promptly to Investigators, to the Institutional Review Boards 
 
 
 
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Protocol CC-90011-ST-002
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Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
(IRBs)/Ethics Committees (ECs) (as applicable), and will be implemented in a protocol 
amendment which will be submitted to the appropriate regulatory authorities.
7.4
Dose Adjustment of Study Treatments 
Any toxicity, unless the event can clearly be determined to be unrelated to the study treatments, 
could be managed according to the recommended guidance listed in Table 12, Table 13, and 
Table 14.
If the Investigator suspects a drug related toxicity, an unscheduled visit with additional laboratory 
assessments may be performed.
If any subject continues to experience unacceptable toxicity after permitted IP adjustments, 1 or 
both IPs will be discontinued permanently.
7.4.1
Permitted Dose Reduction for CC-90011
Permitted dose reductions for CC-90011 are described in Table 11.
7.4.2
Criteria for CC-90011 Dose Adjustment
Recommendations on the dose adjustments for hematologic and nonhematologic toxicities are 
listed in Table 12 and Table 13. Permitted dose reductions are listed in Table 11. CC-90011 may 
be interrupted up to 4 weeks.
7.4.2.1
Recommended Dose Adjustment Guidelines for CC-90011
Table 12 and Table 13 list the recommended dose adjustment guidelines for study treatments 
related to hematologic toxicities and non-hematologic toxicities respectively. 
Table 12:
Recommended Dose Adjustment Guidelines for CC-90011 Related 
Hematologic Toxicities
Toxicity
Action
Grade 2 thrombocytopenia
Hold until resolution to Grade 1 or baseline
Follow complete blood count (CBC) at least every 7 days
When resolution to Grade 1 or baseline, study treatment can be reintroduced 
at the same dose level
In case of repeat occurrence of Grade 2 or worse, hold until recovery to ≤ 
Grade 1 and study treatment can be reintroduced at the lower dose level (if 
available).
Table 11:
Permitted Dose Reduction for CC-90011
Starting Dose
First Reduction
Second Reduction
60 mg
40 mg
20 mg
40 mg
20 mg
None
20 mg
None
None
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
Table 12:
Recommended Dose Adjustment Guidelines for CC-90011 Related 
Hematologic Toxicities
Toxicity
Action
Grade 3 thrombocytopenia
Hold until resolution to Grade 1 or baseline
Follow complete blood count (CBC) at least every 3 to 4 days
If resolution to Grade 1 or baseline occurs ≤ 8 days, study treatment can be 
reintroduced at the same dose level.
If AE resolution occurs > 8 days, study treatment can be reintroduced at the 
lower dose level.
In case of repeat occurrence of Grade 3 or worse, hold until recovery to ≤ 
Grade 1; study treatment can be reintroduced at the next lower dose level (if 
available).
Grade 4 thrombocytopenia
Hold study treatment until recovery to Grade 1 or baseline
Repeat CBC within 24 to 48 hours
Follow CBC at least every 3 to 4 days
Study treatment can be reintroduced at the lower dose level, if available
In case of repeat occurrence of Grade 4, hold until recovery to ≤ Grade 1;
study treatment can be reintroduced at the next lower dose level (if available).
Grade 3 neutropenia
Hold until resolution to Grade ≤ 1 
Follow CBC at least every 3 to 4 days
If AE resolution to Grade ≤ 1 occurs ≤ 8 days, study treatment can be 
reintroduced at the same dose level.
If AE resolution occurs > 8 days, study treatment can be reintroduced at next 
lower dose level lower, if available.
Use of growth factors (GCSF, GMCSF) is permitted at the discretion of the 
Investigator. 
In case of repeat occurrence of Grade 3 or worse, hold until recovery to ≤ 
Grade 1; study treatment can be reintroduced at the next lower dose level (if 
available).
Grade 4 neutropenia
Hold until resolution to Grade 1
Follow CBC at least every 3 to 4 days
Study treatment can be reintroduced at the lower dose level, if available
Use of growth factors (GCSF, GMCSF) is permitted at the discretion of the 
Investigator
In case of repeat occurrence of Grade 4, hold until recovery to ≤ Grade 1;
study treatment can be reintroduced at the next lower dose level (if available).
Febrile neutropenia
Hold further dosing until recovery to Grade ≤ 1 and when febrile neutropenia 
resolves, then resume dosing study treatment at 1 dose level lower, if available.
Follow CBC at least every 3 to 4 days. 
Use of growth factors (GCSF, GMCSF) is permitted at the discretion of the 
Investigator
If recurrence of febrile neutropenia, discontinue treatment.
Any hematological toxicity 
requiring interruption for > 4 
weeks
Discontinue study treatments.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
AE = adverse event; GCSF = granulocyte-colony stimulating factor; GMCSF = granulocyte-macrophage colony 
stimulating factor.
Table 13:
Recommended Dose Adjustment Guidelines for CC-90011 Related 
to Non-hematologic Toxicities
Toxicity
Grade
Action
Gastrointestinal
Diarrhea, nausea, vomiting
Grade 1 or 2
Implement prophylactic antiemetic regimen according to 
local guidelines.
Maintain current CC-90011 dose schedule without dose 
modification.
If persistence or (re)occurrence despite appropriate 
prophylaxis, dose-reduce 1 dose level (see dose reduction 
table) at the next scheduled dose administration.
Grade 3 or 4 
Implement prophylactic antiemetic regimen according to 
local guidelines.
Hold dose until event improves to ≤ Grade 2. Reintroduce at 
a lower dose. 
If (re)occurrence to Grade 3 or 4 despite appropriate 
prophylaxis, hold dosing until event improves to Grade ≤ 2.
Reintroduce at a lower dose. 
In addition, consider other supportive treatment per local 
guidelines.
Other adverse events
Grade 3
Hold dose until event improves to Grade ≤ 2. 
At the next scheduled CC-90011 dose administration, dose-
reduce 1 dose level (see dose reduction table). 
If recurrence to Grade 3, reduce the dose.
If a second recurrence of Grade 3 occurs, permanently 
discontinue.
During continued treatment, if adverse event (AE) has not 
resolved to ≤ Grade 2 (or baseline) by the next scheduled 
dose, skip dose; consider dose reduction with the next 
scheduled dose.
Grade 4
Stop CC-90011 until resolution to < Grade 2 (or baseline).
Discuss with Medical Monitor.
Reintroduce at a reduced dose. If recurrence to Grade 4, 
permanently discontinue in agreement with Medical 
Monitor.
7.4.3
Criteria for Nivolumab Dose Management
For nivolumab dose adjustment, follow local practice, package labels or SmPC, and management 
algorithms (see APPENDIX F). Adverse event management of nivolumab should follow CTCAE 
v5.0.
 
 
 
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Final: 30 Apr 2022
Guidelines for permanent discontinuation or withholding of nivolumab doses are described in 
Table 14. Interrupt or slow the rate of infusion in subjects with mild or moderate infusion reactions. 
Discontinue nivolumab in subjects with severe or life-threating infusion reactions.
Table 14:
Recommended Treatment Modifications for Nivolumab
Adverse Reaction
Severity*
Dose Modification
Gastrointestinal
Colitis or Diarrhea
Grade 2 
Delay dose`
Grade 3 
Delay dosea
Grade 4 
Permanently discontinue
Renal
Serum Creatinine Increased
Grade 2 or 3
Delay doseb
Grade 4
Permanently discontinue
Pulmonary
Pneumonitis
Grade 2 
Delay doseb
Grade 3 or 4 
Permanently discontinue
Hepatic
Aspartate aminotransferase 
(AST), alanine aminotransferase 
(ALT), or total bilirubin (T.bili) 
increased
AST or ALT m> 3 x and ≤5 x upper 
limit of normal (ULN) or T. Bili > 1.5 x
and ≤3 x ULN, regardless of baseline 
value
Delay dosea
AST or ALT > 5 x ULN or T.bili > 3 x
ULN, regardless of baseline value
Permanently discontinue
Concurrent AST or ALT > 3 x ULN and 
T.bili > 2 x ULN, regardless of baseline 
value
Permanently discontinue
Endocrinopathy
Hypophysitis/Hypopituitarism
Symptomatic Grade 1-3 that is also 
associated with corresponding abnormal 
lab and/or pituitary scan
Delay dosec
Grade 4 
Delay dose or permanently 
discontinued
Adrenal Insufficiency
Grade 2 adrenal insufficiency
Delay dosee
Grade 3 or 4 adrenal insufficiency or 
adrenal crisis
Delay dose or permanently 
discontinuef
 
 
 
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Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
Table 14:
Recommended Treatment Modifications for Nivolumab
Adverse Reaction
Severity*
Dose Modification
Hyperglycemia
Hyperglycemia requiring initiation or 
change in daily management (Grade 2 or 
3)
Delay doseg
Grade 4
Delay dose or permanently 
discontinueh
Hyperthyroidism or 
hypothyroidism
Grade 2 or 3
Delay dosei
Grade 4
Delay dose or permanently 
discontinuej
Skin
Rash
Grade 2 rash covering > 30% body 
surface area or Grade 3 rash
Delay dosek
Suspected Stevens-Johnson syndrome 
(SJS), toxic epidermal necrolysis (TEN) 
or drug reaction with eosinophilia and 
systemic symptoms (DRESS)
Delay dosel
Grade 4 rash or confirmed SJS or TEN
Permanently discontinue
Neurological
Guillain-Barre Syndrome (GBS)
Any Grade
Permanently discontinue
Myasthenia Gravis (MG)
Any Grade
Permanently discontinue
Encephalitis
Any Grade encephalitis
Delay dosem
Any Grade drug-related encephalitis
Permanently discontinue
Myelitis
Any Grade myelitis
Delay dosem
Any Grade drug-related myelitis
Permanently discontinue
Neurological (other than GBS, 
MG, encephalitis, or myelitis)
Grade 2
Delay dosea
Grade 3 or 4
Permanently discontinue
Cardiac
Myocarditis
Symptoms induced from mild to 
moderate activity or exertion
Delay dosea
Severe or life threatening, with 
symptoms at rest or with minimal 
activity or exertion, and/or where 
intervention indicated
Permanently discontinue
Other Clinical AE
Pancreatitis:
Amylase or Lipase Increased
Grade 3 with symptoms
Delay dosen
Grade 4
Permanently discontinue
 
 
 
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Final: 30 Apr 2022
Table 14:
Recommended Treatment Modifications for Nivolumab
Adverse Reaction
Severity*
Dose Modification
Uveitis
Grade 2 uveitis
Delay doseo
Grade 3 or 4 uveitis
Permanently discontinue
Other Drug-Related AE (not 
listed above)
Grade 2 non-skin AE, except fatigue
Delay doseb
Grade 3 AE
First occurrence lasting ≤ 7 days
Delay doseb
Grade 3 AE First occurrence lasting > 7 
days
Permanently discontinue
Recurrence of Grade 3 AEs of any 
duration
Permanently discontinue
Life-threatening or Grade 4 adverse 
reaction
Permanently discontinue
Other Lab Abnormalities
Other Drug-Related Lab 
Abnormality (not listed above)
Grade 3
Delay dose
Exceptions:
No delay required for: Grade 3 
lymphopenia
Permanent Discontinuation for: 
Grade 3 thrombocytopenia > 7 
days or associated with bleeding
Grade 4
Permanently discontinue
Exceptions: The following events 
do not require discontinuation of 
study drug:
Grade 4 neutropenia ≤ 7 days
Grade 4 lymphopenia or 
leukopenia
Grade 4 isolated electrolyte 
imbalances/abnormalities that are 
not associated with clinical 
sequelae and are responding to 
supplementation/appropriate 
management within 72 hours of 
their onset
Infusion Reactions (manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, 
hypertension, bronchospasm, or other allergic-like reactions)
 
 
 
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Final: 30 Apr 2022
Table 14:
Recommended Treatment Modifications for Nivolumab
Adverse Reaction
Severity*
Dose Modification
Hypersensitivity
Grade 3 or 4
Permanently discontinue (Refer to 
Section 7.4.4 on Treatment of 
Related Infusion Reactions)
* Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 
(NCI CTCAE v5.0).
a Dosing may resume when AE resolves to baseline.
b Dosing may resume when AE resolves to Grade ≤ 1 or baseline value.
c Dosing may resume if endocrinopathy resolves to be asymptomatic or is adequately controlled with only 
physiologic hormone replacement.
d
Mandatory discussion with and approval from the Medical Monitor needed prior to resuming therapy. If 
endocrinopathy resolves or is adequately controlled with physiologic hormone replacement, subject may not require 
discontinuation of study drug.
e Dosing may resume after adequately controlled with hormone replacement.
f Mandatory discussion with and approval from the Medical Monitor needed prior to resuming therapy. If adrenal
insufficiency resolves or is adequately controlled with physiologic hormone replacement, subject may not require 
discontinuation of study drug.
g Dosing may resume if hyperglycemia resolves to Grade ≤ 1 or baseline value or is adequately controlled with 
glucose-controlling agents.
h Mandatory discussion with and approval from the Medical Monitor needed prior to resuming therapy. If 
hyperglycemia resolves, or is adequately controlled with glucose-controlling agents, subject may not require 
discontinuation of study drug.
i
Dosing may resume if endocrinopathy resolves to be asymptomatic or is adequately controlled with only 
physiologic hormone replacement or other medical management.
j
Mandatory discussion with and approval from the Medical Monitor needed prior to resuming therapy. If 
endocrinopathy resolves or is adequately controls with physiologic hormone replacement or other medical 
management, subject may not require discontinuation of study drug.
k Dosing may resume when rash reduces to ≤ 10% body surface area.
l
Dosing may resume if SJS, TEN, or DRESS is ruled out and rash reduces to is ≤ 10% body surface area.
m After workup for differential diagnosis (ie, infection, tumor-related), if AE is not drug related, then dosing may 
resume when AE resolves.
n Note: Grade 3 increased amylase or lipase without signs or symptoms of pancreatitis does not require dose delay. 
Dosing may resume when subject becomes asymptomatic.
o Dosing may resume if uveitis responds to topical therapy (eye drops) and after uveitis resolves to Grade ≤ 1 or 
baseline. If subject requires oral steroids for uveitis, then permanently discontinue study drug.
Subjects who require a delay of nivolumab should be reevaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when retreatment criteria are met.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 10 weeks, the Celgene 
Medical Monitor (or designee) must be consulted. Tumor assessments should continue as per 
protocol even if dosing is delayed.
 
 
 
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Final: 30 Apr 2022
7.4.4
Treatment of Related Infusion Reactions due to Nivolumab
Infusion reactions related to nivolumab treatment may manifest with fever, chills, rigors, headache, 
rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like 
reactions. All Grade 3 or 4 infusion reactions should be reported as per Section 10 and reported as 
an SAE if it meets the criteria for an SAE. Infusion reactions should be graded according to NCI 
CTCAE v5.0 guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated):

Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (eg, antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDS), 
narcotics, IV fluids); prophylactic medications indicated for ≤ 24 hours):

Stop the study drug infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 
mg; remain at bedside and monitor subject until resolution of symptoms.  Corticosteroid and/or 
bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, 
then restart the infusion at 50% of the original infusion rate when symptoms resolve; if no 
further complications ensue after 30 minutes, the rate may be increased to 100% of the original 
infusion rate. Monitor subject closely. If symptoms recur, then no further study medication 
will be administered at that visit.

For future infusions, the following prophylactic premedications are recommended:

diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 
mg should be administered at least 30 minutes before nivolumab infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for clinical sequelae. Grade 4: Life-threatening 
consequences; urgent intervention indicated):

Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and 
treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100
mg IV (or equivalent), as needed. Subject should be monitored until the Investigator is 
comfortable that the symptoms will not recur. Study drug will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor subject until recovery of the symptoms.
 
