Clinical trial NCT02281084
Conditions: Myelodysplastic Syndromes
Keywords: Keywords provided by Celgene: myelodysplastic syndromes MDS azacitidine oral azacitidine (CC-486) decitabine intermediate-1 intermediate-2 and high risk myelodysplastic syndromes (MDS) proliferative chronic myelomonocytic leukemia (CMML) Chronic iHMA (injectable hypomethylating agents) PD-L1
Sponsor: Celgene
Start date: 2015-07-06; Completion date: 2023-09-14
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluate the safety and efficacy of oral azacitidne (CC-486) twice daily (BID) in subjects with myelodysplastic syndromes who failed to achieve an objective response post injectable hypomethylating agent (iHMA) treatment

Reason for removing the combination arm: Due to difficulties with dose-finding, the durvalumab plus CC-486 combination arm was closed to enrollment.

Extension:

An Extension Phase (EP) has been added to allow subjects who are currently receiving oral azacitidine BID and who are demonstrating clinical benefit as assessed by the Investigator, to continue receiving oral azacitidine until the subject meets the criteria for study discontinuation.

Detailed description:

Arms: arm 1: Oral azacitidine (AZA) 100 mg, 150 mg, or 200 mg tablets twice daily (BID) on days 1 to 21 of each 28-day treatment cycle. Participants continued to receive their assigned study treatment unless disease progression, unacceptable toxicity, lost to follow-up or withdrawal by participant occurred. arm 2: Oral Azacitidine 100 mg oral azacitidine tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab 1500 mg by intravenous (IV) infusion on day 1 of each 28-day treatment cycle; participants continued to receive their assigned study treatment unless disease progression, unacceptable toxicity, lost to follow-up or withdrawal by participant occurred.
Interventions: intervention 1: Oral Azacitidine intervention 2: Durvalumab
Intervention descriptions: intervention 1: Oral azacitidine (AZA) 100 mg, 150 mg, or 200 mg tablets twice daily (BID) on days 1 to 21 of each 28-day treatment cycle. Participants continued to receive their assigned study treatment unless disease progression, unacceptable toxicity, lost to follow-up or withdrawal by participant occurred. intervention 2: Durvalumab 1500 mg by IV infusion on Day 1 of each 28 day treatment cycle.

Protocol documents:
Prot_000.pdf: 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
1
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
TITLE PAGE
A PHASE 2, INTERNATIONAL, MULTICENTER, 
RANDOMIZED, OPEN-LABEL, PARALLEL GROUP
STUDY TO EVALUATE THE EFFICACY AND SAFETY 
OF CC-486 (ORAL AZACITIDINE) ALONE AND IN 
COMBINATION WITH DURVALUMAB (MEDI4736) IN 
SUBJECTS WITH MYELODYSPLASTIC SYNDROMES
WHO FAIL TO ACHIEVE AN OBJECTIVE RESPONSE 
TO TREATMENT WITH AZACITIDINE FOR
INJECTION OR DECITABINE
INVESTIGATIONAL PRODUCT (IP):
CC-486 (oral azacitidine)
Durvalumab (MEDI4736)
PROTOCOL NUMBER:
CC-486-MDS-006
DATE FINAL:
30 Jun 2014
DATE AMENDMENT #1.0 FINAL
08 Sep 2015
DATE AMENDMENT #2.0 FINAL
27 Mar 2017
DATE AMENDMENT #3.0 FINAL
28 Dec 2017
DATE AMENDMENT #4.0 FINAL
17 Jun 2019
EudraCT NUMBER:
2014-002675-29
IND NUMBER:
074618 
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
2
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
 
Title:
Address: 
86 Morris Avenue
Summit, NJ 07901
Phone:
E-mail:
Note: The back-up 24 hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24 Hour Global Emergency Contact Call Center: 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
3
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
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Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
4
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
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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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
5
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
6
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
PROTOCOL SUMMARY
Study Title
A Phase 2, International, Multicenter, Randomized, Open-label, Parallel Group Study to 
Evaluate the Efficacy and Safety of CC-486 (oral azacitidine) Alone and in Combination With 
Durvalumab (MEDI4736) in Subjects With Myelodysplastic Syndromes Who Fail to Achieve an 
Objective Response to Treatment With Azacitidine for Injection or Decitabine
Indication
The treatment of myelodysplastic syndromes (MDS) not responding to prior treatment with 
azacitidine for injection or decitabine.
Objectives
Primary Objective
The primary objective of this study is to investigate the efficacy of CC-486 as monotherapy, 
and in combination with anti-PD-L1 monoclonal antibody, durvalumab (MEDI4736), in 
subjects with MDS that did not respond to treatment with an injectable hypomethylating 
agent (HMA – azacitidine for injection or decitabine), or were unable to tolerate treatment 
with an injectable HMA.
Secondary Objectives
!
Assess the safety and tolerability of CC-486 alone and in combination with 
durvalumab, as treatment for MDS
!
Describe the clinical relevance of objective hematologic and/or biologic responses 
associated with treatment with CC-486 alone and in combination with durvalumab
!
Evaluate the impact (if any) of durvalumab on the pharmacokinetics of CC-486 and 
CC-486 on durvalumab in subjects with MDS
 
 
 
 
Study Design
This is a Phase 2, international, multicenter, randomized, parallel group, open-label study 
consisting of: Screening, Safety run-in, Randomized Treatment, Follow-up, and Extension Phase.  
The randomized portion of the study will be preceded by a non-randomized safety run-in to 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
7
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
evaluate the safety and tolerability of the planned regimens, and to determine the recommended 
dose for the monotherapy and combination therapy arms for the randomized phase.
The safety run-in will utilize a 3+3 design to include at least 3 subjects treated with monotherapy 
at the dose and schedule expected to be used in combination, as well as at least 3 subjects treated 
with combination therapy to evaluate safety and tolerability. The monotherapy arm will be 
enrolled first to confirm the expected safety profile of CC-486 alone at the planned dose and 
schedule in the target population. 
Data from the safety run-in will be reviewed in conjunction with the study investigators, 
Scientific Steering Committee, and Data Monitoring Committee to ensure agreement with the 
recommended Phase 2 dosing regimens prior to beginning enrollment to the randomized 
treatment phase.
The randomized treatment phase will be conducted in 2 stages, with a futility assessment planned 
at the completion of Stage 1 to determine whether the null hypothesis (H0: p <12.5%) can be 
rejected with 3 or more responses in Stage 1. If 3 or more responses have been observed before 
the end of Stage 1, the planned futility assessment may be performed earlier than at the 
completion of Stage 1 to confirm the finding of responses. This earlier analysis will replace the 
futility analysis planned at the completion of Stage 1. This earlier futility assessment will have 
the same integrity as the futility assessment planned at the completion of Stage 1. An analysis 
will be performed at the completion of Stage 2 to estimate the overall response rate of treatment 
of all the subjects in the cohort.  All subjects who receive investigational product (IP) in this 
study will continue to be followed for information related to post-treatment safety and 
subsequent MDS therapies, as described in Section 4.1.5.
Approximately 10-12 evaluable subjects randomized to the combination treatment arm at 
selected study centers will participate in PK sampling procedures as described in Section 6.10.
Extension Phase
At the Investigator’s discretion and following confirmation of eligibility criteria below, subjects 
can enter the Extension Phase (EP):
Eligibility Criteria:
!
Subjects who have signed the informed consent for the EP of the study;
!
Subjects receiving oral azacitidine and continuing in the Treatment Phase 
demonstrating clinical benefit as assessed by the Investigator are eligible to receive 
oral azacitidine in the EP;
!
Subjects who do not meet any of the criteria for study discontinuation (see 
Section 12).
Details for the EP are provided in Appendix J.
The study design is described in detail in Section 4.1.
Study Population
The study will enroll at least 70 to 194 evaluable subjects with MDS who did not respond to an 
adequate course of therapy with an injectable hypomethylating agent (iHMA – azacitidine for 
injection or decitabine) as their last treatment for MDS, or who were unable to tolerate an iHMA 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
8
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
following at least 3 months of attempted treatment. Complete inclusion and exclusion criteria 
for this study, including the definition of an adequate course of therapy, and required parameters 
for hematology, performance status, renal and hepatic function are detailed in Section 7.
At least 3 subjects will be enrolled in each of two treatment groups (monotherapy and 
combination therapy) during the safety run-in phase of the study: The monotherapy treatment 
group will be enrolled first and evaluated for dose-limiting toxicity (Section 4.1.2.1), prior to 
selecting a CC-486 dose and regimen, and initiating enrollment for the combination treatment 
group. Progressive disease (PD) and stable disease (SD) designations are made based on the 
subject’s best response to iHMA therapy determined at the start of the study (see Section 4.1).
A total number of 64 evaluable subjects will be enrolled equally during the first stage of the 
randomized treatment phase into 4 cohorts:  SD monotherapy, PD monotherapy, SD combination 
therapy, and PD combination therapy.  If the required number of objective responses are 
observed in a cohort, the cohort will be continued into the second stage of study to include 25 
more subjects (see Section 4.1, Section 10.3, and Figure 2).
The study is closed to further enrollment with the last subject enrolled in June 2018. A total of 65 
subjects were enrolled in the study. At the time of this amendment, 6 subjects are ongoing in the 
Monotherapy SD/PD cohorts (One subject from Phase 1, and 5 from Phase 2).
Length of Study
The total duration of this study is expected to be approximately 75 months (see Section 4.3).  
Subjects will undergo screening procedures over a period of up to 28 days following the signing 
of their informed consent document (ICD).  Eligible subjects will continue to the safety run-in or 
the randomized treatment phase of the study where they will receive IP for up to six 28-day 
treatment cycles.  Those who derive benefit from the treatment may continue IP until loss of that 
benefit (Section 4.1.3). 
After treatment discontinuation, subjects will be followed for 28 days for CC-486 safety-related
issues and 90 days for durvalumab safety-related issues. After that, subjects will be contacted by 
telephone every 3 months in the follow-up phase of the study.  
The enrollment period for this study is expected to last approximately 39 months.  The treatment 
and follow-up periods are expected to conclude approximately 12 months after the last subject is 
enrolled.  The Extension Phase is expected to last approximately 24 months. Therefore, the total 
duration of the study is expected to be approximately 75 months.  
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the 
Statistical Analysis Plan (SAP), whichever is the later date.
The study will conclude once all subjects have completed or discontinued from the Extension 
Phase. 
Study Treatment (Investigational Product – IP)
CC-486 (Oral Azacitidine)
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
9
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Eligible subjects who are assigned to the monotherapy treatment arm will receive CC-486 at the 
dose and schedule identified during the safety run-in phase of the study.  Dose and schedule 
may be reduced to manage toxicity or increased as described in Section 8.2. Subjects can 
continue treatment with CC-486 as long as all protocol-specified re-treatment criteria continue to 
be met (see Section 8.2.5).  
Durvalumab (MEDI4736)
Eligible subjects who are assigned to the combination therapy treatment arm will receive CC-486 
as described above, and durvalumab 1500 mg on Day 1 of each 28-day treatment cycle by 1-hour 
(± 5 minutes) intravenous (IV) infusion.  For toxicity considered by the investigator to be related 
to treatment with durvalumab, including immune-mediated adverse events (imAEs) or infusion-
type reactions, the infusion of durvalumab may be slowed, interrupted, or discontinued as 
described in Section 8.2.4.2.  Dose reduction for durvalumab is not permitted. Subjects can 
continue treatment with durvalumab in combination with CC-486 as long as all protocol-
specified re-treatment criteria continue to be met (see Section 8.2.5). 
Overview of Efficacy Assessments
The primary efficacy endpoint of this trial is the proportion of subjects achieving an objective 
response (hematologic improvement (HI), partial remission (PR), complete remission (CR), or 
marrow CR – modified from International Working Group (IWG) 2006 criteria – Appendix F) to 
treatment with CC-486 alone and in combination with durvalumab.  To assess this endpoint, 
bone marrow examination will be required prior to beginning IP and following every 2 cycles of 
treatment during the first 6 treatment cycles.  Subjects who continue beyond Cycle 6 will 
undergo bone marrow examination following every 3 treatment cycles or when necessary to 
confirm suspected hematologic response or disease progression.  Bone marrow samples (aspirate 
and/or biopsy), along with a peripheral blood smear and pertinent clinical information will be 
submitted for review by an independent pathologist to provide consistency in determinations of 
disease classification, response, and/or progression.  
Hematologic parameters including complete blood count (CBC) with white blood cell (WBC) 
differential and platelets will be assessed by the central laboratory at the frequency described in 
the Table of Events (Table 2) and Section 6.7.7.
To understand the potential impact of any immunogenic response to durvalumab on the efficacy 
of the treatment, immunogenicity assessment will be performed at the frequency described in the 
Table of Events (Table 2).
Overview of Safety Assessments
!
Adverse events (AEs) including adverse events of special interest (AESIs) (please 
refer to the Durvalumab Investigator’s Brochure; Section 5.4.2 Summary of Risks). 
!
physical examination
!
vital signs and body weight measurement
!
Eastern Cooperative Oncology Group (ECOG) performance status
!
hematology (CBC with differential and platelets)
!
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
10
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
serum chemistry (to include amylase and lipase) and thyroid function tests
!
concomitant medications, therapies, and procedures
!
pregnancy testing (for females of childbearing potential [FCBP] only)
!
electrocardiogram
!
urinalysis 
 
 
 
 
 
 
 
 
 
 
Overview of Pharmacokinetics Assessments
Blood samples for pharmacokinetic analysis will be collected from approximately 10-12
evaluable subjects randomized to the combination treatment arm at selected sites.  This will 
enable assessment of drug-drug interactions.  Subjects participating in PK procedures will agree 
to have blood samples collected as described in Section 6.10.
Sample Size Determination and Statistical Analysis (Randomized Treatment Phase)
The sample size required will be identical for each cohort and is estimated using the optimal 
design of the Simon's two-stage design method (Simon, 1989). The null hypothesis of the
response rate will be tested against a one-sided alternative. 
For each cohort, the null hypothesis of response rate (H0: p ≤ 0.125) will be tested against the 
alternative hypothesis of response rate (H1: p ≥ 0.27) with a type I error rate of 10% and 80% 
power. During the first stage, 16 subjects will be accrued per cohort. If there are 2 or fewer 
responses in these 16 subjects, the cohort will be stopped and no further recruitment will be 
needed. Otherwise, 25 additional subjects will be accrued per cohort for a total of 41 subjects in 
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52


EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
11
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
each cohort. If 8 or more responses are observed in these 41 subjects, the null hypothesis will be 
rejected. 
For each cohort, in addition to the evaluation of treatment responses based on objective response 
criteria, the quality of responses will also be considered for the decision whether to continue the 
cohort to the second stage of the study. Quality of response will be assessed based on the 
magnitude of hematologic and biologic responses observed in individual subjects, with special 
consideration for response duration, and will be specified with more details in the final SAP.
For the primary objective, the response rate at the end of Stage 2 and the associated 95% 
confidence interval will be estimated for each cohort which completes Stage 2. Similar estimates 
for Stage 1 will be provided for any cohort which does not continue to Stage 2. The response 
rates at the end of Stage 2 will be compared between cohorts of SD and PD subjects (if both 
cohorts finished Stage 2) using the relative risk ratio or other appropriate methods. Specifically, 
if relative risk method is used, the ratio of response rates for both cohorts and the associated 95% 
confidence interval will be estimated. Description of methodologies will also be provided in the 
SAP if other methods are used.
For the secondary objectives, Kaplan-Meier’s method will be used to analyze the time-to-event 
variables, which include overall survival, time to response, duration of response, and time to 
disease progression. The safety and tolerability of the regimen in this sample of subjects will be 
estimated and the corresponding 95% confidence intervals will be estimated.
An Independent Data Monitoring Committee will review the safety data during the safety run-in 
phase. The committee will also review the efficacy and safety data during the randomized phase 
of the study, in addition to the recommendation for any cohort to continue to Stage 2 of the 
study. The details of the data monitoring plan will be provided in a separate charter document.
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
12
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................21
1.1.
Myelodysplastic Syndromes ...................................................................................21
1.2.
CC-486 (Azacitidine)..............................................................................................22
1.3.
Durvalumab (MEDI4736).......................................................................................24
1.3.1.
Durvalumab Experience in Solid Tumors................................................................24
1.4.
Study Rationale ......................................................................................................27
1.4.1.
Azacitidine Exposure..............................................................................................27
1.4.2.
Cancer and Immune Function .................................................................................29
1.4.3.
Immune-checkpoint Inhibition................................................................................29
1.4.5.
Rationale for Durvalumab Fixed Dosing Regimen..................................................31
2.
STUDY OBJECTIVES...........................................................................................33
2.1.
Primary Objective...................................................................................................33
2.2.
Secondary Objectives .............................................................................................33
3.
STUDY ENDPOINTS............................................................................................34
3.1.
Primary Endpoint....................................................................................................34
3.2.
Secondary Endpoint(s)............................................................................................34
4.
OVERALL STUDY DESIGN ................................................................................36
4.1.
Study Design ..........................................................................................................36
4.1.1.
Screening Phase......................................................................................................38
4.1.2.
Safety Run-in..........................................................................................................38
4.1.2.1.
CC-486 Monotherapy Dose-Limiting Toxicity........................................................40
4.1.2.2.
Durvalumab / CC-486 Combination Therapy Dose-Limiting Toxicity ....................41
4.1.3.
Randomized Treatment Phase.................................................................................45
4.1.4.
Pharmacokinetics Sub-study...................................................................................49
4.1.5.
Follow-up Phase .....................................................................................................49
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
13
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
4.1.5.1.
Follow-up in Subjects Receiving CC-486 Monotherapy..........................................49
4.1.5.2.
Follow-up in Subjects Receiving Durvalumab / CC-486 Combination 
Therapy ..................................................................................................................50
4.1.6.
Extension Phase......................................................................................................51
4.1.7.
Study Closure .........................................................................................................51
4.2.
Study Design Rationale ..........................................................................................53
4.3.
Study Duration .......................................................................................................54
4.4.
End of Trial ............................................................................................................55
5.
TABLE OF EVENTS.............................................................................................56
6.
PROCEDURES......................................................................................................62
6.1.
Screening................................................................................................................62
6.1.1.
MDS Diagnosis, WHO and FAB Classifications and IPSS(-R) Risk 
Classification..........................................................................................................62
6.1.2.
Demographics and Medical History........................................................................63
6.1.3.
RBC and Platelet Transfusion History ....................................................................63
6.1.4.
Prior Medications and MDS Treatments .................................................................63
6.1.5.
Coagulation Parameters ..........................................................................................64
6.1.6.
Physical Examination .............................................................................................64
6.1.7.
Vital Signs, Body Weight and Height Measurements..............................................64
6.1.8.
Eastern Cooperative Oncology Group Performance Status......................................64
6.1.9.
Electrocardiogram ..................................................................................................64
6.1.10.
Urinalysis ...............................................................................................................65
6.1.11.
Serum EPO, Ferritin, and Transferrin Saturation (Fe/TIBC)....................................65
6.1.12.
Hematology............................................................................................................65
6.1.13.
Serum Chemistry and Thyroid Function Tests ........................................................66
6.1.14.
Pregnancy Testing (FCBP Only).............................................................................66
6.1.15.
Bone Marrow Aspirate, Biopsy, and Peripheral Blood Smear .................................67
6.1.16.
Cytogenetics...........................................................................................................67
6.2.
Information to be Collected on Screen Failures.......................................................67
6.3.
Entering a Subject Into the Study (Enrollment).......................................................68
6.4.
Baseline Measurements ..........................................................................................68
6.5.
CC-486 (Oral Azacitidine)......................................................................................68
6.6.
Durvalumab (MEDI4736).......................................................................................69
&&,
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6.3.
6.3
4


EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
14
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
6.6.1.
Durvalumab Infusion Monitoring............................................................................70
6.7.
Safety.....................................................................................................................70
6.7.1.
Adverse Events.......................................................................................................71
6.7.2.
Progression to AML ...............................................................................................71
6.7.3.
Physical Examination, Vital Signs and Weight .......................................................71
6.7.4.
Urinalysis ...............................................................................................................71
6.7.5.
12-Lead Electrocardiogram.....................................................................................71
6.7.6.
Coagulation Parameters ..........................................................................................71
6.7.7.
Hematology and Serum Chemistry Laboratory Evaluations ....................................72
6.7.8.
Pregnancy Testing ..................................................................................................72
6.7.9.
Concomitant Medications/Significant Non-drug Therapies/Concomitant 
Procedures..............................................................................................................73
6.7.10.
Eastern Cooperative Oncology Group Performance Status......................................73
6.8.
Efficacy..................................................................................................................73
6.8.1.
Bone Marrow Aspirate, Biopsy and Peripheral Blood Smear ..................................73
6.8.2.
Cytogenetics...........................................................................................................74
6.8.3.
International Working Group Modified Response Assessment................................74
6.8.4.
General Disease Status Assessment ........................................................................74
6.8.5.
Hematology............................................................................................................75
6.8.6.
Transfusion Assessment..........................................................................................75
6.8.7.
Survival, Progression to AML, and Subsequent MDS Therapies.............................76
6.9.
Biomarkers .............................................................................................................76
6.10.
Pharmacokinetics....................................................................................................77
6.11.
Immunogenicity Samples of Durvalumab ...............................................................79
6.12.
Unscheduled Visits.................................................................................................79
6.13.
Discontinuation ......................................................................................................79
6.14.
Follow-up...............................................................................................................80
6.15.
Extension Phase......................................................................................................81
7.
STUDY POPULATION.........................................................................................82
7.1.
Number of Subjects and Sites .................................................................................82
7.2.
Inclusion Criteria....................................................................................................82
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( 3
( 3


EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
15
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
7.3.
Exclusion Criteria...................................................................................................85
8.
DESCRIPTION OF STUDY TREATMENTS........................................................88
8.1.
Description of Investigational Product(s)................................................................88
8.1.1.
CC-486 (Oral Azacitidine)......................................................................................88
8.1.2.
Durvalumab (MEDI4736).......................................................................................88
8.2.
Treatment Administration and Schedule .................................................................88
8.2.1.
Investigational Product Dispensation ......................................................................89
8.2.1.1.
CC-486 Dispensation..............................................................................................89
8.2.1.2.
Durvalumab Dispensation.......................................................................................89
8.2.2.
Investigational Product Administration...................................................................90
8.2.2.1.
CC-486 Administration...........................................................................................90
8.2.2.2.
Durvalumab Administration....................................................................................91
8.2.3.
Missing Doses ........................................................................................................92
8.2.4.
Dose Modifications and Toxicity Management.......................................................92
8.2.4.1.
CC-486 (Oral Azacitidine) Dose Modification and Toxicity Management ..............92
8.2.4.2.
Durvalumab Toxicity Management Guidelines .......................................................96
8.2.5.
Re-treatment Criteria ............................................................................................126
8.2.6.
Overdose ..............................................................................................................126
8.2.7.
Discontinuation ....................................................................................................126
8.3.
Method of Treatment Assignment.........................................................................127
8.4.
Packaging and Labeling........................................................................................128
8.5.
Clinical Supplies...................................................................................................128
8.6.
Investigational Product Accountability and Disposal ............................................128
8.7.
Investigational Product Compliance......................................................................129
9.
CONCOMITANT MEDICATIONS AND PROCEDURES..................................130
9.1.
Permitted Concomitant Medications and Procedures.............................................130
9.2.
Prohibited Concomitant Medications and Procedures............................................131
9.3.
Required Concomitant Medications and Procedures..............................................132
10.
STATISTICAL ANALYSES................................................................................133
10.1.
Overview..............................................................................................................133
10.2.
Study Population Definitions ................................................................................133
10.2.1.
Intent-to-Treat Population.....................................................................................133
10.2.2.
Modified Intent-to-Treat Population .....................................................................133
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
16
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
10.2.3.
Safety Population..................................................................................................133
10.2.4.
Evaluable Population............................................................................................134
10.2.5.
Pharmacokinetic Population..................................................................................134
10.3.
Sample Size and Power Considerations.................................................................134
10.4.
Background and Demographic Characteristics......................................................134
10.5.
Subject Disposition...............................................................................................134
10.6.
Efficacy Analysis..................................................................................................134
10.6.1.
Primary Efficacy Analysis ....................................................................................135
10.6.2.
Secondary Efficacy Analyses................................................................................135
10.6.2.1.
Overall Survival ...................................................................................................135
10.6.2.2.
Time to Onset of Response ...................................................................................135
10.6.2.3.
Duration of Response ...........................................................................................136
10.6.2.4.
Progression-free Survival......................................................................................136
10.6.2.5.
Stable Disease ......................................................................................................136
10.6.2.6.
Disease Progression to AML ................................................................................136
10.7.
Safety Analysis.....................................................................................................137
10.8.
Interim Analysis ...................................................................................................137
10.9.
Additional Analyses .............................................................................................137
10.9.2.
CC-486 PK Analysis.............................................................................................137
10.9.2.1.
Plasma Concentrations..........................................................................................137
10.9.2.2.
Pharmacokinetic Parameters.................................................................................138
10.9.2.3.
Pharmacokinetic Methods.....................................................................................139
11.
ADVERSE EVENTS............................................................................................140
11.1.
Monitoring, Recording and Reporting of Adverse Events .....................................140
11.2.
Evaluation of Adverse Events...............................................................................140
11.2.1.
Seriousness...........................................................................................................140
11.2.2.
Severity / Intensity................................................................................................141
11.2.3.
Causality ..............................................................................................................142
11.2.4.
Duration ...............................................................................................................143
11.2.5.
Action Taken........................................................................................................143
11.2.6.
Outcome...............................................................................................................143
11.3.
Abnormal Laboratory Values................................................................................143
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35,


EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
17
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
11.4.
Pregnancy.............................................................................................................143
11.4.1.
Females of Childbearing Potential: .......................................................................143
11.4.2.
Male Subjects.......................................................................................................144
11.5.
Reporting of Serious Adverse Events....................................................................144
11.5.1.
Safety Queries ......................................................................................................145
11.6.
Expedited Reporting of Adverse Events................................................................145
11.7.
Adverse Events of Special Interest........................................................................145
11.7.1.
Progression to AML .............................................................................................146
12.
DISCONTINUATIONS .......................................................................................147
13.
EMERGENCY PROCEDURES...........................................................................149
13.1.
Emergency Contact...............................................................................................149
13.2.
Emergency Identification of Investigational Products ...........................................149
14.
REGULATORY CONSIDERATIONS.................................................................150
14.1.
Good Clinical Practice..........................................................................................150
14.2.
Investigator Responsibilities .................................................................................150
14.3.
Subject Information and Informed Consent...........................................................150
14.4.
Confidentiality......................................................................................................151
14.5.
Protocol Amendments...........................................................................................151
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................151
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee..............152
14.8.
Closure of the Study .............................................................................................152
15.
DATA HANDLING AND RECORDKEEPING...................................................153
15.1.
Data/Documents...................................................................................................153
15.2.
Data Management.................................................................................................153
15.3.
Record Retention..................................................................................................153
16.
QUALITY CONTROL AND QUALITY ASSURANCE......................................155
16.1.
Study Monitoring and Source Data Verification....................................................155
16.2.
Audits and Inspections..........................................................................................155
16.3.
Product Quality Complaint ...................................................................................155
17.
PUBLICATIONS .................................................................................................157
18.
REFERENCES.....................................................................................................158
19.
APPENDICES......................................................................................................164
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16.3
6 .


EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
18
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Appendix A:
Myelodysplastic Syndromes World Health Organization Classification 
System..................................................................................................................164
Appendix B:
French-American-British (FAB) Myelodysplastic Syndrome (MDS) 
Classification System............................................................................................166
Appendix C:
International Prognostic Scoring System Score ................................................167
Appendix D:
International Prognostic Scoring System Score - Revised ................................168
Appendix E:
Eastern Cooperative Oncology Group (ECOG) Performance Status .................170
Appendix F:
Hematologic Response and Improvement According to the International 
Working Group for MDS – modified ....................................................................171
Appendix G:
New York Heart Association Classification for Congestive Heart Failure........174
Appendix H:
Recommendations for Management of Treatment-Induced Diarrhea................175
Appendix I:
List of Abbreviations and Definitions of Terms.................................................176
Appendix J:
Extension Phase................................................................................................181
&&,
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70
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17
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......
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.............
.............


EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
19
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
LIST OF TABLES
Table 1:
CC-486 Dose Levels for Safety Run-in...................................................................40
Table 2:
Table of Events.......................................................................................................56
Table 3:
CC-486 Dose Modification Steps............................................................................93
Table 4:
Guidelines for CC-486 Toxicity Management and Dose Modifications...................95
Table 5:
Durvalumab Treatment Modification and Toxicity Management Guidelines 
for Immune-Mediated Adverse Events....................................................................97
Table 6:
Durvalumab Treatment Modification and Toxicity Management Guidelines 
for Infusion-Related Reactions..............................................................................124
Table 7:
Durvalumab Treatment Modification and Toxicity Management Guidelines 
for Non-Immune-Mediated Reactions...................................................................125
Table 8:
Definitions of Progressive Disease for Clinical Decisions on Discontinuing 
Subjects From the Investigational Product and/or From the Study.........................148
&&,
&(/*(1(35235,(7$5<,1)250$7,21
......97
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
20
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
LIST OF FIGURES
Figure 1:
Safety Run-in Phase Study Design..........................................................................44
Figure 2:
Randomized Treatment Phase Study Design...........................................................52
&&,
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
21
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
1.
INTRODUCTION
1.1.
Myelodysplastic Syndromes
Myelodysplastic syndrome (MDS) is an umbrella term that encompasses a heterogeneous 
collection of hematopoietic stem cell disorders primarily affecting older adults.  MDS is typically 
characterized by bone marrow hyperplasia and peripheral cytopenias that manifest clinically as 
anemia, neutropenia, and/or thrombocytopenia of variable frequency and severity, with 
symptoms of anemia being the most frequently-presenting manifestation.  Anemia is the most 
frequent laboratory finding and it often progresses to red blood cell (RBC) transfusion 
dependence.  Other less common presenting clinical features related to the cytopenias are an 
increased risk of infection and/or hemorrhage and a potential to progress to acute myeloid 
leukemia (AML) (Catenacci, 2005).  The latter clinical features often appear over time and are 
associated with more advanced disease.
Myelodysplastic syndromes are classified according to World Health Organization (WHO) 
criteria by pathologic features on bone marrow examination into the following categories 
(Brunning, 2008; Vardiman, 2009; Appendix A):  
!
Refractory cytopenia with unilineage dysplasia (RCUD)
∀
refractory anemia (RA)
∀
refractory neutropenia (RN)
∀
refractory thrombocytopenia (RT)
!
Refractory Anemia with ringed sideroblasts (RARS)
!
Refractory cytopenia with multilineage dysplasia (RCMD)
!
Refractory anemia with excess blasts-1 (RAEB-1) 
!
Refractory anemia with excess blasts-2 (RAEB-2)
!
Myelodysplastic syndrome -unclassified (MDS-U)
!
MDS associated with isolated del(5q)
Or by French-American-British (FAB) classification system subtypes of MDS (Bennett, 1982; 
Appendix B): 
!
Refractory anemia (RA) 
!
Refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia 
or thrombocytopenia or requiring transfusions)
!
Refractory anemia with excess blasts (RAEB)
!
Refractory anemia with excess blasts in transformation (RAEB-T)
!
Chronic myelomonocytic leukemia (CMML)
A patient’s disease is also assigned to one of 4 prognostic groups (Low, Intermediate-1 [INT-1], 
Intermediate-2 [INT-2], and High risk) according to the International Prognostic Scoring System 
(IPSS - Appendix C) based on cytogenetic features, number of cytopenias, and bone marrow 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
22
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
blast percentages.  Overall survival and risk of progression to AML is significantly different in 
the 4 risk groups.  Median survival for patients in these risk groups being 5.7 years (Low), 3.5 
years (INT-1), 1.2 years (INT-2), and 0.4 years (High).  The median time for 25% of patients to 
progress to AML is 9.4, 3.3, 1.1, and 0.2 years, respectively (Greenberg, 1997).
Allogeneic bone marrow transplantation has been effective, both in patients under the age of 
50 years and in those older than 50 years who are in good health and who have suitable human 
leukocyte antigen (HLA) matched donors.  However, this approach has limited value, since most 
patients with MDS are older than 65 years of age and have significant comorbidities that 
preclude the use of this modality as it is associated with a high morbidity and mortality rate, as 
described in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines: 
MDS (NCCN, 2015).  
For patients diagnosed with, or progressing to, higher-risk disease, the standard of care is 
treatment with a locally-available injectable HMA: azacitidine for injection or decitabine.  
Injectable HMAs can produce hematologic response or improvement in approximately half of 
treated patients, but responses are transient and responding disease will eventually relapse
(Grinblatt, 2008; Lyons, 2009; Musto, 2010; Silverman, 2002).
There are no approved (or proven) treatment options following failure of treatment with an 
injectable HMA.  The mainstay of therapy in this setting among patients not eligible for 
autologous stem cell transplant remains supportive care, including RBC and/or platelet 
transfusions, treatment of infections, and the use of erythropoiesis stimulating agents (ESAs)
such as epoetin alfa or darbepoetin, plus hematopoietic growth factors such as granulocyte 
colony-stimulating factor (G-CSF) when needed (Lübbert, 2000; NCCN, 2015; Kadia, 2011). 
Neither ESAs nor myeloid growth factors are approved for the treatment of MDS.  
Thus, additional data regarding the use of potentially-effective agents in this population is greatly 
needed. 
1.2.
CC-486 (Azacitidine)
CC-486 is an oral formulation of azacitidine.  Azacitidine is an analog of the naturally occurring 
pyrimidine nucleoside cytidine and is classified as an antimetabolite.  In the United States (US), 
azacitidine (Vidaza®) is approved for the treatment of all 5 FAB classification subtypes of MDS: 
RA, RARS, RAEB, RAEB-T, and CMML, but it is not routinely utilized in the lower-risk 
disease setting.  Azacitidine is approved in the European Union (EU) for the treatment of adult 
non-hematopoietic stem cell transplantation-eligible patients with IPSS INT-2 or high-risk MDS, 
CMML with 10% to 29% marrow blasts without myeloproliferative disorder, and AML with 
20% to 30% blasts and multi-lineage dysplasia, according to the WHO classification.  In addition 
to the US and EU, azacitidine is currently approved in 30 other countries, including Canada, 
Switzerland, Australia, and Japan, for the treatment of MDS (approvals for specific subtypes 
vary by country).  Current approved routes of administration include subcutaneous and 
intravenous (approvals vary by country).  Similarly, decitabine (Dacogen®), another 
hypomethylating agent, is approved in the US for treatment of all FAB classification subtypes 
and IPSS INT-1, INT-2 and high-risk MDS.
Azacitidine has strong in vitro and in vivo anti-leukemic activity and the ability to induce 
differentiation at lower concentrations in hematopoietic and non-hematopoietic cell lines.  The 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
23
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
effects of azacitidine may result from multiple mechanisms, including inhibition of 
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein synthesis, incorporation into 
RNA and DNA, and activation of DNA damage pathways.  The ability of azacitidine to cause 
differentiation can be attributed to its activity as a hypomethylating agent.  The degree of 
methylation of cytosine residues in DNA has been demonstrated to play a role in gene 
expression.  Indeed, hypermethylation of cytosine residues of genes critical to ensure orderly cell 
proliferation and maturation (differentiation) is frequently found in primary neoplasms and 
tumor cell lines (Zingg, 1997).  Therefore, use of an inhibitor of DNA methylation, such as 
azacitidine, is a rational approach to reversing these epigenetic aberrations in the malignant clone 
and to re-establishing antiproliferative signals that were extinguished by hypermethylation.  
Preliminary data from the AZA-PH-GL-2003-CL-001 survival study (Herman, 2009) with 
azacitidine in higher-risk MDS patients found, from analysis of pretreatment bone marrow 
methylation density, that the overall survival benefit observed with azacitidine versus 
conventional care regimens (CCR) was independent of the methylation status of the 5 genes 
analyzed (CDKN2B [p15], SOCS1, CDH1 [E-cadherin], TP73, and CTNNA1 [α-catenin]).  
However, increasing methylation was associated with worse overall survival.  Patients with 
lower levels of methylation treated with azacitidine had the best overall survival, suggesting that 
they may derive greater benefit from azacitidine.
Azacitidine has been studied extensively in MDS and has been shown in a large, randomized, 
Phase 3 trial of higher-risk MDS patients to provide a survival advantage of 9.4 months over 
CCR.  The median overall survival of azacitidine-treated patients was 24.5 months compared 
with 15.0 months for the CCR group, which included best supportive care, low-dose cytarabine, 
or intensive chemotherapy (Fenaux, 2009).  The clinical experience with azacitidine in AML is 
smaller, but positive efficacy results have been obtained.  In a subset of 113 patients with WHO-
defined AML (mean age 70 years, 24% with unfavorable karyotype, median bone marrow blasts 
23%) from the larger MDS study discussed above, the median overall survival was 24.5 months 
(n = 55) in the azacitidine arm compared with 16.0 months (n = 58) in the CCR arm (Fenaux, 
2008).  Additionally, the outcome was not significantly different in patients with an unfavorable 
karyotype, although the sample size was small.  Silverman et al, using WHO-defined AML 
criteria for diagnosis, reported a median overall survival of 19.3 months (n = 27) in patients 
treated with azacitidine compared with 12.9 months (n = 25) in patients who received best 
supportive care (Silverman, 2006).  Additionally, Goldberg et al. reported on 33 patients who 
received azacitidine (n = 11, median age 74) or 7+3 intensive chemotherapy (n = 22, median age 
67 years) (Goldberg, 2006).  Median blast count at baseline was 42% in the azacitidine group 
and 65% in the intensive chemotherapy group.  The median overall survival was 13.2 months in 
the patients treated with azacitidine compared with 9.2 months in patients receiving intensive 
chemotherapy (Goldberg, 2006).  All of the above-mentioned studies used the standard injectable 
azacitidine dose of 75 mg/m2/day for 7 days.
Most responses to azacitidine occur by the completion of 6 cycles of treatment, but responses 
may still occur beyond this (Musto, 2010; Silverman, 2006).  Elderly patients (> 70 years of age) 
respond as well as younger patients, and failure to respond to prior therapy with ESAs does not 
preclude possible responses to azacitidine (Musto, 2010). Overall response rates in lower-risk 
MDS subjects have been reported as approximately 50% in various studies (Grinblatt, 2008; 
Lyons, 2009; Musto, 2010; Silverman, 2002). 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
24
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
An oral formulation of azacitidine (CC-486) has been evaluated in 3 clinical studies to date.  
Results from a pilot study (AZA PH US 2007 PK 004) indicated that azacitidine in an oral 
formulation was bioavailable (Garcia-Manero, 2008).  This was confirmed when evaluating 
several different formulations of the drug in a Phase 1 study (AZA PH US 2008 CL 008).  
Results from another Phase 1 study of CC-486 in subjects with MDS, CMML, or AML (AZA 
PH US 2007 CL 005) indicated that administration on different treatment schedules (7-, 14-, and 
21-day once daily [QD] and 14- and 21-day twice daily [BID]) was feasible, generally well-
tolerated, and exhibited biologic and clinical activity (Garcia-Manero, 2009; Garcia-Manero, 
2010).  
1.3.
Durvalumab (MEDI4736)
Durvalumab is briefly described below.  Refer to the current Investigator’s Brochure for further 
details.
Durvalumab is a human immunoglobulin G (IgG)1 kappa monoclonal antibody (mAb) that 
blocks the interaction of programmed cell death ligand 1 (PD-L1) (but not programmed cell 
death ligand-2) with programmed cell death 1 (PD-1) on T-lymphocytes (T-cells) and cluster of 
differentiation (CD) 80 on immune cells and is engineered to reduce antibody-dependent cell-
mediated cytotoxicity (ADCC).
1.3.1.
Durvalumab Experience in Solid Tumors
Study CD-ON-MEDI4736-1108 is a Phase 1, first-time-in-human, multicenter, open-label, dose-
escalation, and dose-expansion study to determine the maximum tolerated dose (MTD) or 
optimal biologic dose, safety, pharmacokinetics (PK), immunogenicity, and antitumor activity of 
durvalumab in adult subjects with advanced solid tumors refractory to standard therapy or for 
which no standard therapy exists. 
As of 12 July 2016, a total of 1012 subjects with advanced solid tumors have been treated in this 
study. Of these subjects, 970 have received durvalumab at 10 mg/kg once every 2 weeks (Q2W), 
either in the dose-escalation or dose-expansion phase of the study. The 10 mg/kg Q2W cohort 
represents combined data from subjects treated with this dosing regimen in either the dose-
escalation or dose-expansion phase. The 10 mg/kg Q2W cohort comprises subjects with non-
small cell lung cancer (NSCLC) (n = 304), urothelial carcinoma (n = 191), squamous cell 
carcinoma of the head and neck (SCCHN) and microsatellite instability high (both n = 62), 
gastro-oesophageal cancer (n = 51), ovarian cancer (n = 47), hepatocellular carcinoma (HCC)
and triple-negative breast cancer (TNBC) (both n = 40), pancreatic adenocarcinoma (n = 31),
uveal melanoma (n = 24), non-SCCHN human papilloma virus (positive) (HPV+) (n = 22), 
advanced cutaneous melanoma and small cell lung cancer (both n = 21), glioblastoma 
multiforme and soft tissue sarcoma (both n = 20) and nasopharyngeal carcinoma (n = 10). 
Subjects in the 10 mg/kg Q2W dose cohort were exposed to a median of 6 doses of durvalumab, 
ranging from 1 to 27 doses.
Of the 970 subjects treated with 10 mg/kg Q2W, 947 subjects (97.6%) had at least 1 adverse 
event (AE) (regardless of causality). AEs (all grades) reported in decreasing order of frequency 
in ≥10% of subjects were fatigue (37.6%), nausea (23.7%), decreased appetite (23.2%), dyspnea 
(21.9%), constipation (20.2%), diarrhea and cough (17.9% each), back pain (16.5%), vomiting 
(15.9%), anemia (15.6%), abdominal pain (14.4%), pyrexia (13.9%), arthralgia (13.1%), edema 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
25
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
peripheral (12.1%), pruritus (11.6%) and headache (11.2%). Across the tumor types, the overall 
incidence of AEs was generally similar.
Grade 3 or higher AEs were reported in 295 subjects (30.4%) and were manageable by general 
treatment guidelines described in the toxicity management guidelines contained in each of the
study protocols. Events occurring in >2% of subjects were anemia (6.2%), dyspnea (6.0%), 
hyponatremia (5.4%), fatigue (3.9%), gamma glutamyltransferase (GGT) increased (3.6%), 
abdominal pain (3.1%), aspartate aminotransferase (AST) increased (2.9%), back pain (2.9%) 
and dehydration (2.6%).
A total of 554 subjects (57.1%) reported AEs that were considered by the investigator to be 
related to investigational product. Treatment-related AEs (all grades) reported in > 5% of 
subjects were fatigue (18.7%), nausea (7.9%), diarrhea (7.6%), pruritus (6.8%), decreased 
appetite (6.7%), hypothyroidism (6.3%) and rash (6.0%). The majority of the treatment-related 
AEs were Grade 1 or Grade 2 in severity with ≥Grade 3 events occurring in 88 subjects (9.1%). 
Treatment-related ≥Grade 3 or 4 events reported in ≥2 subjects were fatigue (1.6%), AST 
increased (1.0%), alanine aminotransferase (ALT) increased (0.8%), GGT increased (0.7%),
hyponatremia and diarrhea (0.5% each), colitis (0.4%), decreased appetite and vomiting (0.3% 
each), and alkaline phosphatase (ALP) increased, anemia, arthralgia, autoimmune hepatitis, 
blood bilirubin increased, dyspnea, hyperglycemia, infusion related reaction, leukopenia, nausea, 
neutropenia, nervous system disorder, rash maculo-papular, thrombocytopenia, transaminases 
increased and weight decreased (0.2% each). Four subjects had a treatment-related Grade 5 
event (autoimmune hepatitis, immune thrombocytopenic purpura, pneumonia and pneumonitis).
Serious adverse events (SAEs) (regardless of causality) have been reported in 504 of 970 
subjects (52.0%) treated with 10 mg/kg durvalumab Q2W. Serious adverse events reported in 
>1% of subjects by descending order of frequency were: NSCLC (4.5%), dyspnea (4.3%), 
abdominal pain and bladder cancer (2.7% each), pneumonia (2.5%), pyrexia and sepsis (2.3% 
each), general physical health deterioration (2.0%), back pain (1.8%), acute kidney injury, 
dehydration, pleural effusion and urinary tract infection (1.5% each), lung neoplasm malignant 
(1.4%), respiratory failure and vomiting (1.2%) and hypercalcemia (1.0%). Thirty-nine subjects 
(4.0%) had SAEs considered by the investigator to be related to durvalumab. Treatment related 
SAEs that occurred in > 1 subject each were colitis and pneumonitis (4 subjects each), nervous 
system disorder (3 subjects), and acute kidney injury, AST increased, and diarrhea (2 subjects 
each). The majority of the treatment-related SAEs were Grade 3 or higher in severity and 
recovered with or without sequelae.
No clinically meaningful difference in the AE profile across doses was observed, including 
Grade 3 or 4 events, SAEs, AEs leading to discontinuation, or treatment-related AEs.
As of 29 April 2016, 304 NSCLC subjects had received durvalumab monotherapy; 144 subjects 
(47%) with non-squamous and 160 subjects (53%) with squamous histology. Subjects with 
tumors defined as PDL1 positive had improved overall rate of objective response (ORR) and 
overall survival (OS). The ORR, was 25% and 6% in PD-L1 positive and negative subjects, 
respectively. The 12-month OS rate was 55.8% and 38.8% in PD-L1 positive and negative
subjects, respectively. 
As of 29 April 2016, 62 subjects with recurrent/metastatic SCCHN had received durvalumab 
monotherapy. Among seven responders, six subjects had a DOR for ≥12 months with longest 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
26
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
DOR being 19.8 months. Six and 12-month OS is 62% and 42%, respectively. Urothelial 
Carcinoma: As of data cut-off (DCO) on 20 November 2015, 61 subjects had been enrolled into 
the urothelial cell cohort. Forty-two subjects who initiated study therapy ≥12 weeks prior to 
DCO were evaluable for response. Confirmed ORR was 46% in the PD-L1 positive subgroup 
compared to 0% in the PD-L1 negative subgroup. ORR in the entire response evaluable 
population was 31% (13/42 subjects).
Other indications: In PD-L1 unselected subjects, the ORR, based on investigator assessment per 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, ranged from 0% in uveal 
melanoma to 17.4% in advanced cutaneous melanoma, and disease control rate (DCR)-24w 
ranged from 4.2% in TNBC to 39.1% in advanced cutaneous melanoma. Across the PD-L1 high 
tumors, ORR was >10% for advanced cutaneous melanoma and HCC (33.3% each). In the PD-
L1-positive subset, DCR- 24w was >10% in advanced cutaneous melanoma (66.7%) and HCC 
(33.3%).
As of 24 July 2016, PK data were available for a total of 977 subjects following treatment with 
0.1 to 10 mg/kg Q2W and 15 mg/kg Q3W (dose escalation), 10 mg/kg Q2W (dose-expansion), 
and 20 mg/kg Q4W (dose-exploration) durvalumab administered as an intravenous (IV) infusion 
over 60 minutes. PK samples were analyzed using an electrochemiluminescence (ECL) method 
for quantitative determination of durvalumab in human serum with lower limit of quantitation 
(LLOQ) of 50 ng/mL in 100% matrix. 
Following the first IV dose, durvalumab exhibited nonlinear PK at doses < 3 mg/kg Q2W likely 
due to saturable target-mediated clearance (CL) and exhibited linear PK at doses ≥3 mg/kg 
Q2W. The area under the concentration-time curve (AUC)0-14 increased dose-proportionally at 
doses of 3 to 20 mg/kg and more than dose-proportionally at doses of < 3 mg/kg, likely due to 
saturable target-mediated CL. Maximum observed concentration (Cmax) increased in a dose-
proportional manner within the dose range examined. The steady state was achieved at 
approximately Week 16. Accumulation of durvalumab was observed following repeated dosing. 
Mean accumulation ratio (AR) ranged from 0.64 to 1.87 and 3.15 to 4.93 for Cmax and trough 
concentration (Ctrough), respectively.
As of 24 July 2016, a total of 790 subjects provided samples for anti-drug antibody (ADA)
analysis. Only 25 of 790 subjects (1 subject each in 0.1 and 3 mg/kg cohorts, 17 subjects from 10 
mg/kg cohort) were ADA positive. One subject in the 10 mg/kg cohort tested positive for anti-
TM antibody. Three subjects were neutralizing ADA (nAb) positive. For the proposed clinical 
dose, of 751 subjects (ADA evaluable population) treated with 10 mg/kg Q2W, 2.8% (21/751) 
had treatment-emergent ADAs and 0.1% (1/751) of subjects were positive for nAb. Based on 
population PK covariate analysis, ADA positive status was not associated with a clinically 
relevant reduction of exposure to durvalumab. At the 10 mg/kg Q2W dose, sPD-L1 suppression 
in ADA positive subjects was similar to that observed in ADA negative subjects. The relevance 
of ADA on safety and efficacy is unknown given the small number of ADA positive subjects.
 
 
 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
27
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.
Study Rationale
The original protocol rationale was to evaluate the efficacy and safety of CC-486 as a 
monotherapy only.  
Currently, this clinical study will evaluate the efficacy and safety of CC-486 alone, and in
combination with durvalumab, in subjects with myelodysplastic syndromes, refractory to 
treatment with azacitidine for injection or decitabine; ie, stable disease or disease progression
was the best response to that treatment.  
1.4.1.
Azacitidine Exposure
While injectable hypomethylating agents (azacitidine for injection and decitabine) remain the 
standard of care in the treatment of IPSS higher-risk MDS, as many as half of affected patients 
do not respond to treatment, and nearly all those who do respond will eventually relapse.  Upon 
failure of treatment with azacitidine for injection and/or decitabine, the prognosis for patients 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
28
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
with higher-risk disease is dismal, with median overall survival on the order of 4-6 months 
(Prebet, 2011; Jabbour, 2010).  Similarly, injectable HMAs are approved for treatment of IPSS 
lower-risk MDS in some countries, and while there are few data to characterize outcomes in 
lower-risk disease following failure of these agents, prognosis is poor and for patients who are 
not eligible for allogeneic stem cell transplant, no proven treatment options currently exist 
(Jabbour, 2013). 
Aberrant hypermethylation of DNA is a feature of myelodysplastic syndromes, and is implicated 
in the pathogenesis and progression of disease (Gore, 2006).  This supports the notion that 
epigenetic changes play an important role in MDS transformation and may be exploited.  
However, association between the degree of constitutive methylation and magnitude of reduction 
in methylation state via treatment with HMAs has not been clearly correlated with treatment 
outcomes (Follo, 2009).  
Azacitidine is a cytidine analog that may, in part, exert its antineoplastic effect by incorporation 
into DNA of cycling cells and subsequent hypomethylation through inhibition of DNA 
methyltransferases.  Optimal drug activity may require an increased window of exposure to 
malignant cells to increase the opportunity for cycling cells to incorporate drug (Mahfouz, 2013; 
Stresemann, 2008). 
An oral formulation of azacitidine provides an opportunity to deliver the drug daily over a more 
prolonged schedule than can be practically achieved with parenteral therapy.  In a Phase 1 dose-
finding study, the safety, bioavailability, and biologic effects of CC-486 were evaluated.  
Compared with 75 mg/m2 subcutaneous (SC) AZA, 300 mg CC-486 QD x 14 days and QD x 21 
days provided mean cumulative exposures (AUC) per cycle of approximately 38% and 56%, 
respectively.  With SC AZA 75 mg/m2 QD, 7/28 days, DNA methylation was significantly 
reduced, with its greatest reduction in global de-methylation score (GDMS – percent of highly-
methylated loci) of -8.8% at Day 15.  However, methylation increased throughout the remaining 
21 days of the cycle to a GDMS of -3.2% by cycle end.  In subjects treated with CC-486 300 mg 
QD,14/28 days and 21/28 days, methylation was significantly reduced at Day 15 (-3.3% and -
5.3%, respectively), Day 22 (-3.8% and -6.7%) and cycle end (-2.4% and -5.0%) (Laille, 2015).  
Despite the reduced bioavailability of CC-486 compared to azacitidine administered 
subcutaneously, the oral agent, given 21/28 days, is associated with greater reductions in GDMS 
through the end of the treatment cycle.  Twice-daily dosing may further enhance target 
engagement and achieve greater reductions in global methylation.  In the study described above, 
though few subjects received BID oral dosing, the largest absolute reductions in DNA 
methylation were associated with BID dosing.  CC-486 200 mg BID taken 21/28 days was 
associated with the greatest reductions in GDMS:  -11.0%, -11.8%, and -9.1% at Day 15, Day 
22, and Day 28, respectively (Laille, 2015).
An orally administered hypomethylating agent may offer several advantages when compared to 
parenterally administered agents. Oral administration eliminates the need for the patient to travel 
for parenteral administration. Furthermore, as no injection is needed, there is the potential to 
decrease adverse events at the site of injection including pain and infection.
Demethylation of several immune checkpoint genes was seen in these analyses which is in line 
with findings that PD-1 and PD-L1 expression was increased after treatment with HMA
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ecreas
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
29
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
(Yang, 2014).  Due to these findings, it is hypothesized that CC-486 could be an effective 
treatment for MDS patients who have failed HMAs. 
The goal in treating this population and in evaluating new potentially therapeutic options is to 
capture or recapture hematologic response or hematologic improvement (Appendix F), to reduce
the rate of disease progression and AML transformation, and to prolong survival.  Despite active 
interest in the post-HMA setting among researchers, there remains a critical unmet medical need.  
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
Investigational Product (IP).  The study will be conducted in compliance with the protocol, Good 
Clinical Practice (GCP), and the applicable regulatory requirements.
1.4.2.
Cancer and Immune Function
The importance of the immune system in cancer development and progression has been 
recognized during the past decade (Hanahan, 2000). Failure of immune surveillance of pre-
neoplastic lesions and micro-metastases is a key step in cancer development. Chronically 
immunosuppressed individuals show higher rates of cancer. This observation led to the 
hypothesis that sporadic cancers among immune-competent individuals are likely to be 
minimally immunogenic, allowing for passive escape from immune surveillance. Recent data 
suggest that this may be an oversimplification. Some sporadic tumors are highly immunogenic, 
but actively suppress the local immune environment through production of immunosuppressive 
cytokines (Shields, 2010). As such, the local tumor environment is likely a highly dynamic 
environment where most tumors grow and metastasize through adaptive responses that modulate 
antitumor immunity. The complexity and redundancy of the immune system offers multiple 
targets that may be manipulated to maximize the body’s inherent immune response to a tumor. 
Immune response may be augmented by directly stimulating effector cells, indirectly stimulating 
effectors by augmenting antigen presentation activity or costimulation, or by suppressing 
immunosuppressive factors, cells, or messages (Monti, 2005). 
1.4.3.
Immune-checkpoint Inhibition
Tumor-infiltrating lymphocytes (TILs) have the capacity to control the growth of many types of 
cancers (Gooden, 2011). Most tumors show infiltration by TILs, but tumors modulate the local 
microenvironment through expression of inhibitory molecules. Engagement of TIL cell-surface 
receptors with these inhibitory ligands leads to a dysfunctional immune response, causes T-cell 
exhaustion, and facilitates tumor progression (Baitsch, 2012; Crespo, 2013). It is increasingly 
appreciated that cancers are recognized by the immune system, and under some circumstances, 
the immune system may control or even eliminate tumors (Dunn, 2004).  Novel monoclonal 
antibodies (mAbs) that block these inhibitory receptors have shown significant clinical activity 
across a number of tumor types (Wolchok, 2009; Hodi, 2010; Robert, 2011; Brahmer, 2010; 
Topalian, 2012). Specifically, blockade of immune-checkpoint inhibitors such as cytotoxic T-
lymphocyte-associated antigen 4 (CTLA-4), PD-1, and PD-L1 have shown clinical activity not 
only in conventionally immune-responsive tumors such as melanoma and renal cell carcinoma 
but also in NSCLC (Brahmer, 2010; Brahmer, 2012; Topalian, 2012; Gordon, 2013), and 
prostate cancer (Harzstark, 2010).  Pembrolizumab and nivolumab are both PD-1 blocking 
antibodies and the first in the anti-PD-1 pathway family of checkpoint inhibitors to gain approval 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
30
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
from the US Food and Drug Administration (FDA), pembrolizumab for melanoma and 
nivolumab for melanoma and squamous cell lung cancer. Both pembrolizumab and nivolumab 
have received European Commission regulatory approval for the treatment of metastatic 
melanoma. The European Commission has also approved nivolumab for the treatment of 
advanced previously treated squamous NSCLC.
The PD-1 receptor, in conjunction with receptor ligands PD-L1 and PD-L2, functions to regulate 
the immune system primarily by down regulating signals of the T-cell receptor.  PD-L1 
expressed on tumor cells binds to PD-1 on T-cells which leads to down-regulation of T-cell 
activity and allows tumor cells to evade the immune response 
Recent advances in immunotherapy offer promise for improving clinical outcomes in patients 
with MDS or AML. Studies in mouse models of transplantable tumors have demonstrated that 
manipulation of costimulatory or co-inhibitory signals can amplify T-cell responses against 
tumors (Peggs, 2009). This may be accomplished by blocking co-inhibitory molecules such as 
CTLA-4 or PD-1 from binding with their ligands, B7 or B7-H1 (PD-L1).
PD-L1 and PD-L2 are expressed on many human lymphomas (Li, 2012; Chen, 2013). PD-L1 has 
been detected on several hematologic malignancies, including Hodgkin lymphoma, primary 
mediastinal B-cell lymphoma, angioimmunoblastic T-cell lymphoma, multiple myeloma, acute 
myeloid leukemia, chronic lymphocytic leukemia, and adult T-cell leukemia/lymphoma (Liu, 
2007; Dorfman, 2006; Rosenwald, 2003; Tamura, 2005; Xerri, 2008). PD-L1 expression has 
been detected on several myeloid cell lines, suggesting that PD-L1 expression continues to 
suppress immune function (Dolen, 2013). In addition, in MDS subtypes, PD-L1 expression on 
myeloblasts has been associated with MDS transformation to AML (Ogata, 2012). Myeloid 
leukemia cell lines that were treated with the hypomethylating agent decitabine were shown to 
have an upregulation of PD-L1 expression (Yang, 2012). Upregulation (≥ 2 fold) of PD-L1 has 
been observed in 25% of AML CD34+ samples, 33% of PD-L2, and 22% of PD-1 (Yang, 2014).
PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to azacitidine; 
therefore, combined blockade of this pathway can be a potential therapy in MDS and AML 
(Yang, 2014).
PD-L1 expression is present in MDS and AML, with increased expression observed in advanced 
disease. In addition, there has been evidence to suggest that PD-L1 is upregulated in myeloblasts 
in MDS subtypes (Yang, 2014). Therefore, a rationale exists for evaluating durvalumab in 
combination with azacitidine in subjects with MDS and AML.
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
31
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
 
 
.
1.4.5.
Rationale for Durvalumab Fixed Dosing Regimen
The dose and schedule for durvalumab monotherapy (20 mg/kg once every 4 weeks [Q4W]) 
were selected based on 2 sets of data: (1) the safety analysis of doses (0.1, 0.3, 1, 3, and 10 
mg/kg once every 2 weeks [Q2W]) administered in Study CD-ON-MEDI4736-1108 (a Phase 1/2 
study to evaluate the safety, tolerability, and PK of IV durvalumab given as monotherapy in 
subjects with advanced solid tumors; and (2) PK profile simulations for durvalumab
administered using 10 mg/kg Q2W and 20 mg/kg Q4W schedules.
Safety and PK characteristics of the studied dose and schedule 10 mg/kg Q2W:
After evaluation of the PK data from subjects enrolled in Study CD-ON-MEDI4736-1108, 
durvalumab exhibited nonlinear (dose-dependent) PK consistent with target-mediated drug 
disposition. Linear PK was observed at doses of 3 mg/kg and higher and is consistent with near 
complete target suppression, as reflected in target trough plasma concentrations of drug >100 
ug/mL. This trough concentration is supported by soluble PD-L1 (sPD-L1) suppression data. 
Furthermore, the 10 mg/kg Q2W dose was not associated with any DLTs in the dose escalation 
portion and was, therefore, selected for further evaluation in the dose-expansion portion of Study 
CD-ON-MEDI4736-1108.
Extrapolation of dose and schedule of 10 mg/kg Q2W to 20 mg/kg Q4W through population PK 
modeling:
A population PK model was developed using durvalumab monotherapy data from Phase 1 of 
Study CD-ON-MEDI4736-1108 (N=292; doses = 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid
tumors) (Fairman, 2014). This population PK model adequately described monotherapy PK data 
and was utilized to predict expected PK exposures following 20 mg/kg Q4W dosing regimens 
(since none of the monotherapy studies explored Q4W regimens). Pharmacokinetic simulations 
indicate that a similar overall exposure as represented by AUCs (4 weeks) is expected following 
both 10 mg/kg Q2W and 20 mg/kg Q4W regimens. However, median Cmax at steady state is 
expected to be higher with 20 mg/kg Q4W (~1.5 fold) and median trough concentration at steady 
state is expected to be higher with 10 mg/kg Q2W (~1.25 fold). 
Justification for fixed dosing over weight-based dosing:
Population PK analysis indicated only minor impact of body weight (WT) on PK of durvalumab
(coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and fixed dosing (750 mg 
Q2W) of durvalumab was evaluated by comparing predicted steady state PK concentrations (5th, 
median, and 95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
32
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
subjects were simulated using body WT distribution of 40 to 120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady state 
PK concentrations with slightly less overall between-subject variability with fixed dosing 
regimen.  
Similar findings have been reported by others (Ng, 2006; Wang, 2009; Zhang, 2012; Narwal, 
2013). Wang and colleagues investigated 12 monoclonal antibodies and found that fixed and 
body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies 
(Wang, 2009). In addition, they investigated 18 therapeutic proteins and peptides and showed 
that fixed dosing performed better for 12 of 18 proteins in terms of reducing the between-subject 
variability in pharmacokinetic/pharmacodynamics parameters (Zhang, 2012). 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body WT of 
75 kg, a fixed dose of durvalumab at 1500 mg Q4W (equivalent to 20 mg/kg Q4W) is included 
in the current study. 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
33
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of this study is to investigate the efficacy of CC-486 as monotherapy and 
in combination with anti-PD-L1 monoclonal antibody, durvalumab (MEDI4736), in subjects 
with MDS that did not respond to prior treatment with an injectable hypomethylating agent 
(HMA – azacitidine for injection or decitabine), or were unable to tolerate treatment with an 
injectable HMA.
2.2.
Secondary Objectives
The secondary objectives of the study are to:
!
Assess the safety and tolerability of CC-486 alone and in combination with 
durvalumab, as treatment for MDS
!
Describe the clinical relevance of objective hematologic and/or biologic responses 
associated with treatment with CC-486 alone and in combination with durvalumab
!
Evaluate the impact (if any) of durvalumab on the pharmacokinetics of CC-486 and 
CC-486 on durvalumab in subjects with MDS
 
 
 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
34
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint
The primary endpoint of this study is the overall rate of objective response (ORR) to treatment 
with CC-486 monotherapy and combination therapy with CC-486 and durvalumab: the 
proportion of subjects achieving an objective response (hematologic improvement [HI], partial 
response [PR], complete remission [CR], or marrow CR) based on modified International 
Working Group (IWG) 2006 criteria - Appendix F.
3.2.
Secondary Endpoint(s)
The secondary endpoints of this study are:
!
Overall survival;
!
Time to onset of responses;
!
Duration of responses;
!
Progression free survival (time to disease progression or death from any cause);
!
Proportion of subjects with progressive disease at baseline achieving stable disease, 
as well as time to achieving stable disease and duration of stable disease;
!
The proportion of subjects progressing to AML and time to AML progression;
!
Safety and tolerability (type, frequency, severity of AEs and relationship of AEs to 
CC-486 and/or durvalumab; monitoring for disease progression to AML, as well as 
immune- and infusion-type reactions);
!
Serum/plasma PK parameters for durvalumab and CC-486, including maximum 
observed concentration (Cmax), AUC, time to maximum concentration (Tmax), terminal 
half-life (½), clearance (CL/F) and volume of distribution (Vz/F).
 
 
 
 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
35
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
 
 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
36
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is a Phase 2, international, multicenter, randomized, parallel group, open-label study 
consisting of 5 study phases: Screening, Safety Run-in, Randomized Treatment, Follow-up, and
Extension.  
The study is closed to further enrollment with the last subject enrolled in June 2018. A total of 65 
subjects were enrolled in the study. At the time of this amendment, 6 subjects are ongoing in the 
Monotherapy SD/PD cohorts (One subject from Phase 1, and 5 from Phase 2).
The study is amended to include an Extension Phase (EP).  The EP allows subjects who are 
currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the 
Investigator, to continue receiving oral azacitidine until the subject meets the criteria for study
treatment discontinuation.  No survival will be followed during the EP.
A Safety Run-in will first explore the safety and tolerability of monotherapy, followed by
combination therapy to confirm that there are no overlapping or synergistic toxicities limiting the 
ability of the two drugs to be delivered in combination (see Figure 1).  
The randomized treatment phase of the study will be conducted in 2 stages.  Following 
identification of dose and schedule in the safety run-in of a treatment arm, enrollment for Stage 1 
of the treatment phase may begin.  Eligible subjects will be randomized to one of two open 
treatment arms:
!
Monotherapy – CC-486 alone, or
!
Combination Therapy – CC-486 plus durvalumab
In the event that only one treatment arm for a cohort is open for accrual due to available safety 
and efficacy data, subjects will be assigned to treatment on the open arm.
Throughout the study, subjects will be categorized as having Progressive Disease (PD) or Stable 
Disease (SD) and these designations are made based on the subject’s best response to iHMA 
therapy determined at the start of this study (see Section 7), and any marked changes in their 
disease prior to beginning treatment in this study (eg, a subject with stable disease as their best 
response to iHMA therapy, but with subsequent disease progression would be assigned to the PD 
group).  Numbers of subjects with PD and SD allocated to each treatment arm will be monitored 
to enable the planned analyses for each sub-population.  Hence there are 4 cohorts being 
evaluated in this study:
!
Monotherapy, progressive disease
!
Monotherapy, stable disease
!
Combination therapy, progressive disease
!
Combination therapy, stable disease
Excluded from participation in this clinical trial is the cohort of patients that initially 
demonstrates a positive response to treatment with an injectable HMA, but subsequently 
relapses.  This group is thought to represent an especially difficult-to-treat sub-population in 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
37
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
which gaining disease control is unlikely with currently-available or experimental options.  Even 
among patients not responding to initial HMA therapy, some will experience rapidly-progressing 
disease characterized by dramatic increases in myeloid precursors and blast cells in the marrow 
or blood.
This multi-center, international study will enroll at least 70 to 194 evaluable subjects (inclusive 
of subjects in the safety run-in and randomized phases). 
At least 6 subjects will be included in the safety run-in: 3 receiving monotherapy, and 3
receiving combination therapy (see Figure 1).  The dose and schedule of CC-486 to be evaluated 
in combination with a fixed dose of durvalumab will be determined as described in Section 4.1.2.
In the randomized treatment phase, eligible subjects will be randomized to receive CC-486 alone 
or in combination with durvalumab.  The randomized treatment phase will be conducted in 2 
stages, with a futility assessment planned at the completion of Stage 1 to determine whether the 
null hypothesis (H0: p <12.5%) can be rejected with 3 or more responses in Stage 1. If 3 or more 
responses have been observed before the end of Stage 1, the planned futility assessment may be 
performed earlier than at the completion of Stage 1 to confirm the finding of responses. This 
earlier analysis will replace the futility analysis planned at the completion of Stage 1. This earlier 
futility assessment will have the same integrity as the futility assessment planned at the 
completion of Stage 1. An analysis will be performed at the completion of Stage 2 to estimate the 
overall response rate of treatment of all the subjects in the cohort (see Figure 2). Additional
analyses will be conducted approximately 12 months after the last subject is enrolled, as 
described in Section 4.1.5 and Section 10.6.2.
During the randomized treatment phase of the study, approximately 32 subjects with PD and 32 
subjects with SD will be randomized evenly to receive either CC-486 alone, or CC-486 + 
durvalumab.  There will be 4 cohorts (16 subjects in each) in Stage 1:  SD treated with 
monotherapy, PD treated with monotherapy, SD treated with combination therapy and PD 
treated with combination therapy. If there are 2 or fewer responses in any cohort during Stage 1, 
enrollment to that arm will be terminated.  Otherwise, the cohort will continue to Stage 2 and 
accrue an additional 25 subjects each.  If 8 or more responses are observed in these 41 subjects, 
the null hypothesis will be rejected for that cohort.  During the course of the study, whenever 
both cohorts of the same patient classification (ie, SD or PD) are open for enrollment, established 
randomization procedures will be followed. During Stage 1, if a cohort is awaiting the decision 
to continue to Stage 2 pending on the response evaluation while the other cohort of the same 
patient classification is open for enrollment, available patients will be assigned to the cohort with 
open enrollment without randomization. If both cohorts of the same patient classification are 
waiting for response evaluations, enrollment of that patient classification will be temporarily 
halted.
Therefore, the total number of subjects for the randomized treatment phase will range from
approximately 64 (at Stage 1) to 164 (Stage 1 plus Stage 2) for the 4 subject cohorts.  More 
subjects can potentially be recruited for replacement of non-evaluable subjects, if needed (see 
Figure 2).
 