 
 
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Final: 30 Apr 2022
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.4.5
Dose Delay and Criteria to Resume in Case of SARS-CoV-2 Infection
Study treatment with CC-90011 and nivolumab should be delayed for a SARS-CoV-2 infection 
that is either confirmed or suspected. Subjects with SARS-CoV-2 infection (either confirmed or 
suspected) may resume treatment after all of the following:

at least 10 days (20 days for severe/critical illness) have passed since symptoms first appeared 
or positive test result (eg, RT-PCR or viral antigen), and

resolution of acute symptoms (including at least 24 hours has passed since last fever without 
fever reducing medications), and

evaluation by the Investigator with confirmation that there are no sequelae that would place 
the participant at a higher risk of receiving investigational treatment, and

consultation by the Medical Monitor
For suspected cases, treatment may also resume if SARS-CoV-2 infection is ruled-out and other 
criteria to resume treatment are met.
7.5
Method of Treatment Assignment
An interactive response technology will be used to track subject assignments. Subjects who enter 
screening will be assigned a 7-digit number consisting of the 3-digit site number plus an 
incrementing number at a site.
7.6
Packaging and Labeling
The label(s) for IP will include Sponsor name, address and telephone number, the protocol number, 
IP name, dosage form and strength (where applicable), amount of IP per container, lot number, 
expiry date (where applicable), medication identification/kit number, dosing instructions, storage 
conditions, and required caution statements and/or regulatory statements as applicable. Additional 
information may be included on the label as applicable per local regulations.
7.7
Investigational Product Accountability and Disposal 
Celgene (or designee) will review with the Investigator and relevant site personnel the process for 
investigational product return, disposal, and/or destruction including responsibilities for the site 
versus Celgene (or designee).
Accountability for IP that is administered during the course of the study is the responsibility of the 
Investigator or designee. Investigational clinical supplies must be received by a designated person 
at the clinical site and kept in a secure and temperature-controlled location. The investigational 
site must maintain accurate records demonstrating dates and amounts of IP received, to whom it 
was administered (subject-by-subject accounting), and accounts of any CC-90011 or nivolumab 
accidentally or deliberately destroyed or returned. Unless otherwise notified, all bottles and vials, 
both used and unused, must be saved for drug accountability. The investigational product should 
be disposed of in accordance with the institutional/regional requirements after drug accountability 
 
 
 
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Final: 30 Apr 2022
has been completed by the monitor. The Investigator must return all unused bottles and vials of IP 
to the Sponsor at the end of the study, or the IP may be destroyed at the clinical site with the 
permission of the Sponsor. For either scenario, the outcome must be documented on the drug 
accountability log. The Sponsor will provide direction for the outcome of all unused bottles and 
vials.
7.8
Investigational Product Compliance
Only the pharmacist, Investigator, or the Investigator’s designee will dispense CC-90011. 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 doses dispensed/administered in the 
appropriate study records.
Subjects will use diary cards to record their weekly self-administration of CC-90011 at home. The 
person completing the diary card will sign/initial and date the cards in accordance with good 
documentation practice. These will be reviewed by study staff each time the subject visits the clinic 
(please refer to Table 6). Entries will be clarified, as necessary, so that appropriate information can 
be captured on the eCRFs. Study site personnel will perform a CC-90011 administration 
compliance check and record this information on the subject’s source documentation and on the 
appropriate eCRF (please refer to Table 6).
Accurate recording of nivolumab IV administration will be made in the appropriate section of the 
subject’s eCRFs 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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Protocol CC-90011-ST-002
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Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
8
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression. 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the Investigator. 
All concomitant treatments, including blood and blood products, used from 28 days prior to 
enrollment until 28 days after the last dose of CC-90011 and 100 days after the last dose of 
nivolumab, must be reported on the eCRF. 
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the Investigators Brochure, local package insert, and/or 
SmPC.
The Investigator will instruct subjects to notify the study staff about any new medications taken 
after signing the ICF.  All medications and significant non-drug therapies (herbal medicines, 
physical therapy, etc) and any changes in dosing with existing medications will be documented on 
the eCRFs. 
8.1
Permitted Concomitant Medications and Procedures
Most concomitant medications and therapies deemed necessary for the care of the subject is 
allowed. All concomitant medications, including all prescription, over-the-counter, herbal 
supplements, and IV medications and fluids will be recorded on the eCRF.
The following are permitted concomitant medications and procedures:

Subjects with ≥ Grade 1 diarrhea should promptly initiate treatment, as per recommendation 
of their treating physician and local guidelines, with diphenoxylate/atropine (Lomotil), or 
loperamide (Imodium) or an alternative over-the-counter remedy for diarrhea.  Premedication 
with antidiarrheal medication for subsequent doses of study treatment may be appropriate and 
should be discussed with Sponsor’s study physician.

Antiemetics will be withheld until subjects have experienced NCI CTCAE ≥ Grade 1 nausea 
or vomiting.  Subjects may then receive prophylactic antiemetics at the discretion of the 
Investigator and per local guidelines, including dexamethasone.  

Therapeutic use of granulocyte growth factors is allowed at any time for subjects experiencing 
febrile neutropenia or Grade 3/4 neutropenia. Routine prophylaxis with granulocyte colony 
stimulating factor or granulocyte-macrophage colony stimulating factor is allowed at the 
Investigator’s discretion after one or more occurrences of neutropenia and/or febrile 
neutropenia.

Routine infectious disease prophylaxis is not required.  However, antibiotic, antiviral, anti-
pneumocystis, antifungal, or other prophylaxis may be implemented during the study at the 
discretion of the Investigator.  

Brain irradiation or other localized treatment for brain metastasis for subjects who progress 
with only brain metastasis, in the absence of other sites of progression, is allowed. During the 
brain irradiation CC-90011 and nivolumab will be held during the treatment and may be 
resumed at the Investigator’s discretion.
 
 
 
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Final: 30 Apr 2022

Focal palliative radiotherapy for treatment of cancer-related symptoms (eg, localized bone 
pain) is allowed during study treatment at the discretion of the Investigator, provided this is 
not indicative of disease progression, in which case the subject should be discontinued from 
study treatment.

Subjects may receive physiologic replacement doses of glucocorticoids (up to the equivalent 
of 10 mg daily prednisone) as maintenance therapy. They may also receive glucocorticoids as 
treatment for immune-related adverse events. 

Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 
10 mg daily prednisone are permitted in the absence of active autoimmune disease. A brief 
(less than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or 
for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by a contact allergen) is permitted.

As a precautionary measure, it is recommended that subjects avoid prolonged exposure to 
ultraviolet light, wear protective clothing and sunglasses, and use ultraviolet-blocking topical 
preparations while taking study treatment.

COVID-19 vaccines that are not live are permitted during the study and after the last dose of 
study treatment. Overlap of study treatment and vaccine administration, should be avoided, if 
possible (for example, at least 2 days, preferably 7 days apart), given that adverse events related 
to vaccine administration may confound potential study treatment infusion reactions.
8.2
Prohibited Concomitant Medications and Procedures
The following medications are prohibited or restricted at Screening and during the study:

Other investigational therapies must not be used while the subject is on the study. 

Treatment with bisphosphonates (eg, pamidronate, zoledronate) or other agents (eg, 
denosumab) used to prevent progression of bone metastases.  

Anticancer therapy (chemotherapy, biologic or investigational therapy, and surgery) other than 
the study treatments must not be given to subjects while the subject is on the study.  If such 
treatment is required, the subject must be discontinued from the study. 

Drug-drug interactions have not been investigated in clinical studies. In vitro studies have 
shown that CC-90011 is primarily metabolized by CYP3A4/5. Hence, drugs that are known 
strong inducers or inhibitors of this enzyme should not be co-administered with CC-90011. 
Should use of these drugs become necessary, the risks and benefits should be discussed with 
the Sponsor’s study physician prior to its concomitant use with CC-90011. Grapefruit juice 
should also be avoided during study treatment.

Examples of these drugs are (not inclusive):

CYP3A4/5 inhibitors:  atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin

CYP3A4/5 inducers:  rifampin and carbamazepine

A more exhaustive list of CYP inhibitors and inducers of potential clinical relevance is 
provided at the following link: https://drug-interactions.medicine.iu.edu/Clinical-
Table.aspx
 
 
 
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Final: 30 Apr 2022

Any complementary medications (eg, herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such medications are allowed if they are used as 
supportive care.

Any live / attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio and
measles, mumps, rubella (MMR)) during treatment and until 100 days post last dose.

Refer to the approved product labeling for nivolumab for complete information regarding drug-
drug interactions.
8.2.1
Medications to be used with Caution
In view of the potential for thrombocytopenia, nonsteroidal anti-inflammatory drugs and aspirins 
(aspirin dose ≤ 150 mg is allowed) should be avoided if possible and paracetamol or 
acetaminophen, should be administered instead.
Treatment with chronic, therapeutic dosing of anticoagulants (eg, warfarin, low molecular weight 
heparin, Factor Xa inhibitors, thrombin antagonists) and short-term, prophylactic dosing of 
anticoagulants may be considered in subjects if medically indicated (eg, hospitalized subjects, 
post-operatively) under careful consideration by the Investigator.
8.3
Required Concomitant Medications and Procedures
Not applicable.
 
 
 
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Final: 30 Apr 2022
9
STATISTICAL CONSIDERATIONS
9.1
Overview
This is a Phase 2, multicenter, open-label, multi-cohort study to assess safety and efficacy of CC-
90011 in combination with nivolumab in subjects with SCLC who progressed after one or two 
lines of therapy, with or without an ICI. The primary objective of the statistical analysis is to 
evaluate the overall response rate (ORR) of subjects treated with CC-90011 in combination with 
nivolumab in 3 cohorts:

Cohort A: SCLC in ICI naïve subjects 

Cohort B: SCLC in ICI progressor subjects 

Cohort C: sqNSCLC in ICI progressor subjects
The sections below provide an overview of the proposed statistical considerations and analyses. 
The final statistical analysis methods will be documented in detail in the statistical analysis plan 
(SAP).
9.2
Study Population Definitions
9.2.1
Enrolled Population
The enrolled population will consist of all subjects who signed the informed consent form and
obtained a subject number.
9.2.2
Treated Population
The treated population will consist of all subjects who enroll and take at least 1 dose of either CC-
90011 or nivolumab.
9.2.3
Per Protocol Population
The per protocol population will include all subjects who have met all the eligibility criteria with 
no important protocol deviations, received at least 1 dose of either CC-90011 or nivolumab, and 
have at least 1 baseline and post baseline efficacy assessment. This definition will be further 
clarified and detailed in the final SAP prior to database lock.
9.3
Sample Size and Power Considerations
In Cohort A, the sample size for the combination is based on an expected ORR for nivolumab 
monotherapy of 14% while target ORR for the combination is 30%. To achieve at least 80% power 
with one-sided type 1 error 0.1, 39 subjects will be enrolled according to a 2-stage group sequential 
design based on a binomial test. In Stage 1, 12 subjects will be enrolled and treated with CC-90011 
in combination with nivolumab. If there are 2 or more subjects responding, Cohort A will continue 
to enroll an additional 27 subjects. If 1 or less subjects respond in Stage 1, Cohort A will stop for 
futility. This futility boundary was determined by rho spending function with ρ = 0.1. Enrolment 
will be held between Stage 1 and 2, unless response is documented prior to enrolment of all 12 
subjects.
 
 
 
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Final: 30 Apr 2022
After 39 subjects are treated, if 9 or more subjects respond to the treatment, the null hypothesis 
would be rejected in favor of CC-90011 in combination with nivolumab treatment. Figure 4 below 
depicts the study power under various true response rates and sample sizes.
Figure 4:
Cohort A - Study Power Under Various True Response Rates and 
Sample Sizes
In Cohort B and C, the sample size for the combination are based on an expected ORR for 
nivolumab monotherapy of 5% while the target ORR for the combination is 15%. To achieve at 
least 80% power with one-sided type 1 error 0.1, 48 subjects will be enrolled according to a 2-
stage group sequential design based on a binomial test. In Stage 1, 14 subjects will be enrolled and 
treated with CC-90011 in combination with nivolumab. If there are 1 or more subjects responding, 
Cohort B and C will continue to enroll an additional 34 subjects each. If 0 subjects respond in 
Stage 1, Cohort B and C will stop for futility. This futility boundary was determined by rho 
spending function with ρ = 0.1. Enrolment will be held in each cohort between Stage 1 and 2, 
unless response is documented prior to enrolment of all 14 subjects.
After 48 subjects are treated, if 5 or more subjects respond to the treatment, the null hypothesis 
would be rejected in favor of CC-90011 in combination with nivolumab treatment. Figure 5 below 
depicts the study power under various true response rates and sample sizes.
 
 
 
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Final: 30 Apr 2022
Figure 5:
Cohorts B and C – Study Power Under Various True Response Rates 
and Sample Sizes
In case of any deviation from the planned sample size, the futility boundary will be adjusted based on the rho spending 
function with ρ = 0.1.
9.4
Background and Demographic Characteristics
Demographic and baseline disease characteristics will be summarized by cohort for the enrolled 
population, treated population and per protocol population. Subject’s age, height, weight, and 
baseline characteristics will be summarized using descriptive statistics (N, mean, standard 
deviation, median, minimum, maximum), while age group, gender, race and other categorical 
variables will be provided using frequency tabulations (count, percent).  Medical history data will 
be summarized using frequency tabulations by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class (SOC) and preferred term (PT).
9.5
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site and by country will be provided. 
Important protocol deviations and protocol deviations will be summarized using frequency 
tabulations. Supportive corresponding subject listings will also be provided.
9.6
Efficacy Analysis
All efficacy analyses will be primarily performed in the treated population by cohort. Key efficacy 
analyses will be performed in the per protocol population as supportive evidence to assess the 
robustness of the efficacy findings. 
9.6.1
Primary Endpoint
Overall Response Rate
 
 
 
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The Overall Response Rate is defined as the proportion of subjects in the treated population who 
had confirmed complete response or confirmed partial response as assessed by Investigator review 
per RECIST v1.1. The point estimate of ORR will be summarized along with a 95% CI using exact 
binomial method proposed by Clopper and Pearson (Clopper, 1934) in the treated population. 
Similar analyses will be performed for the per protocol population.
9.6.2
Secondary Endpoint
Safety and tolerability
Safety and tolerability will be assessed from adverse events (using NCI CTCAE v5.0), laboratory 
tests, vital signs, ECOG performance status, concomitant medications, and dose modifications.
Duration of response
The duration of response is defined as the time from the first occurrence of a confirmed 
documented response (CR or PR) to the time of progression, as determined by Investigator review 
per RECIST v1.1, or death from any cause, whichever comes first. If progression is not 
documented, duration of response will be censored at the date of the last tumor assessment.
Duration of response will be summarized based on Kaplan-Meier method.
Time to response
The time to response is defined as the time from the first dose of study drug to the date of the first 
confirmed documented response (CR or PR), as assessed by Investigator per RECIST v1.1. The 
time to response will be summarized for responders (confirmed CR or PR) using descriptive 
statistics.
Progression-free survival
Progression-free survival is defined as the time from the first dose of the study drug to the date of 
the first objectively documented tumor progression as assessed by Investigator review per RECIST 
v1.1 or death from any cause, whichever occurs first. Subjects who are alive without documented 
progression will be censored at the date of their last response assessment. The PFS will be 
summarized based on Kaplan-Meier method.
Time to first subsequent therapy
The time to first subsequent therapy is defined as the time in days from the date of first dose of 
study drug to the date of the next cancer therapy or death. Subjects who neither receive the next 
therapy nor die at a data cut-off date will be censored at the last known time that the subject was 
alive or the clinical cut-off date whichever is earlier. The time to first subsequent therapy will be 
summarized based on Kaplan-Meier (KM) method.
9.7
Safety Analysis
Adverse events, including treatment-emergent adverse events (TEAEs), laboratory assessments, 
ECG results, ECOG performance status, vital signs, exposure to study treatment, assessment of 
concomitant medications, and pregnancy testing for females of childbearing potential will be 
summarized for the treated population by cohort.
 
 
 
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Final: 30 Apr 2022
Adverse events observed will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA), system organ class (SOC) and preferred term (PT). In the by-subject analysis, a 
subject having the same AE more than once will be counted only once. All adverse events will 
also be summarized by SOC, PT, and NCI CTCAE grade (Version 5.0). Adverse events leading 
to discontinuation of study treatment, those classified as Grade 3 or 4, IP-related AEs, and SAEs 
(including deaths) will be tabulated separately. By-subject listings of all AEs, TEAEs, SAEs 
(including deaths), and their attribution will be provided.
Clinical laboratory results will be summarized descriptively by cohort and visit, which will also 
include a display of changes from baseline. Shift tables demonstrating the changes 
(low/normal/high) from baseline to worst postbaseline laboratory value will be displayed in cross-
tabulations by cohort. Similar shift tables demonstrating the change of NCI CTCAE grades from 
baseline to the worst post-baseline severity grade during the Treatment Period will also be 
presented by cohort for applicable analytes. Listings of abnormal clinical laboratory data according 
to NCI CTCAE severity grades (if applicable), abnormal flags (low or high) and clinical 
significance of the latter will be provided.
Descriptive statistics for vital signs, both observed values and changes from baseline, will be 
summarized by cohort and visit. Shift tables demonstrating the changes from baseline to the worst 
post-baseline value will be displayed in cross-tabulations by cohort. Vital sign measurements will 
be listed by subject and by visit.
ECG parameters and changes from baseline will be summarized by cohort and visit using 
descriptive statistics. Post-baseline abnormal QT corrected (QTc), (QTcF) will be summarized 
using frequency tabulations for the following 5 categories:

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 qualitative assessment of abnormality (ie, “Normal”, 
“Abnormal, not clinically significant”, and “Abnormal, clinically significant” or “Normal” and 
“Abnormal”) will be displayed in cross–tabulations by cohort. A listing of ECG parameters by 
subject and by visit will be provided.
9.8
Interim Analysis
No formal interim analysis will be performed, however, at the end of Stage 1 of each cohort, a 
Data Review Team (DRT) will review all safety and preliminary efficacy data and will conduct a 
futility review for go/no-go decision for Stage 2. 
In Stage 1 of Cohort A, 12 subjects will be enrolled and treated with CC-90011 in combination 
with nivolumab. If 1 or less subjects respond in Stage 1, Cohort A will stop for futility. In Stage 1 
 
 
 
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Final: 30 Apr 2022
of Cohort B and C, 14 subjects will be enrolled and treated with CC-90011 in combination with 
nivolumab. If 0 subjects respond in Stage 1, Cohort B and C will stop for futility.
The DRT will consist of the Celgene Medical Monitors, Celgene lead safety physician, Celgene 
biostatistician, other Celgene functional area representatives, as appropriate, and site 
investigator(s) and/or designees who have enrolled subjects in the Stage(s) 1 of the study. DRT 
meetings will be held as needed to review the data, monitor safety and make expansion decisions.
9.9
Other Topics
9.9.1
Steering Committee
The conduct of this trial will be overseen by a Steering Committee (SC), presided over by the 
coordinating Principal Investigator and if possible, the representative Regional Investigators from 
European countries participating in this study.  The SC will serve in an advisory capacity to the 
Sponsor.  Operational details for the SC will be detailed in a separate SC charter.
9.9.2
Safety Evaluation
A safety evaluation will be conducted to assess the safety of CC-90011 with nivolumab after 6 
subjects (without distinction of cohorts) have completed at least 2 Cycles. A Bayesian method will 
be used to monitor for the rate of thrombocytopenia grade 4 and neutropenia Grade 3 to 4 events.
The expected rate of thrombocytopenia Grade 4 is 20% and the expected rate of neutropenia Grade 
3 to 4 is 12% from CC-90011 alone. No serious overlapping toxicities are expected for the 
combination of CC-90011 with nivolumab.  
After the enrollment of 6 successive subjects completing 2 cycles, the following stopping criteria 
based on the posterior distributions of the rate of thrombocytopenia Grade and neutropenia Grade 
3 to 4 events with a noninformative Jeffreys prior distribution of Beta (1/2, 1/2) will be evaluated:
1) Probability (rate of thrombocytopenia Grade 4 > 0.2|data from 6 subjects) > 0.95 or
2) Probability (rate of neutropenia Grade 3 to 4 > 0.12|data from 6 subjects) > 0.95
If any of these stopping criteria are met, the starting dose of CC-90011 will be reduced to the next 
lower dose level. Enrollment will not be paused during this evaluation. See Section 7.3 for more 
details.
Review of the AEs and SAEs, and any decision to pause enrollment, or modify dose and/or 
schedule of the cohorts, will be determined by the Sponsor in agreement with Steering Committee. 
Decisions to pause enrollment or stop cohorts or modify dose and/or schedule of the cohorts of the 
study will be communicated promptly to Investigators, to the IRBs/ECs (as applicable), and to the 
appropriate regulatory authorities.
9.9.3
Exploratory Analysis
A separate biomarker analysis plan will be developed prior to the sample analysis.
 