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Figure 
igure


EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
38
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Best supportive care measures should be used in combination with study treatment as deemed 
necessary.  Best supportive care includes, but is not limited to, treatment with RBC transfusions 
(packed red blood cells [pRBC] or whole blood), single donor or pooled donor platelet 
transfusions, antibiotic, antiviral and/or antifungal therapy, antiemetic and/or antidiarrheal 
support, nutritional support as needed, and granulocyte/granulocyte macrophage colony-
stimulating factors (G/GM-CSF) for subjects experiencing neutropenic fever/infection, or as 
secondary prophylaxis as described in Section 9.1.  Best supportive care for this study excludes 
the use of ESAs and other hematopoietic growth factors (eg, thrombopoiesis stimulating agents).
4.1.1.
Screening Phase
Screening procedures are conducted within 28 days prior to enrollment and beginning treatment 
in the safety run-in or treatment phase of the study to ensure that all inclusion and exclusion 
criteria are satisfied.
Documentation collected by the study site and laboratory values obtained from the local and/or 
central laboratory are used to review the subject’s eligibility and baseline disease characteristics; 
eg, WHO/FAB classification (Appendix A / Appendix B), IPSS (Appendix C), and International 
Prognostic Scoring System-Revised (IPSS-R) (Appendix D) risk classification.  Bone marrow 
biopsy and aspirate, blood, and relevant clinical documentation obtained during screening will be 
sent for centralized review by an independent pathologist to ensure consistency in determination 
of diagnosis and baseline disease characteristics.  If documentation of MDS diagnosis, 
WHO/FAB classification and IPSS/IPSS-R risk categorization is available and within 2 months 
of screening, results of central review are not required prior to enrollment of the subject in the 
study.  However, the results of central pathology review will be used in classification of subjects 
for analysis.  
A comprehensive blood product transfusion history must be available for at least the 56 days 
immediately preceding and including the day of the first dose of IP.  Transfusion data should 
include the blood product transfused, number of units, reason for transfusion, and date of 
transfusion.  Platelet transfusion data must include the platelet value for which the transfusion 
was deemed necessary and RBC transfusion data must include the hemoglobin (Hgb) value for 
which the transfusion was administered, if available.  All transfusion records for 56 days 
immediately preceding and including the date of enrollment should be collected whenever 
possible.
Screening assessments and procedures are described in Section 6.1.
4.1.2.
Safety Run-in
The safety run-in will utilize a conventional 3+3 design to find a tolerable dose for the 
randomized treatment phase. The subjects will be treated with CC-486 first to confirm the 
expected safety profile of CC-486 alone at the planned dose and schedule in the target 
population. The maximum administered dose (MAD) of CC-486 will not exceed 300 mg BID
(21/28 days). The resulting tolerable dose of CC-486 will then be used to combine with 
durvalumab 1500 mg for the combination therapy. 
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
39
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
The completion of the CC-486 safety run-in has determined 100 mg BID, 21/28 day regimen 
(dose level -2) as the CC-486 dose to proceed into the combination therapy safety run-in.
The dose-finding procedure for CC-486 and CC-486+durvalumab will proceed as following.
Part (A) - starting dose for CC-486 as monotherapy: A group of 3 subjects will receive CC-486 
at dose level 0 (200 mg BID (21/28 days) and will be closely monitored through at least 2 
treatment cycles for dose-limiting toxicities, as defined in Section 4.1.2.1.  If for any reason the 
monotherapy safety run-in starting dose needs to be reduced, the starting dose will follow the 
established levels in Table 1. 
1. If #Subject with DLT = 0/3, the dose will be declared tolerable and used as the starting 
CC-486 dose.
2. If #Subject with DLT = 1/3, recruit another 3 subjects to test the same dose.
a.
If #Subject with DLT = 1/6, the dose will be declared tolerable and used as the 
starting CC-486 dose.
b. If #Subject with DLT ≥ 2/6, the dose will be declared intolerable and the next 
lower dose level of CC-486 according to Table 1 will then be explored. Repeat 
the entire procedure with 3 new subjects.
3. If #Subject with DLT ≥ 2/3, the dose will be declared intolerable and the next lower dose 
level of CC-486 according to Table 1 will then be explored. Repeat the entire procedure 
with 3 new subjects.
The safety run-in for CC-486 monotherapy has been completed as of December 2016.
Part (B) - starting dose for CC-486+durvalumab as combination therapy: A group of 3 subjects 
will receive CC-486 dose determined in Part (A) above plus durvalumab 1500 mg (given by IV 
infusion [over 1 hour ± 5 minutes] on Day 1 of each 28-day treatment cycle) and will be closely 
monitored through at least 2 treatment cycles for dose-limiting toxicities, as defined in
Section 4.1.2.1.  
1. If #Subject with DLT = 0/3, the dose will be declared tolerable and used as the starting 
CC-486 dose plus durvalumab 1500 mg.
2. If #Subject with DLT = 1/3, recruit another 3 subjects to test the same dose.
a.
If #Subject with DLT = 1/6, the dose will be declared tolerable and used as the 
starting CC-486 dose plus durvalumab 1500 mg.
b. If #Subject with DLT ≥ 2/6, the dose will be declared intolerable and the next 
lower dose level of CC-486 according to Table 1 plus durvalumab 1500 mg will 
be explored. Repeat the entire procedure with 3 new subjects.
3. If #Subject with DLT ≥ 2/3, the dose will be declared intolerable and the next lower dose 
level of CC-486 according to Table 1 plus durvalumab 1500 mg will be explored. Repeat 
the entire procedure with 3 new subjects.
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
40
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Table 1:
CC-486 Dose Levels for Safety Run-in
Dose Level
CC-486 Dose/Schedule
Durvalumab Dose/Schedule
0
200 mg BID; 21/28 days
1500 mg IV infusion on Day 1 
of 28 day treatment cycle
-1
150 mg BID; 21/28 days
-2
100 mg BID; 21/28 days
-3
100 mg BID; 14/28 days
BID = twice daily; IV = intravenous.
Subjects who discontinue participation in the safety run-in phase of the study for reasons not
related to study treatment (eg, rapid disease progression or administrative reasons) before they 
can be assessed for DLT will be replaced for the DLT assessment.
Other than the evaluation of DLTs, procedures and assessments to be performed during the 
safety run-in are similar to those performed for the randomized treatment phase of the study (see 
Section 4.1.3).
Data from the safety run-in will be reviewed in conjunction with the study investigators, 
Scientific Steering Committee, and Data Monitoring Committee to ensure agreement with the 
recommended Phase 2 dosing regimens prior to beginning enrollment to the randomized 
treatment phase.
Once the recommended combination regimen is identified, enrollment into the randomized 
treatment phase of the study may begin.
4.1.2.1.
CC-486 Monotherapy Dose-Limiting Toxicity
Dose-limiting toxicities will be evaluated during the DLT evaluation period for the subjects in 
the safety run-in.  For CC-486, the DLT evaluation period will be defined as the time from the 
first dose of CC-486 until the planned first dose of IP in Cycle 3. Subjects are considered 
evaluable for assessment of DLT if they receive ≥ 2 protocol-assigned cycles of CC-486 and 
complete the safety follow-up through the end of the DLT evaluation period, or experience a 
DLT during the DLT evaluation period.  Non-evaluable subjects will be replaced. 
For CC-486, a DLT will be defined as:
!
Grade 5 hematologic events;
!
Grade 4 neutropenia lasting > 10 days or accompanied by fever (defined as > 38.5°C 
requiring hospitalization);
!
Grade ≥3 thrombocytopenia with clinically significant bleeding and, 
!
Any Grade ≥ 3 non-hematologic toxicity or hematologic toxicity other than anemia or 
cytopenia with the following exceptions:
∀
Grade 3 emesis that responds to optimal antiemetic therapy within 72 hours;
∀
Grade 3 diarrhea that responds to optimal medical management within 72 hours;
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
41
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
∀
Grade 3 fatigue in a subject who had Grade 2 fatigue at study entry and that 
recovers to baseline grade or less within 72 hours;
∀
Grade 3 or 4 laboratory abnormalities that are not accompanied by clinical signs 
or symptoms and are not believed by the Investigator to be medically significant.
Grade 3 or 4 events clearly and directly related to the primary disease or to another etiology 
documented by the investigator are not considered DLTs.
Table 4 provides guidance for the management of CC-486-related toxicity, including provisions 
for appropriate delay or discontinuation of treatment.
For acute events of neutropenia, thrombocytopenia, and leucopenia, associated with treatment 
with CC-486, the following formula should be used to calculate the minimum neutrophil, 
platelet, or white blood cell count that would signify “recovery” of marrow function and enable 
initiation of the subsequent treatment cycle.
For example, a subject with a pre-treatment absolute neutrophil count (ANC) of 1.0 x 109/L
experiences a nadir ANC of 0.4 x 109/L (Grade 4) following one cycle of treatment.  The 
subject’s ANC must recover to at least 0.4 + (1.0-0.4)/2, or 0.7 x 109/L before beginning the 
subsequent treatment cycle.  If the event is judged by the investigator to be related to study 
treatment and recovery is not achieved within 14 days of completing Cycle 1, it will be 
considered a dose-limiting toxicity.
4.1.2.2.
Durvalumab / CC-486 Combination Therapy Dose-Limiting Toxicity
Dose-limiting toxicities will be evaluated during the DLT evaluation period for the subjects in 
the safety run-in.  Please refer to Section 4.1.2.1 for CC-486 related dose-limiting toxicity
criteria.
For durvalumab, the DLT evaluation period will be defined as the time from the first dose of 
durvalumab until the planned administration of the third dose of durvalumab. Subjects are 
considered evaluable for assessment of DLT if they receive 2 protocol-assigned doses of 
durvalumab and complete the safety follow-up through the end of the DLT evaluation period, or 
experience a DLT during the DLT evaluation period.  Non-evaluable subjects will be replaced. 
The severity grading of adverse events will be determined according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
For durvalumab, a DLT will be defined as any Grade 3 or higher durvalumab-related toxicity
that occurs during the DLT evaluation period. Toxicity that is clearly and directly related to the 
Nadir count
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
42
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
primary disease or to another etiology is excluded from this definition. The following will be 
considered DLTs:
!
Liver transaminase elevation ≥ 5 x but ≤8 x the upper limit of normal (ULN) that 
does not downgrade to Grade 2 within 5 days after onset with optimal medical 
management, which may include systemic corticosteroids. Transaminase elevation    
> 8 x ULN or total bilirubin > 5 x ULN will be considered a DLT regardless of 
duration or reversibility.
!
Any ≥ Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 7 days of the 
initiation of maximal supportive care.
The definition excludes the following conditions:
!
Grade 3 fatigue for ≤ 7 days
!
Grade 3 or 4 nausea or vomiting that resolves to ≤ Grade 2 with optimal symptomatic 
treatment
!
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the subject becomes asymptomatic
!
Grade 3 inflammatory reaction attributed to an antitumor response (eg, inflammatory 
reaction at sites of lymphomatous disease, etc.) that resolves to ≤ Grade 1 within 30 
days
!
Concurrent vitiligo or alopecia of any AE grade
!
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management
!
Any Grade 3 electrolyte alteration that is reversible to ≤ Grade 1 within 72 hours after 
onset 
!
Grade 3 amylase and/or lipase elevation that is not associated with clinical symptoms 
or radiographic changes suggestive of pancreatitis
!
Any ≥ Grade 3 lymphopenia (unless clinically significant)
!
Grade 3 or 4 neutropenia in the absence of fever or infection that resolves to ≤ Grade 
2 within 7 days after onset
!
Grade 3 or 4 thrombocytopenia without evidence of bleeding that resolves to Grade 2 
within 7 days after onset and does not require a transfusion
!
Grade 3 anemia that resolves to ≤ Grade 2 within 7 days without transfusion support
!
Grade 3 fever lasting ≤ 24 hours with or without medical therapy and is not 
considered an SAE
!
Grade 3 rigors or chills lasting < 6 hours that respond to optimum medical therapy
!
Grade 3 tumor lysis syndrome that resolves to ≤ Grade 2 within 72 hours after 
initiation of maximal medical intervention
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
43
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Immune-mediated adverse events are defined as AEs of immune nature (ie, inflammatory) in the 
absence of a clear alternative etiology. In the absence of clinical abnormality, repeat laboratory
testing will be conducted to confirm significant laboratory findings prior to designation as a 
DLT. An AE not listed above may be defined as a DLT after a consultation with the sponsor and 
investigators, based on the emerging safety profile.
&&,
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
44
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Figure 1: Safety Run-in Phase Study Design
Extension 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
45
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
4.1.3.
Randomized Treatment Phase
Figure 2 depicts the study design of the randomized treatment phase.
The randomized treatment phase of the study will be conducted in 2 stages.  Following 
identification of dose and schedule in the safety run-in of a treatment arm, enrollment for Stage 1 
of the treatment phase may begin.  Eligible subjects will be randomized to one of two open 
treatment arms:
!
Monotherapy – CC-486 alone, or
!
Combination Therapy – CC-486 plus durvalumab
In the event that only one treatment arm for a cohort is open for accrual due to available safety 
and efficacy data, subjects will be assigned to treatment on the open arm.
Subjects with stable disease at the time of enrollment will be included in the stable disease (SD) 
cohort for that treatment arm, and those with progressive disease at the time of enrollment will 
be included in the progressive disease (PD) cohort (see Section 7.2).  Subjects with MDS that
responded to injectable HMA treatment are not eligible for this study, even if their disease 
subsequently relapsed.  
Numbers of subjects with PD and SD allocated to each treatment arm will be monitored to 
enable the planned analyses for each sub-population.  Hence there are 4 cohorts being evaluated 
in this study:
!
Monotherapy, progressive disease
!
Monotherapy, stable disease
!
Combination therapy, progressive disease
!
Combination therapy, stable disease
Excluded from participation in this clinical trial is the cohort of patients that initially 
demonstrates a positive response to treatment with an injectable HMA, but subsequently 
relapses.  This group is thought to represent an especially difficult-to-treat sub-population in 
which gaining disease control is unlikely with currently-available or experimental options.  Even 
among patients not responding to initial HMA therapy, some will experience rapidly-progressing 
disease characterized by dramatic increases in myeloid precursors and blast cells in the marrow 
or blood.
All baseline assessments and procedures should be performed prior to administration of the first 
dose of CC-486 or infusion of durvalumab.  
The subject should begin treatment on the day of randomization via Interactive Response 
Technology System (IRTS) whenever possible, but the dose may be delayed for up to 5 days if 
necessary for logistical reasons.  Any delay greater than 5 days must be discussed with, and 
approved by, the sponsor’s medical monitor and may result in the need to repeat screening.  
Approximately 10-12 evaluable subjects randomized to the combination treatment arm at 
selected centers will participate in PK sampling procedures as described in Sections 4.1.4 and 
6.10.  Subjects in whom Cycle 1 and 2 PK sampling cannot be completed will be replaced for PK 
collection purposes.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
46
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
A subject’s CC-486 dose and schedule may be adjusted as described in Section 8.2.4 for the 
management of unacceptable toxicity.  All efforts should be made to maintain BID dosing.  A 
QD ‘rescue’ regimen is available if the investigator believes a subject’s ability to tolerate 
treatment is limited by twice-daily dosing (see Table 3).  Subjects who cannot tolerate a reduced 
dose and schedule of 100 mg BID (or 200 mg QD), 14/28 days, will discontinue the treatment 
phase of the study and enter the follow-up phase.  
Interruption or delay of treatment with CC-486 for up to 42 days is permitted as outlined in 
Section 8.2.4.1 to enable recovery from IP-related toxicity.  If there is a delay of more than 42 
days (6 weeks) in the start of the next cycle, the medical monitor must be consulted.  When the 
start of a new treatment cycle with CC-486 is delayed for any reason, the infusion of durvalumab
will also be delayed (in subjects randomized to the combination treatment arm), such that 
durvalumab continues to be administered on Day 1 of each treatment cycle.  Study treatment 
should be discontinued if there is a delay of more than 56 days (8 weeks) in the start of the next 
cycle, unless, in the opinion of the investigator and the medical monitor, the subject is 
experiencing clinical benefit.
For toxicity that is thought to be related to treatment with durvalumab, including immune-
mediated AEs (imAEs) or infusion-type reactions, as well as for non-immune mediated 
reactions, the infusion of durvalumab may be slowed or interrupted, or a dose may be withheld, 
as described in Section 8.2.4.2.  Dose reduction of durvalumab is not permitted.
In the absence of unacceptable toxicity, subjects who show signs of worsening disease (clinical
or hematological), who remain in stable disease, or do not experience modified IWG 2006 
hematologic improvement (HI) or better (PR, CR or marrow CR – modified IWG 2006, 
Appendix F) after 2 well-tolerated cycles,  may have their dose increased at the discretion of the 
investigator and in discussion with the medical monitor as described in Section 6.5 and Table 3. 
Again, dose and schedule may be adjusted as described in Section 8.2.4 in order to manage 
toxicity.  
Visits during the randomized treatment phase are scheduled weekly for the first 2 treatment 
cycles, every 2 weeks for the next 10 cycles and monthly once a subject has completed 12 
cycles.
During treatment, subjects will be assessed continuously for safety and efficacy.  Assessments 
and procedures include:
!
AEs including AESI
!
physical examination
!
vital signs
!
ECG (screening and treatment 
discontinuation visit only)
!
body weight measurement
!
Eastern Cooperative Oncology Group 
(ECOG) performance status
!
cytogenetics
!
blood and bone marrow sampling for 
biomarker analysis
!
general disease status assessment
!
modified IWG response assessment 
!
IP dispensation, administration and 
accountability
!
infusion monitoring for those receiving 
durvalumab
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
47
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
concomitant medications, therapies and 
procedures
!
transfusion assessment
!
hematology assessments via central lab
!
peripheral blood smear
!
serum chemistry (to include amylase 
and lipase), thyroid function parameters
via central lab
!
urinalysis
!
pregnancy testing (females of child 
bearing potential [FCBP] only)
!
bone marrow aspirate (or biopsy if an 
adequate aspirate cannot be obtained)
!
subsequent MDS therapies (treatment 
discontinuation visit only)
!
immunogenicity assessment
 
!
PK sample collection in subjects 
receiving combination therapy at 
selected study centers
Because a hematologic response to treatment with durvalumab and/or CC-486 may be delayed, it 
is recommended that subjects receive at least 6 cycles of treatment with the IP; however, subjects 
may be discontinued from treatment at the investigator’s discretion prior to reaching the 
recommended minimum number of cycles for any of the reasons detailed in Section 12.
Subjects’ general disease status will be assessed based on available clinical and laboratory data at 
the end of Cycle 6, prior to starting Cycle 7.
Subjects who satisfy any one of the following criteria may continue on to Cycle 7 and beyond.  
The disease status of these subjects will be assessed at the beginning of every new cycle based 
on available clinical and laboratory assessments:
!
Objective response to treatment:  CR, marrow CR (mCR), PR, or HI (Appendix F), or
!
RBC-transfusion-independence, or
!
≥ 50% reduction in average RBC transfusion requirement in the 56-day (8-week) 
period immediately prior to disease status assessment as compared to the average 
baseline RBC transfusion requirement, or
!
any other clinical benefit, including no evidence of progressive disease (see Table 8
for definitions of progressive disease).
Thereafter, a subject may be discontinued from treatment with IP for any of the reasons detailed 
in Section 12.
Subjects who fail to meet these criteria at the end of Cycle 6 will discontinue IP at that time and 
enter the follow-up phase of the study.
In the event that a subject assigned to the combination treatment arm discontinues treatment with 
durvalumab or CC-486 because of drug-related toxicity, treatment with CC-486 or durvalumab
monotherapy may continue until any discontinuation criterion is met (see Section 12). 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
48
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Prior to discontinuing treatment for a subject, it is recommended that the investigator contact the 
medical monitor and forward appropriate supporting documents for review and discussion.  The 
decision to discontinue a subject remains the responsibility of the treating physician and will not 
be delayed or refused by the sponsor.
All subjects who have received at least one dose of IP will undergo treatment discontinuation 
procedures (Section 6.13) when treatment with IP is discontinued.  If a subject is discontinued 
during a regularly-scheduled visit, that visit will be considered the treatment discontinuation visit 
and all treatment discontinuation procedures should be completed.  If a procedure had been 
performed within 7 days of the treatment discontinuation visit, it does not need to be repeated.
For all enrolled/randomized subjects, the reason for discontinuing treatment will be recorded in 
the case report form (CRF) and in the source document, regardless of whether or not a dose of IP 
was ever administered.
During the randomized treatment phase of the study, approximately 32 subjects with PD and 32 
subjects with SD will be randomized evenly to receive either CC-486 alone, or CC-486 + 
durvalumab.  There will be 4 cohorts (16 subjects in each) in Stage 1: SD treated with 
monotherapy, PD treated with monotherapy, SD treated with combination therapy and PD 
treated with combination therapy. If there are 2 or fewer responses in any cohort during Stage 1, 
enrollment to that arm will be terminated.  Otherwise, the cohort will continue to Stage 2 and 
accrue an additional 25 subjects each.  If 8 or more responses are observed in these 41 subjects, 
the null hypothesis will be rejected for that cohort.
Therefore, the total number of subjects for the randomized treatment phase will range from 
approximately 64 (at Stage 1) to 164 (Stage 1 plus Stage 2) for the 4 cohorts. More subjects can 
potentially be recruited for replacement of non-evaluable subjects, if needed (see Figure 2).
A subject is considered evaluable for response once they have received one cycle of treatment 
with a maximum of 6 cycles of treatment, or have discontinued from the treatment phase for any 
reason.  A subject who discontinues from the treatment phase for any reason not related to IP 
toxicity (eg, disease progression or administrative reasons) before the first post-baseline efficacy 
assessment (following treatment Cycle 2) will be replaced and an additional subject will be 
included in that cohort (PD or SD cohort).  This will ensure a valid statistical assessment in both 
the intent-to-treat (ITT) population, and, if different, the modified ITT (mITT) population
(Section 10.2), excluding those who discontinue study treatment early because of the rapid 
progression of their disease, or leave the study for non-study-related reasons prior to this first 
post-baseline efficacy assessment.
The sponsor, in consultation with the Scientific Steering Committee and Independent Data 
Monitoring Committee, will continue to evaluate each subject’s response to treatment based on 
modified IWG 2006 criteria (Appendix F) until the required number of responses is observed for 
a given cohort to proceed to Stage 2, or when the last active subject in Stage 1 of any cohort 
(monotherapy or combination therapy; PD or SD) reaches the disease status assessment 
following treatment Cycle 6.  At that point a final determination can be made regarding the 
progression of that cohort to Stage 2.
In addition to evaluating responses to treatment based on objective criteria, the sponsor, in 
consultation with the Scientific Steering Committee and Independent Data Monitoring 
Committee, will also evaluate the quality of each objective response.  Quality of response will be 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
49
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
assessed based on the magnitude of hematologic and biologic responses observed in individual 
subjects, with special consideration for response duration.  The sponsor may decide to 
discontinue accrual to one or both cohorts despite observing the required number of objective 
responses if the responses are not thought to be clinically relevant. For example, if a sufficient 
quantity of responses is observed, but all responses are transient hematologic improvements that 
are not thought to convey a meaningful benefit for the subject, the sponsor may choose to not 
continue enrollment to that cohort in Stage 2.  Specific details for what constitutes a quality 
response will be provided in the final Statistical Analysis Plan (SAP).
4.1.4.
Pharmacokinetics Sub-study
Blood samples for pharmacokinetic analysis will be collected from approximately 10-12 
evaluable subjects randomized to the combination treatment arm at selected sites.  This will 
enable assessment of drug-drug interactions.  Subjects participating in PK procedures will agree 
to have blood samples collected as described in Section 6.10.
All subjects receiving durvalumab will have blood samples collected for assessment of 
immunogenicity: development of anti-durvalumab antibodies. 
 
 
.
4.1.5.
Follow-up Phase
4.1.5.1.
Follow-up in Subjects Receiving CC-486 Monotherapy
All subjects who receive at least one dose of CC-486 in the safety run-in or randomized 
treatment phase and discontinue treatment for any reason will be followed for at least 28 days 
after their last dose of CC-486 for the assessment of safety-related parameters (see Section 6.14).  
After the 28-day period, only SAEs made known to the investigator that are suspected of being 
related to treatment with CC-486 need to be reported.
A 28-day follow-up visit will be conducted 28 (±3) days following the last dose of CC-486 or 
during the final treatment phase study visit (whichever date is later) for assessment of the 
following safety-related parameters (see Section 6.14).
!
Survival, 
!
AEs including AESI
!
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!
RBC and platelet transfusions,
!
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!
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Subjects in follow-up will then be contacted every 3 months from the date of the 28-day follow-
up visit until death, loss-to follow-up, withdrawal of consent to further follow-up, or study 
closure to collect information related to: 
!
Survival
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
50
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
Subsequent MDS-related therapies
!
Disease progression to AML.  
This will continue until the last active subject completes approximately 12 months of treatment 
and/or follow-up unless additional follow-up is needed to evaluate time-to-event endpoints (eg, 
progression-free survival [PFS] and survival).  Follow-up contacts will routinely be conducted 
by telephone unless special circumstances exist (eg, the subject will visit the center for a non-
study-related reason).  
Females of childbearing potential should avoid becoming pregnant for 90 days after the last dose 
of IP and male subjects should avoid fathering a child for 90 days after the last dose of IP.
4.1.5.2.
Follow-up in Subjects Receiving Durvalumab / CC-486 Combination Therapy
All subjects who receive at least one dose of durvalumab in the safety run-in or randomized 
treatment phase and discontinue treatment for any reason will be followed for at least 90 days 
after their last infusion of durvalumab for the assessment of safety-related parameters (see 
Section 6.14).  After the 28-day period for CC-486 and the 90-day period for durvalumab, only
SAEs made known to the investigator that are suspected of being related to study treatment need 
to be reported.
Subjects are to return to the study site 28 (±3) days after the End of Trial (EOT) visit and 90 (±3) 
days after the last dose of durvalumab for assessment of the following safety-related parameters:
!
Survival, 
!
AEs including AESI (monitored until 28 days after last dose of CC-486 and 90 days 
after last dose of durvalumab),
!
Concomitant medications, therapies, and procedures (monitored until 90 days after 
last dose of durvalumab),
!
RBC and platelet transfusions,
!
New MDS therapies, or 
!
Disease progression to AML 
Subjects in follow-up will then be contacted every 3 months from the date of the 90-day follow-
up visit until death, loss-to follow-up, withdrawal of consent to further follow-up, or study 
closure to collect information related to: 
!
Survival
!
Subsequent MDS-related therapies
!
Disease progression to AML.  
This will continue until the last active subject completes approximately 12 months of treatment 
and/or follow-up unless additional follow-up is needed to evaluate time-to-event endpoints (eg, 
PFS and survival).  Follow-up contacts will routinely be conducted by telephone unless special 
circumstances exist (eg, the subject will visit the center for a non-study-related reason).  
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
51
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Females of childbearing potential should avoid becoming pregnant for 90 days after the last dose 
of IP and male subjects should avoid fathering a child for 90 days after the last dose of IP.
4.1.6.
Extension Phase
The Extension Phase (EP) allows subjects who are receiving oral azacitidine and demonstrating 
clinical benefit as assessed by the Investigator, to continue to receive oral azacitidine until they 
meet the criteria for study treatment discontinuation.
Subjects will remain at the same dose levels from the main study during the Extension Phase and 
may decrease dose levels following dose modifications (Section 8.2.4 ); however, dose levels 
will not increase. Any potential dose escalation will be considered a treatment failure and the 
subject should be discontinued.
Survival will not be followed in the Extension Phase.
Details for the EP are provided in Appendix J.
4.1.7.
Study Closure
The study will conclude once all subjects have completed or discontinued from the Extension 
Phase.
The study is expected to close when the last subject completes approximately 12 months of 
treatment and/or follow-up, unless additional follow-up is needed to analyze time-to-event
endpoints.  At the investigator’s discretion, upon completion of the study, subjects who continue 
to benefit from treatment with CC-486 and/or durvalumab, without unacceptable toxicities and
who have not met criteria for treatment withdrawal may continue to receive CC-486 and 
durvalumab provided by the sponsor through this protocol or through an open-label ‘rollover’ 
study.
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc.).
In addition, the investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;
!
Falsification of records;
!
Failure to adhere to the study protocol.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
52
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Figure 2:
Randomized Treatment Phase Study Design
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
53
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
4.2.
Study Design Rationale
This is a Phase 2, international, multicenter, randomized, parallel group, open-label study 
designed to evaluate the efficacy and safety of treatment with CC-486 (an orally-available 
cytidine analog) alone and in combination with durvalumab (a monoclonal antibody targeting the 
Programmed Cell Death Ligand 1 [PD-L1]) in subjects with myelodysplastic syndromes when an 
objective response is not achieved through treatment with an injectable hypomethylating agent 
(iHMA). The randomized study design reduces bias in subject selection by treatment group, and 
enables a valid comparison of efficacy and safety between treatment groups.  This will allow for 
selection of the appropriate treatment group for further evaluation in the post-iHMA setting.
The study population represents the group of patients with MDS that have exhausted available
HMA treatment options.  No additional medical intervention is currently approved in this setting 
and prognosis for members of this population is dismal.  
The study will evaluate the two treatment regimens in two subsets of subjects who fail to respond 
to iHMA treatment: those with stable disease (with no hematologic response or improvement) 
associated with the iHMA, and those with disease progression during or following iHMA 
treatment.  The study excludes subjects who respond to injectable therapy but subsequently 
relapse, because this group is thought to represent an especially hard-to-treat segment of the 
population where additional disease control is generally unlikely with this, or other, experimental 
agents.  The SD and PD sub-populations will be analyzed separately for the monotherapy and 
combination therapy treatment arms.
A safety run-in phase of the study will explore the safety and tolerability of CC-486 alone and in 
combination with durvalumab to confirm that there are no overlapping or synergistic toxicities 
limiting the ability of the two drugs to be delivered in combination, and to determine the initial 
dose and schedule to be applied for the randomized portion of the study.  Once a recommended
dose and schedule for the combination has been identified as described in Section 4.1.2, 
enrollment into the randomized treatment phase may begin.
All cohorts will be evaluated using a Simon’s 2-stage design (Section 10.3).  This approach will 
enable safety and efficacy to be formally evaluated following enrollment of Stage 1 for each 
cohort.  In this way, the sponsor can determine if exposure of additional subjects to CC-486
alone or in combination with durvalumab is warranted based on the accumulating data from 
subjects enrolled in Stage 1.  Approximately 64 evaluable subjects will be enrolled in the first 
stage of the randomized treatment phase.  If sufficient objective responses are observed in one or 
more cohorts (SD monotherapy, PD monotherapy, SD combination therapy, PD combination 
therapy), the applicable cohort(s) will be expanded in the second stage of study to include up to 
approximately 25 additional subjects per cohort (see Section 4.1, Section 10.3, and Figure 2).
In addition to evaluating responses to treatment based on objective criteria, the sponsor, together 
with the study’s Scientific Steering Committee and Independent Data Monitoring Committee 
will also evaluate the quality of each objective response.  Quality of response will be assessed 
based on the magnitude of hematologic and biologic responses observed in individual subjects, 
with special consideration for response duration.  The sponsor may decide to discontinue accrual 
to one or more cohorts despite observing the required number of objective responses if the 
responses are not thought to be clinically relevant.  For example, if a sufficient quantity of 
responses is observed, but all responses are transient hematologic improvements that are not 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
54
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
thought to convey a meaningful benefit for the subject, the sponsor may choose not to continue 
enrollment to that cohort in Stage 2.
The first dose and schedule for CC-486 to be tested in the safety run-in phase is 200 mg BID for 
the first 21 days of each 28-day treatment cycle. This dose and schedule has demonstrated 
reasonable tolerability in a prior study (Garcia-Manero, 2009; Garcia-Manero, 2010) and BID 
dosing is hypothesized to contribute to anti-tumor activity by affecting more malignant cells in 
S-phase throughout the treatment cycle compared to a once daily or injectable regimen.  
Durvalumab will be administered on Day 1 of each 28-day treatment cycle as a single 1500 mg 
IV infusion, as described in Section 8.2.2.2.
Subjects should continue to receive IP for at least 6 cycles of treatment before considering 
treatment discontinuation for lack of clinical activity because, based on prior studies with 
parenteral azacitidine therapy, response to treatment may be delayed to allow for adequate cell 
line recovery without dose reduction (Silverman, 2006).  While on treatment, subjects will 
continue to receive best supportive care, thus the requested 6-month minimum treatment period 
does not represent an undue risk to subjects.  In addition, because overall survival is one of the 
endpoints, the effect of extended therapy is being evaluated; suspension of therapy at an early 
time point may blunt any possible clinical benefit.  
Analysis of the primary endpoint will be conducted only after all active subjects have completed 
the modified IWG response assessment following a maximum of 6 cycles of therapy.  
Best supportive care provided to all study subjects is to include RBC (pRBC and whole blood) 
and platelet transfusions (single donor or pooled donor), antibiotic, antiviral and antifungal 
therapy, and nutritional support as needed.  Granulocyte colony-stimulating factors are allowed 
only for subjects experiencing neutropenic fever/infection as well as for secondary prophylaxis 
under certain conditions (see Section 9.1).  
Best supportive care for this study excludes the use of ESAs and other hematopoietic growth 
factors as these therapies are not approved for the treatment of MDS and do not increase platelet 
counts in patients with concomitant thrombocytopenia associated with MDS.  Furthermore, 
ESAs are less effective for RBC transfusion-dependent anemia than for RBC transfusion-
independent anemia (Hellstrom-Lindberg, 2003).  Thus the best supportive care for this study 
should minimize the risk of not providing subjects with appropriate care, while providing the 
potential benefit of achieving additional disease control that was previously not achievable.  
Further consideration for excluding the use of ESAs from best supportive care is the theoretical 
possibility that the combination of ESA with azacitidine may have an additive effect on response
and this could confound the evaluation of efficacy associated with CC-486 itself. Thus
excluding the use of ESAs from best supportive care would mitigate any possible bias in data 
interpretation, and allow accurate assessment of study endpoints.
4.3.
Study Duration 
The enrollment period for this study is expected to last approximately 39 months.  The treatment 
and follow-up phases of study are expected to conclude approximately 12 months after the last 
subject is enrolled. The Extension Phase is expected to last approximately 24 months. Therefore, 
the total duration of the study is expected to be approximately 75 months.  
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
55
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
At the investigator’s discretion, upon completion of the study, subjects who continue to benefit 
from treatment without unacceptable toxicities, and who have not met criteria for treatment 
withdrawal may continue to receive IP provided by the sponsor through this protocol or through 
an open-label ‘rollover’ study.
4.4.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the 
Statistical Analysis Plan, whichever is the later date.
The study will conclude once all subjects have completed or discontinued from the EP.
&&,
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P.