 
 
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9.9.3.1
Subgroup Analysis
Appropriate subgroup analyses will be conducted by age, gender, region, and baseline prognostic 
factors as exploratory analyses, when possible.
9.9.4
Pharmacokinetic Analysis
The PK population includes all subjects who have at least 1 evaluable concentration data to 
calculate the summary statistics of concentrations. The evaluable subjects in the PK population 
will be included in the PK data analysis.
Summary statistics (number of subjects [N], mean, standard deviation, coefficient of variance 
[CV%], geometric mean, geometric CV%, median, minimum, and maximum) may be provided 
for drug concentration data from all evaluable subjects. Results may be presented in tabular and/or 
graphic formats as appropriate. Data permitting, a population pharmacokinetic approach may be 
utilized to characterize the PK of CC-90011 by pooling the PK data across cohorts and other 
studies. The relationship between CC-90011 dose, plasma exposures, and selected clinical 
endpoints (eg, measures of toxicities, efficacy, and/or biomarkers) may also be explored.
Methodology for exploratory analyses including immunogenicity of nivolumab in Cohort C is 
described in the statistical analysis plan.
 
 
 
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Final: 30 Apr 2022
10
ADVERSE EVENTS
10.1
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in 
a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose eCRF. (See Section 7.2 for the definition of overdose.) Any sequela of 
an accidental or intentional overdose of an investigational product should be reported as an AE on 
the AE eCRF. If the sequela of an overdose is an SAE, then the sequela must be reported on an 
SAE report form and on the AE eCRF. The overdose resulting in the SAE should be identified as 
the cause of the event on the SAE report form and eCRF but should not be reported as an SAE 
itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for CC-90011 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-90011 and until 100 days after the last dose of nivolumab as well 
as those SAEs made known to the Investigator at any time thereafter that are suspected of being 
related to CC-90011 or nivolumab.  All SAEs and all AEs (SAEs and non-serious AEs) associated 
with confirmed or suspected SARS-CoV-2 infection must be collected from the date the subject 
signed informed consent until 100 days following discontinuation of study treatment.
All adverse events (serious/non-serious) will be recorded on 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.
The SAE is recorded within the eCRF and the data is transmitted electronically to Celgene Drug 
Safety within 24 hours of the Investigator’s knowledge of the event. In the event electronic 
transmission is not available, a paper SAE Report Form will be completed and sent directly to
Celgene Drug Safety and ensuring the event is recorded on the eCRF as well.
 
 
 
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Final: 30 Apr 2022
Progressive disease is considered a study endpoint and will not be recorded as an AE. However, 
any sign, symptom, or manifestation of progressive disease will be considered as an AE (if they
meet any of the seriousness criteria they will be considered as an SAE).
10.1.1
Immune-Mediated Adverse-Events
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the subject’s case report form.
10.2
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1
Seriousness 
An SAE is any AE occurring at any dose that:

Results in death;

Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate risk of 
death from the AE);

Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization 
is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the subject’s 
ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  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.
 
 
 
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
a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or prolonged 
hospitalization for a complication of such procedures remains a reportable SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social reasons, in 
absence of an AE.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, unrelated to the 
studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
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 Common Terminology Criteria for Adverse Events (CTCAE, 
Version 5.0); https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to the 
following scale:

Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required

Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required

Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible

Grade 4 = Life-threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable

Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is based 
on subject/event outcome or action criteria associated with events that pose a threat to a subject’s 
life or functioning.  
 
 
 
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Final: 30 Apr 2022
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP that 
has not been manufactured or provided by Celgene, please provide the name of the manufacturer 
when reporting the event.
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 IP as a result of an AE or SAE, as applicable (eg, 
discontinuation, interruption, or dose reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
10.2.6
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
All AEs (SAEs and non-serious AEs) associated with confirmed or suspected SARS-CoV-2 
infection will be followed until resolution, the condition stabilizes, the event is otherwise 
explained, the event is deemed irreversible, the subject is lost to follow-up or for suspected cases, 
until SARS-Cov-2 infection is ruled-out.
 
 
 
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Final: 30 Apr 2022
10.2.7
Detecting Immune-Mediated Adverse-Events
Every adverse event must be assessed by the Investigator with regard to whether it is considered 
immune-mediated. For events which are potentially immune-mediated, additional information will 
be collected on the subject’s case report form
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 IP dose, or any other therapeutic intervention; 
or

is judged to be of significant clinical importance, eg, one that indicates a new disease process 
and/or organ toxicity, or is an exacerbation or worsening of an existing condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion need 
to be documented as a serious adverse event.
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 partner of childbearing potential of a male subject are immediately reportable events.  
10.4.1
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated βhCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within 45 days of the subject’s last dose of CC-90011, or within 5 months of the subject’s 
last dose of nivolumab, are considered immediately reportable events.  Investigational product is 
to be discontinued immediately and the subject instructed to return any unused portion of the IP to 
the Investigator. The pregnancy, suspected pregnancy, or positive pregnancy test must be reported 
to Celgene Drug Safety immediately by email, phone or facsimile, or other appropriate method, 
using the Pregnancy Initial Report Form, or approved equivalent form.  
The female subject should be referred to an obstetrician-gynecologist, preferably one experienced 
in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form or approved equivalent form.
 
 
 
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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 within 24 hours of the Investigator’s 
knowledge of the event.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety within 24 
hours of the Investigator’s knowledge of the event.
10.4.2
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP should 
notify the Investigator, and the pregnant female partner should be advised to call their healthcare 
provider immediately.  
10.5
Reporting of Serious Adverse Events
Any AE that meets any serious criterion requires reporting as an SAE within 24 hours of the 
Investigator’s knowledge of the event. This instruction pertains to initial SAE reports as well as 
any follow-up reports.
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of CC-90011 or 
until 100 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 IP.  Serious adverse events occurring prior to 
treatment (after signing the ICF) are to be recorded within the CRF, but do not require reporting 
to Celgene Drug Safety.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant initial 
and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
The SAE is recorded within the eCRF, and the data is transmitted electronically to Celgene Drug 
Safety. In the event electronic transmission is not available, a paper SAE Report Form will be 
completed and sent directly to Celgene Drug Safety, ensuring the event is recorded on the eCRF 
as well.  
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-90011 based on the Investigator Brochure and of events
suspected of being related to nivolumab based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be reported 
in an expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized representative 
will report in an expedited manner to Regulatory Authorities and Ethics Committees concerned, 
 
 
 
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Final: 30 Apr 2022
suspected unexpected serious adverse reactions (SUSARs) in accordance with Directive 
2001/20/EC and the Detailed Guidance on collection, verification and presentation of adverse 
reaction reports arising from clinical trials on investigational products for human use (ENTR/CT3) 
and also in accordance with country-specific requirements. 
Celgene or its authorized representative shall notify the Investigator of the following information:

Any AE suspected of being related to the use of IP in this study or in other studies that is both 
serious and unexpected (ie, SUSAR);

Any finding from tests in laboratory animals that suggests a significant risk for human subjects 
including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of these 
new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC. (See Section 14.3 for record retention information.)
 
 
 
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Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
11
DISCONTINUATIONS
11.1
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):

Adverse event

Progressive disease

Withdrawal by subject from study treatment

Death

Symptomatic deterioration (global deterioration of health status)

Physician decision

Protocol deviation

Lost to follow-up

Other (to be specified on the eCRF)
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, 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.
All subjects discontinued from the protocol prescribed treatment for any reason should undergo 
End of Treatment procedures.
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 from entire study

Death

Physician decision

Lost to follow-up

Study terminated by Sponsor

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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Final: 30 Apr 2022
12
EMERGENCY PROCEDURES
12.1
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on the 
Emergency Contact Information page of the protocol (after title page). This global Emergency Call 
Center is available 24 hours a day and 7 days a week. The representatives are responsible for 
obtaining your call-back information and contacting the on-call Celgene/contract research 
organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for emergency 
calls. 
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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Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
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 International Council on 
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in the 
local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (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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Final: 30 Apr 2022
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.
The IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
 
 
 
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Final: 30 Apr 2022
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;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
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 eCRFs or CD-ROM.
14.2
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through use of programmed 
edit checks specified by the clinical team.  Discrepancies in the data will be brought to the attention 
of the clinical team, and investigational site personnel, if necessary.  Resolutions to these issues 
will be reflected in the database.  An audit trail within the system will track all changes made to 
the data.
14.3
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs 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 case report forms (CRFs) (if paper) and of documentation of corrections for all 
subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, etc.); 

All other documents as listed in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial).
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.  
 
 
 
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Final: 30 Apr 2022
The Investigator must obtain approval in writing from Celgene prior to destruction of any records. 
If the Investigator is unable to meet this obligation, the Investigator must ask Celgene for 
permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
 
 
 
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
15
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative for 
compliance with applicable government regulations with respect to current GCP and SOPs.
15.1
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after the 
study.  All aspects of the study are reviewed with the Investigator and the staff at a study initiation 
visit and/or at an Investigators’ Meeting.  Prior to enrolling subjects into the study, a Celgene 
representative will review the protocol, eCRFs, procedures for obtaining informed consent, record 
keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will include on-site or 
remote 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 Good Clinical Practice Quality Assurance unit 
exists within Celgene.  Representatives of this unit will conduct audits of clinical research activities 
in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice guidelines 
and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, 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.
15.3
Product Quality Complaint
Issues that call into question IMP safety, purity, potency, quality and identity (eg, evidence of 
suspected tampering of product) must be reported as soon as possible to your study Clinical Trial 
Monitor and/or Clinical Trial Manager or designee. Report an issue or concern with all BMS or 
Celgene Corporation supplied IMP, non-investigational IMP or auxiliary medicinal products
suspected to have occurred before the product was transferred to the responsibility of the 
investigational site (eg, during manufacturing, packaging and labeling, storage, and/or 
distribution). 
 
 
 
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Final: 30 Apr 2022
This includes suspected quality issues of components co-packaged with the drug, labelling, and 
IMP device/drug combination products, and medical devices.  
In the event of a suspected product quality issue, the immediate action to be taken by the site is to 
quarantine the affected product. Do not dispose of the product unless retention presents a risk to 
personnel (eg, cytotoxic, risk of injury from broken glass or sharps).  When reporting, provide as 
much product information as possible. Suspected IMP quality issues will be investigated, and a 
response will be provided back to the investigational site.
 
 
 
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Protocol CC-90011-ST-002
Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
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 the study Steering 
Committee (when applicable) and contribution to abstract, presentation and/or publication 
development.
 
 
 
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Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
17
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Celgene Corporation
Protocol CC-90011-ST-002 Amendment 3 
Final: 30 Apr 2022
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Final: 30 Apr 2022
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CA209-003 Study. J Clin Oncol. 2018 Jun 10;36(17):1675-84. 
 
 
 
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Celgene Corporation
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Final: 30 Apr 2022
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut 
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Hamilton G, Rath B. Immunotherapy for small cell lung cancer: mechanisms of resistance. Expert 
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demethylase KDM1A represses inflammatory gene expression in preadipocytes. Obesity (Silver 
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Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, et al. The histone demethylase 
KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012 
Apr 17;21(4):473-87. 
Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T, et al. Overexpression of LSD1 
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18
APPENDICES
APPENDIX A
TABLE OF ABBREVIATIONS
Table 15:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
ADA
Anti-drug antibodies
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
ATP
Adenosine triphosphate
AUC0-24
Area Under the Plasma Concentration Time Curve from 0 to 24 hours
β-hCG
β-subunit of human chorionic gonadotropin
BUN
Blood urea nitrogen
CBC
Complete blood count
CgA
Chromogranin A
CI
Confidence interval
CNS
Central nervous system
COVID-19
Coronavirus disease2019
Cmax
Maximum plasma concentration 
CR
Complete response
CrCl
Creatine Clearance
CRF
Case report form
CSC
Cancer stem cells
CT
Computed tomography
CV%
Coefficient of variance
CYP
Cytochrome P450
DLT
Dose-limiting toxicity
DOR
Duration of response
DNA
Deoxyribonucleic acid
DRT
Data review team
 
 
 
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Table 15:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EEA
European Economic Area
EMA
European Medicines Agency
EOT
End of treatment
EP
Etoposide plus cisplatin
ES SCLC
Extensive stage small cell lung cancer
ESMO
European Society of Medical Oncology
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
FIH
First-in-human
GCP
Good Clinical Practice
GFI1b
Growth factor independence 1b
GI
Gastrointestinal
GLP
Good laboratory practice
H3K4
Histone H3 lysine 4
H3K27
Histone H3 lysine 27
HBV
Hepatitis B virus
HCV
Hepatitis C virus
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HNSTD
Highest non-severely toxic dose
HR
Heart rate
Hazard ratio
IB
Investigator’s Brochure
IC50
Inhibitory concentration, 50%
ICF
Informed consent form
 
 
 
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Table 15:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
ICH
International Council on Harmonisation
ICI
Immune checkpoint inhibitor
IgG
Immunoglobulin G
IMG
Immunogenicity
IMP
Investigational medicinal product
IP
Investigational product
IRB
Institutional Review Board
irAE
Immune-related adverse events
IRT
Interactive Response Technology
IV
Intravenous(ly)
LDH
Lactate dehydrogenase
LSD1
Lysine-specific histone demethylase 1 A
MedDRA
Medical Dictionary for Regulatory Activities
MHC1
Major histocompatibility complex 1
MMD
Monocyte to macrophage differentiation-associated
mOS
Median overall survival
mPFS
Median progression-free survival
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
msec
Milliseconds
MTD
Maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NECs
Neuroendocrine carcinomas
NEN
Neuroendocrine neoplasm
NETs
Neuroendocrine tumors
NOAEL
No observed adverse effect level
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
OS
Overall survival
PCI
Prophylactic cranial irradiation 
 
 
 
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Table 15:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
PD
Pharmacodynamics
PD-1
Programmed cell death protein 1
PD-L1
Programmed death-ligand 1
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetics
Plt
Platelet
PO
Orally
PQC
Product quality complaint
PR
Partial response
PT
Preferred term
Q2W
Once every 2 weeks
QD
Daily
QOD
Every other day
QTc
QT corrected
QTcB
QT corrected based on Bazett’s equation
QTcF
QT corrected based on Fridericia’s equation
QW
Once weekly
RBC
Red blood cell count
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended phase 2 dose
R/R
Relapsed and/or Refractory
RT-PCR
Reverse transcriptase-polymerase chain reaction
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC
Steering committee
SCLC
Small cell lung cancer
SD
Stable disease
 
 
 
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Table 15:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
shRNA
Short hairpin RNA
SmPC
Summary of product characteristics  
SOC
System organ class
SOP
Standard operating procedure
SOX2
SRY (sex determining region Y)-box 2
sqNSCLC
Squamous non-small cell lung cancer
STD10
Severely toxic dose 10%
SUSAR
Suspected unexpected serious adverse reaction
T3
Triiodothyronine
T4
Thyroxine
TdP
Torsades de pointes
TEAE
Treatment-emergent adverse event
TFST
Time to first subsequent therapy
TIL
T infiltrating lymphocytes
TSH
Thyroid-stimulating hormone
TTR
Time to response
ULN
Upper limit of normal
UV
Ultraviolet
WBC
White blood cell
 
 
 
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APPENDIX B
VETERANS AFFAIRS LUNG STUDY
Table 16:
Veterans Affairs Lung Study Group Staging
Limited stage disease
Extensive stage disease
Disease confined to one hemithorax (includes 
ipsilateral, contralateral, and/or supraclavicular nodes)
Disease beyond the ipsilateral hemithorax, including 
malignant pleural or pericardial effusion or 
hematogenous metastases.
(Kalemkerian, 2012).
 
 
 
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APPENDIX C
PERFORMANCE STATUS CRITERIA
Table 17:
Eastern Cooperative Oncology Group Performance Status
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair
5
Dead
(Oken, 1982).
 