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
56
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
5.
TABLE OF EVENTS
Table 2 provides a detailed description of all study events or procedures by time point for each 28-day treatment cycle.
Table 2:
Table of Events
Procedure/Assessment
Screening 
Safety Run-in or Treatment Phase a
Follow-up Phase b
≤ 28 Days 
Prior to 
C1D1
Cycles 1 – 2
Cycles 3 – 12
Cycles 13+
Treatment 
D/C d
Safety
Follow-up 
Visit(s)x
Additional 
Follow-up 
Contacts
Day 1c
Days 8, 
15, 22
Day 1
Day 15
Day 1
Study Entry Assessments
Informed Consent
∃
--
--
--
--
--
--
--
--
Inclusion and Exclusion Criteria
∃
--
--
--
--
--
--
--
--
MDS Diagnosis (WHO and FAB
Classifications) and IPSS/IPSS-R Scores
∃e
--
--
--
--
--
--
--
--
RBC and Platelet Transfusion History
∃f
--
--
--
--
--
--
--
--
Demographics and Medical History
∃
--
--
--
--
--
--
--
--
Prior Treatment for MDS 
∃g
--
--
--
--
--
--
--
--
Prior General Medications
∃h
--
--
--
--
--
--
--
--
Examinations
Physical Examination
∃
∃
--
∃
--
∃
∃
∃
--
Vital Signs i
∃
∃
--
∃
--
∃
∃
∃
--
Body Weight 
∃
∃
--
∃
--
∃
∃
∃
--
Height
∃
--
--
--
--
--
--
--
--
ECOG Performance Status
∃
∃
--
∃
--
∃
∃
∃
--
Electrocardiogram – Local
∃j
--
--
--
--
--
∃
--
--
Laboratory Assessments
Urinalysis
∃k
--
--
∃k
--
∃k
∃
∃
--
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
57
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Table 2:
Table of Events (Continued)
Procedure/Assessment
Screening 
Safety Run-in or Treatment Phase a
Follow-up Phase b
≤ 28 Days 
Prior to 
C1D1
Cycles 1 – 2
Cycles 3 – 12
Cycles 13+
Treatment 
D/C d
Safety 
Follow-up 
Visit(s)x
Additional 
Follow-up 
Contacts
Day 1c
Days 8, 
15, 22
Day 1
Day 15
Day 1
Serum EPO, Ferritin and Transferrin 
Saturation (Fe/TIBC)
∃l
--
--
--
--
--
--
--
--
Hematology m
∃
∃
∃
∃
∃
∃
∃
∃
--
Coagulation Parameters
∃
--
--
--
--
--
--
--
--
Serum Chemistry and Thyroid Function n
∃
∃
∃
∃
--
∃
∃
∃
--
Pregnancy Testing (FCBP only) o
∃
∃
--
∃
--
∃
∃
∃
--
Safety Assessments
Assessing Adverse Events including 
AESIs
After signing ICD, until 28 days after the last dose of CC-486 (90 days after the last dose of durvalumab) or the 
last study visit, whichever date is later
--
Monitoring for Progression to AML
After signing ICD and until death, loss to follow-up, withdrawal of consent for further data collection, or study closure
Concomitant Medications, Therapies, and 
Procedures
--
From the first dose of IP until 28 days after the last dose of CC-486 (90 days after the last dose of 
durvalumab) or the last study visit, whichever date is later
--
Disease Assessments
Bone Marrow Aspirate and/or Biopsy p
∃
--
--
∃p
--
∃p
∃
--
--
Peripheral Blood Smear p
∃
--
--
∃p
--
∃p
∃
--
--
Cytogenetic Testing p
∃
--
--
∃p
--
∃p
∃
--
--
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
58
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Table 2:
Table of Events (Continued)
Procedure/Assessment
Screening 
Safety Run-in or Treatment Phase a
Follow-up Phase b
≤ 28 Days 
Prior to 
C1D1
Cycles 1 – 2
Cycles 3 – 12
Cycles 13+
Treatment 
D/C d
Safety 
Follow-up 
Visit(s)x
Additional 
Follow-up 
Contacts
Day 1c
Days 8, 
15, 22
Day 1
Day 15
Day 1
Durvalumab ADA (Immunogenicity)
 
--
C1D1
C2D1
--
C4D1
C6D1
C10D1
--
C14D1
--
--
--
Pharmacokinetics (select subjects in 
combination treatment arm only) q
C1D-1
C1D1, 
C2D1
Note: 
also 
collect 
PK on 
C1D3 
and 
C2D3
C1D8, 
C1D15, 
C1D22, 
C2D8,  
C2D15,
C2D22
--
--
--
--
--
--
IP Administration and Accountability
CC-486 Dispensation r
--
∃
--
∃
--
∃y
--
--
--
CC-486 Administration s
--
Day 1 to Day 21 of each 28-day treatment cycle 
--
--
--
Durvalumab Administration (combination 
treatment arm only)
--
∃
--
∃
--
∃
--
--
--
Durvalumab Infusion Observation
(combination treatment arm only)
--
∃
--
∃
--
∃
--
--
--
IP Accountability
--
∃t
--
∃
--
∃y
∃y
--
--
Response Assessments
Transfusion Assessment u
--
From the first dose of IP (C1D1) until 90 days after the last dose of IP or the last study visit, 
whichever date is later
--
IWG Response Assessment v
--
∃
--
∃
--
∃
∃
--
--
General Disease Status Assessment w
--
--
--
∃
--
∃
∃
--
--
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
59
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Table 2:
Table of Events (Continued)
Procedure/Assessment
Screening 
Safety Run-in or Treatment Phase a
Follow-up Phase b
≤ 28 Days 
Prior to 
C1D1
Cycles 1 – 2
Cycles 3 – 12
Cycles 13+
Treatment 
D/C d
Safety 
Follow-up 
Visit(s)x
Additional 
Follow-up 
Contacts
Day 1c
Days 8, 
15, 22
Day 1
Day 15
Day 1
Subsequent MDS Therapies 
--
--
--
--
--
--
∃
∃
∃
Survival 
--
--
--
--
--
--
--
--
∃
Abbreviations: ADA = anti-drug antibodies; AE = adverse events; AESIs = adverse events of special interest; AML = acute myeloid leukemia; CRF = case report form; CxDx = 
Day x of Cycle x; D/C = discontinuation; ECOG = Eastern Cooperative Oncology Group; EPO = erythropoietin; FAB = French-American-British myelodysplastic syndrome 
classification system; FCBP = female of childbearing potential; Fe/TIBC = serum iron/serum total iron-binding capacity; ICD = informed consent document; IP = investigational 
product; IPSS(-R) = International Prognostic Scoring System (-Revised); IRTS = Interactive Response Technology System; IWG = International Working Group; MDS = 
myelodysplastic syndromes; PK = pharmacokinetics; RBC = red blood cell; WBC = white blood cell; WHO = World Health Organization.
a. One cycle (28 days or 4 weeks) is considered one month.  The acceptable study visit window in the treatment phase is ±3 days for Cycles 1 and 2, and; ±7 days for Cycle 3 
and beyond, unless otherwise noted for a particular assessment.  Study visits should also take into account the subject’s IP supply.  Only 1 cycle of IP will be dispensed to the 
subject on Day 1 of each cycle.  Day 1 of Cycles 2 and beyond may be delayed from Day 28 of the prior cycle in order for subjects to recover from toxicity and meet criteria 
for re-treatment (see Section 8.2.5).
b. The study visit window for the 28-day Follow-up Visit is ±3 days.  If the visit is conducted prior to post-treatment Day 28, the subject should be contacted on or after post-
treatment Day 28 to obtain any new or updated information related to survival, AEs, concomitant medications, blood product transfusions, additional MDS therapies, and/or 
disease progression to AML.  Additional follow-up contacts may be conducted by telephone and are performed every 3 months (12 weeks ± 14 days) from the date of the 28-
day follow-up visit (90 days for durvalumab) until the last active subject reaches approximately 12 months of treatment, or until death, loss to follow-up, withdrawal of 
consent to further contact or study closure (Section 6.14).
c. The first dose of IP in Cycle 1 should be administered on the day of entering the subject in the treatment phase via IRTS, but may be administered up to 5 days later if 
necessary for logistical reasons (see Section 6.3).  Physical examination, ECOG performance status, hematology and/or serum chemistry do not need to be repeated if the 
screening examination was performed within 7 days of the first dose and all necessary parameters were assessed.  Pregnancy test does not need to be repeated if the screening 
assessment was performed within 72 hours of the first dose of IP.
d. All subjects who received at least one dose of IP should complete the Treatment Discontinuation Visit when the decision to discontinue IP is made. If this is during a 
regularly-scheduled study visit, that visit will be considered the Treatment Discontinuation Visit, and all indicated procedures performed.  The reason for discontinuation will 
be recorded in the CRF and in the source document for all enrolled subjects, even if they never received IP.  Reasons for discontinuation are provided in Section 12.
e. Documentation supporting MDS diagnosis (WHO and FAB classifications - Appendix A and Appendix B), and IPSS/IPSS-R risk classification (Appendix C and   Appendix 
D) will be collected during screening.  If documentation of MDS diagnosis, WHO/FAB classification and IPSS/IPSS-R risk categorization is available and within 2 months 
of screening, results of central review are not required prior to enrollment of the subject in the study.  However, the results of central pathology review will be used in 
classification of subjects for analysis. These assessments will be independently-confirmed through central review of screening bone marrow biopsy, aspirate, and peripheral 
blood samples, along with applicable central laboratory results and relevant clinical documentation.  Thus, bone marrow aspirate and biopsy samples, together with peripheral 
blood samples and clinical documentation, must be collected during screening, as detailed in Section 6.1.15.  Blood samples at screening should be collected on the same day 
as the bone marrow procedure.  Instructions for submission of bone marrow slides and sample collection, processing, storage, and shipment procedures are provided in the 
Central Laboratory Manual.
f. A comprehensive red blood cell and platelet transfusion history must be available for the 56 days immediately preceding the subject’s first dose of IP and will be recorded on 
the appropriate CRF.
g. All prior treatments for MDS, regardless of discontinuation date of treatment, must be recorded as detailed in Section 6.1.4.
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regardless 


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
60
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
h. All non-MDS medications taken in the 4 weeks (28 days) prior to initiation of IP are to be collected on the appropriate CRF.
i. Vital signs include measurements of blood pressure, pulse, body temperature and respiratory rate as detailed in Section 6.1.7.
j. 12-lead electrocardiogram will be performed locally at screening and upon treatment discontinuation, and if clinically indicated. The investigator will review and assess the 
results as detailed in Section 6.1.9.
k. Urinalysis is conducted at the central laboratory.  Urine samples should be collected during screening, prior to administration of IP on Day 1 of every 3rd treatment cycle (ie, 
Cycle 3, 6, 9, etc.), and as indicated in the table above (see also Section 6.1.10).  
l. Serum EPO, ferritin, and transferrin saturation (Fe/TIBC) assessments are to be performed by the central laboratory.  It is not necessary to obtain these values if they were 
assessed within 2 months prior to screening (date of informed consent signature) and values are documented in the subject’s medical record.
m. Hematology includes a complete blood count with WBC differential and platelets as detailed in Section 6.1.12.  Any or all laboratory assessments may be repeated more 
frequently if clinically indicated.  All samples will be analyzed by the central laboratory.  The samples are to be collected at screening, prior to IP administration as detailed in 
Section 6, and at the treatment discontinuation and 28-day follow-up visits.
n. Serum chemistry (to include amylase and lipase) and thyroid function parameters are detailed in Section 6.1.13.  All samples will be analyzed by the central laboratory.  Any 
or all laboratory assessments may be repeated more frequently if clinically indicated.  The samples are to be collected at screening, prior to IP administration as detailed in 
Section 6.7.7, and at the treatment discontinuation and 28-day follow-up visits.
o. A serum pregnancy test is to be completed during screening for all FCBP.  A serum or urine pregnancy test (investigator’s discretion) is to be performed within 72 hours 
before beginning treatment on Day 1 of every cycle in the treatment phase, at the treatment discontinuation visit and safety follow-up (Section 6.1.14).  The subject may not 
receive IP until the investigator has verified that the result of the pregnancy test is negative. Pregnancy testing does not need to be repeated prior to Cycle 1 if the screening 
assessment was performed within 72 hours of the first dose of IP. 
p. Bone marrow and peripheral blood samples are required prior to beginning IP and following every 2 cycles of treatment during the first 6 treatment cycles (ie, Cycle Day 28 
[± 14 days]).  Subjects who continue beyond Cycle 6 will undergo bone marrow examination following every 3 treatment cycles or when necessary to confirm suspected 
hematologic response or disease progression, and again upon treatment discontinuation (See Sections 6.1.15, and 6.8.1 for detail).  Samples will be sent for cytogenetic 
analysis each time a bone marrow sample is collected.  Bone marrow biopsy and aspirate are required during screening.  Thereafter, only aspiration is necessary unless 
adequate aspirate cannot be obtained.  Reports from all bone marrow and cytogenetics analyses performed from the time of MDS diagnosis should be obtained and submitted 
to the sponsor during screening whenever possible.  “Unscheduled” sample collections are also permitted if a subject has disease progression. 
q. Pharmacokinetic samples will be collected from approximately 10-12 evaluable subjects randomized to the combination treatment arm at selected study sites.  Instructions for 
IP dosing and PK sample collection time points are provided in Section 6.10.
r. IP should only be dispensed on Day 1 of each treatment cycle after all Day 1 procedures have been completed and all IP from the previous cycle is accounted for (where 
applicable).  Only 1 cycle of IP will be dispensed to the subject on Day 1 of each cycle (Section 8.2.1).  For FCBP subjects, a negative pregnancy test performed within 
72 hours prior to IP administration must be documented.
s. CC-486 is scheduled to be taken on Day 1 to Day 21 of each cycle (Day -1 of Cycle 1 for PK sub-study subjects), unless there has been a dose or schedule modification due 
to toxicity.  Subjects will self-administer CC-486 (Section 8.2.2).  It is recommended that an antiemetic medication (eg, ondansetron) be taken 30 minutes prior to CC-486 
administration during Cycle 1.  If nausea/vomiting is not significant, further antiemetic prophylaxis may not be needed.  
t. IP accountability is not applicable on Day 1 of Cycle 1.
u. The type of blood product transfused, number of units, reason for transfusion, and date of transfusion is to be collected beginning on C1D1, until 90 days after the last dose of 
IP or until the last study visit, whichever occurs later (see Section 6.8.6).
v. International Working Group Response Assessment based on modified IWG criteria (Appendix F) is to be performed following every 2 cycles of treatment during the first 6
treatment cycles.  Subjects who continue beyond Cycle 6 will have IWG response assessment following every 3 treatment cycles.  The assessment must be performed prior to 
beginning Day 1 procedures for the subsequent treatment cycle (Cycle 3, 5, 7, 10, etc.).  See Section 6.8.3.
w. An assessment of disease status must be performed at the end of Cycle 6, prior to starting Cycle 7, based on available clinical and laboratory evaluations.  
!
Subjects who meet re-treatment criteria (Section 8.2.5) can continue on to Cycle 7 and beyond and disease status will be re-assessed prior to beginning each new cycle of IP.
!
Subjects who fail to meet re-treatment criteria at the end of Cycle 6 will be discontinued from protocol-prescribed therapy and enter the follow-up phase (Section 6.14).
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
61
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Prior to discontinuing a subject, it is recommended that the investigator contact the medical monitor and forward appropriate supporting documents for review and discussion.  
The decision to discontinue a subject remains the responsibility of the treating physician and will not be delayed or refused by the sponsor.
x. Subjects will be followed for safety-related assessments for 28 days (90 days for durvalumab).
y. During the Extension Phase while continuing to receive oral azacitidine.  See details for the EP in Appendix J.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
62
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
6.
PROCEDURES
All required study visits are described in Table 2 with an “X” indicating the procedures to be 
performed during a particular visit.  All data obtained from these assessments must be present in 
the subject’s source documentation.  Unless otherwise noted, acceptable study visit windows are 
as follows:  routine assessments of Cycles 1 and 2 must be performed ± 3 days of the targeted 
day indicated in the table; all routine assessments of Cycles 3 and beyond must be performed ± 7 
days of the targeted day; post-treatment follow-up contacts must be performed within ± 14 days 
of the targeted day of contact.  Procedures are described in detail below.
6.1.
Screening
All screening procedures and assessments are performed during a subject’s screening period in 
order to establish eligibility and to document relevant medical and demographic data (eg, 
medical history and prior/concomitant medications).  Written informed consent must be obtained 
before any study-specific procedures are performed and any samples are collected for study-
specific analysis.  Per inclusion criterion number 5, there may not be more than 16 weeks 
between a subject’s last dose of injectable HMA and the date of their informed consent signature.  
Also, there may not be less than 3 weeks between the subject’s last dose of injectable HMA and 
the planned first dose of IP in this study (inclusion criterion number 6).  Given this timeframe, 
subjects may begin screening after the last dose of prior injectable HMA. 
Subject eligibility is established by the investigator by confirming all inclusion and exclusion 
criteria are satisfied.  Documentation used to establish eligibility should be forwarded to the 
sponsor to ensure documentation is sufficient from a regulatory and quality perspective.  The 
sponsor may contact the study site for additional information if there is any deficiency in the 
documentation provided.  Failure to satisfy any entry criterion will preclude a subject from 
enrolment into the safety run-in or treatment phase of the study.  Unless otherwise specified, 
screening assessments must take place, and eligible subjects enrolled in the study within 28 days 
after the date of informed consent signature.  Refer to Section 6.2 for information to be collected 
for screen failures: screened subjects who do not meet inclusion/exclusion criteria during 
screening, or who are not enrolled in the treatment phase for any reason.
A subject who becomes a screen failure can be rescreened if it is reasonable to believe they will 
meet eligibility criteria during rescreening. Please note that if a subject is to be rescreened, they 
must reconsent to participation in the study by signing a new and current Informed Consent 
Document and the date of signature must again be within 16 weeks of the last dose of injectable 
HMA.
6.1.1.
MDS Diagnosis, WHO and FAB Classifications and IPSS(-R) Risk Classification
MDS diagnosis, WHO classification (Appendix A), FAB classification (Appendix B), IPSS risk 
classification (Appendix C), and IPSS-R risk classification (Appendix D) will be established 
through documentation collected during screening.  
!
Morphological assessment: Pathology reports from each bone marrow examination 
(screening biopsy and/or aspirate) performed from the time of MDS diagnosis should 
be obtained and submitted to the sponsor for review whenever possible.  Inability to 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
63
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
clearly establish the diagnosis of MDS and disease progression or stable disease 
(without HI) as the best response to treatment with an injectable hypomethylating 
agent may preclude the subject from entering the study. 
!
Cytogenetics:  Reports from any cytogenetics analyses performed from the time of 
MDS diagnosis should be obtained and submitted to the sponsor for review whenever 
possible.  
!
Hematology:  Reports from any hematologic analyses from the time of MDS 
diagnoses that are relevant to establishing the subject’s eligibility or baseline disease 
state (PD vs. SD) should be obtained and submitted to the sponsor for review 
whenever possible.  
All hematology and bone marrow pathology reports used to establish a subject’s eligibility 
should be sent for sponsor review at least 48 hours ahead of the planned IP start date to allow 
time for any deficiencies in documentation to be addressed.  This includes documentation of the 
subject’s prior treatment with an adequate course of injectable HMA and prior blood product 
transfusion records (see Sections 6.1.3 and 6.1.4).  A checklist will be provided to the site to 
assist in compiling all necessary documentation during screening.
Note:  Any time subject-specific documentation is sent to the sponsor, all subject-
identifying information must be redacted, and the subject’s study-specific ID number 
added to the document. 
6.1.2.
Demographics and Medical History
The subject’s date of birth, sex, race and ethnicity will be recorded on the appropriate CRF, as 
permitted by local regulations.  Relevant medical history and current medical conditions, 
including those symptoms related to MDS (eg, anemia), must be recorded on the appropriate 
CRF at screening.  
6.1.3.
RBC and Platelet Transfusion History
Documentation of all red blood cell and platelet transfusions received by the subject within 8 
weeks (56 days) prior to the first dose of IP should be gathered during the screening period, if 
possible, and recorded on the appropriate CRF.  Transfusion data should include the type of 
transfusion, number of units, reason for, and date of transfusion.  RBC transfusion data should 
include the hemoglobin concentration prior to transfusion and platelet transfusion data should 
include the pre-transfusion platelet value.  It is important that all transfusions received by the 
subject during the 56 days leading to the first dose of IP are known and recorded, even when not 
all requested data are available.
6.1.4.
Prior Medications and MDS Treatments
All prior and current medications, including, prescription, over-the-counter, and herbal 
preparations taken for any indication within the 4 weeks (28 days) prior to the first dose of IP 
will be recorded on the appropriate CRF.
All prior treatments for MDS will be recorded on the respective CRF(s) regardless of dates of 
treatment.  
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
64
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Documentation of the subject’s prior treatment with an adequate course of injectable HMA (see 
inclusion criterion number 3) should be sent to the sponsor at least 48 hours ahead of the planned 
date of first dose to allow time for sponsor review prior to initiating IP.  Failure to clearly 
establish refractory disease (no objective response of HI or better) during or following an 
adequate course of injectable HMA will preclude the subject from being enrolled into the study.
Per inclusion criterion number 5, the last dose of injectable HMA must have been within 16
weeks prior to the subject’s informed consent signature date in order to be considered for this 
study. Also, there may not be less than 3 weeks between the subject’s last dose of injectable 
HMA and the planned first dose of IP in this study (inclusion criterion number 6).
6.1.5.
Coagulation Parameters
Coagulation parameters, including prothrombin time/international normalized ratio (PT/INR), 
activated partial thromboplastin time (aPTT), and fibrinogen will be recorded during screening.  
Re-testing of coagulation parameters throughout the study is only necessary if clinically 
indicated. 
6.1.6.
Physical Examination
Information about the screening physical examination must be present in the subject’s source 
documentation.  Significant findings will be recorded on the appropriate CRF.
6.1.7.
Vital Signs, Body Weight and Height Measurements
The following routine assessments must be present in the subject’s source documentation and 
recorded on the appropriate CRF: 
!
blood pressure
!
pulse
!
body temperature
!
respiratory rate 
!
body weight
Height is collected during screening only.
6.1.8.
Eastern Cooperative Oncology Group Performance Status
Performance status at screening will be assessed using ECOG criteria provided in Appendix E.  
Refer to Section 6.7.10 for timing of ECOG performance status assessments during the study.
6.1.9.
Electrocardiogram
Electrocardiograms (ECGs) at screening and at treatment discontinuation are conducted locally.  
Electrocardiograms should be performed using the internationally recognized 12-leads.  The 
investigator will review the results and assess as normal, abnormal - not clinically significant, or 
abnormal - clinically significant, and report abnormal finding(s) on the appropriate CRF.  If the 
ECG is abnormal, the investigator should consult a cardiologist as appropriate.  For purposes of 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
65
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
this study, ECGs will only be performed during screening and upon treatment discontinuation 
unless additional monitoring is deemed necessary by the investigator.
6.1.10.
Urinalysis
During screening, a urine sample will be sent for analysis by the central laboratory.  Urinalysis 
includes examination by a standard stick test for specific gravity, glucose, ketones, blood, pH, 
and protein, and microscopic analysis if indicated.  A urine sample should be collected prior to 
IP administration on Day 1 of every 3rd treatment cycle (ie, Cycles 3, 6, 9, etc.), at treatment 
discontinuation and safety follow-up and sent to the central lab for analysis.  Specific 
requirements for urine sample collection, handling, and shipping are provided in the Central 
Laboratory Manual.
6.1.11.
Serum EPO, Ferritin, and Transferrin Saturation (Fe/TIBC)
Serum erythropoietin (EPO), ferritin, and serum iron/serum total iron-binding capacity
(Fe/TIBC) are assessed by the central laboratory during screening to rule-out confounding 
conditions associated with anemia.  It is not necessary to perform these tests if these parameters 
were assessed within 2 months prior to screening (date of informed consent signature) and values 
are documented in the subject’s medical record.
6.1.12.
Hematology
Blood samples for hematology assessment will be sent for analysis by the central laboratory.  
Any or all laboratory assessments may be repeated more frequently if clinically indicated.  Refer 
to Section 6.7.7 for timing of required hematology assessments during the safety run-in or
treatment phase of the study.  Complete blood count (CBC) for hematology assessment includes:
!
RBC count
!
hemoglobin
!
hematocrit
!
reticulocyte
!
mean corpuscular volume (MCV)
!
red cell distribution width (RDW)
!
platelet count
!
White blood cell (WBC) count with differential
∀
absolute and percent neutrophils
∀
absolute and percent lymphocytes
∀
absolute and percent monocytes
∀
absolute and percent eosinophils
∀
absolute and percent basophils
∀
percent blasts
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∀


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
66
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific requirements for blood sample collection, handling, and shipping are provided in the 
Central Laboratory Manual.
6.1.13.
Serum Chemistry and Thyroid Function Tests
Samples for serum chemistry assessment will be sent for analysis by the central laboratory.  Any 
or all laboratory assessments may be repeated more frequently if clinically indicated.  Refer to 
Section 6.7.7 for timing of required serum chemistry assessments during the study.  Serum 
chemistry assessments include:
!
sodium
!
potassium
!
chloride
!
bicarbonate (if available)
!
calcium
!
magnesium
!
phosphorus
!
uric acid
!
total and direct/indirect bilirubin
!
aspartate aminotransferase (AST) or 
serum glutamic-oxaloacetic 
transaminase (SGOT)
!
blood urea nitrogen (BUN)
!
creatinine
!
glucose
!
albumin
!
total protein
!
alkaline phosphatase
!
lactate deyhydrogenase (LDH)
!
alanine aminotransaminase 
(ALT)/serum glutamate pyruvate 
transaminase (SGPT)
!
thyroid stimulating hormone (TSH), free 
T4, free T3
!
amylase
!
lipase
Specific requirements for serum sample collection, handling, and shipping are provided in the 
Central Laboratory Manual.
6.1.14.
Pregnancy Testing (FCBP Only)
This protocol defines a FCBP as a sexually mature woman who:  
1. has not undergone a hysterectomy or bilateral oophorectomy, or 
2. has not been naturally postmenopausal for at least 24 consecutive months (ie, has had 
menses at any time in the preceding 24 consecutive months).  
Amenorrhea following cancer therapy does not rule out childbearing potential.
The investigator will appraise a female subject as a FCBP according to this definition.  
Justification must be recorded in the CRF and the source document.  Pregnancy testing is not 
required for non-FCBP subjects.  
A medically supervised serum pregnancy test with sensitivity of at least 25 mIU/mL is to be 
administered and assessed locally during screening for any FCBP.  A negative result must be 
verified by the investigator prior to administration of IP.  Refer to Section 6.7.8 for details 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
67
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
regarding pregnancy testing during the safety run-in and treatment phases of the study and to 
inclusion criterion numbers 8 and 9 for contraception requirements of the protocol.
6.1.15.
Bone Marrow Aspirate, Biopsy, and Peripheral Blood Smear
A bone marrow aspirate and biopsy are to be obtained during screening.  Whenever a bone 
marrow sample is collected, a peripheral blood smear is to be prepared as well. Bone marrow 
and peripheral blood samples are then required following every 2 cycles of treatment during the 
first 6 treatment cycles (ie, Cycle Day 28 [± 14 days]).  Subjects who continue beyond Cycle 6 
will undergo bone marrow examination following every 3 treatment cycles or when necessary to 
confirm suspected hematologic response or disease progression, and again upon treatment 
discontinuation.  Samples will be sent for cytogenetic analysis each time a bone marrow sample 
is collected.  Bone marrow biopsy and aspirate are required during screening.  Thereafter, only 
aspiration is necessary unless adequate aspirate cannot be obtained.  
Samples will be processed as described in the Central Laboratory Manual and submitted for 
central review along with any pertinent clinical information.  If documentation of MDS 
diagnosis, WHO/FAB classification and IPSS/IPSS-R risk categorization is available within 2
months of screening, results of central review are not required prior to enrollment of the subject 
in the study.  
Instructions for submission of blood and bone marrow slides/samples, along with relevant 
clinical information, for central review are provided in the Central Laboratory Manual.  Samples 
and documentation should be prepared and sent to the central reviewer as early in the screening 
process as possible, and not more than 3 weeks after the subject signs informed consent; this will 
enable resolution of any issues prior to the subject being enrolled into the study.  Therefore, the 
informed consent process and screening procedures (including bone marrow collection) should 
be planned with careful consideration for the 28-day screening period to avoid any potential need 
for re-screening due to exceeding the 28-day limit.  Special handling requests such as return of 
materials to the site will be managed on an individual basis.
6.1.16.
Cytogenetics
Bone marrow cytogenetic testing will be completed by the central laboratory whenever a bone 
marrow aspirate (or biopsy) is obtained.  Note that specific handling of the sample is required in 
order to be used for cytogenetics testing.  See the Central Laboratory Manual for handling 
instructions.
6.2.
Information to be Collected on Screen Failures
The following must be collected for all subjects who provide informed consent, but fail to satisfy 
inclusion criteria, or for any other reason, are not enrolled in the treatment phase of the study:
!
informed consent date;
!
date of biomarker sample collection;
!
date of any request for biomarker sample destruction received from a subject;
!
demographics;
!
reason subject did not qualify for the study;
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
68
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
investigator’s signature 
Any adverse events experienced by a screen failure subject will be collected from the date of 
signing informed consent to the day the subject is declared a screen failure.  This information 
will be captured in the subject’s source documents and appropriate CRF(s).  Relevant 
information will also be recorded on a Screening Log.  Subjects can be re-screened following 
discussion with the medical monitor.  
6.3.
Entering a Subject Into the Study (Enrollment)
Written consent must be obtained prior to any study-specific procedures being conducted.  All 
the screening evaluations must be completed and eligibility criteria must be verified by the 
responsible investigator and appropriate documentation reviewed by the sponsor prior to 
enrolling a subject. Enrollment will occur via IRTS to enable automated tracking and 
replenishment of IP.  Specific contact information and instructions will be provided to each study 
site.
The IRTS enrollment call should be performed as close as possible to the planned first dose of IP 
to avoid enrolling a subject who ultimately does not receive IP for any reason.
The first dose of IP should be administered at the site on the day of enrollment whenever 
possible, but may be delayed for up to 5 days if necessary for logistical reasons.  Any delay 
greater than 5 days must be discussed with and approved by the sponsor’s medical monitor, and 
may result in the need to repeat screening.
Subjects enrolled in the safety run-in phase of the study will be assigned to the monotherapy arm 
or the combination therapy arm.  Subjects enrolled in the treatment phase of the study will be 
randomly assigned to one of the two treatment arms, while controlling for the numbers of 
subjects with PD and SD required in each arm for the planned analysis.
Approximately 10-12 evaluable subjects randomized to the combination treatment arm at 
selected sites will participate in PK sampling procedures.  Subjects participating in PK sample 
collection will have their first dose of CC-486 on Day -1 of Cycle 1, after collection of required 
samples on that day.  See Section 6.10 for details.  
6.4.
Baseline Measurements
Baseline values are defined as the last assessment of a particular parameter (eg, vital signs, 
weight, or laboratory assessments) prior to administration of the subject’s first dose of IP, unless 
noted otherwise for a particular assessment.  In most cases, baseline assessments are those 
performed before dosing on Cycle 1, Day 1.
Baseline physical examination, ECOG performance status, hematology and/or serum chemistry 
do not need to be repeated prior to dosing if the screening examination was performed within 7 
days of the first dose of IP and all necessary parameters were assessed.  
6.5.
CC-486 (Oral Azacitidine)
All eligible subjects will receive treatment with CC-486 at the dose and schedule identified during 
the safety run-in.  Dose and schedule may be decreased as described in Section 8.2.4 in order to 
manage toxicity.  In the absence of unacceptable toxicity, subjects who show signs of worsening 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
69
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
disease (clinical or hematological), who remain in stable disease, or do not experience modified 
IWG 2006 hematologic improvement (HI) or better (PR, CR or marrow CR – modified IWG 
2006, Appendix F) after 2 well-tolerated cycles, may have their dose increased at the discretion 
of the investigator and in discussion with the medical monitor as defined in Table 3. Again, dose 
and schedule may be adjusted as described in Section 8.2.4 in order to manage toxicity.  
After at least 2 treatment cycles at the increased dose, the assigned dose can be further increased 
if it is well-tolerated but no objective response is observed.  
Special attention should always be given to potential drug-related toxicity and/or tolerability 
issues so dose and/or schedule can be reduced appropriately (Section 8.2.4).
Subjects can continue treatment with CC-486 as long as all protocol-specified re-treatment
criteria continue to be met (see Section 8.2.5).
Best supportive care should be used in combination with study treatment as deemed necessary.  
Best supportive care includes, but is not limited to, treatment with RBC transfusions (pRBC or 
whole blood), single donor or pooled donor platelet transfusions, antibiotic, antiviral and/or 
antifungal therapy, antiemetic and/or antidiarrheal support, nutritional support as needed, and 
granulocyte (or granulocyte macrophage) colony-stimulating factors for subjects experiencing 
neutropenic fever or infection, and may be given as secondary prophylaxis (Section 9.1).  Best 
supportive care for this study excludes the use of ESAs and other hematopoietic growth factors, 
except as noted for G- or GM-CSF in Section 9.1.  It is recommended that an antiemetic 
medication such as ondansetron or an appropriate locally-available equivalent be taken 30 
minutes prior to CC-486 administration during Cycle 1 of the treatment phase.  If 
nausea/vomiting is not significant, further antiemetic prophylaxis may not be needed.  
Refer to Section 8.2 for details regarding IP dispensation, administration, and accountability.
6.6.
Durvalumab (MEDI4736)
Subjects assigned to the combination treatment arm will receive durvalumab 1500 mg by 1-hour 
(± 5 minutes) IV infusion on Day 1 of each 28-day treatment cycle.  Guidance for management 
of toxicity that is determined by the investigator to be related to treatment with durvalumab is 
provided in Section 8.2.4.2.  Durvalumab dosing may be delayed until resolution of toxicity, but 
dose reductions for durvalumab are not permitted.
Durvalumab will be supplied by Celgene Corporation in single use vials in single count cartons. 
Each 10 mL vial will be supplied as a vialed liquid solution containing 500 mg (nominal) of 
investigational product at a concentration of 50 mg/mL. Durvalumab should be stored in 
accordance with the product label. 
Site to supply the following:
!
IV infusion bags of normal saline (0.9% [w/v] sodium chloride injection, 250 mL 
size). Saline bags must be latex-free and can be made of polypropylene, polyethylene, 
polyolefin copolymers, or polyvinyl chloride. Infusion lines should contain a 0.2-μm 
in-line filter.  
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
70
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Since the compatibility of durvalumab with other IV medications and solutions, other than 
normal saline, is not known, the durvalumab solution should not be infused through an IV line in 
which other solutions or medications are being administered.
Refer to Section 8.2 for details regarding IP dispensation, administration, and accountability.
6.6.1.
Durvalumab Infusion Monitoring
Subjects will be monitored during and after infusion of durvalumab. Vital signs will be 
measured:
!
prior to durvalumab administration (± 30 minutes),
!
every 15 minutes (± 5 minutes) during durvalumab administration, 
!
at the end of durvalumab infusion (± 5 minutes), 
!
30 minutes (± 5 minutes) post-infusion,
!
60 minutes (± 5 minutes) post infusion 
followed by a 2-hour (± 15 minutes) period of observation.
6.7.
Safety
Safety assessments include:
!
AEs including AESI
!
post-infusion monitoring for infusion- or immune-mediated AEs
!
physical examination
!
vital signs
!
body weight 
!
ECOG performance status
!
hematology (CBC with WBC differential and platelets – see Section 6.1.12) 
!
serum chemistry (to include amylase and lipase) and thyroid function tests (see 
Section 6.1.13)
!
concomitant medications, therapies and procedures
!
pregnancy testing (for FCBP subjects)
!
urinalysis 
!
ECG
!
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
71
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
6.7.1.
Adverse Events
All subjects will be monitored for AEs including AESIs during the study.  Refer to Section 11
for details regarding monitoring, recording, and reporting of AEs, including serious adverse 
events (SAEs) and AESIs.  
Information about common side effects already known about azacitidine and durvalumab will be 
included in the subject informed consent document and should be discussed with the subject as 
needed during the study.  This information can also be found in the Investigator’s Brochure (IB)
or will be communicated between IB updates in the form of investigator notifications.
6.7.2.
Progression to AML 
Progression to AML will be monitored as an AESI and will be included as part of the safety 
assessment throughout the course of the study.  Progression to AML should be reported if 
documented at any time from signing of informed consent through death, loss to follow-up, 
withdrawal of consent for further data collection, or study closure, whether or not thought to be
related to treatment with IP.
Events of disease progression to AML are reported in the same way as SAEs using the 
seriousness criterion of “important medical event” if no other seriousness criteria apply.  This 
information must also be documented on the appropriate CRFs and in the subject’s source 
documents.  Documentation supporting the diagnosis of progression to AML (eg, confirmatory
histology or cytology results, etc.) must be provided at the time of reporting as an SAE.  Refer to 
Section 11.2 for evaluation of AEs.  
6.7.3.
Physical Examination, Vital Signs and Weight
Physical examinations, vital signs (blood pressure, pulse, temperature, and respiratory rate) and 
weight measurements are to be performed as specified in Table 2.  Significant findings must be 
included on the appropriate CRF.
6.7.4.
Urinalysis
A urine sample obtained during screening and at the frequency specified in Table 2 will be 
submitted for analysis to the central laboratory according to the procedure detailed in the Central 
Laboratory Manual.
6.7.5.
12-Lead Electrocardiogram
A standard 12-lead ECG is to be performed during screening, upon treatment discontinuation, 
and whenever clinically indicated.  
Electrocardiograms will be conducted locally as described in Section 6.1.9.
6.7.6.
Coagulation Parameters
Coagulation parameters, including PT/INR, aPTT, and fibrinogen will be recorded during 
screening.  Re-testing of coagulation parameters throughout the study is only necessary if 
clinically indicated. 
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.7.6.
.7.6.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
72
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
6.7.7.
Hematology and Serum Chemistry Laboratory Evaluations
Hematology and serum chemistry central laboratory analyses, including thyroid function tests,
are to be performed according to the schedule in Table 2.  The same parameters assessed during 
screening are to be evaluated throughout the treatment period, upon treatment discontinuation 
and at the 28-day follow-up visit (see Section 6.1 for details).  
Samples for hematology analysis will be collected prior to IP administration on Day 1 of each 
treatment cycle and prior to IP administration on other required days, when possible.  Samples 
will be processed as detailed in the study laboratory manual and sent to the central laboratory for 
analysis and reporting.  The schedule of hematology assessments for enrolled subjects is as 
follows: 
!
Cycles 1-2 – Days 1, 8, 15 and 22
!
Cycles 3-12 – Days 1 and 15
!
Cycles ≥13 – Day 1 
!
Treatment Discontinuation Visit
!
28-day Follow-up Visit
Samples for serum chemistry analysis will be collected prior to IP administration on Day 1 of 
each treatment cycle and prior to IP administration on other required days during the first 2 
cycles of treatment, if possible.  Samples will be processed as detailed in the study laboratory 
manual and sent to the central laboratory for analysis and reporting.  The schedule of serum 
chemistry assessments for enrolled subjects is as follows: 
!
Cycles 1-2 – Days 1, 8, 15 and 22
!
Cycles ≥3 – Day 1 
!
Treatment Discontinuation Visit
!
28-day Follow-up Visit
Any or all laboratory assessments may be repeated more frequently if clinically indicated.  In the 
event that an immediate laboratory assessment is required to acutely manage a subject, local 
laboratory tests may be used.  In addition to collecting the local laboratory sample, a second 
sample should be processed for shipment to the central laboratory.  If the subject management 
decision made based on the local laboratory result differs from the decision which the central lab 
result would have resulted in (when available), the applicable local laboratory result(s) should be 
recorded in the appropriate CRF.
Refer to Section 11.3 for guidance on the reporting of abnormal laboratory values and test results 
as AEs.
6.7.8.
Pregnancy Testing
For all female subjects of childbearing potential (FCBP – see Section 6.1.14), a serum or urine 
pregnancy test (investigator’s discretion) is required within 72 hours prior to beginning treatment 
in the study.  The screening serum pregnancy test can be used to satisfy this requirement if it is 
performed within 72 hours prior to the first dose of IP.  
&&,
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for 
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6.7.8.
6.7
r al