 
 
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APPENDIX D
CALCULATED CREATININE CLEARANCE (COCKCROFT AND 
GAULT, 1976)
This formula should be used for calculating creatinine clearance (CrCl) from local laboratory 
results only. 
(A). Weight-Based Formula for Calculated Creatinine Clearance for Men
For serum creatinine concentration in mg/dL:
CrCl (mL/min) = [(140 – age*) X (weight in kg) X 1.0] / [72 X serum creatinine (mg/dL)]
For serum creatinine concentration in µmol/L:
CrCl(mL/min) = [(140 – age*) X (weight in kg) X 1.0] / [0.81 X serum creatinine (µmol/L)]
(B). Weight-Based Formula for Calculated Clearance for Women
For serum creatinine concentration in mg/dL:
CrCl (mL/min) = [(140 – age*) X (weight in kg)] X 0.85] / [72 X serum creatinine (mg/dL)]
For serum creatinine concentration in µmol/L:
CrCl (mL/min) = [(140 – age*) X (weight in kg) X 0.85] / [0.81 X serum creatinine (µmol/L)]
* Age in years.
Source: (Cockcroft, 1976)
 
 
 
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APPENDIX E
THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1
The following information is extracted/summarized from (New Response Evaluation Criteria in 
Solid Tumors: Revised RECIST Guideline (Version 1.1). Please refer to the primary reference for 
further information (Eisenhauer, 2009).
Definitions
At screening, tumor lesions/lymph nodes will be categorized as measurable or non-measurable.
Measurable Disease
Tumor Lesions.  Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable)

20 mm by chest X-ray
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed.
Non-measurable Disease
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Tumor Response Evaluation
Target lesions
When more than one measurable tumor lesion is present at baseline all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target lesions 
should be selected on the basis of their size (lesions with the longest diameter), be representative 
of all involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological nodes must meet the measurable criterion of a short axis of 
≥ 15 mm by CT scan and only the short axis of these nodes will contribute to the baseline sum. All 
other pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-
 
 
 
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target lesions. Nodes that have a short axis < 10 mm are considered non-pathological and should
not be recorded or followed. At baseline, the sum of the target lesions (longest diameter of tumor 
lesions plus short axis of lymph nodes:  overall maximum of 5) is to be recorded.
After baseline, a value should be provided on the eCRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately measured 
but are deemed to be present, a default value of 5 mm may be used. If lesions are too small to 
measure and indeed are believed to be absent, a default value of 0 mm may be used.
Non-target lesions
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above those 
listed as target lesions are considered non-target lesions. Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present,” “absent,” or “unequivocal 
progression.”
Response Criteria
Target and non-target lesions are evaluated for response separately, and then the tumor burden as 
a whole is evaluated as the overall response.
Target Lesion Response
Target lesions will be assessed as follows:

Complete Response (CR).  Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.

Partial Response (PR).  At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters.

Progressive Disease (PD).  At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note:  the appearance of one or more new lesions is 
also considered progression).

Stable Disease (SD).  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.

Non-target Lesion Response

Non-target lesions will be assessed as follows:

Complete Response (CR).  Disappearance of all non-target lesions and normalisation of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis).

Non-CR/Non-PD.  Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.

Progressive Disease (PD).  Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).
When the Subject Also Has Measurable Disease:  In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of substantial 
 
 
 
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worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the Subject Has Only Non-Measurable Disease:  This circumstance arises in some Phase 
3 trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition:  if all lesions 
are truly non-measurable) a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: ie, an increase in tumor burden representing an additional 73% increase 
in “volume” (which is equivalent to a 20% increase diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from “trace” to “large,” an increase in lymphangitic 
disease from localized to widespread or may be described in protocols as “sufficient to require a 
change in therapy.” If “unequivocal progression” is seen, the subject should be considered to have 
had overall PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so: therefore, the 
increase must be substantial.
Overall Response
Overall response should be assessed according to Table 18 for subjects with target lesions, and 
Table 19 for subjects with only non-target lesions.
Table 18:
Time Point Response: Subjects with Target (± Non-target) Disease
Target Lesions Response
Non-target Lesion Response
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/ non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
 
 
 
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Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = 
stable disease.
Table 19:
Time Point Response: Subjects with Non-target Disease Only
Nontarget Lesions Response
New Lesions
Overall Response
CR
No
CR
Non-CR/ non-PD
No
Non-CR/ non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = 
stable disease.
a
“Non-CR/non-PD” is preferred over “stable disease” for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised.
Symptomatic Deterioration
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as ‘symptomatic 
deterioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. The objective response status of such subjects 
is to be determined by evaluation of target and non-target disease.
 
 
 
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APPENDIX F
NIVOLUMAB ADVERSE EVENT MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low 
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
 
 
 
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APPENDIX G
RISK BENEFIT ASSESSMENT
 
 
 
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BENEFIT AND RISK ASSESSMENT
STUDY TITLE:
A Phase 2 multicenter, open-label, multi-cohort 
study to assess safety and efficacy of CC-90011 
in combination with nivolumab in subjects with 
advanced cancers
PROTOCOL NUMBER:
CC-90011-ST-002(also known as CA069-P05)
EudraCT NUMBER
2019-004194-95
VERSION:
Date:
4.0
23 Mar 2022
 
 
 
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1
POTENTIAL BENEFITS
This is a Phase 2, multicenter, open-label, multi-cohort study designed to assess the safety and 
efficacy of CC-90011 in combination with nivolumab in subjects with small cell lung cancer or
squamous non-small cell lung cancer who have progressed after 1 or 2 lines of therapy.
The primary objective is to evaluate in each individual cohort the overall response rate (ORR) in 
subjects with small cell lung cancer (SCLC) or squamous non-small cell lung cancer (sqNSCLC) 
treated with CC-90011(also known as BMS-986363) in combination with nivolumab.
The secondary objectives
are
to
evaluate
in each individual cohort
the
following 
endpoints/outcomes in subjects with SCLC or sqNSCLC receiving CC-90011 in combination with
nivolumab:

Safety and tolerability

Duration of response (DoR)

Time to response (TTR)

Progression-free survival (PFS) assessed by the Investigator using Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1

Overall survival (OS)

Time to first subsequent therapy (TFST)
The exploratory objectives in each individual cohort are to:
 
 
 
 

Explore the relationship between pharmacokinetics (PK), pharmacodynamic (PD) 
biomarkers and/or clinical outcomes of CC-90011 in combination with nivolumab

Evaluate the disease control rate

Assess the pharmacokinetics and immunogenicity of nivolumab in SCLC and 
sqNSCLC cohort subjects
 
 
 
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
Assess the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
serologic status on subjects and to support health authority requests
For the purpose of this protocol, immune checkpoint inhibitor (ICI) means anti-PD-1 or anti-PD-
L1 treatments.
Approximately 135 subjects total globally will be enrolled into one of the following cohorts in 2 
stages:

Cohort A: SCLC in ICI naïve subjects

Cohort B: SCLC in ICI progressor subjects

Cohort C: sqNSCLC in ICI progressor subjects
Small cell lung cancer (SCLC)
SCLC accounts for up to 13% to 15% of all lung cancer diagnoses, with 250,000 cases diagnosed 
annually worldwide. It is the sixth most-common cause of cancer-related mortality (Govindan, 
2006; Jemal, 2007; Lozano, 2012). SCLC is an aggressive high-grade neuroendocrine tumor 
associated with a short doubling time, a high growth fraction, and early development of widespread 
metastases, which contribute to the extremely poor disease prognosis (Sabari, 2017). These aspects 
of SCLC, as well as the limited success of current treatments, perhaps due to cancer stem cells 
(CSCs), highlight the unmet medical need for the development of new therapeutics for SCLC,
particularly in relapsed disease.
In contrast to the rapidly changing status of non-small cell lung cancer (NSCLC), where significant 
inroads have been made with targeted agents and immunotherapies, SCLC is a recalcitrant tumor 
without significant treatment advances in the limited stage (LS) setting for 30 years (Oronsky, 
2017; van Meerbeeck, 2011). For these reasons, alternative approaches to the treatment of SCLC 
are needed.
Current treatment for first line extensive stage SCLC
Standard first-line treatment for ES SCLC consists of platinum-based chemotherapy, mainly 4 to
6 cycles of cisplatin or carboplatin plus etoposide (Fruh, 2013; Kalemkerian, 2018). In patients 
with ES SCLC, response rates of 60% to 70% can be achieved with combination chemotherapy
alone. Despite the initial chemosensitivity, almost all patients relapse and have limited or no 
response to subsequent therapy.
Many strategies have been evaluated to improve the treatment regimen for ES SCLC, including 
the addition of a third agent. However, they have shown modest survival benefit with increased 
toxicity.
The introduction of immune checkpoint inhibitors (ICI) has provided an important advancement. 
On 18 Mar 2019, the United States Food and Drug Administration (FDA), and on 06 Sep 2019, 
the European Medicines Agency (EMA), approved atezolizumab, an anti-PD-L1, in combination 
with carboplatin plus etoposide, followed by maintenance atezolizumab as first line treatment for 
 
 
 
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ES SCLC. The addition of an anti-PD-L1 to chemotherapy resulted in 0.9 months improvement in
mPFS, and a 2-month benefit in mOS, from 10.3 to 12.3 months. However, the confirmed overall 
response rate (ORR) was similar in both groups, 60.2% versus 64.4%, with 5 patients (2.5%) 
having a completed response (CR) in the atezolizumab group and two patients (1%) with a CR in 
the chemotherapy alone group (Horn, 2018). Similar results from a clinical trial of durvalumab 
(anti-PD-L1) in addition to the standard chemotherapy, cisplatin or carboplatin plus etoposide in
first line ES SCLC were recently presented (Paz-Ares, 2019).
Despite the recent approval of atezolizumab as first-line treatment for ES SCLC, and the positive 
but still modest results with the addition of durvalumab, overall attempts to improve long-term 
survival rates have failed to yield significant advantages. Given the efficacy of immunotherapy in 
SCLC is observed in a minority of subjects, a predictive biomarker study is warranted for finding 
patients most likely to benefit (Ahn, 2019).
Despite the rationale to combine chemotherapy with ICI, based on immunogenic cell death 
induction and immunogenicity of tumor cells modulation by chemotherapy, the benefit observed 
are modest (Ahn, 2019). Explanation of this resistance could be found in the nature the SCLC 
tumor with characteristics of a “cold tumor”: limited PD-L1 expression, decreased major 
histocompatibility complex 1(MHC1) expression, activation or accumulation of suppressors cells,
myeloid derived suppressor cells, regulatory lymphocytes, ineffective priming or activation of
dendritic cells and lymphocytes T cells, and finally low rate of immune cell infiltration (Hamilton, 
2019). Modifying one of these characteristics by using CC-90011 would have the potential to 
enhance ICI activity.
Most patients relapse despite the initial chemosensitivity indicating the inability to eradicate 
residual tumor cells and suggesting the existence of cancer stem cells (CSC) that are resistant to 
radiation and cytotoxic therapy. The CSC theory is a key component of cancer cell biology and is 
hypothesized to be associated with aggressive cancer spread and metastatic progression, as well as 
resistance to therapy (Codony-Servat, 2016). After relapse, these patients have a median survival 
of only 4 to 5 months when treated with further systemic therapy (Owonikoko, 2012). Therefore, 
exploring treatment strategies that target CSC and address this mechanism of resistance appears 
to be essential (Nunes, 2018).
Current treatment for second- and third-line extensive stage SCLC
Subsequent systemic therapy provides significant palliation in many patients; however, the 
likelihood of response is highly dependent on the time from initial therapy to relapse. While there 
are numerous systemic therapy options for patients who have relapsed 6 months or less after initial 
therapy, the likelihood of response is low, and duration of response is very limited. Recommended 
subsequent systemic therapies for these patients
include topotecan, cyclophosphamide, 
doxorubicin and vincristine (CAV), and bendamustine (Cheng, 2007; Kalemkerian, 2018).
In third-line treatment, both nivolumab and pembrolizumab were approved by FDA for subjects 
with ES SCLC with disease progression on or after platinum-based chemotherapy and at least one
other prior line of therapy. Nivolumab has demonstrated an ORR of 12%. Responses were durable 
 
 
 
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for 6 months or longer in 77%, 12 months or longer in 62%, and 18 months or longer in 39% of 
the 13 responding patients (Antonia, 2016).
Activity of ICIs after progression on platinum-based chemotherapy is modest with low response 
rates and low progression-free and overall survival rates, thus prompting the testing of combination
therapy as a potential modality to enhance ICI efficacy and improve outcomes in SCLC patients. 
However, the durable DoR observed is supporting the use of ICIs in second line but understanding 
how to enhance efficacy and enrich subject selection are key.
Squamous Non-Small Cell Lung Cancer (sqNSCLC)
Non-small cell lung cancer accounts for 80% to 90% of lung cancers. Squamous histology account 
for approximately 20% to 30% and is associated with shorter survival than non-squamous
histology (Cheng, 2016; Lortet-Tieulent, 2014; Soldera, 2017).
Advanced squamous non-small cell lung cancer (sqNSCLC) remains a recalcitrant disease. While 
non-squamous NSCLC has benefited from advances in chemotherapy doublets (pemetrexed and 
platinum), VEGF targeted therapy (bevacizumab) and tumor profiling with actionable mutations 
for therapeutic interventions (ie, EGFRmut, ALK, BRAF, ROS1), the same has not occurred in
the setting of sqNSCLC. Together, these factors make sqNSCLC an especially challenging disease
to manage (Socinski, 2016) such that new therapies, especially ICI and combinations, could have
a large impact.
Current Treatment for First Line Squamous Non-Small Cell Lung Cancer
Platinum-based doublet chemotherapy (cisplatin or carboplatin) has been the standard first-line 
treatment for sqNSCLC for decades. Taxanes (including paclitaxel, albumin-bound paclitaxel 
[nab®]-paclitaxel or docetaxel) or gemcitabine commonly complete the standard chemotherapy 
backbone as the initial systemic therapy for patients with advanced sqNSCLC without major 
comorbidities and with a performance status of 0 to 2 (Scarpace, 2015).
More recently, the introduction of ICIs in combination with first line platinum doublets has 
resulted in improvements in ORR, PFS and OS. This has resulted in the FDA approval of 
pembrolizumab, an anti-PD-1 and atezolizumab.
Current Treatment for Second Line Squamous Non-Small Cell Lung Cancer
Three anti-PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, and atezolizumab) have been 
approved by the FDA and the EMA as second-line treatment based on Phase 3 studies 
demonstrating improved survival rates, longer duration of response, and fewer adverse events in 
comparison to docetaxel. However, these therapies were evaluated in immunotherapy-naïve 
patients, prior to approval of ICIs in the first line setting.
Treatment options are limited for sqNSCLC patients who are intolerant to immunotherapy or for 
patients whose disease has progressed on anti-PD-1/PD-L1 therapy. In this case, retreatment with 
platinum-based doublet chemotherapy, docetaxel (with or without ramucirumab), or gemcitabine 
is recommended (Planchard, 2019).
 
 
 
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As switching to another PD-l/PD-L1 inhibitor is not routinely recommended after a patient 
progresses on PD-1/PD-L1 inhibitor (Ettinger, 2018), there are several combinations involving 
ICIs that are being investigated in patients who progressed during or after an ICI therapy.
CC-90011
 
 Lysine-specific histone demethylase 1A is an eraser of the epigenetic code, thereby
regulating the expression of many genes important in cancer progression and cell proliferation 
(Hoffmann, 2012; Lynch, 2012; Scoumanne,
2007). LSD1 over-expression
promotes 
proliferation, migration, and tumor invasion (Lv, 2012) and has been documented in many human
solid tumors including bladder, breast, colorectal, prostate and SCLC (Hayami, 2011; Kahl, 2006; 
Kauffman, 2011; Serce, 2012). Moreover, LSD1 over-expression has been correlated with poor
prognosis in hepatocellular carcinoma, neuroblastoma, prostate cancer, non small cell lung cancer, 
and estrogen receptor negative breast cancer (Chen, 2015; Kahl, 2006; Lim, 2010; Lv, 2012; 
Schulte, 2009; Zhao, 2012).
LSD1 is required for normal differentiation in adult as well as embryonic cells (Wang, 2007). The 
importance of LSD1 in normal differentiation suggests that aberrant gene expression resulting
from dysregulation of LSD1 may result in alterations in pathways associated with a stem-cell like
phenotype. Moreover, LSD1 plays a part in stem cell maintenance, regulation of epithelial-to-
mesenchymal transition (Adamo, 2011; McDonald, 2011), and has been shown to be an essential 
regulator of leukemia stem cell potential (Harris, 2012). LSD1 is a master regulator of normal
stem cell phenotype, which is required for regulation of pluripotency genes, such as the 
transcription factor SRY (sex determining region Y)-box 2 (SOX2) and NANOG (Whyte, 2012), 
and which represses expression oflineage commitment genes (Adamo, 2011). In mouse embryonic
stemcell lines, 2 experiments, ribonucleic acid (RNA) interference–mediated knockdown of LSD1 
expression and treatment by small molecule LSD1 inhibitor, have demonstrated inhibition of the 
proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and 
seminoma or embryonic stem cells that express the stem cell markers OCT4 and SOX2, while 
displaying minimum growth-inhibitory effects on non- pluripotent cancer or normal somatic cells 
(Wang, 2011). 
 