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
73
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
A serum or urine pregnancy test (investigator’s discretion) is to be done within 72 hours prior to 
dosing on Day 1 of every treatment cycle and at the treatment discontinuation and safety follow-
up visits.
The subject may not receive IP until the investigator has verified that the result of a pregnancy 
test is negative.  
Guidance for pregnancy testing during screening is provided in Section 6.1.14.
6.7.9.
Concomitant Medications/Significant Non-drug Therapies/Concomitant 
Procedures
All prescription, over-the-counter, or herbal medications and therapeutic procedures received 
within 4 weeks (28 days) prior to the first dose of IP, until 28 days after the last dose of CC-486 
and 90 days after durvalumab (or until the treatment discontinuation visit, whichever period is 
longer) must be recorded on the appropriate CRF page.  Concomitant medications, therapies, and 
procedures are those that are received by the subject during their participation in the treatment 
phase of the study.  If a medication, therapy, or procedure ended or was stopped prior to the first 
dose of IP, it will be recorded as a prior medication or as a part of the subject’s medical history, 
as appropriate.  See Section 9 for details regarding concomitant medications and procedures.
6.7.10.
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group Performance Status (Appendix E) is to be assessed during
screening, before IP dispensation on Day 1 of each treatment cycle and at the treatment 
discontinuation and 28-day follow-up visits.
6.8.
Efficacy
6.8.1.
Bone Marrow Aspirate, Biopsy and Peripheral Blood Smear
During study treatment, bone marrow aspirate (or biopsy if adequate aspirate cannot be obtained) 
is collected:
!
after completion of dosing in Cycle 2, Cycle 4, and Cycle 6,
!
then after completion of dosing in every 3rd treatment cycle (9, 12, 15, etc.),
!
to confirm suspected disease response or progression, and
!
upon treatment discontinuation.
This sample, along with peripheral blood and blood smear slide(s) must be collected after the last 
dose of IP for that cycle, but before Day 1 of the next cycle.  Samples will be processed 
according to instructions provided in the Central Laboratory Manual and sent for:
!
central pathology review,
!
central cytogenetics analysis, and
!
Results from central pathology review of blood and bone marrow samples will be used for:
&&,
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
74
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
modified IWG response assessment,
!
general disease status assessment, and
!
monitoring for progression to AML.
Whenever a bone marrow sample is collected, a peripheral blood sample and peripheral blood
smear is to be prepared as well.  Specific requirements for submission of bone marrow samples 
for central review are detailed in the Central Laboratory Manual.
6.8.2.
Cytogenetics
Bone marrow cytogenetic testing is to be completed by the central pathology laboratory 
whenever a bone marrow aspirate or biopsy is collected for disease assessment.  Note that 
specific handling of the biopsy is required in order to be used for cytogenetics testing.  See the 
Central Laboratory Manual for handling instructions.
6.8.3.
International Working Group Modified Response Assessment
Hematologic response or improvement according to criteria modified from that of the 
International Working Group (IWG) (Appendix F) is to be assessed following every 2 treatment
cycles during the first 6 months of treatment.  Subjects who continue treatment will have IWG 
assessment repeated after every 3 cycles and at treatment discontinuation.
Due to the turnaround time required to obtain results from review of bone marrow aspirate 
and/or biopsy, peripheral blood smear and cytogenetics, IWG response assessment may be done 
at any time prior to starting the next cycle of treatment.  Decisions regarding dose-modification 
and treatment continuation following IWG response assessment may be made based on available 
local assessments, if necessary, ahead of central hematology and bone marrow pathology 
assessments becoming available.  However, after at least 6 cycles of treatment with IP, if central 
pathology assessment conveys disease progression, the subject must be notified as soon as 
possible (not later than the next scheduled study visit) to discontinue further study treatment and 
to schedule the treatment discontinuation visit, as appropriate.
6.8.4.
General Disease Status Assessment
A general assessment of disease status must be performed at the completion of Cycle 6, prior to 
treatment in Cycle 7, based on available clinical and laboratory assessments.
!
Subjects who meet any one of the following criteria can continue on to Cycle 7 and 
beyond, and will have disease status re-assessed prior to beginning each new cycle of 
IP based on available clinical and laboratory evaluations and at treatment 
discontinuation.  Bone marrow examination will only be performed after Cycles 2, 4, 
6, and every 3 cycles thereafter, as described in Section 6.8.1 above, unless additional 
bone marrow examination is deemed necessary by the investigator:
∀
Objective response to treatment: CR, mCR, PR, or HI (Appendix F), or
∀
RBC-transfusion-independence, or
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bo


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
75
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
∀
≥ 50% reduction in average RBC transfusion requirement in the 56-day (8-week) 
period immediately prior to disease status assessment as compared to the average 
baseline RBC transfusion requirement, or
∀
any other clinical benefit, including no evidence of progressive disease (see
Table 8 for definitions of progressive disease).
Thereafter, subjects may be discontinued from protocol-prescribed therapy for any of 
the reasons detailed in Section 12.
!
Subjects who fail to meet these criteria at the end of Cycle 6 will be discontinued 
from protocol-prescribed therapy and enter the follow-up phase.
Prior to discontinuing a subject, it is recommended that the investigator contact the medical 
monitor and forward appropriate supporting documents for review and discussion.  The decision 
to discontinue a subject remains the responsibility of the treating physician and will not be 
delayed or refused by the sponsor.
Confirmation of an RBC-transfusion-independent response requires that the investigator 
documents the dates, numbers of units, reason for transfusion, and pre-transfusion hemoglobin 
levels for all RBC transfusions received by the subject throughout the study in the subject’s 
medical record.  This will be compared to the subject’s RBC transfusion history over the 56 days 
leading to enrollment, as recorded in the appropriate CRFs during screening.
In the event that immediate hematology values are needed for general disease status assessment
prior to beginning a subsequent treatment cycle, local laboratory results may be used pending the 
outcome of the central laboratory assessment.  However, matching samples must always be sent 
to the central laboratory and clinical decisions and assessments (such as General Disease Status 
Assessment) must be reconciled with the results of the central laboratory. Tests not required per-
protocol, and not related to the conduct of the study, do not need to be duplicated by the central 
lab.
6.8.5.
Hematology
Hematology results obtained from the central lab will be used to monitor subject safety and 
evaluate response to treatment.  
In the event that immediate hematology values are needed for clinical decisions, local laboratory 
results may be used pending the outcome of the central laboratory assessment.  However, 
matching samples must always be sent to the central laboratory and clinical decisions and 
assessments (such as continuation of treatment beyond Cycle 6) must be reconciled with the 
results of the central laboratory. 
See Section 6.1.12 for a list of hematology parameters being assessed by the central laboratory 
for this study.
6.8.6.
Transfusion Assessment
The following will be recorded for all transfusions the subject received within 56 days (8 weeks) 
prior to the first dose of IP, until 90 days after the last dose of CC-486 or durvalumab or the 
treatment discontinuation visit, whichever occurs later:
&&,
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medical
edical
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will not 
t the invest
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transfus
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the study i
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ansfusio
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during scree
uring scre
ed fo
for r gene
gen
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aboratory
wever, mat
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and assessm
nd assess
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ults of the 
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nt. 
ediate hema
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d pending t
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6.1.1
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6.8.6.
6.8


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
76
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
type of transfusion (eg, pRBC or platelet)
!
number of units
!
reason for transfusion 
!
date of transfusion
!
hemoglobin value for which any RBC transfusion is given
!
platelet value for which any platelet transfusion is given
RBC transfusions administered for surgical procedures, significant hemorrhagic events, or other 
reasons documented as unrelated to MDS-associated anemia will not be counted in the 
assessment of baseline RBC transfusion requirements, efficacy, or progressive disease status.
RBC-transfusion-independent response or improvement will be assessed according to criteria 
modified from that of the International Working Group (Appendix F).
6.8.7.
Survival, Progression to AML, and Subsequent MDS Therapies
All subjects discontinued from protocol-prescribed therapy for any reason should undergo 
treatment discontinuation procedures (Section 6.13) and be followed for survival, disease 
progression to AML, and subsequent MDS therapies (Section 6.14).  Data regarding subsequent 
therapies, determination of disease progression, and date and cause of death will be recorded in 
the appropriate CRF.  
6.9.
Biomarkers
Subjects participating in this study must consent to the future use of bone marrow and blood 
samples collected during screening, throughout treatment, and upon treatment discontinuation for 
biomarker analyses.  Screening samples may be obtained at any point after signing the informed 
consent document, up until taking the first dose of IP.  
Saliva, whole blood, and bone marrow aspirate and biopsy samples will be collected and
analyzed at the following time points to evaluate protein, nucleic acid and cellular biomarkers
that relate to durvalumab treatment.
Saliva sample for biomarkers will be collected at screening.
Blood samples for biomarkers will be collected at the following time points:
!
Screening for sPD-L1, soluble factors, immunophenotyping, peripheral blood 
mononuclear cells (PBMCs)
!
C1D1 (predose) for sPD-L1, soluble factors, immunophenotyping, whole blood DNA
!
C1D8 (predose) for soluble factors, immunophenotyping
!
C1D15 (predose) for soluble factors, immunophenotyping
!
C2D1 (predose) for sPD-L1, soluble factors, immunophenotyping, whole blood DNA
!
C2D15 (predose) for soluble factors, immunophenotyping
!
C3D15 (predose) for soluble factors, PBMCs
&&,
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other 
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se status
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6.14).  Dat
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d cause of 
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C1
C1
!


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
77
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
C4D15 (predose) for soluble factors
!
C5D1 (predose) and every 3 cycles thereafter (C8D1, C11D1 etc.) sPD-L1, PBMCs
!
EOT (predose) for soluble factors, whole blood DNA, PBMCs
 
 
 
Planned bone marrow sampling will be performed:
!
during screening,
!
after the completion of dosing in Cycle 2, Cycle 4, and Cycle 6,
!
then after the completion of dosing in every 3rd treatment cycle (9, 12, 15, etc.),
!
to confirm suspected disease response or progression, and
!
upon treatment discontinuation.
as indicated in the Table of Events (Section 5).
Peripheral blood samples for future biomarker analyses should be collected on the same day as 
the screening bone marrow biopsy procedure.  If samples for biomarker assessment are not 
collected in conjunction with other screening procedures, or are in any way unfit for analysis, the 
sample may be obtained on Day 1, prior to IP administration.  
Consent for biomarker sampling procedures will be obtained through signature of a biomarker-
specific component of the informed consent document.  All subjects participating in this study 
will consent to biomarker sampling procedures, as described.
 
 
 
 
6.10.
Pharmacokinetics 
Blood samples for pharmacokinetic analysis will be collected from approximately 10-12 
evaluable subjects randomized to the combination treatment arm at selected sites.  This will 
enable assessment of drug-drug interactions.  Subjects will receive CC-486 approximately one 
hour after completion of the durvalumab infusion except on Day -1.
&&,
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12, 15, etc
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6.10.
6.1
52
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
78
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Subjects participating in PK procedures will agree to have blood samples collected as described 
below (see also Section 8.2.2).  
!
Dosing for subjects participating in PK procedures:
∀
Cycle 1:
o
CC-486: established Phase 2 dose on Day (-1) and Days 2 to 21 of a 28-day 
cycle
o
Durvalumab: on Day 1, 1500 mg administered IV over a 1-hour period (± 5 
minutes)
∀
Cycle 2:
o
CC-486: established Phase 2 dose on Day 1 to 21 of a 28-day cycle
o
Durvalumab: on Day 1, 1500 mg administered IV over a 1-hour (± 5 minutes) 
period
!
PK sample collection timepoints:
∀
CC-486:
o
Cycle 1 Day (-1): predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 
hours post-dose
o
Cycle 2 Day 1: predose, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours 
post-dose
Prior to each CC-486 PK sampling day, subjects must fast overnight (refer to
Section 8.2.2.1 for fasting details).
∀
Durvalumab:
o
Cycle 1 Day 1: pre-infusion (-30 to -5 minutes prior to dose), end of infusion 
(EOI), 2 hours (± 1 hour), 8 hours (± 1 hour), 48 hours (C1D3) (± 2 hour), 168 
hours (C1D8) (± 2 hour), 336 hours (C1D15) (± 2 hour) and 504 hours 
(C1D22) (± 2 hour) after administration of durvalumab on C1D1
o
Cycle 2 Day 1: pre-infusion (-30 to -5 minutes prior to dose), end of infusion 
(EOI), 2 hours (± 1 hour), 8 hours (± 1 hour), 48 hours (C2D3) (± 2 hour), 168 
hours (C2D8) (± 2 hour), 336 hours (C2D15) (± 2 hour) and 504 hours 
(C2D22) (± 2 hour) after administration of durvalumab on C2D1
o
PK samples collected at the following timepoint to match immunogenicity 
sample collections: Cycle 4 Day 1, Cycle 6 Day 1, Cycle 10 Day 1, and Cycle 
14 Day 1: pre-infusion (-30 to -5 minutes prior to dose)
NOTE: for immunogenicity, samples should be collected from all subjects dosed with 
durvalumab, 
. Samples will 
be stored and ADA assessment will be explored.
&&,
CCI
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ycle
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durvalum
durvalum
sto
sto


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
79
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
6.11.
Immunogenicity Samples of Durvalumab
Immunogenicity samples will be collected as follows:
!
Pre-dose samples on C1D1, C2D1, C4D1, C6D1, C10D1 and C14D1.
NOTE: for immunogenicity, samples should be collected from all subjects dosed with 
durvalumab, 
. Samples will 
be stored and ADA assessment will be explored.
6.12.
Unscheduled Visits
Should it become necessary to repeat an evaluation (eg, laboratory tests, vital signs, etc.) outside 
of scheduled study visits, the results of the repeat evaluation should be recorded in an 
unscheduled visit CRF.  These evaluations should also appear in the subject’s chart and/or other 
source documentation.
6.13.
Discontinuation
Prior to discontinuing a subject, it is recommended that the investigator contact the medical 
monitor and forward appropriate supporting documents for review and discussion. The decision 
to discontinue a subject remains the responsibility of the treating physician and will not be 
delayed or refused by the sponsor.
All subjects who have received at least one dose of IP should undergo treatment discontinuation
procedures when IP is discontinued, including: 
!
AEs including AESI
!
physical examination
!
electrocardiogram
!
vital signs
!
body weight 
!
ECOG performance status
!
hematology 
!
serum chemistry (to include amylase and lipase) and thyroid function tests
!
urinalysis
!
pregnancy test (FCBP only)
!
concomitant medications, therapies and procedures
!
transfusion assessment
!
bone marrow aspirate/biopsy and peripheral blood smear
!
whole blood sample for biomarker analysis
!
cytogenetics
&&,
CCI
&(/*(1(35235,(7$5<,1)250$7,21
) outside
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n
rt and/or ot
and/or o
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hould unde
hould und
ance status
nce statu
y
chemistry
hemistry (
nalysis
alysis
pregnancy
pregnanc
!
conco
onc
!
t


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
80
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
IWG response assessment
!
general disease status assessment
!
IP accountability
!
Subsequent MDS therapies (following IP discontinuation, if applicable)
If a subject is discontinued during a regularly scheduled visit, all treatment discontinuation 
procedures should be completed at that visit.  If a procedure had been performed within 7 days of 
the treatment discontinuation visit, it does not need to be repeated.
The reason for discontinuation will be recorded in the CRF and in source documents for all 
enrolled subjects, whether or not they ever received a dose of IP.  Guidance for reporting of 
reasons for discontinuation is provided in Section 12.
In the event that a subject assigned to the combination treatment arm discontinues treatment with 
durvalumab or CC-486 because of drug-related toxicity, treatment with single-agent durvalumab 
or CC-486 may continue until any discontinuation criterion is met (see Section 12).  
6.14.
Follow-up
All subjects discontinued from treatment with IP for any reason will be followed for a period of 
at least 28 days after the last dose of CC-486 (90 days for durvalumab) or until the date of the 
treatment discontinuation visit, whichever is later.  During Safety Follow-up Visits, the following 
assessments will be performed:
!
AEs including AESIs (monitored until 28 days after last dose of CC-486 or 90 days 
after last dose of durvalumab, whichever date is later)
!
physical examination
!
vital signs
!
body weight 
!
ECOG performance status
!
hematology
!
serum chemistry (to include amylase and lipase) and thyroid function tests
!
pregnancy testing (FCBP only) 
!
urinalysis
!
concomitant medications, therapies and procedures
!
transfusion assessment
!
subsequent MDS therapies
Females of childbearing potential should avoid becoming pregnant for at least 90 days after the 
last dose of IP and male subjects should avoid fathering a child for at least 90 days after the last 
dose of IP. The ICF will address any country-specific requirements, as needed.
&&,
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f f 
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)
will
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g g Safety
Safety Fo
F
28 days aft
28 days aft
ever
ever date i
date
e status
e status
mistry
mistry (to i
(to
ancy testing
ancy testing
rinalysis
rinalysis
concomi
concom
!
tran
tran
!
emale
emale


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
81
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
All subjects discontinued from protocol-prescribed therapy for any reason will also be contacted 
by telephone every 3 months (12 weeks ± 14 days) following the treatment discontinuation visit 
until the last active subject reaches 12 months of treatment, or until death, loss to follow-up, 
withdrawal of consent to further follow-up, or study closure to collect information related to: 
!
survival
!
subsequent MDS therapies
!
disease progression to AML
The investigator must make every effort to obtain information regarding the subject’s follow-up 
status.  All attempts to contact the subject must be documented and appropriate due diligence 
must be demonstrated before the subject can be considered lost to follow-up (eg, 3 unsuccessful 
attempts by telephone and one unanswered written attempt sent by certified or traceable post).  
6.15.
Extension Phase
During the Extension Phase, ongoing subjects will continue to receive oral azacitidine.  See 
details for the EP in Appendix J.
&&,
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w-up 
-up 
gence
gence
nsuccessful
nsuccessfu
ceable post
eable pos
ral azacit
l azac id


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
82
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
This multi-center, international study will enroll at least 70 to 194 evaluable subjects (inclusive 
of subjects in the safety run-in and randomized phases).
At least 6 evaluable subjects will be included in the safety run-in phase of the study: 3 receiving 
monotherapy, and 3 receiving combination therapy.
During the randomized treatment phase of the study, approximately 32 subjects with PD and 32 
subjects with SD will be randomized evenly to receive either CC-486 alone, or CC-486 + 
durvalumab.  There will be 4 cohorts (16 subjects in each) in Stage 1: SD treated with 
monotherapy, PD treated with monotherapy, SD treated with combination therapy and PD 
treated with combination therapy.
If there are 2 or fewer responses in either cohort during Stage 1, enrollment to that cohort will be 
terminated.  Otherwise, the cohort will continue to Stage 2 and accrue an additional 25 subjects 
each. If 8 or more responses are observed in these 41 subjects, the null hypothesis will be 
rejected for that cohort.
Therefore, the total number of subjects for the randomized treatment phase will range from 
approximately 64 (at Stage 1) to 164 (Stage 1 plus Stage 2) for the 4 cohorts. More subjects can 
potentially be recruited for replacement of non-evaluable subjects, if needed (see Figure 2).
The study population may include subjects with both lower- and higher-risk disease who meet
the following criteria.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Male or female, ≥ 18 years of age at the time of signing the informed consent document
2. Documented diagnosis of MDS, classified according to FAB classification criteria 
(Appendix B)
3. Adequate course of treatment with an injectable hypomethylating agent (azacitidine for 
injection or decitabine) as the last therapeutic intervention for MDS prior to beginning 
screening for this study 
Adequate is defined as: 
∀
having received at least 6 consecutive 4-week treatment cycles with azacitidine 
for injection, or
∀
having received at least 4 consecutive 6-week treatment cycles with decitabine (3-
day regimen) or at least 6 consecutive 4-week treatment cycles with decitabine (5-
day regimen), or
∀
having demonstrated inability to tolerate treatment with an injectable 
hypomethylating agent because of unacceptable drug-related toxicity after at least 
&&,
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d 32 
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and PD 
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having
having
fo
for
∀


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
83
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
3 months of attempted treatment:  Three 28-day cycles of azacitidine for injection 
or decitabine 5-day regimen; two 42-day cycles of decitabine 3-day regimen.
4. Documented disease progression or stable disease as best response to treatment (or 
attempted treatment) with azacitidine for injection or decitabine.  Those achieving an 
objective response to treatment regimen with an injectable HMA (Appendix F) are 
excluded from participation in this study.
Definitions of disease progression are modified from IWG 2006 criteria (Appendix F) 
and include:
∀
Pre-injectable HMA baseline bone marrow myeloblasts:
o
Less than 5%: 
≥100% increase to ≥8% blasts
o
≥ 5%: 
≥50% increase to ≥10% blasts
Note:  ≥ 30% blasts is considered AML per FAB classification.  Subjects known to 
have ≥ 30% blasts are not eligible for inclusion in this study.  Recognizing limitations 
of blast cell quantification, this protocol will allow subjects with pre-enrollment bone 
marrow blast counts up to 33% on the screening bone marrow examination to be 
considered for inclusion.  Assessment may be made according to local bone marrow 
examination to facilitate enrollment of eligible subjects into the treatment phase of the 
study.  
∀
Any clinical worsening from pre-injectable HMA baseline condition, including:
o
sustained clinically-significant worsening (investigator’s assessment) from 
baseline granulocyte, platelet, or hemoglobin values (≥ 2 values, separated by 
≥ 2 weeks)

worsening granulocytes should be ≥ 50% decrease from pre-injectable 
HMA baseline value

worsening platelets should be ≥ 50% decrease from pre-injectable
HMA baseline value (untransfused)

worsening hemoglobin should be ≥ 1.5 g/dL decrease from pre-
injectable HMA baseline value in subjects not receiving RBC 
transfusions
o
meaningful worsening in RBC or platelet transfusion requirement
Definition of stable disease is based on modified IWG 2006 criteria (Appendix F):
∀
Failure to achieve any objective response (CR, PR, mCR, or HI), but no evidence 
of disease progression within the 8 weeks leading to the subject’s first dose of IP
in this study (Cycle 1, Day 1).
5. Have the last dose of the prior treatment regimen (injectable HMA – azacitidine for 
injection or decitabine) not more than 16 weeks prior to screening for this study (date of 
informed consent signature).
6. No less than 3 weeks between the last dose of the prior treatment regimen (injectable 
HMA – azacitidine for injection or decitabine) and the planned date of first dose of IP.
&&,
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5. H


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
84
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
7. Have an ECOG performance status of 0, 1, or 2 (Appendix E)
8. Females subjects of childbearing potential1 may participate, providing they meet the 
following conditions:
a.
Have two negative pregnancy tests as verified by the investigator prior to starting any 
IP therapy: serum pregnancy test at screening and negative serum or urine pregnancy 
test (investigator’s discretion) within 72 hours prior to starting treatment with IP 
(Cycle 1, Day 1). They must agree to ongoing pregnancy testing during the course of 
the study (before beginning each subsequent cycle of treatment), and after the last 
dose of any IP. This applies even if the subject practices complete abstinence2 from 
heterosexual contact.
b. Agree to practice true abstinence2 (which must be reviewed on a monthly basis and 
source documented) or agree to the use of highly effective methods of contraception 
from 28 days prior to starting durvalumab or azacitidine, and must agree to continue 
using such precautions while taking durvalumab or azacitidine (including dose 
interruptions) and for up to 90 days after the last dose of durvalumab or azacitidine.  
Cessation of contraception after this point should be discussed with a responsible 
physician. 
c.
Agree to abstain from breastfeeding during study participation and for at least 90 days
after the last dose of IP.
d. Refrain from egg cell donation while taking durvalumab and for at least 90 days after 
the last dose of durvalumab.
Note that the screening serum pregnancy test can also be used as the test prior to 
starting IP if it is performed within the 72-hour timeframe.
9. Male subjects must:  
a.
Either practice true abstinence2 from heterosexual contact (which must be reviewed 
on a monthly basis) or agree to avoid fathering a child, to use highly effective 
methods of contraception, male condom plus spermicide during sexual contact with a 
pregnant female or a female of child bearing potential (even if he has undergone a 
successful vasectomy) from starting dose of IP (Cycle 1 Day 1), including dose 
interruptions through 90 days after receipt of the last dose of durvalumab or 
azacitidine.
b. Refrain from semen or sperm donation while taking IP and for at least 90 days after 
the last dose of IP. 
10. Understand and voluntarily sign an informed consent document prior to any study-related 
assessments or procedures conducted. 
                                               
1 A female subject 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 does not rule out childbearing potential) for at least 24 consecutive months 
(ie, has had menses at any time during the preceding 24 consecutive months).
2 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable 
methods of contraception.
&&,
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1 A female
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has no
has no


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
85
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
11. Be able to adhere to the study visit schedule and other protocol requirements.
12. Understand and voluntarily sign a biomarker-specific component of the informed consent 
document prior to any study-related procedures conducted.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from participation in the study:
1. Rapidly-progressing MDS, defined as:
a.
Known clinically-significant doubling in marrow or peripheral blood blast percentage 
(to ≥20%) in the 8-week period leading to the first dose of IP (Cycle 1, Day 1) or
b. ≥100% increase in WBC count (myeloid cell line and monocyte series) within the 8-
week period leading to Cycle 1, Day 1
2. Acute myelogenous leukemia (AML – FAB classification:  ≥30% blasts in bone 
marrow).  Subjects known to have ≥ 30% blasts are not eligible for inclusion in this 
study.  Recognizing limitations of blast cell quantification, this protocol will allow 
subjects with pre-enrollment (screening/baseline) bone marrow blast counts up to 33% to 
be considered for inclusion.  
3. Prior allogeneic stem cell transplant
4. Prior exposure to the investigational oral formulation of decitabine, or other oral 
azacitidine derivative at any time in the subject’s prior history
5. Prior or ongoing response (IWG 2006: HI, PR, CR, or marrow CR) to treatment with 
azacitidine for injection or decitabine, at any time in the subject’s prior history, which 
includes relapsed disease
6. Ongoing medically significant adverse events from previous treatment, regardless of the 
time period
7. Use of any of the following within 28 days prior to the first dose of IP:
a.
thrombopoiesis-stimulating agents ([TSAs]; eg, Romiplostim, Eltrombopag, 
Interleukin-11)
b. ESAs and other RBC hematopoietic growth factors (eg, interleukin-3)
c.
hydroxyurea
8. Concurrent use of corticosteroids unless the subject is on a stable or decreasing dose for 
≥ 1 week prior to enrollment for medical conditions other than MDS
9. History of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis), celiac 
disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other 
gastrointestinal disorder or defect that would interfere with the absorption, distribution, 
metabolism or excretion of the IP and/or predispose the subject to an increased risk of 
gastrointestinal toxicity 
10. Prior history of malignancies, other than MDS, unless the subject has been free of the 
disease for ≥ 3 years.  However, subjects with the following history/concurrent conditions 
are allowed:
&&,
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1


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
86
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
a.
Basal or squamous cell carcinoma of the skin
b. Carcinoma in situ of the cervix
c.
Carcinoma in situ of the breast
d. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, 
metastasis [TNM] clinical staging system)
11. Significant active cardiac disease within the previous 6 months, including:
a.
New York Heart Association (NYHA) class IV congestive heart failure (see 
Appendix G);
b. Unstable angina or angina requiring surgical or medical intervention; and/or
c.
Myocardial infarction
12. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing 
signs/symptoms related to the infection without improvement despite appropriate 
antibiotics, antiviral therapy, and/or other treatment)
13. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or 
evidence of active Hepatitis B Virus (HBV) infection
14. Any of the following laboratory abnormalities:
a.
Serum AST/SGOT or ALT/SGPT > 2.5 x ULN
b. Serum total bilirubin > 1.5 x ULN.  Higher levels are acceptable if these can be 
attributed to active red blood cell precursor destruction within the bone marrow (ie, 
ineffective erythropoiesis).  Subjects are excluded if there is evidence of autoimmune 
hemolytic anemia manifested as a corrected reticulocyte count of
> 2% with either a positive Coombs’ test or over 50% of indirect bilirubin
c.
Serum creatinine > 2.5 x ULN
d. Absolute WBC count ≥ 20 x 109/L
15. Known or suspected hypersensitivity to azacitidine, mannitol, or durvalumab, its 
constituents, or to any other humanized monoclonal antibody
16. Pregnant, planning to become pregnant starting from 28 days prior to receiving CC-486 
or durvalumab, throughout your participation in the study, and for at least 90 days 
following your last dose of study treatment, or breast-feeding females
17. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study
18. Any condition including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study
19. Any condition that confounds the ability to interpret data from the study, including 
known or suspected conditions other than MDS, associated with anemia
20. Having received any prior MAb against CTLA-4, PD-1, or PD-L1 or having received
other investigational MAbs within 6 months
21. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, or CNS 
leukemia
&&,
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cted reticul
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test or ove
est or ove
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come preg
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vent the sub
ent the sub
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nditioion inc
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ect at unac
ect at unac
Any condi
Any condi
known 
known 
20.
20. Hav
Hav


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
87
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
22. Current or prior use of immunosuppressive medication within 14 days prior to the first 
dose of durvalumab. The following are exceptions to this criterion:
a.
Intranasal, inhaled, topical or local steroid injections (eg, intra-articular injection);
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent;
c.
Steroids as premedication for hypersensitivity reactions (eg, computed tomography 
[CT] scan premedication).
23. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the 
exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable 
bowel disease, or other serious gastrointestinal chronic conditions associated with 
diarrhea; systemic lupus erythematosus; Wegener’s syndrome [granulomatosis with 
polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis, 
uveitis; etc) within the past 3 years prior to the start of treatment. The following are 
exceptions to this criterion:
a.
Subjects with vitiligo or alopecia;
b. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement for ≥ 3 months; or
c.
Subjects with psoriasis not requiring systemic treatment
24. History of primary immunodeficiency
25. Receipt of live, attenuated vaccine within 30 days prior to the first dose of durvalumab
(NOTE: Subjects, if enrolled, should not receive live vaccine during the study and 30 
days after the last dose of durvalumab)
26. Active myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia 
(CMML)
&&,
&(/*(1(35235,(7$5<,1)250$7,21
itable
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with
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receive live
eceive liv
ms (MPN) 
ms (MPN) 


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
88
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Product(s)
Investigational product supply will be managed by IRTS.  All IP must be stored in accordance 
with the product label in a secured area to prevent unauthorized access.
8.1.1.
CC-486 (Oral Azacitidine)
Celgene Corporation will supply CC-486 100-, 150-, and 200-mg tablets for oral administration.  
Each tablet is formulated using excipients that are generally regarded as safe and are used in 
marketed drug products.  A list of excipients included in the formulation is provided in the 
azacitidine IB.
After Amendment 4 approval, the CC-486 supply will be limited to 100-mg tablets for oral 
administration.
All tablets will be packaged in blister cards.  Only sufficient IP for one cycle of treatment will be 
provided to each subject at the start of each treatment cycle.  All tablets should be swallowed 
whole, and should not be broken or chewed.
Shelf-life evaluation of the intact blister card is ongoing.  Investigational Product will be 
monitored for stability for the duration of the study.
8.1.2.
Durvalumab (MEDI4736)
Durvalumab will be supplied by Celgene Corporation in single use vials in single count cartons. 
Each 10mL vial will be supplied as a vialed liquid solution containing 500 mg (nominal) of 
investigational product at a concentration of 50 mg/mL. Durvalumab is stored at 2%C - 8%C
(36%F to 46%F) and must be used before the individually assigned expiry date on the label.
Durvalumab will no longer be supplied during the Extension Phase as no subjects are being 
treated with durvalumab.
8.2.
Treatment Administration and Schedule
After the safety run-in is complete and the CC-486 dose and regimen to be used in combination 
with durvalumab is established, eligible subjects will be randomized to receive CC-486 alone or 
in combination with durvalumab in the randomized treatment phase of the study.  All 
randomized subjects will receive CC-486 orally administered tablets at the established dose and 
schedule. The schedule will include BID dosing on days 1-21 of each 28-day treatment cycle. 
Subjects randomized to the combination therapy arm will receive durvalumab, 1500 mg on    
Day 1 of each 28-day treatment cycle by IV infusion over approximately 1 hour (± 5 minutes).
CC-486 tablets should be ingested approximately 1 hour after completion of the durvalumab 
infusion on Day 1 of each treatment cycle (except for Cycle 1 in which CC-486 is given on
Day -1 for PK sub-study subjects) as described in Section 8.2.2.  In the event of unacceptable 
toxicity, CC-486 dose and schedule may be modified (see Section 8.2.4).  Infusions of 
durvalumab may be interrupted, slowed, or discontinued in order to address toxicity, but dose 
reduction of durvalumab is not permitted (see Section 8.2.4.2).  
&&,
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on.  
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d during th
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ministrat
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fofo
xixiciciti


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
89
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
In the absence of unacceptable toxicity, subjects who show signs of worsening disease (clinical
or hematological), who remain in stable disease, or do not experience modified IWG 2006 
hematologic improvement (HI) or better (PR, CR or marrow CR – modified IWG 2006, 
Appendix F) after 2 well-tolerated cycles, may have their dose increased at the discretion of the 
investigator and in discussion with the medical monitor as described in Section 8.2.4 and
Table 3. Again, dose and schedule may be adjusted as described in Section 8.2.4 in order to 
manage toxicity.  
Subjects may continue to receive the protocol-prescribed therapy for as long as they benefit from 
the treatment (Section 4.1.3) or until treatment is discontinued for reasons detailed in Section 12.  
Prior to discontinuing a subject, it is recommended that the investigator contact the medical 
monitor and forward appropriate supporting documents for review and discussion.  However, the 
decision to discontinue a subject remains the responsibility of the treating physician and will not 
be delayed or refused by the sponsor.
8.2.1.
Investigational Product Dispensation
8.2.1.1.
CC-486 Dispensation
CC-486 will be dispensed on Day 1 of each treatment cycle (except for Cycle 1 in which CC-486 
is given on Day -1 for PK sub-study subjects).
Only 1 cycle of IP will be dispensed to the subject at this time unless extreme extenuating 
circumstances apply and other arrangements are agreed to by the sponsor’s medical monitor in 
writing.  
The subject may not receive IP for each treatment cycle until all Day 1 procedures have been 
completed and all IP from the previous cycle is accounted for (where applicable).  
For FCBP subjects, a pregnancy test must be performed, and a negative result verified by the 
investigator, within 72 hours prior to IP administration on Day 1 of each treatment cycle.
8.2.1.2.
Durvalumab Dispensation
Total in-use storage time from needle puncture of durvalumab vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F). If in-
use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to equilibrate to room temperature prior to commencement of 
administration. Durvalumab does not contain preservatives and any unused portion must be 
discarded.
Sites should follow standard and local aseptic procedures and the clinical study protocol for all 
activities. All dispensing activities should be documented according to local procedures.
The shelf lives stated above are based on chemical and physical stability; assignment of 
microbial shelf life is the responsibility of the clinical center and should be aligned with local 
procedure for managing microbial risk as long as the times specified in this section are not 
exceeded. Vials should be used for the specific subjects to whom they are assigned, and must not 
be shared between subjects. 
&&,
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m
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12. 
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st be per
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ies. All dis
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microbial
microbial
roced
roced