 
 
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Nivolumab
Nivolumab is a human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that
targets the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface 
membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B
lymphocytes. Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-
L2), results in the down-regulation of lymphocyte activation. Inhibition of the interaction between 
PD-1 and its ligands promotes immune responses and antigen-specific T-cell responses to both
foreign antigens as well as self-antigens. Nivolumab monotherapy (OPDIVO™) was first 
approved on 04 Jul 2014 in Japan for unresectable melanoma and has since been approved in
multiple countries, including the US and EU, and has been approved for several other indications 
(eg, metastatic NSCLC, advanced RCC, cHL, SCCHN, urothelial carcinoma, HCC, RCC,
adjuvant treatment of melanoma).
Study Rationale and Purpose
For the purpose of this protocol, ICI means anti-PD-1 or anti-PD-L1 treatments.
The use of ICIs in the treatment for lung cancer has proven efficacy as demonstrated by the 
increasing OS, PFS, ORR and longer DoR compared to chemotherapy alone. However, only 
limited number of subjects have long term benefit with ICI treatment.
The LSD-1 inhibition sequentially or in combination with cytoreductive therapy could improve 
disease-free survival by preventing the emergence of resistant clones through treatment of 
tumorigenic stem cells. This mechanism of action is applicable to many earlier stages of solid 
tumors where existing standard of care does not result in long term disease control for all patients.
The LSD-1 could prove to have a role in treating tumors resistant to current immune check-point 
blockade, an area of high unmet need for multiple solid tumors where ICIs are either not effective,
or where ICIs are currently employed.
CC-90011 has the potential to mitigate primary and acquired resistance to ICI, due to its expected 
reversal of the CSC phenotype and T cell exclusion in SCLC and sqNSCLC.
In addition, recognizing the multiple mechanisms of resistance, this studywill examine biomarkers 
in blood and tissue that could be used to identify responsive patients and improve outcomes. SCLC 
and sqNSCLC have high expression of potential predictive biomarkers for CC- 90011 (eg, SOX-
2 and an LSD1-associated molecular signature), which will be evaluated for potential future use 
for patient enrichment.
In this study, cohort A tests the hypothesis that CC-90011 could enhance nivolumab responses in 
SCLC “cold tumor” phenotype. In this cohort, the proportion of enrolled subjects who respond to 
treatment is expected to increase by the action of CC-90011. Tumors with higher expression of an
LSD1-associated molecular signature and low tumor T infiltrating lymphocytes (TILs) may have 
the best response to the combination of ICI with CC-90011, based on CC-90011 hypothesized 
mechanism of action of increasing T cell infiltration into tumors. Cohorts B and C tests whether 
CC-90011 can mitigate acquired resistance to ICI in SCLC as well as sqNSCLC. For these cohorts, 
 
 
 
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the trial will be enrolling subjects who have an initial response or stable disease to ICI, but progress
within the first 9 months after completion of the chemotherapy treatment.
Combination of CC-90011 with Immune Checkpoint Inhibitors
The effectiveness of ICIs is grounded on a pre-existent anti-tumoral cellular immune response, 
which is usually recognized by the presence of tumor T-lymphocytic infiltrates that are, however, 
most often ineffective because of expression of co-inhibitory (or checkpoint) receptors such as 
PD-1, CTLA-4, and others. Blocking these checkpoint receptors or their ligands restores T cell 
function and leads to clinical responses.
PD-1 is expressed on activated CD8+ T cells, as well as B cells and natural killer cells, in the
setting of chronic antigen exposure. PD-1 ligand (PD-L1) expression is induced by localized 
inflammatory stimuli, such as interferons released by the infiltrating T cells. Although PD-1 and 
PD-L1 checkpoint blockade can result in dramatic therapeutic responses, this therapy is effective 
only in a subset of subjects, and many of them are only partial responders to therapy (Nowicki,
2017). Subjects who do not respond to initial therapy with PD-1/PD-L1 blockade are referred to 
as having “primary resistance” to therapy (Sharma, 2017). Furthermore, a growing subset of 
subjects show robust initial response to therapy, but later have progressive disease. This 
phenomenon, in which the disease is either refractory to resumption of therapy or develops despite
continuation of therapy,
is known as
“acquired resistance” to
PD-1/PD-L1 blockade 
immunotherapy (O'Donnell, 2016). In all, almost four-fifths of patients either do not respond or 
lose their responsiveness to ICI. These limitations have made it necessary to explore combination 
treatment methods which are generally aimed at enhancing or activating antitumor immunity.
The tumor microenvironment can encompass multiple immunosuppressive mechanisms including 
dysfunctional T cells and lack of T cell infiltration or recognition by T cells, which prevent subjects 
to respond to anti-PD-1/PD-L1 therapy (Sharma, 2017; Zou, 2016). These mechanisms provide a 
basis for selecting appropriate combinations to complement the anti-PD-1/PD-L1 action. For
example, the presence of T cytotoxic tumor infiltrates (defining the so-called “hot tumors”) 
justifies targeting other checkpoint inhibitors and enhance anti-tumor immune response. With
modest and immunosuppressed infiltrates, new therapy should be aimed at inhibitory mediators
(such as TGF-β, IL-10, etc), immune suppressive cells (such as myeloid derived suppressor cells, 
regulatory lymphocyte T cells), or immune ignored cancer stem cells. Also, when T cells are 
excluded from the tumor bed and accumulate at the tumor border, then potentially effective
combinations might be aimed at reactivating or supplanting T cell recruiting signals (eg,
chemokines). Finally, when T cells are absent (“cold tumors”), then various modalities to increase 
tumor immunogenicity and restart antigen-presentation or T cell priming might prove useful.
Based on current understanding, CC-90011, a potent and selective reversible inhibitor of LSD1 
can be a combination partner for ICIs due to (1) its direct effects on tumor cells, as inhibition of
LSD1 reduces cell proliferation and stem cell maintenance while promoting cell differentiation 
and reducing tumor growth in preclinical models (Mohammad, 2015); and (2) due to its potential 
immunomodulatory effects via its abilities to impact lymphocytic infiltrates and immunogenicity
of tumors. In addition, we have found that tumors which lack T cell infiltration (cold tumors) have 
 
 
 
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higher mRNA expression of LSD1 and an LSD1-associated molecule, which could be used to 
identify patients susceptible to the action of CC-90011 with ICI.
Preclinical data provide strong mechanistic rationale for the combination of CC-90011 and an ICI 
in SCLC. Although checkpoint inhibitors have demonstrated some efficacy in SCLC, the 
magnitude of benefit has been relatively modest, and only a subset of patients respond. These 
clinical results may be related to the low abundance of T cells in SCLC tumors. CC-90011 is 
expected to reverse this phenotype, allowing T cells to infiltrate the tumor. Preclinical data in the 
literature and from Celgene, including survival data in mice with tumors, suggest that CC-90011 
could induce pro-inflammatoryand T cell permissive changes in the tumor microenvironment and,
thus, enhance efficacy of checkpoint inhibitors, such as nivolumab.
Direct Anti-Tumor Action of CC-90011 Mediated via SOX2
LSD1 appears to play a significant role in the development and progression of malignancies with 
stem cell features. Accumulating evidence suggests that transcription factor SOX2 drives cancer 
stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug 
stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug 
resistance mechanisms like epithelial-to-mesenchymal transition, adenosine triphosphate (ATP)-
binding cassette drug transporters, anti-apoptotic or pro-survival signaling, lineage plasticity, and 
evasion of immune surveillance (Mamun, 2018). Cancer stem cells, which are quiescent and 
express drug efflux pumps, may avoid killing by cytotoxic agents. Cancer stem cells are believed 
to be immune privileged, at least in part by expression of immune-modulatory factors (Bruttel,
2014). By driving differentiation of stem cells, LSD1 inhibition may re-sensitize these cells. 
Inhibition or genetic silencing of LSD1 has been shown to promote differentiation and reduce 
proliferation, migration, and invasion in vitro (Augert, 2019; Lv, 2012) and to reduce tumor growth 
in preclinical models (Augert, 2019; Mohammad, 2015)
The SOX2 is the most frequently altered gene in human squamous cell carcinoma (skin, lung and 
esophageal carcinomas) (Mamun, 2018). The SOX2 gene expression is amplified in more than
20% of tumors, including 27% of SCLC tumors, and is associated with stemness and an un-
differentiated state (Hayami, 2011; Rudin, 2012). The SOX2 protein expression is overexpressed 
in 60% to 90% of tumors, including gliomas, breast, lung, head and neck carcinoma, sarcoma,
pancreatic ductal carcinoma, ovarian cancer, colorectal cancer, melanoma, gastric cancers, and
medulloblastoma (Mamun, 2018). The SOX2 is frequently amplified and/or over-expressed in
SCLC and is involved in the induction of pluripotent stem cells (Takahashi, 2006). 
In agreement with these findings, the LSD1 inhibitor CC-90011 can downregulate SOX2 and 
decrease proliferation and colony formation in SCLC cell lines. CC-90011 induced significant
dose-dependent tumor growth inhibition in multiple cell line-derived xenografts and PDXs in vivo 
at doses ranging from 2.5 to 10 mg/kg QD, while being well tolerated in all models tested.
CC-90011 may induce differentiation of CSCs. CSCs can be resistant to treatments, including 
checkpoint inhibitors (Bruttel, 2014). The LSD1 is keyregulator of stemness (Zhang, 2018). SOX2
is over-expressed in some SCLC tumors and is a driver of SCLC cell growth (Rudin, 2012; Sholl,
 
 
 
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2010; Zhang, 2018). LSD1 inhibitors can decrease SOX2 mRNA expression (Zhang, 2013). LSD1 
prevents SETD7-Driven proteolysis of SOX2 (Zhang, 2018), providing another mechanism by
which LSD1 inhibitors would decrease SOX2 protein levels.
Therefore, inhibition of LSD1 by CC-90011 may be a useful therapeutic approach for tumors with
CSC involvement such as SCLC and sqNSCLC, which are known to have high expression of
SOX2 (Karachaliou, 2013; Wuebben, 2017; Ying, 2016). Overexpression of LSD1 is associated
with poor prognosis in NSCLC, and promotes tumor cell proliferation, migration and invasion in
NSCLC (Lv, 2012). Inhibition of LSD1 inhibits SCLC cell proliferation (Takagi, 2017).
Immunomodulatory Activities of CC-90011
CC-90011 may increase the number of tumor T infiltrating lymphocytes (TIL). This could be 
related to the observation that LSD1 ablation can lead to activation of type 1 interferon and 
stimulate anti-tumor T cell immunity (Sheng, 2018); and it can also result in enhanced tumor 
immunogenicity and T cell infiltration in poorly immunogenic tumors. LSD1 inhibition can also 
result in re-expression of effector T cell-attracting chemokines (CCL5, CXCL9, and CXCL10) 
(Qin, 2019).
In addition, CC-90011 may inhibit CSC self-renewal and induce their differentiation. The CSCs 
are known to be resistant to chemotherapy and at least in part by their expression of immune- are 
known to be resistant to chemotherapy and at least in part by their expression of immune-
inhibitory factors to immunotherapy as well (Bruttel, 2014). A tumor without a CSC compartment
would remain sensitive to killing by cytoreductive agents or immune regulators. This impact on 
CSC suggests that CC-90011 could also help mitigate acquired resistance (eg, responders that 
relapse after a period of response). However, given potential mechanisms of acquired resistance,
such as loss of T cell function, lack of T cell recognition by downregulation of tumor antigen
presentation, and development of escape mutation variants in the cancer (Sharma, 2017), it is 
expected that the other immune activities
of CC-90011,
increasing TIL, stimulating
immunogenicity and anti-tumor T cell immunity (Sheng, 2018), would also contribute to CC-
90011 activity in relapsed subjects.
One of the best predictors of response to immunotherapy is the number and activity of tumor 
infiltrating CD8+ cytotoxic T lymphocytes recruited to the tumor site (Qin, 2019). Consistent with
their biological role, tumor infiltrated lymphocytes have been associated with improved outcome
in several tumor types, including melanoma, colorectal and breast cancer (Fridman, 2013). Tumor
CD8+ T cell infiltration has been linked to antitumor activity of immune checkpoint inhibitors 
(ICI) in subjects with advanced melanoma or NSCLC (Sharma, 2017; Thomas, 2019).
High levels of tumor infiltrating immune cells are associated with improved overall survival in 
SCLC, irrespective of tumor stage, subject performance status, or type of treatment received 
(Wang, 2013). In SCLC, tumor responses were observed in all cases where pretreatment tumors 
were T cell inflamed. In extended or relapsed SCLC, pre-existing CD8+ T cell response may be 
predictive of benefit from ICI-based therapies (Thomas, 2019).
 
 
 
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As an LSD1 inhibitor, CC-90011 may switch cold tumors (lacking T cells) into hot tumors (T cell 
infiltrated). Internal analyses of tumor data in The Cancer Genome Atlas (TCGA) identified > 100 
genes which negatively correlate with T cell infiltration. Expression of LSD1 and an LSD1-
associated molecule anti-correlated with T cells in tumors. The LSD1 complex regulates 
embryonic stem cells property and substitutes for SOX2 in reprogramming somatic cells to 
pluripotency (Yang, 2011). Approximately 50% of SCLC and approximately 33% of sqNSCLC 
had a gene expression pattern which may predict for LSD1 activity and thus response to CC-
90011, when combined with anti-PD1 or anti-PD-L1.
CC-90011 may enhance tumor immunity in “cold” tumors. LSD1 expression is inversely 
associated with that of cytotoxic T cell-attracting chemokines and PDL1 (Qin, 2019). LSD1 
knock-down increases inflammatory gene expression (Hanzu, 2013; Qin, 2019). LSD1 KO or 
inhibition increases T cell trafficking into tumors and check-point inhibitor efficacy in preclinical 
models (Qin, 2019; Sheng, 2018). LSD1 inhibitors upregulate PDL1 expression in cell lines (Qin, 
2019).
Subsequently, LSD1 knockdown was shown to enhance efficacy of anti-PD1, as evidenced by 
decreased tumor size and increased mouse survival in syngeneic tumor models (Sheng, 2018). In 
a separate study, LSD1 inhibition plus an anti-PD-1 antibody significantly suppressed tumor 
growth and pulmonary metastasis and augmented CD8+ T cell infiltration into xenograft tumors 
of triple negative breast cancer (Qin, 2019). Thus, CC-90011 is expected to enhance response to 
ICI, such as anti-PD1, when used in combination.
 
 
 
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2
POTENTIAL RISKS AND PRECAUTIONS
Pre-clinical data – CC-90011
Exploratory and GLP-compliant repeated-dose toxicity studies of oral CC-90011 for up to 3
months in mice and dogs following several dosing schedules (mouse = QD, QDx5/week, and 
QODx3/week; dog = QW, BIW, and Q2W) were conducted to 1) assess the systemic exposure and
toxicities over a range of dose levels and dose schedules, 2) to aid in dose and dose schedule 
selection for clinical trials, and 3) to further characterize CC-90011-related toxicity.
In 4-week studies, treatment-related mortality was observed at 45 mg base/kg/dose in mice 
following a QDx5/week dose schedule; and at ≥ 0.375 mg base/kg/dose in dogs following a QW 
dose schedule. The cause of mortality in mice was not determined; the moribund condition of dogs
was due to CC-90011-related GI toxicity and ensuing septicemia.
In mice dosed at up to 45 mg base/kg/dose for 4 weeks, there was dose-proportional marrow 
toxicity, evidenced by a myeloid shift and/or marrow hypocellularity. The marrow space was 
replaced by fibrosis in the sternum and/or femur, with hyperostosis of endosteal, periosteal, and 
trabecular bone surfaces of affected sternebrae. Collectively, these changes persisted through a 
recovery period at the highest dose only. Some increase in marrow megakaryocytes (without 
peripheral correlate) was noted at all doses, also persisting at the highest dose. Marrow toxicity 
occurred in concert with declines in peripheral red cell mass (RBC count, hemoglobin, and 
hematocrit), and declines in platelet, reticulocyte and/or leukocyte counts along with significant 
are particularly sensitive). Depletion of splenic marginal zone lymphocytes was observed in all but
the lowest dose groups but did not persist through a recovery period.
In dogs dosed for 4 weeks, findings were more clearly inflammatory in nature. The predominant
finding centered on GI inflammation which in some instances was ulcerative and associated with 
secondary septicemia and mortality at higher doses. Changes in the bone marrow (BM) reflected
peripheral demand, with myeloid hypercellularity and variable evidence of marrow toxicity
reflected in the peripheral blood as either a decrease or increase in peripheral leukocyte numbers; 
unlike mice, no reactive bone alterations were noted.
In one 4-week dog study, there was mortality at ≥0.375 mg base/kg/dose, with morbidity generally 
attributed to gastric inflammation and/or ulceration. Slight to marked, acute to subacute 
inflammation was observed variably in the esophagus, stomach, small and/or large intestines, 
and/or rectum of dogs dying early. Findings that correlated with these microscopic changes 
included dehydration, abnormal feces (liquid, red), red vomitus, decreased food consumption and 
body weight, hypoactivity, fever, and/or GI tract discomfort. Related clinical pathology findings 
included decreased albumin, albumin:globulin ratio, calcium, and inorganic phosphorous; increased
monocytes, large unstained cells, and neutrophils; and decreased red cell mass, platelets,
reticulocytes, and eosinophils. Other findings in these animals were attributed to generalized
inflammation and/or septicemia secondary to mucosal ulceration in the GI tract (inflammation in
multiple lymph nodes, subcutaneous edema, acute inflammation in the heart or liver), and/or
physiologic stress, including extramedullary hematopoiesis in the spleen and an increased
myeloid:erythroid ratio in the sternal marrow. In surviving animals, only minimal to moderate 
 
 
 