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
90
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
8.2.2.
Investigational Product Administration
8.2.2.1.
CC-486 Administration
Investigational product administration will be accurately recorded including, but not limited to, 
date of administration, dose and any changes in dose administration (eg, interruption or reduction 
in dose due to an adverse event).
Investigational product is scheduled to be taken on the first 21 days of each 28-day treatment 
cycle, unless there has been a schedule modification of CC-486 administration due to toxicity.  
Subjects will be instructed to take CC-486 twice daily, in the morning and evening, at 
approximately the same times each day.  It is recommended that an antiemetic medication be 
taken 30 minutes prior to CC-486 administration during Cycle 1.  If nausea / vomiting is not 
significant, antiemetic prophylaxis may not be needed.  Subject will ingest CC-486 tablets with 
approximately 240 mL (8 ounces) of room temperature water.  Investigational product may be 
taken on an empty stomach or with food (a light breakfast or meal of up to approximately 600 
calories can be provided as a guidance).
Subjects assigned to the combination treatment arm will take their first dose of CC-486 on Day 1 
of each treatment cycle approximately one hour after completion of the durvalumab infusion.  If 
an antiemetic medication is to be administered, it should be taken about 30 minutes prior to 
dosing with CC-486.
For subjects enrolled in the PK population, the treatment administration of the first dose of CC-
486 on PK days (ie, Cycle 1 Day -1 and Cycle 2 Day 1) is described below:
!
After performing the required overnight fast, taking antiemetic premedication with 
240 mL of water for nausea and vomiting (eg, ondansetron), and completing the 
required predose assessments (including the predose PK sample), subjects will ingest 
CC-486 with 240 mL of room temperature water in the clinic approximately 30 
minutes after antiemetic administration on each PK dosing day.  Each dose of CC-486
should be given at approximately the same time each day.  The exact date and time of 
dosing will be recorded in the source documents and appropriate CRF.
Dietary restrictions on PK days (ie, Cycle 1 Day -1 and Cycle 2 Day 1): 
!
Subjects should be instructed to limit their coffee intake to one 8-ounce cup of black 
coffee (no cream or sugar) and to not consume alcohol, tea, chocolate, or cola 
beverages within 2 hours prior to collecting PK samples.
!
Subjects should not ingest food for a minimum of 8 hours prior and 2 hours after CC-
486 is administered.  Water can be allowed as desired except for 1 hour before and 
after CC-486 administration.  The only water permitted in the 1-hour period before 
CC-486 administration is the 240 mL of water for antiemetic ingestion.
On Cycle 2 Day 1, the first dose of CC-486 will be administered approximately one hour after 
the completion of the durvalumab infusion.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
91
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
8.2.2.2.
Durvalumab Administration
Preparation of durvalumab and preparation of the IV bag are to be performed aseptically. Vials 
should be used for the specific subjects to whom they are assigned, and must not be shared 
between subjects.
!
Three (3) vials of durvalumab (500 mg/vial; 50 mg/mL) are used to prepare a single 
infusion of the per-protocol dose of 1500 mg.
!
Vials containing durvalumab may be gently inverted for mixing, but should not be 
shaken. All durvalumab vials should be equilibrated to room temperature for 30 minutes 
prior to dose preparation.
8.2.2.2.1. Preparation of infusion bags
The preparation of infusion bags should be done under aseptic conditions by trained personnel; 
they should not be prepared on the ward.
!
A total of 30 mL durvalumab (contained in 3 vials) is added to an IV bag containing 250 
mL normal saline (Section 6.6), supplied by the site.  The bag is mixed by gentle 
inversion to ensure homogeneity of the dose in the bag.
!
Following preparation of the dose, the entire contents of the IV bag should be 
administered.
!
Flush the IV line with a volume of normal saline equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and 
document if the line was not flushed.
8.2.2.2.2. Infusion schedule and rates
Durvalumab will be administered as a 1-hour (± 5 minutes) IV infusion on Day 1 of each 28-day 
treatment cycle.  
8.2.2.2.3. Monitoring of dose administration
Subjects will be monitored during and after infusion of durvalumab. Vital signs will be measured 
within 30 minutes prior to durvalumab administration, every 15 minutes (± 5 minutes) during 
durvalumab administration, within 5 minutes of completing the durvalumab infusion, and at 30 
minutes (± 5 minutes) and 60 minutes (± 5 minutes) post infusion of durvalumab, followed by a 
2-hour (± 15 minutes) period of observation.
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of durvalumab may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. For subjects with a ≤Grade 2 
infusion-related reaction, subsequent infusions may be administered at 50% of the initial rate.
Acetaminophen and/or an antihistamine (eg, diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator. If the 
infusion-related reaction is ≥Grade 3 or higher in severity, IP will be discontinued.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
92
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary.
8.2.3.
Missing Doses
All efforts should be made to administer IP on all of the scheduled days of each 28-day treatment 
cycle.  Any missed doses of CC-486 during that period should not be taken after the last 
scheduled day of administration, but should be returned by the subject for IP accountability.
8.2.4.
Dose Modifications and Toxicity Management
8.2.4.1.
CC-486 (Oral Azacitidine) Dose Modification and Toxicity Management
All efforts should be made to maintain treatment with CC-486 according to schedule without 
cycle delay, dose interruption, or reduction.  Subjects will be monitored for hematologic toxicity 
and non-hematologic toxicity with the NCI CTCAE Version 4.03 used as a guide for the grading 
of severity.
If adverse events are observed that are considered by the investigator to be at least possibly 
related to treatment, CC-486 dosing may be interrupted, delayed or modified.  The investigator is 
encouraged to contact the medical monitor prior to any treatment adjustment, if possible.
For any adverse event that would put a subject at unacceptable risk in the investigator´s opinion 
(eg, Grade 4 neutropenia), CC-486 dosing may be interrupted, delayed or modified, even if not 
considered by the investigator to be at least possibly related to treatment.
A minimum CC-486 dose and schedule of 100 mg BID 14/28d (or 200 mg QD 14/28d) is 
permitted in the event of toxicity (see Table 3).  Subjects who cannot tolerate this minimum dose 
and schedule should discontinue the treatment phase of the study and enter follow-up.  
Subjects who have their CC-486 dose reduced or treatment schedule modified may return to their 
original dose and/or schedule in a stepwise fashion upon discussion and documented agreement 
between the investigator and the medical monitor, provided that at least two treatment cycles 
have proven tolerable at the current dose and schedule.  The treatment schedule should first be 
increased from 14/28 days to 21/28 days at 100 mg BID (or 200 mg QD if the rescue dosing 
option was utilized), followed by a stepwise escalation in dose (eg, 100 mg BID to 150 mg BID 
or 200 mg QD to 300 mg QD, etc.).  At least two treatment cycles without unacceptable drug-
related toxicity should precede any increase in dose or schedule.
In the absence of unacceptable toxicity, subjects who show signs of worsening disease (clinical
or hematological), who remain in stable disease, or do not experience modified IWG 2006 
hematologic improvement (HI) or better (PR, CR or marrow CR – modified IWG 2006, 
Appendix F) after 2 well-tolerated cycles,  may have their dose increased at the discretion of the 
investigator and in discussion with the medical monitor as described in Section 6.5 and Table 3. 
Again, dose and schedule may be adjusted as described in Section 8.2.4 in order to manage 
toxicity.  
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Appendix
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
93
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
After Amendment 4 approval, dose increases will no longer be allowed. Dose decreases 
following Table 3 are still allowed. Subjects will continue at the same dose levels during the 
Extension Phase. Any potential dose escalation will be considered a treatment failure and the 
subject should be discontinued.
Refer to Section 8.2.5 if, despite temporary interruption, delay or modification of study 
treatment, the toxicity persists for more than 42 days and is considered by the investigator to be 
at least possibly related to study treatment.
Following any modification of study treatment or if a dose is missed, the subject should stay on 
the visit schedule as specified in Table 2.  Unscheduled visits may occur to monitor the subject’s 
toxicities if necessary.  
Table 3:
CC-486 Dose Modification Steps
Dose 
Modification 
Step
BID Dose and Schedule
Days
Rescue Step
Rescue (QD) Dose and 
Schedule (Days)
+2
300 mg BID, 21/28 
+1
250 mg BID, 21/28 
0a
200 mg BID, 21/28 
-1
150 mg BID, 21/28 
R+2
300 mg QD, 21/28 
-2
100 mg BID, 21/28 
R+1
200 mg QD, 21/28 
-3b
100 mg BID, 14/28 
Rescue (R)
200 mg QD, 14/28 
BID = twice daily; QD = once daily; R = rescue dose step.
a Highest starting dose to be evaluated.
b Any subject who cannot tolerate dose modification Step -3 (or R) will discontinue IP and enter the follow-up 
period.
Dose adjustment options from current dose/regimen.  Dose/schedule reduction does not need to be taken stepwise.
Dose Modification for Febrile Neutropenia
Any subject who experiences febrile neutropenia ≥Grade 3 that persists for up to 3 days may, 
with concomitant antibiotic, antiviral, and/or antifungal therapy, continue to receive IP 
uninterrupted at the investigator’s discretion.  If the event exceeds 3 days, IP should be 
temporarily interrupted.  Dose modification may be considered as summarized in Table 4.
Dose Modification for Neutropenia Grade 4
For subjects entering the study with pre-existing Neutropenia Grade 4, treatment should be 
started at the regular starting dose and schedule of 200 mg BID 21/28d.  However, if neutropenia 
continues to worsen under treatment, dose modification may be considered as summarized in 
Table 4.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
94
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
For any subject who experiences a worsening of neutropenia to Grade 4 for ≥ 4 days, 
independent of whether considered related to IP or not, a dose modification may be considered as
summarized in Table 4.
Dose Modification for Diarrhea
It is recommended that subjects experiencing diarrhea be managed according to the guidelines 
provided in Appendix H.  Anti-diarrhea medication may be administered as prophylaxis against
diarrhea and for treatment of any adverse events of diarrhea.  Recommended dose modification 
steps for diarrhea (≥Grade 2) are summarized in Table 4.  If further dose-reduction beyond 
modification Step -3 (or the QD rescue regimen) is thought to be necessary, IP should be 
discontinued and the treatment discontinuation visit scheduled.
Dose Modification for Nausea and Vomiting
A serotonin (5-HT3) receptor antagonist (eg, ondansetron) or other comparable medication may 
be administered as an antiemetic prophylaxis approximately 30 minutes prior to IP 
administration if necessary.  Antiemetic pretreatment is recommended during the first cycle of 
the treatment phase.  If the subject does not experience significant nausea and/or vomiting, 
further use of antiemetic medications may not be necessary.  Antiemetic medication(s) should be 
administered for treatment of any adverse events of nausea and/or vomiting.  Recommended 
dose modifications for nausea and vomiting (≥Grade 3) are summarized in Table 4.  If further 
dose-reduction beyond modification Step -3 (or the QD rescue regimen) is thought to be 
necessary, IP should be discontinued and the treatment discontinuation visit scheduled.
Dose Modification for Renal Dysfunction and Abnormal Serum Electrolytes
If unexplained elevations of serum creatinine or electrolyte disturbances occur, dose or schedule 
modifications may be implemented as summarized in Table 4.  If further dose-reduction beyond 
modification Step -3 (or the QD rescue regimen) is thought to be necessary, IP should be 
discontinued and the treatment discontinuation visit scheduled.
Dose Modification for Weight Change
No dose adjustment should be made for weight loss or gain alone; however, the reason for 
weight loss (eg, significant nausea, vomiting, anorexia, etc.) or weight gain (eg, peripheral 
edema) should be investigated and may require a dose modification as specified in Table 4.  
Dose Modification for Any Other Adverse Event 
Any subject who experiences any hematologic or non-hematologic adverse event ≥ Grade 2, that 
is a worsening from baseline state (see Section 6.4 for baseline definition) and would put a 
subject at unacceptable risk in the investigator´s opinion, may have IP dosing temporarily 
interrupted until the adverse event returns to ≤ Grade 1 or baseline state.  This decision is not 
dependent on the relationship between the AE and IP (related or not).  Recommended dose 
modifications for other ≥Grade 2 hematologic or non-hematologic adverse events are 
summarized in Table 4.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
95
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Table 4:
Guidelines for CC-486 Toxicity Management and Dose Modifications
NCI CTCAE Toxicity Grade 
Action
Febrile Neutropenia
(≥Grade 3)
!
Continue IP at the discretion of the investigator
-
If episode persists for ≥ 4 days despite adequate/maximal 
antibiotic, antiviral and/or antifungal therapy, IP should be 
temporarily interrupted.
-
Resume IP at the same dose after the fever has resolved and 
the ANC has improved or stabilized (as assessed by the 
investigator).  IP should not be resumed for at least 3 days 
following resolution of fever.  Guidance for the use of growth 
factors and prophylactic antibiotics is provided in Section 9.1.
!
If a subject experiences febrile neutropenia in 2 consecutive 
cycles, the steps noted above should be followed, but the IP dose 
should be reduced by at least 1 step upon resumption of treatment 
with IP.  Secondary prophylaxis with G-CSF may be considered.
If subject continues to experience febrile neutropenia episodes that are 
deemed to be related to IP by the investigator, the dose and schedule may 
be modified further according to Table 3.
Neutropenia Grade 4
(related or unrelated to IP)
Pre-existing Neutropenia Grade 4
!
Continue IP at the discretion of the investigator
-
If the neutropenia continues to worsen significantly under 
treatment in the investigator’s opinion, treatment may be 
temporarily interrupted.
-
Resume IP after the ANC has improved or stabilized (as 
assessed by the investigator).  IP dose/schedule may be 
reduced at the investigator´s discretion (see Table 3).
!
If the subject continues to experience Grade 4 neutropenia during 
2 consecutive cycles, IP dose/regimen should be reduced by at 
least 1 step (Table 3).  Secondary prophylaxis with G-CSF may be 
considered.
Subjects experiencing worsening of Neutropenia to Grade 4 during
IP treatment
!
Continue IP at the discretion of the investigator
-
If episode persists for ≥ 4 days, IP may be temporarily 
interrupted.
-
Resume IP after the ANC has improved or stabilized (as 
assessed by the investigator).  IP dose/schedule may be 
reduced at the investigator´s discretion (see Table 3).
!
If the subject continues to experience Grade 4 neutropenia during 2 
consecutive cycles, IP dose/regimen should be reduced by at least 
1 step (Table 3).  Secondary prophylaxis with G-CSF may be 
considered.
Diarrhea (≥Grade 2)
!
Interrupt IP and provide adequate/maximum medical intervention
!
Resume IP at same dose when toxicity resolves to & Grade 1
!
If event reoccurs upon re-challenge or during the subsequent 
treatment cycle, modify IP dose/schedule by at least 1 step 
according to Table 3.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
96
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Table 4:
Guidelines for CC-486 Toxicity Management and Dose Modifications 
(Continued)
NCI CTCAE Toxicity Grade 
Action
Nausea and/or Vomiting  
(≥ Grade 3)
!
Interrupt IP and provide adequate/maximal medical intervention
!
Resume IP at same dose when toxicity resolves to & Grade 1
!
If event reoccurs upon re-challenge or during the subsequent 
treatment cycle, modify IP dose/schedule by at least 1 step
according to Table 3.
Renal Dysfunction
!
For unexplained elevations of serum creatinine, delay the start of 
the next cycle of treatment until values return to baseline.  Reduce 
IP dose in the next cycle of treatment by at least 1 step.
!
The treatment dose and/or schedule can be reduced per Table 3 if 
the elevation of serum creatinine recurs in the subsequent cycle.  
!
Discontinue IP if similar unexplained renal and/or electrolyte 
disturbances subsequently persist or recur during the next cycle of 
treatment.
Other # Grade 2 AEs
!
Consider interrupting IP and provide medical intervention as 
appropriate
!
Resume IP at same dose when toxicity resolves to & Grade 1
!
If event reoccurs upon re-challenge or at same intensity during 
next treatment cycle, modify IP dose/schedule according to
Table 3.
Abbreviations: AE = Adverse Event; ANC = Absolute Neutrophil Count; CTCAE = Common Terminology Criteria 
for Adverse Events; G-CSF = granulocyte colony-stimulating factor; IP = Investigational Product; NCI = National
Cancer Institute.
8.2.4.2.
Durvalumab Toxicity Management Guidelines
Dose reduction of durvalumab is not permitted in this study.  Guidelines for management of 
durvalumab-related toxicities are presented in Table 5, Table 6 and Table 7 below.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
97
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Table 5:
Durvalumab Treatment Modification and Toxicity Management Guidelines for Immune-Mediated Adverse 
Events
Dose Modifications
Toxicity Management
General Considerations
Drug administration modifications of IP/study regimen will be 
made to manage potential immune-mediated AEs based on severity 
of treatment-emergent toxicities graded per NCI CTCAE v4.03.
In addition to the criteria for permanent discontinuation of IP/study 
regimen based on CTC grade/severity (table below), permanently 
discontinue IP/study regimen for the following conditions: 
!
Inability to reduce corticosteroid to a dose of ≤ 10 mg of 
prednisone per day (or equivalent) within 12 weeks after 
last dose of IP/ study regimen
!
Recurrence of a previously experienced Grade 3 
treatment-related AE following resumption of dosing. 
Grade 1 - No dose modification
Grade 2 - Hold IP/study regimen dose until Grade 2 resolution to
≤ Grade 1
!
If toxicity worsens, then treat as Grade 3 or Grade 4
!
IP/study treatment can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper
!
Subjects with endocrinopathies who may require 
prolonged or continued steroid replacement can be 
retreated with IP/study regimen on the following 
conditions: 1) the event stabilizes and is controlled, 2) the 
subject is clinically stable as per Investigator or treating 
physician’s clinical judgement, and 3) doses of 
prednisone are at less than or equal to 10 mg/day or 
equivalent.
Grade 3 - Depending on the individual toxicity, IP/study regimen 
may be permanently discontinued. Please refer to guidelines below
Grade 4 - Permanently discontinue IP/study regimen 
It is recommended that management of immune-mediated adverse 
events (imAEs) follow the guidelines presented in this table
-
It is possible that events with an inflammatory or immune-
mediated mechanism could occur in nearly all organs, some 
of them not noted specifically in these guidelines.  Whether 
specific immune-mediated events (and/or laboratory 
indicators of such events) are noted in these guidelines or not, 
subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, concomitant 
medications, infections, etc.) to a possible immune-mediated 
event. 
-
In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related.  General 
recommendations follow.
-
Symptomatic and topical therapy should be considered for 
low-grade (Grade 1 or 2, unless otherwise specified) events.
-
For persistent (greater than 3 to 5 days) low-grade (Grade 2) 
or severe (Grade ≥ 3) events promptly start oral prednisone 1-
2 mg/kg/day PO or IV equivalent.
-
Some events with high likelihood for morbidity and/or 
mortality – eg, myo-carditis, or other similar events even if 
they are not currently noted in the guidelines – should 
progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is 
Grade 2, and if clinical suspicion is high and/or there has been 
clinical confirmation. Consider, as necessary, discussing with 
the study physician, and promptly pursue specialist 
consultation.
-
If symptoms recur or worsen during corticosteroid tapering 
(28 days of taper), increase the corticosteroid dose 
(prednisone dose [eg, up to 2-4 mg/kg/day PO or IV 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
98
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
IP Note: IP/study regimen should be permanently 
discontinued in Grade 3 events with high likelihood for 
morbidity and/or mortality – eg, myocarditis, or other 
similar events even if they are not currently noted in the 
guidelines. Similarly, consider whether IP/study regimen 
should be permanently discontinued in Grade 2 events 
with high likelihood for morbidity and/or mortality – eg, 
myocarditis, or other similar events even if they are not 
currently noted in the guidelines – when they do not 
rapidly improve to Grade <1 upon treatment with 
systemic steroids and following full taper
!
Note: There are some exceptions to permanent 
discontinuation of IP for Grade 4 events (ie, 
hyperthyroidism, hypothyroidism, Type 1 diabetes)
equivalent]) until stabilization or improvement of symptoms, 
then resume corticosteroid tapering at a slower rate (> 28 days 
of taper).
−
More potent immunosuppressives such as TNF inhibitors (eg
infliximab) – (also refer to individual sections of the immune 
mediated adverse events for specific type of 
immunosuppressive) should be considered for events not 
responding to systemic steroids.  Progression to use of more 
potent immunosuppressives should proceed more rapidly in 
events with high likelihood for morbidity and/or mortality –
eg, myocarditis, or other similar events even if they are not 
currently noted in the guidelines – when these events are not 
responding to systemic steroids.
−
With long-term steroid and other immunosuppressive use, 
consider need for Pneumocystis jirovecii pneumonia (PJP, 
formerly known as Pneumocystis carinii pneumonia) 
prophylaxis, gastrointestinal protection, and glucose 
monitoring.
-
Discontinuation of IP is not mandated for Grade 3 / Grade 4 
inflammatory reactions attributed to local tumor response (eg, 
inflammatory reaction at sites of metastatic disease, lymph 
nodes, etc.). Continuation of IP in this situation should be 
based upon a benefit/risk analysis for that subject.
AE = adverse event; CTC = Common Toxicity Criteria; CTCAE = Common Terminology Criteria for Adverse Events; imAE = immune-mediated adverse event; 
IP = investigational product; IV = intravenous; NCI = National Cancer Institute; PO = By mouth; TNF = tumor necrosis factor
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
99
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Pneumonitis/Interstitial 
Lung Disease (ILD)
Any Grade
General Guidance
For Any Grade:
−
Monitor subjects for signs and symptoms of 
pneumonitis or ILD (new onset or worsening shortness 
of breath or cough). Subjects should be evaluated with 
imaging and pulmonary function tests, including other 
diagnostic procedures as described below.
−
Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry (resting 
and exertion), laboratory work-up, and high- resolution 
CT scan.
Grade 1
(asymptomatic, 
clinical or diagnostic 
observations only; 
intervention not 
indicated)
No dose modifications required. 
However, consider holding IP/study 
regimen dose as clinically appropriate 
and during diagnostic work-up for 
other etiologies.
For Grade 1 (radiographic changes only):
−
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated.
−
Consider Pulmonary and Infectious disease consult.
Grade 2
(symptomatic; 
medical intervention 
indicated; limiting 
instrumental ADL)
Hold IP/study regimen dose until 
Grade 2 resolution to Grade ≤1.
!
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
!
If toxicity improves to Grade ≤1, 
then the decision to reinitiate 
IP/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper.
For Grade 2 (mild to moderate new symptoms):
−
Monitor symptoms daily and consider hospitalization.
−
Promptly start systemic steroids (eg, prednisone 1 to 
2 mg/kg/day PO or IV equivalent).
−
Reimage as clinically indicated.
−
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started
−
If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
100
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation])a
−
Consider pulmonary and infectious disease consult.
−
Consider, as necessary, discussing with study physician.
Grade 3 or 4
(Grade 3: severe 
symptoms; limiting 
self-care ADL; 
oxygen indicated)
(Grade 4: life-
threatening 
respiratory 
compromise; urgent 
intervention 
indicated [eg, 
tracheostomy or 
intubation])
Permanently discontinue IP/study 
regimen.
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life-threatening):
−
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.
−
Obtain Pulmonary and Infectious disease consult; 
consider, as necessary, discussing with study physician.
−
Hospitalize the subject.
−
Supportive care (eg, oxygen).
−
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with 
additional immunosuppressive therapy such as TNF 
inhibitors (eg, infliximab at 5 mg/kg every 2 weeks’ 
dose) started. Caution: rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab.
−
Once subject is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, 
antifungals, and, in particular, anti-PJP treatment (refer 
to current NCCN guidelines for treatment of cancer-
related infections [Category 2B recommendation]).a
Diarrhea/Colitis
Any Grade
General Guidance
For Any Grade:
−
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or 
changes in bowel habits such as increased frequency 
over baseline or blood in stool) or related to bowel 
perforation (such as sepsis, peritoneal signs, and ileus).
−
Subjects should be thoroughly evaluated to rule out any 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
101
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
alternative etiology (eg, disease progression, other 
medications, or infections), including testing for 
clostridium difficile toxin, etc.
−
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order 
to prevent potential progression to higher grade event.
−
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis.
Grade 1
(Diarrhea: stool 
frequency of <4 over 
baseline per day)
(Colitis: 
asymptomatic; 
clinical or diagnostic 
observations only)
No dose modifications.
For Grade 1:
−
Monitor closely for worsening symptoms.
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment.
Grade 2
(Diarrhea: stool 
frequency of 4 to 6 
over baseline per 
day) (Colitis: 
abdominal pain; 
mucus or blood in 
stool)
Hold IP/study regimen until 
resolution to Grade ≤1
!
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
!
If toxicity improves to Grade ≤1, 
then IP/study regimen can be 
resumed after completion of 
steroid taper.
For Grade 2:
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide.
−
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.
−
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, GI consult should be obtained for 
consideration of further workup, such as imaging and/or 
colonoscopy, to confirm colitis and rule out perforation, 
and prompt treatment with IV methylprednisolone 2 to 4 
mg/kg/day started.
−
If still no improvement within 3 to 5 days despite 2 to 4 
mg/kg IV methylprednisolone, promptly start 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
102
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
immunosuppressives such as infliximab at 5 mg/kg once 
every 2 weeksa. Caution: it is important to rule out 
bowel perforation and refer to infliximab label for 
general guidance before using infliximab.
−
Consider, as necessary, discussing with study physician 
if no resolution to Grade ≤1 in 3 to 4 days.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
Grade 3 or 4
(Grade 3 diarrhea: 
stool frequency of ≥7 
over baseline per 
day;
Grade 4 diarrhea: 
life- threatening 
consequences)
(Grade 3 colitis: 
severe abdominal 
pain, change in 
bowel habits, medi-
cal intervention indi-
cated, peritoneal 
signs;
Grade 4 colitis: life-
threatening 
consequences, urgent 
intervention 
indicated)
Grade 3
Permanently discontinue IP/study 
regimen for Grade 3 if toxicity does 
not improve to Grade ≤1 within 
14 days; IP/study regimen can be 
resumed after completion of steroid 
taper.
Grade 4
Permanently discontinue 
IP/study regimen. 
For Grade 3 or 4:
−
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent.
−
Monitor stool frequency and volume and maintain 
hydration.
−
Urgent GI consult and imaging and/or colonoscopy as 
appropriate.
−
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, 
promptly start further immunosuppressives (eg, 
infliximab at 5 mg/kg once every 2 weeks). Caution: 
Ensure GI consult to rule out bowel perforation and 
refer to infliximab label for general guidance before 
using infliximab.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
103
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Hepatitis 
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-mediated
hepatitis.
Any Grade
General Guidance
For Any Grade:
−
Monitor and evaluate liver function test: AST, ALT, 
ALP, and TB.
−
Evaluate for alternative etiologies (eg, viral hepatitis, 
disease progression, concomitant medications).
Grade 1
(AST or ALT >ULN 
and ≤3.0×ULN 
and/or TB > ULN 
and  ≤1.5×ULN)
!
No dose modifications.
!
If it worsens, then treat as Grade 
2 event.
For Grade 1:
−
Continue LFT monitoring per protocol.
Grade 2
(AST or 
ALT >3.0×ULN and 
≤5.0×ULN and/or 
TB >1.5×ULN and  
≤3.0×ULN)
!
Hold IP/study regimen dose until 
Grade 2 resolution to Grade ≤1.
!
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
!
If toxicity improves to Grade ≤1 
or baseline, resume IP/study 
regimen after completion of 
steroid taper.
For Grade 2:
−
Regular and frequent checking of LFTs (eg, every 1 to 2 
days) until elevations of these are improving or 
resolved.
−
If no resolution to Grade ≤1 in 1 to 2 days, consider, as 
necessary, discussing with study physician.
−
If event is persistent (>3 to 5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent.
−
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional work up and start prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day.
−
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (ie, mycophenolate mofetil).a
Discuss with study physician if mycophenolate mofetil 
is not available. Infliximab should NOT be used.
−
Once the subject is improving, gradually taper steroids
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
PLEASE SEE 
shaded area 
immediately below
this section to find
guidance for
management of
“Hepatitis (elevated 
LFTs)” in HCC 
patients
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
104
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Grade 3 or 4
(Grade 3: AST or 
ALT >5.0×ULN and 
≤20.0×ULN and/or 
TB >3.0×ULN and  
≤10.0×ULN)
(Grade 4: AST or 
ALT >20×ULN 
and/or 
TB >10×ULN)
For Grade 3:
For elevations in transaminases 
≤8 × ULN, or elevations in bilirubin 
≤5 × ULN:
!
Hold IP/study regimen dose until 
resolution to Grade ≤1 or baseline
!
Resume IP/study regimen if 
elevations downgrade to Grade 
≤1 or baseline within 14 days and 
after completion of steroid taper.
!
Permanently discontinue IP/study 
regimen if the elevations do not 
downgrade to Grade ≤1 or 
baseline within 14 days
For elevations in transaminases 
>8 × ULN or elevations in bilirubin 
>5 × ULN, discontinue IP/study 
regimen.
Permanently discontinue IP/study 
regimen for any case meeting Hy’s 
law criteria (AST and/or ALT >3 × 
ULN + bilirubin >2 × ULN without 
initial findings of cholestasis (ie, 
elevated alkaline P04) and in the 
absence of any alternative cause.b
For Grade 4:
Permanently discontinue IP/study 
regimen.
For Grade 3 or 4:
−
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent.
−
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, 
promptly start treatment with immunosuppressive 
therapy (ie, mycophenolate mofetil). Discuss with study 
physician if mycophenolate is not available. Infliximab 
should NOT be used.
−
Perform hepatology consult, abdominal workup, and 
imaging as appropriate.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
105
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Hepatitis 
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-mediated
hepatitis.
See instructions at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation
Any Grade
General Guidance
For Any Grade:
−
Monitor and evaluate liver function test: AST, ALT, 
ALP, and TB.
−
Evaluate for alternative etiologies (eg, viral hepatitis, 
disease progression, concomitant medications, 
worsening of liver cirrhosis [eg, portal vein 
thrombosis]).
−
For HBV+ subjects: evaluate quantitative HBV viral 
load, quantitative HBsAg, or HBeAg
−
For HCV+ subjects: evaluate quantitative HCV viral 
load
−
Consider consulting hepatologist/Infectious disease 
specialist regarding change/implementation in/of 
antiviral medications for any subject with an elevated 
HBV viral load >2000 IU/ml
−
Consider consulting hepatologist/Infectious disease 
specialist regarding change/implementation in/of 
antiviral HCV medications if HCV viral load increased 
by ≥2-fold
−
For HCV+ with HBcAB+: Evaluate for both HBV and 
HCV as above
Grade 1
(Isolated AST or 
ALT >ULN and 
≤5.0×ULN, whether 
normal or elevated at 
baseline) 
!
No dose modifications.
!
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat 
as Grade 2 event.
For all grades, see instructions at 
bottom of shaded area if transaminase 
rise is not isolated but (at any time) 
occurs in setting of either increasing 
bilirubin or signs of DILI/liver 
decompensation
THIS shaded area 
is guidance only for
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
106
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Grade 2
(Isolated AST or 
ALT >5.0×ULN and 
≤8.0×ULN, if normal 
at baseline)
(Isolated AST or 
ALT >2.0×baseline 
and ≤12.5×ULN, if 
elevated >ULN at 
baseline)
!
Hold IP/study regimen dose until 
Grade 2 resolution to Grade ≤1 or 
baseline.
!
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
If toxicity improves to Grade ≤1 or 
baseline, resume IP/study regimen 
after completion of steroid taper.
For Grade 2:
−
Regular and frequent checking of LFTs (eg, every 1 to 3 
days) until elevations of these are improving or 
resolved.
−
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver 
perfusion.
−
Consider, as necessary, discussing with study physician.
−
If event is persistent (>3 to 5 days) or worsens, and 
investigator suspects toxicity to be immune-mediated 
AE, recommend to start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent.
−
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup and treatment with IV 
methylprednisolone 2 to 4 mg/kg/day.
−
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, consider 
additional abdominal workup (including liver biopsy) 
and imaging (ie, liver ultrasound), and consider starting 
immunosuppressives (ie, mycophenolate mofetil).a
Discuss with study physician if mycophenolate mofetil 
is not available. Infliximab should NOT be used.
Grade 3
(Isolated AST or 
ALT >8.0×ULN and 
≤20.0×ULN, if 
normal at baseline)
(Isolated AST or 
!
Hold IP/study regimen dose until 
resolution to Grade ≤1 or baseline
!
Resume IP/study regimen if 
elevations downgrade to Grade 
≤1 or baseline within 14 days and 
after completion of steroid taper.
!
Permanently discontinue IP/study 
For Grade 3:
−
Regular and frequent checking of LFTs (eg, every 1-2 
days) until elevations of these are improving or 
resolved.
−
Consult hepatologist (unless investigator is 
hepatologist); obtain abdominal ultrasound, including 
Doppler assessment of liver perfusion; and consider 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
107
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
ALT >12.5×ULN 
and ≤20.0×ULN, if  
elevated >ULN at 
baseline)
regimen if the elevations do not 
downgrade to Grade ≤1 or 
baseline within 14 days
Permanently discontinue IP/study 
regimen for any case meeting Hy’s 
law criteria, in the absence of any 
alternative cause.b
liver biopsy.
−
Consider, as necessary, discussing with study physician.
−
If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent.
−
If no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, 
obtain liver biopsy (if it has not been done already) and 
promptly start treatment with immunosuppressive 
therapy (mycophenolate mofetil). Discuss with study 
physician if mycophenolate is not available. Infliximab 
should NOT be used.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PCP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
Grade 4
(Isolated AST or 
ALT >20×ULN,  
whether normal or 
elevated at baseline)
Permanently discontinue IP/study 
regimen.
For Grade 4:
Same as above 
(except would recommend obtaining liver biopsy early)
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 
2×baseline, if >ULN at baseline) or signs of DILI/liver decompensation (eg, fever, elevated INR):
-
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise
-
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise
-
Grade 3-4: Permanently discontinue IP/study regimen
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
108
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Nephritis or renal 
dysfunction
(elevated serum 
creatinine)
Any Grade
General Guidance
For Any Grade:
−
Consult with nephrologist.
−
Monitor for signs and symptoms that may be related to 
changes in renal function (eg, routine urinalysis, 
elevated serum BUN and creatinine, decreased 
creatinine clearance, electrolyte imbalance, decrease in 
urine output, or proteinuria).
−
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression or 
infections).
−
Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 
2), in order to prevent potential progression to higher 
grade event.
Grade 1
(Serum creatinine 
> 1 to 1.5 × baseline; 
> ULN to 1.5 × 
ULN)
No dose modifications.
For Grade 1:
−
Monitor serum creatinine weekly and any 
accompanying symptoms.
!
If creatinine returns to baseline, resume its 
regular monitoring per study protocol.
!
If creatinine worsens, depending on the 
severity, treat as Grade 2, 3, or 4.
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.
Grade 2
(serum creatinine 
>1.5 to 3.0 × 
baseline; >1.5 to 3.0 
× ULN)
Hold IP/study regimen until 
resolution to Grade ≤1 or baseline. 
!
If toxicity worsens, then treat as 
Grade 3 or 4.
!
If toxicity improves to Grade ≤1 
or baseline, then resume IP/study 
For Grade 2:
−
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics.
−
Carefully monitor serum creatinine every 2 to 3 days 
and as clinically warranted.
−
Consult nephrologist and consider renal biopsy if 
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phrologist.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
109
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
regimen after completion of 
steroid taper.
clinically indicated.
−
If event is persistent (>3 to 5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent.
−
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should be considered and 
prompt treatment with IV methylprednisolone at 2 to 
4 mg/kg/day started.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
−
When event returns to baseline, resume IP/study 
regimen and routine serum creatinine monitoring per 
study protocol.
Grade 3 or 4
(Grade 3: serum 
creatinine 
>3.0 × baseline; >3.0 
to 6.0 × ULN;
Grade 4: serum 
creatinine >6.0 × 
ULN)
Permanently discontinue IP/study 
regimen.
For Grade 3 or 4:
−
Carefully monitor serum creatinine on daily basis.
−
Consult nephrologist and consider renal biopsy if 
clinically indicated.
−
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.
−
If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should be considered and 
prompt treatment with IV methylprednisolone 2 to 
4 mg/kg/day started.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
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Managemen
7,2
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
110
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Rash
(excluding bullous skin 
formations)
Any Grade
(refer to NCI 
CTCAE v 4.03 for 
definition of 
severity/grade 
depending on type of 
skin rash)
General Guidance
For Any Grade:
−
Monitor for signs and symptoms of dermatitis (rash and 
pruritus).
−
IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED 
AND IP DISCONTINUED.
Grade 1
No dose modifications.
For Grade 1:
−
Consider symptomatic treatment, including oral 
antipruritics (eg, diphenhydramine or hydroxyzine) and 
topical therapy (eg, urea cream).
Grade 2
For persistent (>1 to 2 weeks) 
Grade 2 events, hold scheduled 
IP/study regimen until resolution to 
Grade ≤1 or baseline.
!
If toxicity worsens, then treat as 
Grade 3.
!
If toxicity improves to Grade ≤1 
or baseline, then resume 
drug/study regimen after 
completion of steroid taper.
For Grade 2:
−
Obtain dermatology consult.
−
Consider symptomatic treatment, including oral 
antipruritics (eg, diphenhydramine or hydroxyzine) and 
topical therapy (eg, urea cream).
−
Consider moderate-strength topical steroid.
−
If no improvement of rash/skin lesions occurs within 3 
to 5 days or is worsening despite symptomatic treatment 
and/or use of moderate strength topical steroid, consider, 
as necessary, discussing with study physician and 
promptly start systemic steroids such as prednisone 1 to 
2 mg/kg/day PO or IV equivalent.
−
Consider skin biopsy if the event is persistent for >1 to 
2 weeks or recurs.
Grade 3 or 4
For Grade 3:
Hold IP/study regimen until 
resolution to Grade ≤1 or baseline.
If temporarily holding the IP/study 
regimen does not provide 
improvement of the Grade 3 skin rash 
For Grade 3 or 4:
−
Consult dermatology.
−
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.
−
Consider hospitalization.
−
Monitor extent of rash [Rule of Nines].
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
111
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
to Grade ≤1 or baseline within 
30 days, then permanently 
discontinue IP/study regimen.
For Grade 4:
Permanently discontinue IP/study 
regimen.
−
Consider skin biopsy (preferably more than 1) as 
clinically feasible.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
−
Consider, as necessary, discussing with study physician.
Endocrinopathy
(e.g., hyperthyroidism, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section)
Any Grade
(depending on the 
type of 
endocrinopathy, refer 
to NCI CTCAE 
v4.03 for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
−
Consider consulting an endocrinologist for endocrine 
events.
−
Consider, as necessary, discussing with study physician.
−
Monitor subjects for signs and symptoms of 
endocrinopathies. Non-specific symptoms include 
headache, fatigue, behavior changes, changed mental 
status, vertigo, abdominal pain, unusual bowel habits, 
polydipsia, polyuria, hypotension, and weakness.
−
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression including 
brain metastases, or infections).
−
Depending on the suspected endocrinopathy, monitor 
and evaluate thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine and related labs 
(eg, blood glucose and ketone levels, HgA1c).
−
For modest asymptomatic elevations in serum amylase 
and lipase, corticosteroid treatment is not indicated as 
long as there are no other signs or symptoms of 
pancreatic inflammation.
−
If a subject experiences an AE that is thought to be 
possibly of autoimmune nature (eg, thyroiditis, 
pancreatitis, hypophysitis, or diabetes insipidus), the 
investigator should send a blood sample for appropriate 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
112
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
autoimmune antibody testing.
Grade 1
No dose modifications.
For Grade 1 (including those with asymptomatic TSH 
elevation):
−
Monitor subject with appropriate endocrine function 
tests.
−
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment 
of early-morning ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test (though it 
may not be useful in diagnosing early secondary adrenal 
insufficiency).
−
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently 
out of range in 2 subsequent measurements, include free 
T4 at subsequent cycles as clinically indicated and 
consider consultation of an endocrinologist.
Grade 2
For Grade 2 endocrinopathy other 
than hypothyroidism and Type 1 
diabetes mellitus, hold IP/study 
regimen dose until subject is 
clinically stable.
!
If toxicity worsens, then treat as 
Grade 3 or Grade 4.
IP/study regimen can be resumed 
once event stabilizes and after 
completion of steroid taper.
Subjects with endocrinopathies who 
may require prolonged or continued 
steroid replacement (eg, adrenal 
insufficiency) can be retreated with 
IP/study regimen on the following 
conditions:
For Grade 2 (including those with symptomatic 
endocrinopathy):
−
Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan.
−
For all subjects with abnormal endocrine work up, 
except those with isolated hypothyroidism or Type 1 
DM, and as guided by an  endocrinologist, consider 
short-term corticosteroids (eg, 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone 
replacement (eg, hydrocortisone, sex hormones).
−
Isolated hypothyroidism may be treated with 
replacement therapy, without IP/study regimen 
interruption, and without corticosteroids.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
113
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
1.
The event stabilizes and is 
controlled.
2.
The subject is clinically stable 
as per investigator or treating 
physician’s clinical judgement.
3.
Doses of prednisone are 
≤10 mg/day or equivalent.
−
Isolated Type 1 diabetes mellitus (DM) may be treated 
with appropriate diabetic therapy, without IP/study
regimen interruption, and without corticosteroids.
−
Once subjects on steroids are improving, gradually taper  
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
−
For subjects with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory 
assessments/MRI as clinically indicated.
Grade 3 or 4
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism and Type 
1 diabetes mellitus, hold IP/study 
regimen dose until endocrinopathy 
symptom(s) are controlled. 
IP/study regimen can be resumed 
once event stabilizes and after 
completion of steroid taper.
Subjects with endocrinopathies who 
may require prolonged or continued 
steroid replacement (eg, adrenal 
insufficiency) can be retreated with 
IP/study regimen on the following 
conditions:
1.
The event stabilizes and is 
controlled.
2.
The subject is clinically stable as 
per investigator or treating 
physician’s clinical judgement.
3.
Doses of prednisone are 
For Grade 3 or 4:
−
Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan. Hospitalization recommended.
−
For all subjects with abnormal endocrine work up, 
except those with isolated hypothyroidism or Type 1 
DM, and as guided by an endocrinologist, promptly 
initiate empiric IV methylprednisolone 1 to 2 mg/kg/day 
or equivalent, as well as relevant hormone replacement 
(eg, hydrocortisone, sex hormones).
−
For adrenal crisis, severe dehydration, hypotension, or 
shock, immediately initiate IV corticosteroids with 
mineralocorticoid activity.
−
Isolated hypothyroidism may be treated with 
replacement therapy, without IP/study regimen 
interruption, and without corticosteroids.
−
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without IP/study regimen 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
114
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
≤10 mg/day or equivalent.
interruption, and without corticosteroids.
−
Once subjects on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP 
treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections [Category 2B 
recommendation]).a
Neurotoxicity
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia
Gravis and Guillain-
Barre)
Any Grade
(depending on the 
type of neurotoxicity, 
refer to NCI CTCAE 
v4.03 for defining 
the CTC 
grade/severity)
General Guidance
For Any Grade:
−
Subjects should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes, or medications).
−
Monitor subject for general symptoms (headache, 
nausea, vertigo, behavior change, or weakness).
−
Consider appropriate diagnostic testing 
(eg, electromyogram and nerve conduction 
investigations).
−
Perform symptomatic treatment with neurological 
consult as appropriate.
Grade 1
No dose modifications.
For Grade 1:
−
See “Any Grade” recommendations above.
Grade 2
For acute motor neuropathies or 
neurotoxicity, hold IP/study regimen 
dose until resolution to Grade ≤1.
For sensory neuropathy/neuropathic 
pain, consider holding IP/study 
regimen dose until resolution to 
Grade ≤1.
If toxicity worsens, then treat as 
Grade 3 or 4.
IP/study regimen can be resumed 
For Grade 2:
−
Consider, as necessary, discussing with the study 
physician.
−
Obtain neurology consult.
−
Sensory neuropathy/neuropathic pain may be managed 
by appropriate medications (eg, gabapentin or 
duloxetine).
−
Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent.
−
If no improvement within 3 to 5 days despite 1 to 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
115
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
once event improves to Grade ≤1 and 
after completion of steroid taper.
2 mg/kg/day prednisone PO or IV equivalent, consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (eg, IVIG).
Grade 3 or 4
For Grade 3:
Hold IP/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue IP/study 
regimen if Grade 3 imAE does not 
resolve to Grade ≤1 within 30 days.
For Grade 4:
Permanently discontinue IP/study 
regimen.
For Grade 3 or 4:
−
Consider, as necessary, discussing with study physician.
−
Obtain neurology consult.
−
Consider hospitalization.
−
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent.
−
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and 
promptly treat with additional immunosuppressants (eg, 
IVIG).
−
Once stable, gradually taper steroids over ≥28 days.
Peripheral neuromotor 
syndromes
(such as Guillain-Barre 
and myasthenia gravis)
Any Grade
General Guidance
For Any Grade:
−
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain 
subjects may unpredictably experience acute 
decompensations that can result in substantial morbidity 
or in the worst case, death. Special care should be taken 
for certain sentinel symptoms that may predict a more 
severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory 
insufficiency or autonomic instability.
−
Subjects should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in subjects 
with underlying cancer, due to the multiple potential 
confounding effects of cancer (and its treatments) 
throughout the neuraxis. Given the importance of 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
116
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
prompt and accurate diagnosis, it is essential to have a 
low threshold to obtain a neurological consult.
−
Neurophysiologic diagnostic testing 
(eg, electromyogram and nerve conduction 
investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon 
suspicion of such conditions and may be best facilitated 
by means of a neurology consultation.
−
It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Subjects requiring treatment 
should be started with IVIG and followed by 
plasmapheresis if not responsive to IVIG.
Grade 1
No dose modifications.
For Grade 1:
−
Consider, as necessary, discussing with the study 
physician.
−
Care should be taken to monitor subjects for sentinel 
symptoms of a potential decompensation as described 
above.
−
Obtain a neurology consult.
Grade 2
Hold IP/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue IP/study 
regimen if it does not resolve to 
Grade ≤1 within 30 days or if there 
are signs of respiratory insufficiency 
or autonomic instability.
For Grade 2:
−
Consider, as necessary, discussing with the study 
physician.
−
Care should be taken to monitor subjects for sentinel 
symptoms of a potential decompensation as described 
above.
−
Obtain a neurology consult
−
Sensory neuropathy/neuropathic pain may be managed 
by appropriate medications (eg, gabapentin or 
duloxetine).
MYASTHENIA GRAVIS:
o
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
117
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
myasthenia gravis. It is important to consider 
that steroid therapy (especially with high doses) 
may result in transient worsening of 
myasthenia and should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist.
o
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candidates for treatment with plasmapheresis or 
IVIG. Such decisions are best made in 
consultation with a neurologist, taking into 
account the unique needs of each subject.
o
If myasthenia gravis-like neurotoxicity is 
present, consider starting AChE inhibitor 
therapy in addition to steroids. Such therapy, if 
successful, can also serve to reinforce the 
diagnosis.
GUILLAIN-BARRE:
o
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-
Barre is not typically considered effective.
o
Subjects requiring treatment should be started 
with IVIG and followed by plasmapheresis if 
not responsive to IVIG.
Grade 3 or 4
For Grade 3:
Hold IP/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue IP/study 
regimen if Grade 3 imAE does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency or autonomic 
For Grade 3 or 4 (severe or life-threatening events):
−
Consider, as necessary, discussing with study physician.
−
Recommend hospitalization.
−
Monitor symptoms and obtain neurological consult.
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
118
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
instability.
For Grade 4:
Permanently discontinue IP/study 
regimen.
supervision of a consulting neurologist.
o
Subjects unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or 
IVIG.
o
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in 
addition to steroids. Such therapy, if successful, 
can also serve to reinforce the diagnosis.
GUILLAIN-BARRE:
o
It is important to consider here that the use of 
steroids as the primary treatment of Guillain-
Barre is not typically considered effective.
o
Subjects requiring treatment should be started 
with IVIG and followed by plasmapheresis if 
not responsive to IVIG.
Myocarditis
Any Grade
General Guidance
Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis.
For Any Grade:
−
The prompt diagnosis of immune-mediated myocarditis 
is important, particularly in subjects with baseline 
cardiopulmonary disease and reduced cardiac function. 
−
Consider, as necessary, discussing with the study 
physician.
−
Monitor subjects for signs and symptoms of myocarditis 
(new onset or worsening chest pain, arrhythmia, 
shortness of breath, peripheral edema). As some 
symptoms can overlap with lung toxicities, 
simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (eg, pulmonary 
embolism, congestive heart failure, malignant 
pericardial effusion). A Cardiology consultation should 
be obtained early, with prompt assessment of whether 
and when to complete a cardiac biopsy, including any 
other diagnostic procedures.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
119
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
−
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), 
monitoring of oxygenation via pulse oximetry (resting 
and exertion), and additional laboratory work-up as 
indicated. Spiral CT or cardiac MRI can complement 
ECHO to assess wall motion abnormalities when 
needed.
−
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, or infections)
Grade 1
(asymptomatic with 
laboratory (eg, BNP) 
or cardiac imaging 
abnormalities)
No dose modifications required 
unless clinical suspicion is high, in 
which case hold IP/study regimen 
dose during diagnostic work-up for 
other etiologies. If IP/study regimen 
is held, resume after complete 
resolution to Grade 0.
For Grade 1 (no definitive findings):
-
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms,  BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-up 
as clinically indicated.
-
Consider using steroids if clinical suspicion is high.
Grade 2, 3 or 4
(Grade 2: Symptoms 
with mild to 
moderate activity or 
exertion)
(Grade 3: Severe 
with symptoms at 
rest or with minimal 
activity or exertion;
intervention 
indicated)
(Grade 4: Life-
threatening 
- If Grade 2 -- Hold IP/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly 
improves to Grade 0, then the 
decision to reinitiate IP/study 
regimen will be based upon 
treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue IP/study regimen.
If Grade 3-4, permanently 
discontinue IP/study regimen.
For Grade 2-4:
−
Monitor symptoms daily, hospitalize.
−
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
or equivalent after Cardiology consultation has 
determined whether and when to complete diagnostic 
procedures including a cardiac biopsy.
−
Supportive care (eg, oxygen).
−
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
120
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
consequences; urgent
intervention 
indicated (eg, 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support))
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
Myositis/Polymyositis 
(“Poly/myositis”)
Any Grade
General Guidance
For Any Grade:
−
Monitor subjects for signs and symptoms of 
poly/myositis. Typically, muscle weakness/pain occurs 
in proximal muscles including upper arms, thighs, 
shoulders, hips, neck and back, but rarely affects the 
extremities including hands and fingers; also difficulty 
breathing and/or trouble swallowing can occur and 
progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset 
falling, difficulty getting up from a fall, and trouble 
climbing stairs, standing up from a seated position, 
and/or reaching up.
−
If poly/myositis is suspected, a Neurology consultation 
should be obtained early, with prompt guidance on 
diagnostic procedures. Myocarditis may co-occur with 
poly/myositis; refer to guidance under Myocarditis. 
Given breathing complications, refer to guidance under 
Pneumonitis/ILD. 
Given possibility of an existent (but previously 
unknown) autoimmune disorder, consider 
Rheumatology consultation.
−
Consider, as necessary, discussing with the study 
physician.
−
Initial work-up should include clinical evaluation, 
creatine kinase, aldolase, LDH, BUN/creatinine, 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
121
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
erythrocyte sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional laboratory work-
up as indicated, including a number of possible 
rheumatological/antibody tests (ie, consider whether a 
rheumatologist consultation is indicated and could guide 
need for rheumatoid factor, antinuclear antibody, anti-
smooth muscle, antisynthetase [such as anti-Jo-1], 
and/or signal-recognition particle antibodies).
Confirmatory testing may include electromyography, 
nerve conduction studies, MRI of the muscles, and/or a 
muscle biopsy. Consider Barium swallow for evaluation 
of dysphagia or dysphonia.
Subjects should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other medications, 
or infections).
Grade 1
(mild pain)
- No dose modifications.
For Grade 1:
−
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated.
−
Consider Neurology consult.
−
Consider, as necessary, discussing with the study 
physician.
Grade 2
(moderate pain 
associated with 
weakness; pain 
limiting instrumental 
activities of daily 
living [ADLs])
Hold IP/study regimen dose until 
resolution to Grade ≤1.
- Permanently discontinue IP/study 
regimen if it does not resolve to 
Grade ≤1 within 30 days or if there 
are signs of respiratory 
insufficiency.
For Grade 2:
−
Monitor symptoms daily and consider hospitalization.
−
Obtain Neurology consult, and initiate evaluation.
−
Consider, as necessary, discussing with the study 
physician.
−
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), 
promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from 
Neurology consultant 
−
If clinical course is not rapidly progressive, start 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
122
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
systemic steroids (eg, prednisone 1 to 2 mg/kg/day PO 
or IV equivalent); if no improvement within 3 to 5 days, 
continue additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day
−
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 days, 
consider start of immunosuppressive therapy such as 
TNF inhibitors (eg, infliximab at 5 mg/kg every 2 
weeks). Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance before 
using infliximab.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
Grade 3 or 4
(pain associated with 
severe weakness; 
limiting self-care 
ADLs)
For Grade 3:
Hold IP/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue IP/study 
regimen if Grade 3 imAE does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency.
For Grade 4:
- Permanently discontinue IP/study 
regimen.
For Grade 3 or 4 (severe or life-threatening events):
−
Monitor symptoms closely; recommend hospitalization.
−
Obtain Neurology consult, and complete full evaluation.
−
Consider, as necessary, discussing with the study 
physician.
−
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from 
Neurology consultant.
−
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 days, 
consider start of immunosuppressive therapy such as 
TNF inhibitors (eg, infliximab at 5 mg/kg every 2 
weeks). Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance before 
using infliximab.
−
Consider whether subject may require IVIG, 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
123
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
plasmapheresis.
−
Once the subject is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a
AChE = Acetylcholine esterase; ADL = Activities of daily living; AE = Adverse event; ALP = Alkaline phosphatase test; ALT = Alanine aminotransferase; AST 
= Aspartate aminotransferase; BNP = brain natriuretic peptide; BUN = Blood urea nitrogen; CT = Computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events; DILI = drug-induced liver injury; DM = diabetes mellitus; ECG = electrocardiogram; HBcAB = hepatitis B core antibody; HBeAg 
= hepatitis B e-antigen;  HBsAg = hepatitis surface antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma;  HCV = hepatitis C virus;  HgA1c = 
hemoglobin A1c; IG = immunoglobulin; ILD = Interstitial lung disease; imAE = immune-mediated adverse event; INR = international normalized ratio; IP = 
investigational product; IV = Intravenous; IVIG = intravenous immunoglobulin; GI = Gastrointestinal; LDH = lactic dehydrogenase; LFT = Liver function 
tests; LLN = Lower limit of normal; MRI  = Magnetic resonance imaging; NCI  = National Cancer Institute; NCCN  = National Comprehensive Cancer 
Network; PJP = Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO = By mouth; T3 = Triiodothyronine; T4 = 
Thyroxine; TB = Total bilirubin; TNF = Tumor necrosis factor; TSH = Thyroid-stimulating hormone; ULN = Upper limit of normal.
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
b FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
124
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Table 6:
Durvalumab Treatment Modification and Toxicity Management Guidelines for Infusion-Related Reactions
Infusion-Related Reactions
Severity Grade
of the Event 
(NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General guidance
For Any Grade:
-
Management per institutional standard at the discretion of investigator
-
Monitor subjects for signs and symptoms of infusion-related reactions 
(eg, fever and/or shaking chills, flushing and/or itching, alterations in 
heart rate and blood pressure, dyspnea or chest discomfort, skin rashes 
) and anaphylaxis (eg, generalized urticaria, angioedema, wheezing, 
hypotension, tachycardia.).
Grade 1
The infusion rate of IP/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the 
event
For Grade 1 or Grade 2:
-
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator
-
Consider premedication per institutional standard prior to subsequent 
doses
-
Steroids should not be used for routine premedication of ≤ Grade 2 
infusion reactions
Grade 2
The infusion rate of IP/study regimen may be decreased 
50% or temporarily interrupted until resolution of the 
event
Subsequent infusions may be given at 50% of the initial 
infusion rate
Grade 3/4
For Grade 3 or 4: 
Permanently discontinue IP/study regimen
For Grade 3 or 4:
-
Manage severe infusion-related reactions per institutional standards 
(eg, IM epinephrine, followed by IV diphenhydramine and ranitidine, 
and IV glucocorticoid)
Abbreviations:
IM = intramuscular; IP = investigational product; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
125
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Table 7:
Durvalumab Treatment Modification and Toxicity Management Guidelines for Non-Immune-Mediated 
Reactions
Non-Immune-Mediated Reactions
Severity Grade of 
the event 
(NCI CTCAE 
version 4.03)
Dose Modification
Toxicity Management
Any Grade
Note: dose modifications are not required for adverse events not deemed to be 
related to study treatment (i.e., events due to underlying disease) or for laboratory 
abnormalities not deemed to be clinically significant.
Treat accordingly as per institutional 
standard 
Grade 1
No dose adjustment 
Treat accordingly as per institutional 
standard 
Grade 2
Hold IP/study regimen until resolution to ≤Grade 1 or baseline
Treat accordingly as per institutional 
standard 
Grade 3
Hold IP/study regimen until resolution to ≤Grade 1 or baseline
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to ≤Grade 1 or 
baseline within 14 days, resume IP/study regimen administration. Otherwise, 
discontinue IP/study regimen
Treat accordingly as per institutional 
standard 
Grade 4
Discontinue IP/study regimen (Note for Grade 4 labs: the decision to discontinue 
would be based on accompanying clinical signs/symptoms and as per the 
Investigator’s clinical judgment and in consultation with the sponsor) 
Treat accordingly as per institutional 
standard
Abbreviations:
AEs = adverse events; IP = investigational product; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study 
Physician.”
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
126
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
8.2.5.
Re-treatment Criteria
In order to proceed to the next cycle, subjects must continue to meet entry criteria regarding 
renal and hepatic function (see Section 7.3).  Thus subjects will have laboratory assessments 
performed to evaluate organ function prior to starting each cycle (including Cycle 1).  Because of
the time it takes to obtain results from the central laboratory, samples should be collected early 
enough prior to starting the next cycle in order to allow sufficient time for review.  In the event 
that immediate laboratory assessment is needed, local laboratory measurement is acceptable for 
starting the next cycle pending the outcome of the central laboratory assessment (ie, in addition 
to collecting the local laboratory sample, a matching sample should always be sent to the central 
laboratory).
The start of the next cycle will be delayed if the subject does not meet entry criteria regarding 
renal and hepatic function.  If there is a delay of more than 42 days (6 weeks) in the start of the 
next cycle, the medical monitor must be consulted.  Study treatment should be discontinued if 
there is a delay of more than 56 days (8 weeks) in the start of the next cycle, unless, in the 
opinion of the investigator and the medical monitor, the subject is experiencing clinical benefit.  
Justification of the subject continuing in the study must be recorded in the source documents.
Prior to discontinuing a subject, it is recommended that the investigator contact the medical 
monitor and forward appropriate supporting documents for review and discussion.  The decision 
to discontinue a subject remains the responsibility of the treating physician and will not be 
delayed or refused by the sponsor.
8.2.6.
Overdose
Overdose, as defined for this protocol, refers to CC-486 and durvalumab dosing only.
On a per dose basis, an overdose is defined as any amount over the protocol-specified dose of 
CC-486 or durvalumab assigned to a given subject, regardless of any associated adverse events 
or sequelae.
On a schedule or frequency basis, an overdose is defined as any amount more frequent than the 
protocol-required schedule or frequency. On an infusion rate basis, an overdose is defined as any 
rate faster than the protocol-specified rate. 
!
For oral, any amount over the protocol-specified dose
!
For IV, 10% over the protocol-specified dose
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form. See Section 
11.1 for the reporting of adverse events associated with overdose.
8.2.7.
Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:
!
Lack of efficacy
!
Progressive disease
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
127
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
Withdrawal by subject
!
Adverse event(s)
!
Death
!
Loss to follow-up
!
Protocol violation
!
Study termination by the Sponsor
!
Pregnancy
!
Recovery
!
Non-compliance with IP
!
Transition to commercially available treatment
!
Physician decision
!
Disease relapse
!
Symptomatic deterioration
!
Protocol violation
!
Other (to be specified on the eCRF)
Because a hematologic response to treatment with CC-486 may be delayed, it is recommended 
that subjects receive at least 6 cycles of treatment with the IP; however, subjects may be 
discontinued from treatment at the investigator’s discretion prior to reaching the recommended 
minimum number of cycles for any of the reasons detailed above.  The reason for discontinuation 
should be recorded in the CRF and in the source documents.
8.3.
Method of Treatment Assignment
Subjects will be enrolled via IRTS to ensure timely registration and to facilitate subject tracking 
and IP resupply needs.
Investigator or designated site staff will be assigned password protected, coded identification 
numbers that give them authorization to call into the IRTS to enroll a subject.  At screening, the 
investigator or designated staff will call into the IRTS and provide the requested identifying 
information for the subject.  The IRTS will then confirm the assignment of a unique subject 
number.  Once assigned to a subject, the subject number will not be reused.  If a subject is 
screened but not enrolled, the screen-failure must be registered using the IRTS.  During the 
treatment phase, calls will be placed to the IRTS for each new allocation of IP to a subject, to 
acknowledge receipt of additional IP shipments to the site, and to register changes in a subject’s 
status (eg, drug hold, dose modification, or treatment discontinuation).  Details regarding use of 
the IRTS are found in the IRTS User Manual.
&&,
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status (
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eg
he IRT
IRT


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
128
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
8.4.
Packaging and Labeling
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
No blinding is applied in this study.
8.5.
Clinical Supplies
The investigator(s) or designee(s) is responsible for taking an inventory of each shipment of IP 
received and comparing it with the accompanying shipping order form.  The investigator(s) or 
designee(s) will verify the accuracy of the information on the form and call the IRTS to register 
the IP received at the site.  
At the study site, all IP will be stored according to the storage conditions described on the IP 
packaging label in a locked, safe area to prevent unauthorized access.  The IP must be stored as 
directed on the package label at a controlled temperature, and a temperature log must be 
maintained in the source documents.
8.6.
Investigational Product Accountability and Disposal 
Investigational product accountability will be assessed by the investigator or designee.  
Applicable information such as lot number, tablet or vial count, and expiration date should be 
collected, as well as information provided by the subject or the caregiver (eg, subject dosing 
diary).  
Investigational product accountability should be assessed before drug dispensing for each 
subsequent treatment cycle in the treatment phase, starting on Day 1 of Cycle 2, and at the 
treatment discontinuation visit.
The investigator(s) or designee(s) is responsible for accounting for all IP that is issued and 
returned by the subject during the course of the study according to applicable regulatory 
requirements.  Any unused IP must be returned by a study subject and retained by the 
investigative site for accountability to be conducted by a Celgene representative (or designee).  If 
any IP is lost or damaged, its disposition should be documented.  At periodic monitoring visits, a 
Celgene representative (or designee) will conduct IP accountability and address any 
discrepancies.  Upon satisfactory reconciliation of all IP, returned IP may be destroyed.  At the 
conclusion of the study, all remaining IP will be counted, reconciled with dispensing records, 
documented, and destroyed at the clinic site or allocated drug destruction location after 
completion of drug accountability by a Celgene representative (or designee).  The Celgene 
representative (or designee) will ensure that a final report of drug accountability to the unit dose 
level (ie, tablet) be prepared and placed in both the investigator study file and the central clinical 
study file.
A copy of the site’s Standard Operating Procedure (SOP) for drug destruction may be collected 
by the sponsor (or designee).  Any revisions to a site’s destruction process must be provided and 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
pment of IP
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evel (
evel (iei


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
129
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
approved by the sponsor (or designee) prior to implementation of this protocol.  Any site without 
a sponsor (or designee)-approved destruction SOP and process will be required to return IP to 
Celgene. Celgene (or designee) will review with the investigator and relevant site personnel the 
process for Investigational Product return, disposal, and/or destruction including responsibilities 
for the site versus Celgene (or designee).  
8.7.
Investigational Product Compliance
Subjects will self-administer CC-486 doses in the treatment phase.  Durvalumab will be 
administered at the study site.  Documentation of dosing during treatment will be recorded in a 
study-specific diary card.  Investigational product administration diary cards will be provided by 
the sponsor to study site personnel, who will in turn distribute them to study subjects.  Study site 
personnel will enter the scheduled daily doses, the number of tablets to be taken each day, and 
any other applicable information.  Study site personnel will review the dosing information with 
the subject (or legally authorized representative) on scheduled clinic visit days.  Subjects (or 
legally authorized representative) will be asked to record IP dosing information in the diary card 
and to bring the diary card and unused tablets in the blister card (or the blister card packaging 
even if it is empty) with them to scheduled clinic visits (ie, prior to the start of the next treatment 
cycle).  A diary card and tablet compliance check will be performed by study personnel.  Diary
cards must be saved and kept with the source documentation.  Study site personnel will perform 
an IP administration compliance check and record this information in the subject’s source 
documentation and on the appropriate CRF.
Administration of all IP will be recorded, including dispensing, dosing, and any changes in 
dosage administration such as interruption or reduction in dosing due to an AE.
&&,
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dispensing, 
dispensin
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uction in d


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
130
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
9.
CONCOMITANT MEDICATIONS AND PROCEDURES
All prior and concomitant medications (prescription and non-prescription), treatments, and 
therapies taken from 28 days (4 weeks) prior to the first dose of IP, up to 28 days after the last 
dose of CC-486 (90 days for durvalumab), or up to the last study visit, whichever date is later, 
must be recorded on the appropriate CRF.  
All prior treatments for MDS, including ESAs, thrombopoiesis-stimulating agents (TSAs), iron-
chelating agents, chemotherapy, cytotoxic therapy, investigational agents, or other medications 
considered supportive care for MDS should be recorded on the respective CRF(s) regardless of 
discontinuation date of treatment.
Concomitant medications should be kept to a minimum during the study.  However, if
considered necessary for the subject’s welfare and are unlikely to interfere with the IP, they may 
be given at the discretion of the investigator.
9.1.
Permitted Concomitant Medications and Procedures
Best supportive care may be used in combination with study therapy if deemed necessary.  Best 
supportive care for this study includes, but is not limited to, treatment with RBC or whole blood 
transfusions, fresh frozen plasma transfusions, single donor or pooled donor platelet transfusions, 
antibiotic, antiviral and/or antifungal therapy, nutritional support as needed, and myeloid growth 
factors (G-CSF and GM-CSF) for subjects experiencing neutropenic infections. The use of 
myeloid growth factors is also allowed for secondary prophylaxis under certain conditions as 
described below.  The use of these products will be considered as concomitant treatment and 
documented as concomitant medications, therapies or procedures.  
Blood product support (RBCs and platelets) may be administered according to institutional 
standards.  RBC and platelet transfusions will be considered concomitant procedures and should 
be collected on the appropriate CRF.
Subjects who are currently using iron-chelating agents should be on a stable or decreasing dose 
for at least 8 weeks (56 days) prior to enrollment.  Initiation, modification, and/or 
discontinuation of iron-chelating agents during the treatment phase of the study is discouraged 
and should be discussed with the medical monitor first whenever possible.
Subjects may be administered supportive and palliative care (eg, pain control) as clinically 
indicated throughout the study.
It is recommended that an antiemetic medication such as a serotonin 5-HT3 receptor antagonist 
(eg, ondansetron) be taken 30 minutes prior to IP administration during Cycle 1 of the treatment 
phase.  If nausea/vomiting is not significant, further antiemetic prophylaxis may not be needed.  
Pre-treatment or post-treatment with a serotonin 5-HT3 receptor antagonists, or other locally 
available and appropriate antiemetic medication, will be considered concomitant treatment and 
should be recorded on the appropriate CRF.
Treatment with antidiarrheal medications is recommended at the first sign of diarrhea as per the 
guidelines in Appendix H.  Pre-medication with antidiarrheal medication for subsequent doses of 
CC-486 and/or durvalumab may be appropriate.  Pre- and post-treatment with an antidiarrheal 
must be recorded in the CRF as concomitant medication.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
of 
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atm
tment or p
nt or p
ilable and a
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houl
hould be re
d be re
Treatme
Treatm
d


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
131
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Myeloid growth factors (G-CSF and GM-CSF) may be given per investigator’s discretion for the 
treatment of neutropenic fever/infections as well as for secondary prophylaxis if the subject had a 
previous event of neutropenic fever/infection or neutropenia Grade 4 during the treatment phase 
of the study and the safety of the subject is considered jeopardized by subsequent episodes of 
neutropenic fever/infections or Grade 4 neutropenia.
For subjects who develop an ANC < 0.5 x 109/L (or per institutional standards), administration 
of prophylactic fluoroquinolone antibiotics (eg, ciprofloxacin or levofloxacin) or other 
recognized prophylactic antibiotics may be considered and documented as a concomitant
medication on the appropriate CRF.  If neutropenic fever/infection occurs, treatment should 
consist of a broad spectrum antibiotic, and if the investigator deems the use of a myeloid growth 
factor to be medically important, myeloid growth factors may also be administered.  For
secondary prophylaxis with myeloid growth factors, the dose modification guidelines detailed in
Section 8.2.4 remain applicable.  Discontinuation of secondary prophylaxis with myeloid growth 
factors should be considered by the investigator as clinically appropriate.  
Concurrent systemic corticosteroids for medical conditions other than MDS are allowed, 
provided the subject is on a stable or decreasing dose for ≥ 1 week prior to the first dose of IP.  
Initiation, modification, and/or discontinuation of corticosteroids during the treatment phase of 
the study is discouraged and should be discussed with the medical monitor first whenever 
possible.
9.2.
Prohibited Concomitant Medications and Procedures
Best supportive care for this study specifically excludes cancer surgery, immunotherapy, 
biologic therapy, radiotherapy, anticancer hormonal therapy, and systemic chemotherapy where 
the goal is to eradicate or slow the progression of the disease.
The following concomitant medications are specifically prohibited during the course of the 
study:
!
Cytotoxic, chemotherapeutic, targeted, or investigational agents/therapies
!
Azacitidine for injection, decitabine, or other demethylating agents
!
Lenalidomide, thalidomide, and other immunomodulatory drugs (IMiDs)
!
Erythropoiesis stimulating agents and other hematopoietic growth factors (eg,
interleukin-3)
!
Romiplostim and other TSAs (eg, Interleukin-11, Eltrombopag)
!
Hydroxyurea
!
Androgens, unless to treat hypogonadism
!
Oral retinoids (topical retinoids are permitted)
!
Arsenic trioxide
!
Interferon
!
Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, 
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O


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
132
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the 
management of investigational product-related AEs or in subjects with contrast 
allergies is acceptable. In addition, use of inhaled, topical, intranasal corticosteroids 
or local steroid injections (eg, intra-articular injection) is permitted. Temporary uses 
of corticosteroids for concurrent illnesses (eg, food allergies, CT scan contrast 
hypersensitivity, moderate to severe infusion-related reactions, etc.) are acceptable 
upon discussion and agreement with the medical monitor. 
!
Live attenuated vaccines during the study through 30 days after the last dose of 
durvalumab.
Refer to Section 7.3 for exclusion criteria pertaining to prohibited concomitant medications.
9.3.
Required Concomitant Medications and Procedures
There are no required concomitant medications, although prophylactic treatment with an 
antiemetic or antidiarrheal medication may be considered and is recommended during the first 
cycle of treatment.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
ons.s.
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ded during


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
133
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
10.
STATISTICAL ANALYSES
The sections below provide an overview of the proposed statistical considerations and analyses.
10.1.
Overview
This is an open-label, randomized 2-arm study to estimate the efficacy of CC-486 as a mono-
therapy and CC-486 + durvalumab as a combination therapy in subjects with MDS who fail to 
achieve an objective response to treatment with azacitidine for injection or decitabine.
The study consists of 5 phases: Screening, Safety Run-in, Randomized Treatment, Follow-up, and
Extension. The randomized treatment phase will be conducted in 2 stages, with a futility 
assessment planned at the completion of Stage 1 to determine whether the null hypothesis (H0: p 
<12.5%) can be rejected with 3 or more responses in Stage 1. If 3 or more responses have been 
observed before the end of Stage 1, the planned futility assessment may be performed earlier 
than at the completion of Stage 1 to confirm the finding of responses. This earlier analysis will 
replace the futility analysis planned at the completion of Stage 1. This earlier futility assessment 
will have the same integrity as the futility assessment planned at the completion of Stage 1. An 
analysis will be performed at the completion of Stage 2 to estimate the overall response rate of 
treatment of all the subjects in the cohort.
The primary objective is to evaluate the treatment response with CC-486 monotherapy and 
combination therapy in this sample of subjects. The secondary objectives include the evaluation 
of overall survival, time to response, duration of responses, time to disease progression, and 
safety and tolerability of the regimen in this population. 
This section defines the subject populations for various statistical data analyses, the justifications
of sample sizes for the cohorts, and the methodologies that will be used for the efficacy and
safety analyses. All statistical analyses specified in this protocol will be conducted using SAS® 
Version 9.2 or higher unless otherwise specified.
10.2.
Study Population Definitions
10.2.1.
Intent-to-Treat Population
The intent-to-treat population will include all enrolled subjects who received at least one dose of 
IP.
10.2.2.
Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population includes all ITT subjects who have at least one 
post-baseline efficacy assessment performed, met all inclusion/exclusion criteria, and received a 
minimum of one cycle of treatment.
10.2.3.
Safety Population
The safety population will include all enrolled subjects who have received at least 1 dose of IP 
and had at least 1 post-dose safety assessment.  
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he overall r
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ith CC
ith CC-486
-4
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on. 
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Definition
Definition
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wil il
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on
0.2.3.
0.2.3.
The saf
The saf
h


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
134
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
10.2.4.
Evaluable Population
Intent-to-treat subjects who have at least 1 post-baseline efficacy assessment performed, 
experienced no major protocol deviations during the study, and have received a minimum of 1 
cycle of treatment are considered to be in the evaluable population.  This definition will be 
further clarified in the final statistical analysis plan before database lock.
10.2.5.
Pharmacokinetic Population
The pharmacokinetic population will include enrolled subjects who have evaluable concentration 
data to determine the pharmacokinetic parameters from at least one dose of IP.
10.3.
Sample Size and Power Considerations
The sample size required will be identical for each treatment arm in each cohort and is estimated 
using the optimal design of the Simon's two-stage design method (Simon, 1989). The null 
hypothesis of the response rate will be tested against a one-sided alternative. 
For each cohort, the null hypothesis of the response rate (H0: p ≤ 0.125) will be tested against the 
alternative hypothesis of the response rate (H1: p ≥ 0.27) with a type I error rate of 10% and 80% 
power. During the first stage, 16 subjects will be accrued per cohort. If there are 2 or fewer 
responses in these 16 subjects, the cohort will be stopped and no further recruitment will be 
needed. Otherwise, 25 additional subjects will be accrued per cohort for a total of 41 subjects in 
each cohort. If 8 or more responses are observed in these 41 subjects, the null hypothesis will be 
rejected. 
For each cohort, in addition to the evaluation of treatment responses based on objective response 
criteria, the quality of responses will also be considered for the decision whether to continue the 
cohort to the second stage of the study. Quality of response will be assessed based on the 
magnitude of hematologic and biologic responses observed in individual subjects, with special 
consideration for response duration and will be specified with more details in the final Statistical 
Analysis Plan (SAP).
10.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations.  Medical history data will be summarized using frequency tabulations by system 
organ class and preferred term.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percentage for both 
treatment and follow-up phases.  A summary of subjects enrolled by site will be provided. 
Protocol deviations will be summarized using frequency tabulations.
10.6.
Efficacy Analysis
All efficacy analyses will be performed on the ITT population. 
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Protoco


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
135
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Supportive efficacy analyses will also be performed using the evaluable population.
10.6.1.
Primary Efficacy Analysis
The primary assessment of efficacy will be the overall rate of response (defined as CR, PR, or 
mCR), and HI as determined using the modified IWG 2006 response criteria for MDS
(Appendix F).  For hematologic response, CR, PR, and mCR will be determined by investigator
assessment (with confirmation by central reviewer), while HI will be derived.  The percentage of 
subjects with the other response outcomes of stable disease, failure, relapse after CR or PR, and 
disease progression will also be presented.  Percentages will also be presented separately for CR, 
PR, mCR, and HI.
The percent of responders will be estimated using 95% confidence intervals for proportions.  
Hematologic response (Complete Remission [CR], Partial Remission [PR], Marrow CR [mCR], 
Stable Disease [SD], Failure, Relapse after CR or PR, and Cytogenetic Response) is defined 
according to modified IWG 2006 criteria (Appendix F).  Subjects will be classified according to 
their best response achieved during treatment for the response categories of CR, PR, mCR, SD, 
and failure.  Only subjects who achieve CR or PR will be included in the Relapse after CR or PR 
category.  Subjects will be evaluated for cytogenetic response regardless of their response status 
in other categories.  For cytogenetic response, subjects will be classified as having a complete or 
partial response based on the best response achieved during treatment.  Hematologic response 
will be presented descriptively using counts and percentages. 
The response rates at the end of Stage 2 and the associated 95% confidence interval will be 
estimated for each cohort which completes Stage 2. Similar estimates for Stage 1 will be 
provided for any cohort which does not continue to Stage 2. The response rates at the end of 
Stage 2 will be compared between cohorts of SD and PD subjects (if both cohorts finished   
Stage 2) using the relative risk ratio or other appropriate methods. Specifically, if relative risk 
method is used, the ratio of response rates for both cohorts and the associated 95% confidence 
interval will be estimated. 
10.6.2.
Secondary Efficacy Analyses
10.6.2.1.
Overall Survival
Overall survival (OS), time to death from any cause, will be calculated using date of first dose 
and date of death, or date of last follow-up for censored subjects. Time to death from any cause 
is defined as the time between first dose and death from any cause. All subjects will be followed 
until drop-out, death, or study termination. Drop-out may be due to withdrawal of consent from 
further data collection or loss to follow-up. Subjects who drop-out or are alive at study 
termination will have their OS times censored at the time of last contact, as appropriate.  The OS 
curve will be estimated using Kaplan-Meier (KM) method.  
10.6.2.2.
Time to Onset of Response
Time to onset of first response is defined as the time between the date of first IP dose and the 
earliest date any response (CR, PR, mCR, or HI) is first observed.  Subjects who do not achieve 
any defined response during the treatment period will be censored at the date of treatment 
discontinuation, disease progression, or death, whichever occurs first.  Time to onset of best 
&&,
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10.6.2.2.
0.6.2.2.