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acute inflammation of the intestines and/or rectum was observed at ≤ 0.75 mg/kg/dose, with
complete recoverability following a 4-week non-dosing interval. In a 4-week study at lower doses 
(0.125 or 0.25 mg base/kg/dose QW or 0.5 mg/kg/dose Q2W), there was no mortality, and findings 
were of lower severity, with acute inflammation in the cecum, ileum, and/or gut-associated
lymphoid tissue of dogs from the highest dose-groups from each dosing-interval. Changes were 
minimal when dosed Q2W, becoming marked when dosed QW. Other findings included minimal 
extramedullary hematopoiesis in animals from the highest dose groups of either dosing regimen.
All CC-90011-related findings in mice and dogs demonstrated evidence of partial to complete
reversibility following a 4-week treatment-free period.
In mice dosed daily for up to 3 months at up to 10 mg/kg/dose, further evidence of CC-90011-
related systemic inflammation was observed. Inflammation affected multiple tissues, with
instances of mortality (10 mg/kg/dose level) being associated with more severe inflammatory foci. 
Specifically, scattered neutrophilic inflammatory cell infiltrates occurred at 10 mg/kg/day in the 
heart valve, epididymides, eye sclera, and/or periocular tissue. Some instances of periocular 
inflammation were clearly an extension of peripheral glandular inflammation and, in general, the 
interior of the eye was unaffected. At 3 mg/kg/day, such infiltrates became minimal and were 
restricted to the periocular tissues; no such findings were seen at the 1 mg/kg/day. At the
nontolerated dose level, ophthalmology examination revealed hyporeflection and reduced pallor 
in the fundus of the eye. Also, at 10 mg/kg/day, mortality was associated with focal abscessation
in the Harderian glands and/or skin/subcutis. Reactive alterations in affected dose groups included
increased (myeloid) marrow cellularity, and extramedullary hematopoiesis in the liver (with some 
necrosis at the highest dose), spleen and/or adrenal glands.
In dogs dosed QW for 3 months, CC-90011 was well tolerated up to 0.25 mg/kg/dose, the highest 
dose level administered, with no signs of toxicity.
Safety pharmacology evaluations were performed to determine the potential effects of CC-90011 
on CV-related endpoints and respiratory rates. In an in vivo CV study in male Dunkin Hartley 
guinea pigs, an increase of QTcB interval of up to 16% at 10 to 18 minutes after infusion initiation
was observed. CC-90011 caused a slight decrease in HR with a maximum suppression of 19% at 
9 minutes into the 10-minute infusion. There were no remarkable CC-90011 related effects on 
arterial pressure, PR interval, QRS duration, or qualitative ECG parameters. The NOAEL in
guinea pigs was 10 mg base/kg after IV infusion, with a mean plasma concentration of 2362 ng/mL 
at the end of the 10-minute infusion. This NOAEL plasma concentration was approximately 3000-
fold higher than the predicted Cmax at the clinical starting dose of 1.25 mg base (0.80 ng/mL). In 
the 4-week oral gavage pivotal toxicity study in the dog, no CC-90011-related abnormalities in
rhythm or waveform morphology or on HR, RR interval, PR interval, QRS duration, QT interval, 
or QTc interval were found at any dose level with CV and respiratory endpoints evaluated (ie, <
1.5 mg base/kg/dose). Therefore, the NOEL for CV and respiratory changes were 0.75 mg 
base/kg/dose (QW) and 0.375 mg base/kg/dose (BIW), the highest dose levels with CV and 
 
 
 
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respiratory endpoints evaluated. Steady state Cmax values at 0.75 mg base/kg/dose QW were 36.2
ng/mL (males) and 40.8 ng/mL (females); and at 0.375 mg base/kg/dose BIW were 17.7 ng/mL 
(males) and 19.0 ng/mL (females). These NOEL plasma concentrations were approximately 20-
to 50-fold higher than the predicted Cmax at the clinical starting dose of 1.25 mg base (0.80 
ng/mL). In the clinical CC-90011-ST-001 Part A study, the human mean Cmax taken on Day 22
was 0.42 ng/mL at the starting dose of 1.25 mg, and 20.43 ng/mL at the RP2D (60 mg).
The IC50 of the hERG cardiac potassium ion channel current was 3.4 μM CC-90011 (Hill 
coefficient = 1.2), indicating moderate inhibition. Together, the hERG and CV safety 
pharmacology data suggest CV-related risk to patients is low.
Potential CNS-related effects were monitored in the GLP-compliant repeat-dose dog and mouse 
studies and no clinical observations were considered CNS-related.
CC-90011 was non- mutagenic based on the results obtained from the in vitro mutagenicity assays.
Overall, CC-90011 exhibits an acceptable safety profile in preclinical species for a clinical drug 
candidate in an advanced oncology setting and the toxicology program for CC-90011 adequately
supports the conduct of clinical trials in oncology subjects.
Clinical data
CC-90011
Clinical experience with CC-90011 in humans is based on 2 ongoing clinical Phase 1 studies, CC-
90011-ST-001 (monotherapy) and CC-90011-SCLC-001 (combination therapy).
Study CC-90011-ST-001 is an open-label, Phase 1, multicenter, dose escalation (Part A) and 
expansion (Part B), first-in-human (FIH) clinical study
to assess the safety (including an 
assessment of maximum tolerated dose [MTD]), PK, and preliminary efficacy of oral CC-90011 
in adult subjects with relapsed and/or refractory (R/R) advanced solid tumors and R/R advanced 
non-Hodgkin lymphomas.
Study CC-90011-SCLC-001 is an open-label, Phase 1b, multicenter, dose-finding study to assess 
the safety, tolerability, PK, PD, and preliminary efficacy of CC-90011 given in combination with 
cisplatin or carboplatin and etoposide, defined as Chemotherapy, followed by CC-90011 single 
agent in maintenance, and CC-90011 given in combination with Chemotherapy plus nivolumab 
followed by CC-90011 plus nivolumab in maintenance, to adult subjects with first line, extensive 
stage (ES) SCLC. The study consists of a dose-finding Chemotherapy Treatment Period, where 
increasing oral doses of CC-90011 are given in combination with standard dose of Chemotherapy
with or without nivolumab and a Maintenance Treatment Period, following completion of the 
chemotherapy regimen, where CC-90011 up to 60 mg is administered as a single agent or with
nivolumab for responding subjects.
Study CC-90011-ST-001
As of 11 Sep 2020, 50 subjects were enrolled in Part A of the study and received escalating oral 
doses of CC-90011 QW at 9 dose levels from 1.25 mg to 120 mg/dose and 17 subjects (14 subjects 
with low/intermediate-grade lung neuroendocrine tumors [NETs] [typical and atypical carcinoid]
 
 
 
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and 2 subjects with prostate neuroendocrine carcinomas [NECs], and 1 subject with MZL were 
enrolled in Part B of the study and received oral CC-90011 QW at 60 mg. The Part A of the study
has been completed and the primary objectives were met. Seven out of the 47 evaluable subjects 
experienced a DLT and all DLTs were Grade 3 or 4 thrombocytopenia. Thrombocytopenia, an on-
target effect, occurred at and beyond 60 mg QW and were successfully managed with dose 
interruption and/or dose reductions. The NTD was established at 120 mg QW with all 4 treated 
subjects experiencing Grade 3 (N = 2) or Grade 4 (N = 2) thrombocytopenia (requiring platelet
transfusion). The MTD has been identified at 80 mg QW since the expanded cohort to 10 subjects 
identified 2 subjects with DLT, ie, one Grade 3 and one Grade 4 thrombocytopenia (requiring
platelet transfusion). One subject at 60 mg QW experienced a Grade 4 thrombocytopenia requiring
transfusion.
In Part A of the study (N=50), the most frequently reported treatment emergent adverse events 
(TEAEs) (in at least 10% of subjects) were thrombocytopenia (46.0%), vomiting (28.0%), anemia
(28.0%), fatigue (26.0%), nausea, constipation and asthenia (22.0% each), diarrhea, pyrexia, and 
decreased appetite (20.0% each), musculoskeletal pain (16.0%), back pain (14.0%), neutropenia, 
abdominal pain, increased alanine aminotransferase (ALT), increased aspartate aminotransferase 
(AST), and cough (12.0% each), and tumor pain, headache, and dyspnea (10.0% each). Overall,
24 (48.0%) subjects experienced at least one Grade 3 or 4 TEAE and the most frequently reported 
Grade 3 or 4 TEAEs (in at least 2 subjects) were thrombocytopenia (24.0%), neutropenia (8.0%), 
anemia (6.0%), and general physical health deterioration, increased ALT, increased blood 
bilirubin, increased lipase, and hypophosphatemia (4.0% each). Grade 3 or 4 thrombocytopenia
occurred from the dose level of 40 mg and Grade 3 or 4 neutropenia occurred from the dose level
of 80 mg and only after clinically significant thrombocytopenia. Three (6.0%) subjects 
experienced at least one TEAE leading to discontinuation of study treatment (1 subject at 2.5 mg 
had Grade 3 portal acute vein thrombosis assessed as not related to study drug and 2 subjects at 
120 mg had Grade 3 thrombocytopenia, assessed as related to study treatment). Overall, 33 
(66.0%) subjects died during Part A mainly due to progression of malignant disease in this heavily
treated population. No death due to drug-related toxicity occurred during the study.
CC-90011 demonstrated preliminary evidence of antitumor activity in this difficult-to-treat patient
population with very few treatment options. Among 27 neuroendocrine neoplasm (NEN) subjects,
7 subjects have demonstrated prolonged stabilization of disease (stable disease [SD] > 4 months).
Notably, 3 subjects with bronchial NEN had prolonged SD of > 6 months and 2 subjects with
prostate NEN stayed over 6 months under study drug treatment due to clinical benefit. The R/R
non-Hodgkin’s lymphoma subject (transformed marginal zone lymphoma) experienced a 
complete metabolic response.
In Part B of the study (N = 17), the most frequently reported TEAEs (in at least 10% of subjects)
were thrombocytopenia (70.6%), asthenia (41.2%), anemia (35.3%), constipation, diarrhea, and 
nausea (29.4% each), neutropenia and dysgeusia (23.5% each), decreased appetite, arthralgia, 
musculoskeletal pain, cough and epistaxis (17.6% each), and leucopenia, stomatitis, vomiting, 
fatigue, hepatic pain, bronchitis, lipase increased, hypokalemia, bone pain, neck pain, dizziness, 
peripheral sensory neuropathy, sciatica, confusional state, dyspnea, and pruritus (11.8% each). 
 
 
 
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Overall, 13 (76.5.0%) subjects experienced at least one Grade 3 or 4 TEAE and the most frequently 
reported Grade 3 or 4 TEAEs (in at least 2 subjects) were thrombocytopenia (35.3%), neutropenia
(17.6%), and asthenia (11.8%). No subject experienced TEAE leading to discontinuation of study
treatment. Overall, 9 (52.9%) subjects died during Part B due to progression of malignant disease 
(N = 6), occurrence of an adverse event (AE) (N = 2), and unknown cause (N = 1).
No death due to drug-related toxicity occurred during the study.
In the 14 subjects with low/intermediate-grade lung NET, a best response of SD was observed in 
10 (71.4%) subjects, including 7 subjects with SD ≥4 months. The 2 subjects with 
 NEC
and the MZL subject progressed.
The study demonstrates that CC-90011 is well-tolerated in the heavily pretreated subjects with 
advanced tumors. The majority of treatment emergent adverse events (TEAEs) were mild or 
moderate in severity, transient, and manageable by dose adjustments and/or supportive treatment. 
Study CC-90011-SCLC-001
As of 11 Sep 2020, safety and efficacy data are available for 19 enrolled subjects with first line ES 
SCLC, who received escalating doses of oral CC-90011 at 20 mg (Cohort 1; N = 8) and 40 mg 
(Cohort 2; N = 7), and 60 mg (Cohort 3; N = 4), in combination with etoposide plus cisplatin (EP).
One subject, who received CC-90011 20 mg, and 2 subjects, who received CC-90011 60 mg plus 
EP experienced a DLT during Chemotherapy Treatment Period. No DLT was observed in the 6 
evaluable subjects treated at the dose of 40 mg. The NTD was determined to be 60 mg and the CC-
90011 recommended phase 2 dose (RP2D) was 40 mg on Days 1 and 8 of each 21-day 
chemotherapy cycle.
During the Chemotherapy Treatment Period (N = 19), the most frequently reported TEAEs (in at 
least 20% of subjects) were anemia (78.9%), thrombocytopenia and neutropenia (68.4% each), 
asthenia (52.6%), nausea (42.1%), constipation (31.6%), blood alkaline phosphatase (ALP) 
increased (26.3%),
and
mucosal
inflammation,
pyrexia,
diarrhea,
decreased
appetite, 
hyponatremia, dyspnea, and alopecia (21.1% each). Overall, 16 (84.2%) subjects experienced at 
least one Grade 3 or 4 TEAE and the most frequently reported Grade 3 or 4 TEAEs (in at least 2 
subjects) were neutropenia (63.2%), thrombocytopenia (42.1%), febrile neutropenia (15.8%), and 
anemia (10.5%).
As of 11 Sep 2020, a best objective response of PR was observed in the 16 of the 19 treated 
subjects.
The most current summary of clinical data is available in the most current version of the IB.
Potential toxicities for CC-90011 include those identified in the currently ongoing clinical studies 
and from nonclinical studies with CC-90011. On target, reversible and manageable 
thrombocytopenia has been established as a treatment emergent serious adverse event meeting the 
threshold or criteria for inclusion as related adverse events in the reference safety information 
(RSI) for CC-90011. Neutropenia has been established as a TEAE and is included as an adverse 
drug reaction (ADR) in the CC-90011 IB.
 
 
 
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Bone marrow hypocellularity findings emphasize the importance of frequent blood count 
monitoring. Episodes of thrombocytopenia have been observed in the ongoing clinical studies and 
usually recover in one week’s time with interruption of study drug, with recovery to Grade 
1/baseline allowing continuation of study drug. Grade 1 thrombocytopenia events do not preclude 
the study drug administration and subjects with Grade 2 events have been safely dosed according 
to investigator´s judgment of the overall patient´s status. Grade 3 and 4 thrombocytopenia require 
dose interruption until recovery to Grade 1/baseline.
In the current proposed study, CC-90011-ST-002, subjects must have adequate laboratory values 
for platelet count, absolute neutrophil count (ANC), hemoglobin and white blood cells (WBC) to 
be included in the study (refer to protocol inclusion criteria for details). Subjects who are enrolled 
into the study will have ongoing safety laboratory analyses, including complete blood count (CBC)
with differential and platelet count.
The protocol includes recommended dose adjustment guidelines for CC-90011 related 
hematological toxicities (refer to protocol section 7.4). Therapeutic use of granulocyte growth
factors is allowed at any time for subjects experiencing febrile neutropenia or Grade 3/4 
neutropenia. Routine prophylaxis with granulocyte colony stimulating factor or granulocyte-
macrophage colony stimulating factor is allowed at the Investigator’s discretion after one or more 
occurrences of neutropenia and febrile neutropenia.
Due to potential GI toxicity, subjects with the following are excluded from participating in the 
study: subject has persistent diarrhea due to a malabsorptive syndrome (National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI CTCAE) ≥ Grade 2, despite medical 
management), or any other significant gastrointestinal (GI) disorder; subject with symptomatic or
uncontrolled ulcers (gastric or duodenal), particularly with a history of and/or risk of perforation 
and GI tract hemorrhages or subject with any hemorrhage/bleeding event CTCAE > Grade 2 or 
haemoptysis > 1 teaspoon within 4 weeks prior to the first dose.
During study participation, subjects with ≥ Grade 1 diarrhea should promptly initiate treatment, as 
per recommendation of their treating physician and local guidelines.
Premedication with
antidiarrheal medication for subsequent doses of study treatment may be appropriate. Antiemetics
will be withheld until subjects have experienced ≥ Grade 1 nausea or vomiting. Subjects may then 
receive prophylactic antiemetics at the discretion of the Investigator and per local guidelines.
The protocol also provides detailed guidance on dose reduction for study related hematological 
and non-hematological toxicities.
Nivolumab
The overall safety experience with nivolumab is based on experience in approximately 23, 507
subjects as either monotherapy or in combination with other therapeutics. Overall, the safety 
profile of nivolumab monotherapy is manageable. Most AEs were low-grade (Grade 1 to 2) with 
relatively few related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, 
severity, or causality of AEs with respect to nivolumab dose level.
 
 
 
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In general, for monotherapy, the safety profile is similar across tumor types. The only exception
is pulmonary inflammation AEs, which may be numerically greater in subjects with NSCLC,
possibly because in some cases, it can be difficult to distinguish between nivolumab-related and
unrelated causes of pulmonary symptoms and radiographic changes.
The most common adverse reactions (≥20%) in patients treated by nivolumab as monotherapy were
fatigue, rash,
musculoskeletal pain,
pruritus, diarrhea, nausea, asthenia, cough, dyspnea,
constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia,
headache, abdominal pain and vomiting.
Nivolumab is associated with immune-mediated adverse reactions including but not limited to 
pneumonitis, colitis, hepatitis, nephritis, endocrinopathies, skin adverse reactions (including rash,
Stevens-Johnson syndrome, toxic epidermal necrolysis), encephalitis, and other immune 
mediated adverse reactions (myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, 
facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune 
neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response 
syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi 
lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic 
syndrome). 
Management algorithms have been developed for the treatment of these immune-mediated adverse 
reactions.  For nivolumab monotherapy and combination therapy, the majority of these AEs 
have been managed successfully with supportive care and, in more severe cases, a combination of 
dose delay, permanent discontinuation, and/or use of corticosteroids or hormone replacement
therapy (endocrinopathies) as instructed in the management algorithms.
The proposed study includes these management algorithms to be used by the investigators. Early 
recognition and treatment is critical to management. Subjects should have a thorough diagnostic 
work-up to evaluate potential drug and non-drug related diagnoses.
Infusion reactions following administration of nivolumab are uncommon. Investigators are 
advised to monitor for fever, chills, shakes, headaches, itching, rash, hypertension or hypotension, 
or difficulty in breathing during and immediately after administration of nivolumab. Treatment 
recommendations are descried in the protocol (section 7.4.4), including interruption in patients 
with mild or moderate infusion related reactions or discontinuation of nivolumab in patients with 
severe or life-threatening infusion related reactions.
Overlapping toxicity
The safety profile of nivolumab combination therapy varies with the agent combined with
nivolumab, but is generally consistent with the safety profiles observed with either agent alone
and, in some cases, both frequency and severity of AEs were greater than that observed with
either agent alone.
CC-90011 has not been associated with immune mediated adverse events, but instead has mainly 
haematologic toxicities. In part A of the CC-90011-ST-001 study, (in 50 patients treated), the most 
frequently reported Grade 3 or 4 TEAEs included thrombocytopenia, neutropenia and anemia at 
 
 
 
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24.0%, 8.0% and 6.0% respectively. In part B of the CC-90011-ST-001 study, (in 17 patients 
treated as of 11 Sep 2020), the most frequently reported Grade 3 or 4 TEAEs included 
thrombocytopenia at 35.3% and neutropenia at 17.6%. 
In the CC-90011-SCLC- 001 study, (as of 11 Sep 2020, in 19 patients treated with CC-90011 in 
combination with EP), the most frequently reported Grade 3 or 4 TEAEs included neutropenia at 
63.2%, thrombocytopenia at 42.1%, and anemia at 10.5%.
Severe haematologic toxicities are not expected with nivolumab, most observed haematology 
laboratory abnormalities were low grade, and the immune mediated adverse events affect less than 
10% of the patients treated by nivolumab alone. In patients treated with nivolumab alone (pooled 
dataset of 2578 patients), the proportion of patients who experienced a shift from baseline to a 
Grade 3 or 4 laboratory abnormality was as follows: 5.2% for anaemia (all Grade 3), 1.0% for 
thrombocytopenia, 1.1% for neutropenia, (Opdivo summary of product characteristics [SmPC]).
The safety profile of CC-90011 is not as well-known as the safety profile for nivolumab. There is 
a possibility of overlapping haematologic events and patients will be monitored for this.
The emerging platelet (safety) profile of CC-90011 and nivolumab combination and decision to
proceed at a reduced dose of CC-90011 40 mg, in the current study,  supports assessment of 
benefit/risk from the perspective of population pharmacokinetics (PK) and exposure-response
relationship with the safety and efficacy endpoints for the combination treatment. From available 
data thus far, it appears that there is some synergistic thrombocytopenia at precedented exposures 
of CC-90011; thus, having a composite exposure-response model for this combination will help to 
better characterize the overall thrombocytopenia profile. Currently, protocolamendment 1 collects
nivolumab immunogenicity (IMG) samples from Cohort C at the scheduled timepoints: Cycle 1
Day 1 pre- dose, Cycle 2 Day 1 pre-dose, Cycle 3 Day 1 pre-dose, and every 4th cycle after Cycle 
3 Day 1 pre-dose. In amendment number 2, both PK and IMG sample collections for nivolumab 
at the previously scheduled time points will be added and extended to all 3 cohorts.
Other overlapping toxicities are not known at this time and there will be careful monitoring of the 
combined safety profile and how it may differ from the known monotherapy safety profiles.
 
 
 
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3
ADDITIONAL PRECAUTIONS
Steering committee
The conduct of this trial will be overseen by a Steering Committee (SC), presided over by the 
coordinating Principal Investigator and if possible, the representative Regional Investigators from
European countries participating in this study. The SC will serve in an advisory capacity to the 
Sponsor. Review of AEs and SAEs and any decision to pause enrollment, or modify the dose 
and/or schedule of the cohorts, will be determined by the Sponsor with Steering Committee.
Initial Safety evaluation (protocol section 7.3.1) 
A safety evaluation will be conducted to assess the safety of CC-90011 with nivolumab after 6 
subjects have completed at least 2 Cycles. A Bayesian method will be used to monitor for the rate 
of thrombocytopenia Grade 4 and neutropenia Grade 3 to 4 events. The expected rate of 
thrombocytopenia Grade 4 is 20% and the expected rate of neutropenia Grade 3 to 4 is 12% from
CC-90011 alone. No serious overlapping toxicities are expected for the combination of CC-90011
with nivolumab. No immune-related adverse events (irAEs) have been observed in the first-in-
human study with CC-90011.
After the enrollment of 6 successive subjects completing 2 cycles, or sooner per protocol section 
7.3.2, the following stopping criteria based on the posterior distributions of the rate of 
thrombocytopenia Grade 4 and neutropenia Grade 3 to 4 events with a noninformative Jeffreys
prior distribution of Beta (1/2, 1/2) will be evaluated:
1. Probability (rate of thrombocytopenia Grade 4 > 0.2|data from 6 subjects) > 0.95 or
2. Probability (rate of neutropenia Grade 3 to 4 > 0.12|data from 6 subjects) > 0.95
If any of these stopping criteria are met, the starting dose of CC-90011 will be reduced to the next 
lower dose level 40 mg. The first criterion is equivalent to observing 3 or more thrombocytopenia
events Grade 4 out of 6 and the second criterion is equivalent to observing 3 or more neutropenia
events Grade 3 to 4.  Enrollment will not be paused during this evaluation.
Once the starting dose is reduced to 40 mg, the same rule will be applied. If any of these stopping 
criteria are met for the 6 subjects treated at 40 mg, the starting dose of CC-90011 will be reduced 
to the next lower dose level 20 mg.
Once the initial 6 subjects at a given dose level do not trigger the dose reduction rule, subjects’ 
safety data will be closely monitored on an ongoing basis and individual dose delays and/or 
reduction recommendations will be followed. In case the starting dose is reduced to a lower dose 
level, it will be ensured that the sample size at the selected dose meets the planned number of 
subjects.
Safety evaluation for CC-90011 starting dose of 40 mg (protocol section 7.3.1.1) 
As of 14 Aug 2020, the Sponsor, in agreement with the Steering Committee made the decision to
reduce the starting dose of CC-90011 from 60 mg to 40 mg. Implementation of this dose reduction 
was not considered an urgent safety measure. The same stopping criteria as specified in Sections
7.3.1 and 7.3.2 will be applied to the reduced starting dose of 40 mg.
 
 
 
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To further evaluate if the RP2D of 60 mg that was established in the first-in-human study can be 
safely administered in this study and in order to maximize the potential efficacy of CC-90011 and
level of target engagement, re-escalation to 60 mg may be considered after review of the overall 
data and AEs/SAEs by the Sponsor in agreement with the Steering Committee. Specifically, if in 
the first 2 cycles, there are no reports of Grade 4 thrombocytopenia or Grade 3 or 4 neutropenia, 
in any of the 6 subsequent subjects (without distinction of cohorts) who received 40 mg, then re-
escalation of the starting dose to 60 mg for subsequent  subjects may be considered.
If the stating dose is  re-escalated to 60 mg, an additional 4 subjects (without distinction of cohorts) 
will be treated so that 6 subjects in total (including the 2 subjects in which Grade 4 
thrombocytopenia [n=2] and Grade 3 neutropenia [n=1] was reported) will have received 60 mg. 
There will be staggered dosing, where the second subject to receive 60 mg will not be dosed until 
at least 15 days after the first subject has been treated and safety has been reviewed. This sentinel 
dosing scheme may or may not be continued for the rest of the 60 mg subjects, depending on the 
findings in the first subject and the overall safety profile to date.
The stopping criteria in protocol Sections 7.3.1 and 7.3.2 will be applied to these 6 subjects. 
Therefore, if in the first 2 cycles, there are no reports of Grade 4 thrombocytopenia and 1 or less 
reports of Grade 3 or 4 neutropenia, in any of the 4 subsequent subjects who received 60 mg, then 
60 mg will be declared as the starting dose of CC-90011 and the dose to continue with in this study.
If in the first 2 cycles, there is at least 1 report of Grade 4 thrombocytopenia or at least 2 reports 
of Grade 3 or 4 neutropenia, in any of the 4 subsequent subjects who received 60 mg, then 40 mg 
will be declared as the starting dose of CC-90011 and the dose to continue with in the study.
Definition of Stopping Criteria (protocol section 7.3.2)
If any of these stopping criteria are met for the 6 subjects treated at 20 mg, the trial will be stopped.
Events to be monitored with special interest and which may trigger the above stopping criteria 
include but are not limited to:

Serious adverse events (SAEs) related to IPs of the same nature or organ system

Clinically significant SAEs related to IPs of the same nature or organ system which 
would prevent further dosing of an individual subject
Review of the AEs and SAEs, and any decision to pause enrollment, or modify the dose and/or 
schedule of the cohorts, will be determined by the Sponsor in agreement with Steering Committee.
Decisions to pause enrollment or stop cohorts or modify dose and/or schedule of the cohorts of the
study will be communicated promptly to Investigators, to the Institutional Review Boards 
(IRBs)/Ethics Committees (ECs) (as applicable), and will be implemented in a protocol 
amendment which will be submitted to the appropriate regulatory authorities.
Drug-drug Interactions
CC-90011
Drug-drug interactions have not been investigated in clinical studies. In vitro studies have shown
that CC-90011 is primarily metabolized by CYP3A4/5. Hence, drugs that are known strong 
inducers or inhibitors of this enzyme should not be co-administered with CC-90011. Should use 
 
 
 
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of these drugs become necessary, the risks and benefits should be discussed with the Sponsor’s
studyphysician prior to its concomitant use with CC-90011. Examples of these drugs are described 
in the protocol.
In view of the potential for thrombocytopenia, nonsteroidal anti-inflammatory drugs and aspirins 
(aspirin dose ≤ 150 mg is allowed) should be avoided if possible and paracetamol or 
acetaminophen, should be administered instead.
Nivolumab
Nivolumab is a human monoclonal antibody, as such pharmacokinetic interaction studies have not 
been conducted. As monoclonal antibodies are not metabolised by cytochrome P450 (CYP) 
enzymes or other drug metabolising enzymes, inhibition or induction of these enzymes by 
co-administered medicinal products is not anticipated to affect the pharmacokinetics of nivolumab.
Pregnancy, Lactation, and Fertility
Pregnant and lactating women are excluded from the proposed study.
CC-90011 has not been studied in pregnant women and the effects on the human fetus are 
unknown. CC-90011 should not be administered to pregnant women. No reproductive or fertility
studies have been conducted with CC-90011. Therefore, prohibition of semen donation and 
fathering children for male subjects, and conceiving or donating ova for female subjects, is 
recommended for the appropriate follow-up period, as specified in the study protocol.
There are no data on the use of nivolumab in pregnant women. Studies in animals have shown 
embryofoetal toxicity. Human IgG4 is known to cross the placental barrier and nivolumab is an 
IgG4; therefore, nivolumab has the potential to be transmitted from the mother to the developing 
foetus. Nivolumab is not recommended during pregnancy and in women of childbearing potential 
not using effective contraception unless the clinical benefit outweighs the potential risk. Studies 
to evaluate the effect of nivolumab on fertility have not been performed. Thus, the effect of 
nivolumab on male and female fertility is unknown.
It is not known whether CC-90011 or its metabolites are excreted in human milk. There are no 
data on the presence of nivolumab in human milk, the effects on the breastfed child, or the effects 
on milk production.
Female subjects of childbearing potential must have a negative serum or urine pregnancy test prior 
to Day 1 dosing with study treatment and must agree to have pregnancy tests as specified in the 
study protocol. Female subjects of childbearing potential must agree to use effective contraception 
while participating in the study and for the appropriate follow-up periods, as specified in the study
protocol.
Males must practice true abstinence or agree to use barrier contraception (latex condom
recommended) when engaging in sexual activity with pregnant females or females of childbearing 
potential from the time of signing the informed consent form and for the appropriate protocol-
specified time periods, even if he has undergone a successful vasectomy.
 
 
 
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Women should not breastfeed while receiving CC-90011 or nivolumab and for any subsequent 
protocol specified time periods.
Phototoxicity
Comprehensive studies to evaluate the phototoxicity potential of CC-90011 have not been 
conducted. As a precautionary measure, it is recommended that subjects avoid prolonged exposure
to ultraviolet (UV) light, wear protective clothing and sunglasses, and use UV-blocking topical 
preparations while taking study treatment.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 
2019 (COVID-19)
At this time, the risk of COVID-19 in subjects receiving CC-90011 is unknown. Current available 
clinical data from the ongoing CC-90011-ST-002 study suggest an overall favorable safety profile 
and no specific evidence of elevated risk of infection. However, since at least a theoretical risk of
increased infection rates cannot be ruled out, measures to mitigate risk associated specifically with
COVID-19 will include the following:

Continuous safety assessments will be utilized by the Investigators and Sponsor to 
determine whether additional safety measures are required. In addition, AEs and SAEs 
associated with confirmed or suspected SARS-CoV-2 infection will be collected from 
the date the subject signs informed consent until 100 days following discontinuation of 
study treatment. Adverse events will be reviewed on an ongoing basis by the Medical 
Monitor
(or designee)
and
Global
Pharmacovigilance
and
Epidemiology
representatives to monitor for any safety signals or trends. The testing capability for
SARS-CoV-2 to provide prompt results is not uniformly available. Due to these 
challenges, testing for SARS-CoV-2 will be deferred to local or regional policies.
However, study subjects who test positive for SARS-CoV-2 during screening may be 
rescreened after meeting criteria in Section 6.1.1 of the protocol.

Subjects with previous SARS-CoV-2 infection either suspected or confirmed within 4 
weeks prior to screening are excluded until symptoms have completely resolved and 
based on investigator assessment in consultation with the Medical Monitor, there are 
no sequelae that would place the subject at a higher risk of receiving investigational 
treatment.

Subjects currently in other interventional trials for COVID-19 may not participate in 
the study until the protocol specific washout period is achieved. If a study participant has
received an investigational COVID-19 vaccine prior to screening, enrollment must be 
delayed until the biologic impact of the vaccine is stabilized, as determined by 
discussion between the Investigator and the Medical Monitor. It is also advised to avoid
overlap of study treatment and vaccineadministration, if possible (for example, at least 
2 days, preferably 7 days apart), given that adverse events related to vaccine 
administration may confound potential study treatment infusion reactions.

SARS-CoV-2 may have short- and long-term impact on the study population, which 
may affect the safety profile and outcome of investigational products. Thus, serologic 
testing will be implemented at screening, during study treatment, after a documented 
 
 
 
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or suspected SARS-CoV-2
infection,
and
at
follow-up for potential future 
measurements of anti-SARS-CoV-2 serology.

Dose delay and criteria to resume study treatment in cases when a subject develops
confirmed or suspected SARS-CoV-2 is included in Section 7.4.5 of the protocol.
It is important to acknowledge the widespread impact of SARS-CoV-2 and the potential risks 
SARS-CoV-2 may have on this study population. However, there are limited treatment options 
available to individuals with advanced lung cancer who have a poor prognosis and few, if any, 
curative options. The absence of other available treatments supports the urgent need to develop 
therapeutic options for these serious diseases while not negating the implementation of mitigation
measures to protect the safety of the study population.
 
 
 
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CONCLUSIONS
This protocol amendment 3, is being done to modify the survival follow-up period by removing 
the up to 2-year duration and adding in that survival follow-up the 100-day safety follow-up visit 
of the last subject on study 
Refer to the protocol for complete detailed changes.
The LSD-1 inhibition could prove to have a role in treating tumors resistant to current immune 
check-point blockade. CC-90011 has the potential to mitigate primary and acquired resistance to 
ICI, due to its expected reversal of the CSC phenotype and T cell exclusion in SCLC and 
sqNSCLC.
This multi-cohort lung cancer study will evaluate the ability of CC-90011 to increase response 
rates in 3 different lung cancer populations: PD-1 inhibitor naïve (Cohort A, SCLC) and a PD-1 
inhibitor “experienced” (Cohort B, SCLC; and Cohort C, sqNSCLC) when given in combination 
with nivolumab. 
Nivolumab is associated with immune-mediated adverse events. CC-90011 has mainly 
haematologic toxicities and has not been associated with immune mediated adverse events. During 
the conduct of this study we will be carefully monitoring the combined safety profile and how it 
may differ from the known monotherapy safety profiles.
Subject enrollment into this study will be evaluated with strict exclusion and inclusion criteria. 
Subjects will be monitored for possible toxicity through laboratory tests including haematology 
panel and chemistry panel in accordance with the schedule described in the protocol. The protocol 
provides detailed guidance on dose adjustments of study treatments for treatment related toxicities. 
Ongoing safety evaluation will be conducted and stopping criteria are defined in the protocol.
The risk-benefit assessment to support the use of the combination of CC-90011 and nivolumab in 
patients considers the potential adverse effects of the drug and its potential benefit to the patients. 
The safety profiles seen with CC-90011 and nivolumab are clinically manageable and appropriate 
measures to monitor and treat any expected safety events, as well as guidance to manage SARS-
CoV-2/ COVID-19, have been incorporated into the protocol. Therefore, the combination of CC-
90011 and nivolumab has an acceptable risk-benefit profile and supports the development in 
patients with advanced cancers.
 
 
 
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5
REFERENCES
Refer to the CC-90011 IB, nivolumab IB and study protocol for the full list of references.
Opdivo ® (nivolumab) [Summary of Product Characteristics]. Ireland: Bristol-Myers Squibb 
Pharma EEIG; 2015. https://www.ema.europa.eu/en/documents/product-information/opdivo-
epar-product-information_en.pdf. Accessed September 23, 2020
 
 
 
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EDMS Doc. Number: 25438971 - 24928712
CC-90011
Summary of Changes CC-90011-ST-002
Celgene Corporation
Confidential and Proprietary
3
CC-90011-ST-002 Amendment #2 Final: 02 Mar 2021
1.
JUSTIFICATION FOR AMENDMENT
The primary purpose of this protocol amendment is to include a risk benefit assessment and 
additional language for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2)/coronavirus-19 (COVID-19), as well as to update nivolumab guidance for male contraception 
and update adverse event management algorithms based on the nivolumab Investigator’s 
Brochure (IB) version 19 addendum 01 and to extend pharmacokinetics and immunogenicity 
collection to all cohorts. 
Significant changes included in this amendment are summarized below:

SARS-CoV-2/COVID-19
In 2019, a new coronavirus was identified as the cause of a widespread disease outbreak. As a 
result, health authorities, including the European Medicines Agency (EMA) have issued 
guidance on the management of clinical trials during the COVID-19 pandemic. In consideration 
of this guidance, the safety of study subjects and risks of involvement particularly in the times of 
COVID-19 was assessed against the anticipated benefit of study treatment, and additional 
measures to mitigate the risk have been incorporated in this amendment.

Added Section 1.3.4 Benefit/Risk Assessment Due to SARS-CoV-2/COVID-19 
infection to follow EMA guidance as referenced above.

An additional Exploratory Objective and Study Endpoint to assess the impact of 
SARS-CoV-2 serologic status on subjects and to support health authority 
requests. Exploratory Endpoints will include measurements of SARS-CoV-2 
serology (anti-SARS-CoV-2 total or immunoglobulin G [IgG]) and the potential 
association between these measurements and selected endpoints related to safety, 
efficacy, and/or biomarkers. To support this exploratory analysis, SARS-CoV-2 
serology will be taken at screening, every 6 months during study treatment, 
approximately 4 weeks after a documented or suspected SARS-CoV-2 infection, 
and at follow-up. These collection timepoints are outlined in Table 6 and Table 
10, and an additional footnote has been added to the tables for clarification.

The Exclusion Criteria has been updated to include SARS-CoV-2/COVID-19 
relevant information. Exclusion criterion 2 and 21 have been removed and 
condensed into Exclusion Criterion 1 to reduce redundancies and increase 
readability; Exclusion Criterion 22 and 23 have been added.
1. Subject has any significant medical condition, including active or uncontrolled 
infection, or the presence of laboratory abnormalities, or psychiatric illness 
which places the subject at unacceptable risk if he/she were to participate in 
the study.
22. Subject who is currently in other interventional trials, including those for 
COVID-19, may not participate in Bristol Myers Squibb (BMS) or Celgene 
Corporation clinical trials until the protocol specific washout period is 
achieved. If a study subject has received an investigational COVID-19 
vaccine or other investigational product designed to treat or prevent COVID-
19 prior to screening, enrollment must be delayed until the biologic impact of 
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CC-90011
Summary of Changes CC-90011-ST-002
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CC-90011-ST-002 Amendment #2 Final: 02 Mar 2021
the vaccine or investigational product is stabilized, as determined by 
discussion between the Investigator and the Medical Monitor.
23. Previous SARS-CoV-2 infection either suspected or confirmed within 4 
weeks prior to screening.
a.
Acute symptoms must have resolved and based on investigator assessment 
in consultation with the Medical Monitor, there are no sequelae that would 
place the subject at a higher risk of receiving investigational treatment.

Sections 6.1.1 Resting During Screening Period and 7.4.5 Dose Delay and 
Criteria to Resume in Case of SARS-CoV-2 Infection have been added to address 
the criteria a subject needs to meet to continue study and/or treatment when there 
is a confirmed or suspected SARS-CoV-2 infection.

Additional guidance has been added in Section 8.2 Permitted Concomitant 
Medications and Procedures regarding COVID-19 vaccines and administration.

Added language in Section 5 Table of Events and 10.2.6 Outcome to reinforce the 
continuous monitoring and reporting of adverse events, including serious and 
non-serious, associated with confirmed or suspected SARS-CoV-2 infection.
Revised sections: Protocol Summary, Section 1.3.4 (added, Benefit/Risk Assessment Due to 
SARS-CoV-2/COVID-19 Infection), Section 2 (Study Objectives and Endpoints), Section 4.3 
(Exclusion Criteria), Section 5 (Table of Events), Section 6 (Procedures), Section 6.1.1 (added, 
Retesting During Screening Period), Section 6.7.1 (added, Other Assessment), Table 10 (added, 
SARS-CoV-2 Samples Schedule), Section 7.4.5 (Dose Delay and Criteria to Resume in Case of 
SARS-CoV-2 Infection), Section 8.2 (Permitted Concomitant Medications and Procedures), 
Section 10.2.6 (Outcome).

Nivolumab Guidance for Male Contraception and Adverse Event Management 
Algorithms per Nivolumab IB Version 19 Addendum 01
The nivolumab IB version 19 addendum 01 includes adverse event management algorithms 
based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
version 5.0 (NCI CTCAE v5.0) and the removal of male contraception language after last dose 
of nivolumab. The protocol has been revised to align with this updated language and guidance.
Revised sections: Section 4.2 (Inclusion Criterion Number 11), Section 7.4.3 (Criteria for 
Nivolumab Dose Management), Table 14 and footnotes (Recommended Treatment 
Modifications for Nivolumab), Appendix F (Nivolumab Management Algorithms).

Addition of Pharmacokinetics and Immunogenicity Sample Collection for Nivolumab 
in all 3 Cohorts
The emerging platelet (safety) profile of CC-90011 and nivolumab combination and decision to 
proceed at a reduced dose of CC-90011 supports assessment of benefit/risk from the perspective 
of population pharmacokinetics (PK) and exposure-response relationship with the safety and 
efficacy endpoints for the combination treatment. From available data thus far, it appears that 
there is some synergistic thrombocytopenia at precedented exposures of CC-90011; thus, having 
a composite exposure-response model for this combination will help to better characterize the 
overall thrombocytopenia profile. Currently, protocol amendment 1 collects nivolumab 
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EDMS Doc. Number: 25438971 - 24928712
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Summary of Changes CC-90011-ST-002
Celgene Corporation
Confidential and Proprietary
5
CC-90011-ST-002 Amendment #2 Final: 02 Mar 2021
immunogenicity (IMG) samples from Cohort C at the scheduled timepoints: Cycle 1 Day 1 pre-
dose, Cycle 2 Day 1 pre-dose, Cycle 3 Day 1 pre-dose, and Every 4th cycle after Cycle 3 Day 1 
pre-dose. In this amendment, both PK and IMG sample collections for nivolumab at the 
previously scheduled time points will be added and extended to all 3 cohorts.
Revised sections: Protocol Summary (Exploratory Objective), Section 2 (Study Objectives and 
Endpoints), Section 5 (Table of Events), Section 6.2 (Treatment Period), Section 6.5.1 
(Collection of Blood Samples for Nivolumab Pharmacokinetics and Immunogenicity).
The amendment also includes other clarifications and administrative changes:

Removal of Medical Monitor address

Update in Section 1.2.5 to align with CC-90011 IB edition 6.0.

Update in Section 1.2.6.1 to align with current version of Nivolumab Essentials
Protocol Elements

Update in Section 7.2.1 and 8.1 to include caution of avoiding grapefruit juice during 
study treatment.

Update in Table 5 footnote and Section 7.2.2 to clarify nivolumab dosing window.

Update in Section 15.1 to clarify that monitoring can include on-site or remote visits.

Update in Section 15.3 to align with updated Sponsor guidance on Investigational 
Medicinal Product Quality Complaint reporting.

Minor formatting, editorial changes and corrections throughout.
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EDMS Doc. Number: 24928566 - 24928712
CC-90011
Summary of Changes Protocol CC-90011-ST-002
Celgene Corporation
Confidential and Proprietary
3
CC-90011-ST-002 Amendment 1 Final: 21 Sep 2020
1.
JUSTIFICATION FOR AMENDMENT
The primary purpose of this protocol amendment is to address the 2 serious adverse events
(SAEs) reported in the first two subjects treated in Study CC-90011-ST-002, and the resulting 
implementation to reduce the starting dose of CC-90011 to 40 mg. Implementation of this dose 
reduction was communicated to all participating sites through an administrative letter on 18 Aug 
2020. This dose reduction is consistent with Protocol CC-90011-ST-002 language in Section 
7.3.2 and the 2 SAEs of Grade 4 thrombocytopenia are consistent with the known safety profile 
of CC-90011. Therefore, the implementation of this dose reduction is not considered an urgent 
safety measure. The protocol is also being amended for other topics, clarifications, and 
administrative changes and are summarized below.
Significant changes included in this amendment are summarized below:

Reduction of CC-90011 Starting Dose to 40 mg
Two SAEs of Grade 4 thrombocytopenia were reported in the first 2 subjects in this ongoing 
Study CC-90011-ST-002. On 14 Aug 2020, Celgene reviewed the 2 SAEs with the treating 
Investigator, the Steering Committee, and the Medical Monitor. On Cycle 1 Day 1 (C1D1), both
subjects, who are also from the same site, received their first dose of CC-90011 60 mg and 
nivolumab 480 mg, and on C1D8, they received their second dose of CC-90011 60 mg. Both 
subjects were treated with prior chemotherapy, and followed a similar course, with normal 
platelet count at baseline and a decrease in platelet count (within normal protocol limits) at 
C1D8. On C1D15, both subjects were diagnosed with Grade 4 thrombocytopenia for which they 
were hospitalized and have since recovered. Both subjects received platelet transfusions and 
demonstrated an increase in platelet count over the course of a week. The events were assessed 
by the Investigator as related to CC-90011. Per protocol, study treatment was resumed upon 
resolution of the events with a dose reduction of CC-90011 to 40 mg. Thrombocytopenia 
occurred in both subjects around C1D15 and were consistent with observations from the early 
CC-90011 monotherapy studies. 
As a result of the first 2 subjects developing Grade 4 thrombocytopenia, which both followed a 
similar course, Celgene in agreement with the Steering Committee concluded that new subjects 
enrolled in Study CC-90011-ST-002 will receive CC-90011 at a reduced starting dose of 40 mg
unless otherwise determined during the ongoing safety evaluation in Section 7.3.1.1. The dose of 
nivolumab will remain at 480 mg. 
Revised sections: Section 1.2.5.1.3 (added, Study CC-90011-ST-002), Sections 7.3.1.1 (added, 
Safety Evaluation for CC-90011 Starting Dose of 40 mg)

Safety Evaluation for CC-90011 Starting Dose of 40 mg
The same stopping criteria as specified in Sections 7.3.1 and 7.3.2 will be applied to the reduced 
starting dose of 40 mg. To further evaluate if the recommended phase 2 dose of CC-90011 60 mg 
as established in the first-in-human study can be safely administered and in order to maximize 
the potential efficacy of CC-90011 and level of target engagement (see first-in-human data, 
Figure 2), re-escalation to 60 mg may be considered after review of the overall data and 
AEs/SAEs by the Sponsor in agreement with the Steering Committee. Specifically, if in the first 
2 cycles, there are no reports of Grade 4 thrombocytopenia or Grade 3 or 4 neutropenia, in any of 
the 6 subsequent subjects (without distinction of cohorts) who received 40 mg, then re-escalation 
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EDMS Doc. Number: 24928566 - 24928712
CC-90011
Summary of Changes Protocol CC-90011-ST-002
Celgene Corporation
Confidential and Proprietary
4
CC-90011-ST-002 Amendment 1 Final: 21 Sep 2020
of the starting dose to 60 mg for subsequent subjects may be considered. The decision to re-
escalate the starting dose to 60 mg will be determined by the Sponsor in agreement with the 
Steering Committee. 
If the starting dose is re-escalated to 60 mg, an additional 4 subjects (without distinction of 
cohorts) will be treated so that 6 subjects in total (including the 2 subjects in which Grade 4 
thrombocytopenia [n=2]and Grade 3 neutropenia [n=1] was reported) will have received 60 mg. 
There will be staggered dosing, where the second subject to receive 60 mg will not be dosed until 
at least 15 days after the first subject has been treated and safety has been reviewed. This sentinel 
dosing scheme may or may not be continued for the rest of the 60 mg subjects, depending on the 
findings in the first subject and the overall safety profile to date.  
The stopping criteria in Sections 7.3.1 and 7.3.2 will be applied to these 6 subjects. Therefore, if 
in the first 2 cycles, there are no reports of Grade 4 thrombocytopenia and 1 or less reports of 
Grade 3 or 4 neutropenia, in any of the 4 subsequent subjects who received 60 mg, then 60 mg 
will be declared as the starting dose of CC-90011 and the dose to continue with in this study. If 
in the first 2 cycles, there is at least 1 report of Grade 4 thrombocytopenia or at least 2 reports of 
Grade 3 or 4 neutropenia, in any of the 4 subsequent subjects who received 60 mg, then 40 mg 
will be declared as the starting dose of CC-90011 and the dose to continue with in the study.
Revised sections: Section 7.3.1 (Initial Safety Evaluation), Section 7.3.1.1 (added, Safety 
Evaluation for CC-90011 Starting Dose of 40 mg)

Addition of Blood Samples Collection for Assessment of Nivolumab 
Immunogenicity (only applicable to Cohort C, squamous non-small cell lung 
cancer)
Blood samples will be collected to measure immunogenicity of nivolumab in squamous non-
small cell lung cancer subjects (NSCLC) to assess the prevalence of anti-nivolumab antibodies 
(ADA) in this cohort of subjects. Samples will be collected pre-dose on the following visits: 
Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, and Day 1 of every 4th cycle after Cycle 3. The 
assessment of nivolumab immunogenicity in this cohort of subjects is added as an exploratory 
objective. Collection of nivolumab ADA blood samples will enable exploration of nivolumab 
ADA incidence rate, and its potential impact on selected efficacy and safety endpoints, in the 
comibation with CC-90011, as mentioned in the protocol. Nivolumab ADA incidence in 
combination with ipilimumab is higher in NSCLC compared to nivolumab monotherapy, with 
~40% versus 10%, respectively (CA209-227 Clinical Study Report; CA209-9LA Clinical Study 
Report). The nivolumab ADA incidence rate is unknown in combination with CC-90011. As 
such, these data will help to further characterize nivolumab immunogenicity in NSCLC. 
Revised sections: Protocol Summary, Section 2 (Study Objectives and Endpoints), Section 5 
(Table of Events), Section 6.5.1 (added, Collection of Blood Samples for Nivolumab 
Immunogenicity), Section 9.9.4 (Pharmacokinetic Analysis)
 
 
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EDMS Doc. Number: 24928566 - 24928712
CC-90011
Summary of Changes Protocol CC-90011-ST-002
Celgene Corporation
Confidential and Proprietary
5
CC-90011-ST-002 Amendment 1 Final: 21 Sep 2020
 
 

Removal of Preliminary Efficacy by imRECIST as an Exploratory Endpoint and 
Objective
The exploratory objective to assess the preliminary efficacy of CC-90011 in combination with 
nivolumab based on Investigator assessed immune modified Response Evaluation Criteria in 
Solid Tumors (imRECIST) has been removed. This method of assessment is not yet thoroughly 
validated or established in the clinical setting. Furthermore, this study has a small sample size 
and therefore this endpoint would not provide additional value.
Revised sections: Protocol Summary, Section 2 (Study Objectives and Endpoints), Section 6.4 
(Efficacy Assessment)

Addition of Time to Response and Time to First Subsequent Therapy as 
Secondary Endpoints and Objectives and Addition of Disease Control Rate at 12 
weeks as an Exploratory Endpoint and Objective
To further support the primary and secondary objectives in the original protocol, time to 
response and time to first subsequent therapy were added as secondary endpoints and disease 
control rate as an exploratory endpoint. Time to response, time to first subsequent therapy and 
disease control rate will provide important context to the primary endpoint, overall response rate 
and the secondary endpoint of overall survival across the three different cohorts. Additionally, 
considering the mechanism of action of CC-90011 and the proposed mechanism of CC-90011 in 
combination with nivolumab, time to response and disease control rate may be worthwhile to 
explore and will provide information that could guide future studies with this combination.
Revised sections: Protocol Summary, Section 2 (Study Objectives and Endpoints), Section 9.6 
(Efficacy Analysis)
This amendment also includes other minor changes that are clarifications to existing 
information and/or corrections of some inadvertently inaccurate statements:

Update of Medical Monitor email address.

Change of Celgene Therapeutic Area Head.

Update of Section 1.2.5 to align with CC-90011 Investigator’s Brochure (IB) Edition 
5.

Update in Sections 2, 9.6.2, and 9.7 to remove physical exam from safety assessment
analysis.

Clarification of language in Protocol Summary, Sections 3.1 and 7.2.1 to reflect the 
CC-90011 dose that subjects will be receiving.

Correction in Exclusion Criteria 16b to clarify that adrenal replacement steroid doses 
> 10 mg daily prednisone or equivalent are permitted in the absence of active 
autoimmune disease, in alignment with Section 8.1.
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EDMS Doc. Number: 24928566 - 24928712
CC-90011
Summary of Changes Protocol CC-90011-ST-002
Celgene Corporation
Confidential and Proprietary
6
CC-90011-ST-002 Amendment 1 Final: 21 Sep 2020

 

Addition of footnote to Table 6 to clarify nivolumab dosing window.

Update of language in Section 6.2 to clarify that on-treatment vital signs will be 
source documented and collected in the electronic case report form.

Update of language in Section 6.3.1 to clarify that adverse event evaluation for 
nivolumab should include assessment by the Investigator regarding whether it is 
considered immune-mediated.

Addition of language in Section 6.4 to clarify that all subjects with evidence of tumor 
response (complete response or partial response) should have the response confirmed 
with repeat assessments at the next scheduled scan, but no less than 4 weeks after 
initial response.

Update in Section 6.4.1 to the treatment beyond progression timepoint of a follow-up 
scan to 6-8 weeks of the original progression of disease in accordance to the original 
protocol schedule of tumor assessments.

Clarification of language in Section 6.5 regarding the pharmacokinetic blood sample 
collection timepoints to be in relation to CC-90011 dose.

Addition of footnote language to Table 8 to clarify that triplicate electrocardiogram
(ECG) should be done within 2 minutes at each nominal timepoint.
 
 

Clarification in Section 7.3.2 regarding communication to regulatory authorities.

Update in Table 10 and Section 7.4.2 to clarify permitted CC-90011 dose reductions 
and adjustments.

Addition of language in Section 7.4.3 to include consultation with the Medical 
Monitor (or designee) regarding re-initiating nivolumab treatment in a subject with a 
dosing delay lasting > 10 weeks.

Clarification in Section 7.4.3 that adverse event management of nivolumab should 
follow Common Terminology Criteria for Adverse Events (CTCAE) version 4 in 
alignment with the current nivolumab Investigator Brochure.

Correction of language in Section 7.5 regarding subject assignment number.

Update in Section 9.2.1 to the definition of Enrolled Population, which will consist of 
all subjects who signed the informed consent form and obtained a subject number.

Minor formatting and editorial changes and corrections throughout.
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