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
136
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
response will be defined in a similar manner. Time to onset of first response and best response 
for the treatment group will be estimated using KM method.  
10.6.2.3.
Duration of Response
Duration of hematologic response/improvement will be determined only for subjects who 
achieve a response on treatment.  Duration of hematologic response/improvement is defined as 
the time from the date response/improvement is first observed until the date the subject has a 
subsequently documented relapse or disease progression as defined by the modified IWG 2006 
criteria.  Subjects who maintain hematologic response/improvement through the end of the 
treatment period will be censored at the date of treatment discontinuation or death, whichever 
occurs first.  Duration of response will be assessed for both first response and best response.  
Duration of hematologic response/improvement for the treatment group will be estimated using 
KM method.
10.6.2.4.
Progression-free Survival
Progression-free survival (PFS), time to disease progression or death from any cause, will be 
calculated using date of first dose of IP and the earliest of date of disease progression or date of 
death, or date of last follow-up for censored subjects. Time to disease progression or death from 
any cause is defined as the time between first dose and the earliest of disease progression or 
death from any cause. All subjects will be followed until drop-out, death, or study termination. 
Drop-out may be due to withdrawal of consent from further data collection or loss to follow-up. 
Subjects who drop-out or are alive without disease progression at study termination will have 
their PFS times censored at the time of last contact, as appropriate.  The PFS curve will be 
estimated using Kaplan-Meier (KM) method.
10.6.2.5.
Stable Disease
!
A subject will be considered as having a stable disease if the disease neither 
responded nor progressed during or after the treatment. 
!
The duration of stable disease will be defined as the time between any two 
observations of objective disease progression (modified IWG criteria – Appendix F), 
starting from the first day of dosing with IP.  Note, objective disease progression 
requires two observations demonstrating progressive disease, at least 8 weeks apart.  
The date of disease progression will be that of the earliest observation that is not 
followed by a discordant observation within the subsequent 8 weeks.  
!
Subjects who maintain stable disease through the end of the treatment period will be 
censored at the date of study termination.  
!
Duration of stable disease will be estimated using KM method.
10.6.2.6.
Disease Progression to AML
!
Time to AML progression is defined as the time from the date of first dose of IP until 
the date the subject has documented progression to AML. 
!
Subjects who do not progress to AML will be censored at the date of last follow-up, 
the date of death, or the date of study termination. 
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10.6.2.6.
0.6.2.6.


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
137
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
Time to AML progression will be estimated using KM method.
10.7.
Safety Analysis
The safety population will be used for all safety evaluations.
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA).  
Adverse event listings will include the verbatim term and the MedDRA preferred term.  Adverse 
events will be summarized by worst severity grade. Adverse events, as well as treatment-
emergent AEs, will be summarized by system organ class, and preferred term.  Adverse events 
leading to death or to discontinuation from treatment, events classified as NCI CTCAE (Version 
4.03) Grade 3 or Grade 4, adverse events related to IP, serious adverse events and Adverse 
Events of Special Interest (AESI) will be summarized separately.  
Clinical laboratory results will be summarized descriptively and will include a display of change 
from baseline.  Laboratory values outside of the normal ranges will be identified.  Clinically 
significant hematologic and non-hematologic laboratory abnormalities that meet Grade 3 or 
Grade 4 criteria according to the CTCAE will be listed and summarized. 
Vital sign measurements will be listed for each subject at each visit.  Descriptive statistics for 
vital signs, both observed values and changes from baseline, will be summarized.
10.8.
Interim Analysis
An Independent Data Monitoring Committee will review the safety data during the safety run-in 
phase. The committee will also review the efficacy and safety data during the randomized phase 
of the study, in addition to the recommendation for any cohort to continue to Stage 2 of the 
study. The details of the data monitoring plan will be provided in a separate charter document.
10.9.
Additional Analyses
 
10.9.2.
CC-486 PK Analysis
10.9.2.1.
Plasma Concentrations
By-subject listing of pharmacokinetic blood sample collection times as well as derived sampling 
time deviations will be provided.  CC-486 plasma concentrations will be summarized using 
descriptive statistics (N, arithmetic mean, standard deviation, standard error, minimum, median, 
maximum, percent coefficient of variation, geometric mean, and geometric percent coefficient of 
variation) for each cycle, if/when appropriate.  Concentrations that are below the limit of 
quantification (BLQ) will be treated as zero for the computation of descriptive statistics. Missing 
concentrations and concentrations from blood samples collected more than ± 10% of nominal 
time will be omitted from the calculation of descriptive statistics.
&&,
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352
35


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
138
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Individual subject concentration-time data and mean concentration-time data for each cycle will 
be graphically presented on linear and semi-logarithmic scales.
Following single dose administration, predose samples that are BLQ or missing will be assigned 
a numerical value of zero for the calculation of AUC.  Any anomalous concentration values 
observed at predose will be identified in the clinical study report and used for the computation of 
AUC.  Pharmacokinetic parameters will be computed if the anomalous value is not greater than 
5% of the Cmax.  If the anomalous value is greater than 5% of Cmax, the computed 
pharmacokinetic parameters for the given subject will be dropped from the pharmacokinetic 
analysis.  
Any other BLQ concentrations will be assigned a value of zero if they precede quantifiable 
samples in the initial portion of the profile.  A BLQ value that occurs between quantifiable data 
points, especially prior to Cmax, will be evaluated to determine if an assigned concentration of 
zero makes sense, or if reanalysis or exclusion of the data is warranted.  Following Cmax, BLQ 
values embedded between 2 quantifiable data points will be treated as missing when calculating 
AUC.  BLQ values occurring at the end of the collection interval (after the last quantifiable 
concentration) will be treated as missing data.  If consecutive BLQ concentrations are followed 
by quantifiable concentrations in the terminal portion of the concentration curve, these quantified 
values will be excluded from the pharmacokinetic analysis by assigning them a value of missing, 
unless otherwise warranted by the concentration-time profile.  For the purpose of analysis, these 
trailing BLQ values may be designated as zero in the dataset if the pharmacokinetic program 
used to do the analysis (such as WinNonlin®) will treat trailing zero values as missing when 
calculating AUC.
Actual sampling times will be used in the calculations of pharmacokinetic parameters that will be 
derived using noncompartmental methods with Phoenix™ WinNonlin® Professional Version 6.3, 
or higher, (Pharsight®, a Certara™ company, St. Louis, Missouri).  Graphics may be prepared 
with SAS Version 9.1, or higher; or Excel 2007, or higher; Phoenix™ WinNonlin® Professional 
6.3, or higher; or S-Plus 8.2., or higher (MS MIAMI, Miami, Florida).
10.9.2.2.
Pharmacokinetic Parameters
The following PK parameters will be calculated for CC-486:
AUCinf
Area under the plasma concentration-time curve from Time 0 
extrapolated to infinity, calculated as [AUCt + Ct/∋z].  Ct is the last 
quantifiable concentration. No AUC extrapolation will be performed 
with unreliable ∋z.  If AUC %Extrap is ≥25%, AUCinf will not be 
reported
AUCt
Area under the plasma concentration-time curve from Time 0 to the time 
of the last quantifiable concentration, calculated by linear trapezoidal 
method when concentrations are increasing and the logarithmic 
trapezoidal method when concentrations are decreasing.
Cmax
Maximum observed plasma concentration, obtained directly from the 
observed concentration versus time data.
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Area und
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extrap
qua
qua
AUC
AUCt


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
139
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Tmax
Time to Cmax, obtained directly from the observed concentration versus 
time data.
t1/2
Terminal phase half-life in plasma, calculated as [(ln 2)/ ∋z].  t1/2 will 
only be calculated when a reliable estimate for ∋z can be obtained.  
CL/F
Apparent total clearance, calculated as [Dose/AUCinf]. 
Vz/F
Apparent volume of distribution, calculated as [(CL/F)/∋z ].
The following PK parameters for CC-486 will be calculated for diagnostic purposes and listed, 
but they will not be summarized:
∋z
Apparent terminal rate constant, calculated by linear regression of the 
terminal portion of the log-concentration versus time curve in plasma.  
Visual assessment will be used to identify the terminal linear phase of 
the concentration versus time profile.  A minimum of three data points 
will be used for calculation.  
∋z will not be estimated if the terminal phase of the log-concentration 
versus time profile does not exhibit a linear decline phase, or if the 
regression coefficient < 0.8.  
∋z lower
Lower limit of time (h) included in the calculation of ∋z. 
∋z N
Number of data points used in the calculation of ∋z.
∋z upper
Upper limit of time (h) included in the calculation of ∋z.
Rsq
Regression coefficient for calculation of ∋z.  
AUC % Extrap
Percentage of AUCinf due to extrapolation from the last quantifiable time 
point to infinity.
10.9.2.3.
Pharmacokinetic Methods
By-subject listing of pharmacokinetic parameters will be provided.  The values of the 
pharmacokinetic parameters will also be summarized using descriptive statistics (N, arithmetic 
mean, standard deviation, standard error, minimum, median, maximum, percent coefficient of 
variation, geometric mean, and geometric percent coefficient of variation) for each cycle.  Also, 
when appropriate, graphical representations (ie, scatter plots, box plots, etc) may be used to 
visualize the results.
The effect of durvalumab on the PK of CC-486 will be assessed using graphic comparison and 
descriptive stats.
 
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he ef


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
140
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, 
including laboratory test values (as specified by the criteria in Section 11.3), 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 CRF rather than the individual signs or symptoms of 
the diagnosis or syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF. (See Section 8.2.6 for the definition of overdose.) Any sequelae
of an accidental or intentional overdose of an investigational product should be reported as an 
AE on the AE CRF. If the sequelae of an overdose is an SAE, then the sequelae must be 
reported on an SAE report form and on the AE CRF. The overdose resulting in the SAE should 
be identified as the cause of the event on the SAE report form and CRF but should not be 
reported as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for CC-486 or 
durvalumab 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-486, 90 days after the last dose of durvalumab, or until the 
Treatment Discontinuation Visit, whichever is later and those SAEs made known to the 
investigator at any time thereafter that are suspected of being related to IP.  Adverse events and 
SAEs will be recorded on the AE page of the CRF and in the subject’s source documents.  All 
SAEs must be reported to Celgene Drug Safety within 24 hours of the investigator’s knowledge 
of the event by facsimile, or other appropriate method, using the SAE Report Form, or approved 
equivalent form.
11.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all adverse events as to: 
11.2.1.
Seriousness 
A serious adverse event (SAE) is any AE occurring at any dose that:
!
Results in death;
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qualified
.2.1
2 1


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
141
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
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:
!
The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
A procedure for protocol/disease-related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE.
!
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
A procedure that is planned (ie, planned prior to starting of treatment on study); must 
be documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
!
An elective treatment of or an elective procedure for a pre-existing condition 
unrelated to the studied indication. 
!
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
11.2.2.
Severity / Intensity
For both AEs and SAEs, the investigator must assess the severity / intensity of the event. 
&&,
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nship
1.2.2
1 2 2


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
142
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
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 4.03).
AEs that are not defined in the CTCAE should be evaluated for severity / intensity according to 
the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may 
be needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable
!
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
11.2.3.
Causality 
The investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means a causal relationship of the adverse event to IP 
administration is unlikely or remote, or other medications, 
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event.
Suspected:
Means there is a reasonable possibility that the administration 
of IP caused the adverse event.  ‘Reasonable possibility’ means 
there is evidence to suggest a causal relationship between the IP 
and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
&&,
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inform
nformati
ailab
ailab


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
143
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
11.2.4.
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
11.2.6.
Outcome
The investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered or death (due to the 
SAE). 
11.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE 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.
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 CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
11.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject or partner of a 
male subject are immediately reportable events.
11.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 90 days of the 
subject’s last dose of IP, are considered immediately reportable events.  IP 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 facsimile, or other appropriate method, using the Pregnancy Initial 
Report Form, or approved equivalent form.  
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subject’s
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me


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
144
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.  
The investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
11.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant while the male subject is on IP, 
or within 90 days of the male subject’s last dose of IP, the male subject taking IP should notify 
the investigator, and the pregnant female partner should be advised to call their healthcare 
provider immediately.  Where applicable, the IP may need to be discontinued in the male subject, 
but may be resumed later at the discretion of the investigator and medical monitor.
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF. All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE reports as well as any follow-up reports.
The investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
from the time the subject signs informed consent until 28 days after the last dose of CC-486, 90 
days after the last dose of durvalumab, or until the Treatment Discontinuation Visit, whichever is 
later, and any SAE made known to the investigator at any time thereafter that are suspected of 
being related to IP.  SAEs occurring prior to treatment (after signing the ICF) will be collected.
The SAE report should provide a detailed description of the SAE and include a concise summary
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the investigator is responsible for informing the IRB/EC of 
the SAE and providing them with all relevant initial and follow-up information about the event. 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
145
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
The investigator must keep copies of all SAE information on file including correspondence with 
Celgene and the Institutional Review Board (IRB)/Ethics Committee (EC).
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to CC-486 based on the Investigator’s 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, 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.  
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the other IP, durvalumab, based on the 
Durvalumab Investigator’s Brochure for the product.
Celgene or its authorized representative shall notify the investigator of the following information 
!
Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
11.7.
Adverse Events of Special Interest
An adverse event of special interest is one of scientific and medical interest specific to 
understanding of the IP and may require close monitoring and rapid communication by the 
investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of 
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1.7.


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
146
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
AESIs allows ongoing surveillance of these events in order to characterize and understand them 
in association with the use of these IPs.
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 
combination therapy. An immune-mediated adverse event (imAE) is defined as an adverse event 
that is associated with drug exposure and is consistent with an immune-mediated mechanism of 
action and where there is no clear alternate etiology. Serologic, immunologic, and histologic 
(biopsy) data, as appropriate, should be used to support an imAE diagnosis. Appropriate efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of 
the imAE.
If the investigator has any questions in regards to an adverse event (AE) being an imAE, the 
investigator should promptly contact the Medical Monitor.
Further information on these AESIs (eg presenting symptoms) can be found in the current 
version of the Durvalumab Investigator’s Brochure (section 5.4.2 Summary of Risks).
11.7.1.
Progression to AML
Progression to AML will be monitored as an event of special interest and must be reported as an 
SAE regardless of causal relationship to IP, occurring at any time for the duration of the study, 
from the time of signing the ICD until death, loss to follow-up, withdrawal of consent for further 
data collection, or study closure.  
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
147
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
12.
DISCONTINUATIONS
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:
!
Lack of Efficacy
!
Progressive Disease
!
Withdrawal by Subject
!
Adverse Event
!
Death
!
Loss to Follow-up
!
Protocol Violation
!
Study Terminated by Sponsor
!
Pregnancy
!
Recovery
!
Non-compliance with IP
!
Transition to commercially available treatment
!
Physician decision
!
Disease relapse
!
Symptomatic deterioration
!
Protocol violation
!
Other (to be specified on the eCRF)
Definitions for progressive disease to be applied under different circumstances (eg, following a 
RBC-transfusion-independent response to treatment) are provided in Table 8, below.  Although 
lack of efficacy or progressive disease is considered a sufficient reason for discontinuing a 
subject from IP, the investigator should continue to treat the subject until the investigator 
considers IP to be no longer beneficial to the subject, or the change of disease state renders the 
subject unacceptable for further treatment in the judgment of the investigator. Because a 
hematologic response to treatment with CC-486 may be delayed, it is recommended that subjects 
receive at least 6 cycles of treatment with the IP; however, subjects may be discontinued from 
treatment at the investigator’s discretion prior to reaching the recommended minimum number of 
cycles for any of the reasons detailed above.  
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, it 
is recommended that the investigator contact the medical monitor and forward appropriate 
supporting documents for review and discussion.
The reason for discontinuation should be recorded in the CRF and in the source document for all 
enrolled subjects, regardless of whether they are dosed or not.
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reco
reco


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
148
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
All subjects discontinued from protocol-prescribed therapy for any reason should undergo 
treatment discontinuation procedures (Section 6.13), and will be followed for a period of at least 
28 days following the last dose of CC-486 (90 days after last dose of durvalumab) or until the 
date of the last study visit, whichever period is longer, as described in Section 6.14.
All subjects discontinued from protocol-prescribed therapy for any reason will also be followed 
for survival, subsequent MDS therapies, and progression to AML as described in Section 6.14.
Table 8:
Definitions of Progressive Disease for Clinical Decisions on Discontinuing 
Subjects From the Investigational Product and/or From the Study
Category 
Progression/Relapse Criteria 
Progression in 
Bone Marrow 
For subjects with:  
!
Less than 5% blasts at baseline:  ≥100% increase to ≥ 8% blasts 
!
≥ 5% blasts at baseline:  ≥ 50% increase to ≥ 10% blasts 
Note: A 2nd bone marrow sample should be collected within 4 weeks to confirm 
progression before discontinuing subjects from treatment.
Progression in RBC 
Transfusion 
Requirement a
For subjects not RBC-transfusion-dependent at baseline:
Development of RBC transfusion dependence:  ≥ 2 RBC transfusions in any 
56-day (8-week) period during study treatment.
For subjects RBC transfusion-dependent at baseline who do not achieve RBC 
transfusion independence ≥ 56 days (8 weeks) during study treatment:
> 50% increase in the average RBC transfusion requirement during any 56-
day (8-week) period during study treatment compared to the average RBC 
transfusion requirement in the 56 days (8 weeks) prior to enrollment.
Relapse in RBC 
Transfusion 
Requirement a
For subjects RBC transfusion-dependent at baseline who do achieve RBC 
transfusion independence ≥ 56 days (8 weeks) during study treatment:
Relapse is defined as a return to baseline RBC transfusion requirement or 
worse.
Progression in 
Platelet Transfusion
Requirement
For subjects not platelet transfusion-dependent at baseline:
Development of platelet transfusion dependence:  ≥ 2 platelet transfusions in 
any 56-day (8-week) period during study treatment.
For subjects platelet transfusion-dependent at baseline who do not achieve 
platelet transfusion independence ≥ 56 days (8 weeks) during study treatment:
> 50 % increase in platelet transfusion requirement during any 56-day (8-
week) period during study treatment compared to the 56-day (8-week) 
period prior to enrollment.
Relapse in Platelet 
Transfusion 
Requirement
For subjects platelet transfusion-dependent at baseline who achieve platelet 
transfusion independence ≥ 56 days (8 weeks) during study treatment:
Relapse is defined as a return to baseline requirement or worse.
Abbreviations:  MDS = myelodysplastic syndrome; RBC = red blood cell.
a RBC transfusions administered for surgical procedures, significant hemorrhagic events, or other reasons 
documented as unrelated to MDS-associated anemia will not be counted in the assessment of baseline RBC 
transfusion requirements, efficacy, or progressive disease status.
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BC


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
149
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the investigator should contact the responsible Clinical Research 
Physician/medical monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/medical monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on call Celgene/Contract 
Research Organization (CRO) medical monitor, who will then contact you promptly.
Note: The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or medical monitor or designee for 
emergency calls. 
13.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
150
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
14.
REGULATORY CONSIDERATIONS
14.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and investigator abide by GCP, as described in International Council for Harmonisation (ICH) 
Guideline E6 and in accordance with the general ethical principles outlined in the Declaration of 
Helsinki. The study will receive approval from an IRB/EC prior to commencement. The 
investigator will conduct all aspects of this study in accordance with applicable national, state, 
and local laws of the pertinent regulatory authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
investigators who in turn will select their staff.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions. 
The investigator should maintain a list of sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties.
The investigator is responsible for keeping a record of all subjects who sign an informed consent 
document and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The investigator, or a designated member of the investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The investigator must ensure timely and accurate completion of CRFs and queries.
14.3.
Subject Information and Informed Consent
The investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICD 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 ICD 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 ICD.  The revised informed consent document signed 
and dated by the study subject and by the person consenting the study subject must be 
maintained in the investigator’s study files and a copy given to the study subject.  
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
151
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
14.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent document, it is the responsibility of the investigator to obtain 
such permission in writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/medical monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/EC approval but will be submitted to the IRB/EC for 
information purposes.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document, and any other 
appropriate documents will be submitted to the IRB/EC with a cover letter or a form listing the 
documents submitted, their dates of issue, and the site (or region or area of jurisdiction, as 
applicable) for which approval is sought. If applicable, the documents will also be submitted to 
the authorities in accordance with local legal requirements.
IP can only be supplied to an investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the informed consent document 
should also be revised.
&&,
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
152
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
The investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a coordinating investigator and the IRB/EC. This statement also applies to any 
communication between the investigator (or coordinating investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
14.7.
Ongoing Information for Institutional Review Board / Ethics 
Committee
If required by legislation or the IRB/EC, the investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
14.8.
Closure of the Study
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc.).
In addition, the investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;
!
Falsification of records;
!
Failure to adhere to the study protocol.
The sponsor may consider closing this trial when data supporting key endpoints and objectives of 
the study have been analyzed.  In the case where there are subjects in the Extension Phase
continuing to receive investigational product who, in the opinion of the investigator(s) would 
continue to receive benefit from treatment, the sponsor may choose to initiate an open-label 
rollover study under a separate protocol to allow these subjects to continue receiving oral 
azacitidine.  
&&,
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under a se


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
153
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
15.
DATA HANDLING AND RECORDKEEPING 
15.1.
Data/Documents
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
15.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene SOPs. This 
data will be electronically verified through use of programmed edit checks specified by the 
clinical team.  Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary.  Resolutions to these issues will be reflected in the 
database.  An audit trail within the system will track all changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. The investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer.  Essential documents include, but are not limited to, the following:
!
Signed informed consent documents for all subjects;
!
Subject identification code list, screening log (if applicable), and enrollment log;
!
Record of all communications between the investigator and the IRB/EC;
!
Composition of the IRB/EC;
!
Record of all communications between the investigator, Celgene, and their authorized 
representative(s);
!
List of sub-investigators and other appropriately qualified persons to whom the 
investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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!


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
154
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the investigator is unable to meet this obligation, the investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents.
&&,
tion of 
tion of 


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
155
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the investigator and the staff at a study 
initiation visit and/or at an investigator meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the investigator.  Monitoring will 
include on-site visits with the investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, 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 CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the investigator and/or his/her 
staff. Monitoring procedures require that informed consent documents, adherence to 
inclusion/exclusion criteria and documentation of SAEs and their proper recording be verified.  
Additional monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, United States Food and Drug 
Association [FDA], European Medicines Agency [EMA], Health Canada) and company 
authorized representatives.  The investigator should make every effort to be available for the 
audits and/or inspections.  If the investigator is contacted by any regulatory authority regarding 
an inspection, he/she should contact Celgene immediately.
16.3.
Product Quality Complaint
A Product Quality Compliant (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
after it is released for distribution. PQCs may reduce the usability of the product for its intended 
function or affect performance of the product and therefore pose a significant risk to the patient.  
&&,
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
156
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
seal/packaging breach, product missing/short/overage, contamination, suspected falsified, 
tampered, diverted or stolen material, and general product/packaging damage.  If you become 
aware of a suspected PQC, you are obligated to report the issue immediately.  You can do so by 
emailing 
or by contacting the Celgene Customer Care Center 
33'
33'
&&,


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
157
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
17.
PUBLICATIONS
The results of this study may be published in a medical publication, journal, or may be used for 
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.  Selection of first authorship 
will be based on several considerations, including, but not limited to study participation, 
contribution to the protocol development, and analysis and input into the manuscript, related 
abstracts, and presentations in a study.
&&,
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
158
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
18.
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al. 
al. 
n Oncol.
Oncol.
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ficat
ficatioion of 
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po E, Har
ificat
ification o
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p. 87
p. 87-93.
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splastic syn
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aggressive
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erg PL, Ben
rg PL, Be
n and prop
n and prop
ia inin myelo
mye
Sun H, Wel
un H, Wel
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en Y, Esen
en Y, Esen
responses a
esponses a
Immu
mu
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no
n


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
159
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
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l. Efficacy 
l. Efficacy
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ma S. A pi
ma S. A p
ng Y, MacB
ng Y, MacB
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m
ract 117.
act 117.
Jabbour EJ
Jabbour EJ
ment s
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y SD, Don
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oid Leuk
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h ess trans
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k GH, Leff
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lymphocy
lymphocy
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er Res. 20
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ystem f
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
160
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
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&&,
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19.
APPENDICES
Appendix A: Myelodysplastic Syndromes World Health Organization 
Classification System
Myelodysplastic Syndromes World Health Organization Classification System
Category
Definition
Peripheral Blood Smear Evaluation
Bone Marrow Evaluation
Refractory cytopenia with unilineage 
dysplasia (RCUD): (refractory anemia 
[RA]; refractory neutropenia [RN]; 
refractory thrombocytopenia [RT])
Unicytopenia or bicytopeniaa
No or rare blasts (< 1%)b
Unilineage dysplasia:  ≥ 10% of the cells 
in one myeloid lineage
< 5% blasts
< 15% of erythroid precursors are ringed 
sideroblasts
Refractory anemia with ringed 
sideroblasts (RARS)
Anemia
No blasts
≥ 15% of erythroid precursors are ringed 
sideroblasts
Erythroid dysplasia only
< 5% blasts
Refractory cytopenia with
Multilineage dysplasia (RCMD)
Cytopenia(s)
No or rare blasts (< 1%)b
No Auer rods
< 1x109/L monocytes
Dysplasia in ≥ 10% of the cells in
≥ 2 myeloid lineages (neutrophil and/or 
erythroid precursors and/or 
megakaryocytes)
< 5% blasts in marrow
No Auer rods
±15% ringed sideroblasts
Refractory anemia with excess
blasts-1 (RAEB-1)
Cytopenia(s)
< 5% blastsb
No Auer rods
< 1x109/L monocytes
Unilineage or multilineage
dysplasia
5%-9% blastsb
No Auer rods
Refractory anemia with excess
blasts-2 (RAEB-2)
Cytopenia(s)
5%-19% blasts!
Auer rodsc
< 1x109/L monocytes
Unilineage or multilineage
dysplasia
10%-19% blastsc
Auer rodsc
Myelodysplastic syndrome -
unclassified (MDS-U)
Cytopenias
< 1% blastsb
Unequivocal dysplasia in < 10% of cells 
in one or more myeloid lineages when 
accompanied by a cytogenetic 
abnormality considered as presumptive 
evidence for a diagnosis of MDS
!
MDS associated with isolated
del(5q)
Anemia
Usually normal or increased platelet 
count
No or rare blasts (< 1%)
Normal to increased
megakaryocytes with
hypolobated nuclei
< 5% blasts
Isolated del(5q) cytogenetic
abnormality
No Auer rods
a Bicytopenia may occasionally be observed.  Cases with pancytopenia should be classified as MDS-U.
b If the marrow myeloblast percentage is < 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic classification is 
RAEB-1.  Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as MDS-U.
c Cases with Auer rods and < 5% myeloblasts in the blood and less than 10% in the marrow should be classified as RAEB-2.  
Although the finding of 5% to 19% blasts in the blood is, in itself, diagnostic of RAEB-2, cases of RAEB-2 may have 5% 
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blasts in the blood if they have Auer rods or 10% to 19% blasts in the marrow or both.  Similarly, cases of RAEB-2 may have < 
10% blasts in the marrow but may be diagnosed by the other 2 findings, Auer rods + and/or 5% to 19% blasts in the blood.
d Includes unbalanced abnormalities -7 or del(7q), -5 or del(5q), i(17q) or t(17p), -13 or del(13q), del(11q), del(12p) or t(12p), 
del(9q), idic(X)(q13), balanced abnormalities t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1), t(1;3)(p36.3;q21.1), T2;11)(p21;q23), 
inv(3)(q21q26.2), and t(6;9)(p23;q34), and complex karyotype (3 or more chromosomal abnormalities) involving one of more 
of the listed abnormalities.
Sources: Brunning RD, Bennett JM, Flandrin G, Matutes E, Head D, Vardiman JW, et al.  Pathology and genetics of tumors of 
hematopoietic and lymphoid tissues.  In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors.  World Health Organization 
classification of tumors.  Lyon (France): IARC Press; 2001. p. 63-73.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al.  The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute myeloid leukemia: rationale and important changes.  
Blood. 2009; 114(5):937-51.
&&,
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Appendix B: French-American-British (FAB) Myelodysplastic Syndrome 
(MDS) Classification System
MDS Subtype
Peripheral 
Blasts (%)
Bone 
Marrow 
Blasts 
(%)
AML 
Transformation
Median 
Survival 
(months)
MDS 
Diagnoses 
(%)
Refractory anemia 
(RA)
≤1
<5
10-20
30-65
10-40
Refractory anemia 
with ringed 
sideroblasts (RARS)
≤1
<5
10-35
34-83
10-35
Refractory anemia 
with excess blasts 
(RAEB)
<5
5-20
>50
8-18
25-30
Refractory anemia 
with excess blasts in 
transformation 
(RAEB-T)
≥5
21-29
60-100
4-11
10-30
Chronic 
myelomonocytic 
leukemia (CMML)
<5
≤20
>40
15-32
10-20
AML = acute myeloid leukemia; MDS = myelodysplastic syndrome.
Data from Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic 
syndromes. Br J Haematol 1982; 51:189–199.
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Appendix C: International Prognostic Scoring System Score
International Prognostic Scoring System for MDS
Prognostic Variable
Score Value
0
0.5
1.0
1.5
2.0
Bone Marrow Blasts (%)
< 5
5-10
-
11-20
21-30
Karyotypea
Good
Intermediate
Poor
-
-
Cytopeniasb
0 or 1
2 or 3
-
-
-
a Good:  normal, -Y, del(5q), del(20q); Poor:  complex (# 3 abnormalities) or chromosome 7 anomalies; 
Intermediate:  other abnormalities.
b Defined as:  Hemoglobin < 100 g/L, absolute neutrophil count < 1.8 x 109/L, and platelet count < 100 x 109/L.
Note:  Scores for risk groups are as follows:  Low = 0; INT-1 = 0.5-1.0; INT-2 = 1.5-2.0; and High:  # 2.5.
Source:  Greenberg, P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al.  International scoring system for 
evaluating prognosis in myelodysplastic syndromes.  Blood 1997; 89:2079-88.
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Appendix D: International Prognostic Scoring System Score - Revised
IPSS-R Cytogenetic risk groups*,**
Cytogenetic prognostic 
subgroups
Cytogenetic abnormalities
Very good
-Y, del(11q)
Good
Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate
del(7q), +8, +19, i(17q), any other single or double independent 
clones
Poor
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 
abnormalities
Very poor
Complex: >3 abnormalities
IPSS-R Prognostic Score Values*
Prognostic variable
0
0.5
1
1.5
2
3
4
Cytogenetics
Very 
Good
-
Good
-
Intermediate
Poor
Very 
Poor
Bone Marrow Blast (%)
≤2
-
>2 - <5
-
5 - 10
>10
-
Hemoglobin (g/dL)
≥10
-
8 - <10
<8
-
-
-
Platelets (x109/L)
≥100
50 -
<100
<50
-
-
-
-
ANC (x109/L)
≥0.8
<0.8
-
-
-
-
-
IPSS-R Prognostic Risk Categories/Scores*
RISK CATEGORY
RISK SCORE
Very Low
≤1.5
Low
>1.5 - 3
Intermediate
>3 - 4.5
High
>4.5 - 6
Very High
>6
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IPSS-R: Prognostic Risk Category Clinical Outcomes*
No. pts
Very 
Low
Low
Intermediate
High
Very 
High
Patients (%)
7012
19%
38%
20%
13%
10%
Survival***
-
8.8
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3.0
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AML/25%***,^
-
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1.4
0.7
*Greenberg, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic scoring 
system for myelodysplastic syndrome. Blood. 2012;120(12):2454-65.
**Schanz J, Tüchler H, Solé F, Mallo M, Luño E, Cervera J, et al. New comprehensive cytogenetic scoring system 
for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from 
an international database merge. J Clin Oncol. 2012;30(8):820-9.
***Medians, years.
^Median time to 25% AML evolution.
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Appendix E: Eastern Cooperative Oncology Group (ECOG) Performance 
Status
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG
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 house work, 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.
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity and response 
criteria of the Eastern Cooperative Oncology Group.  Am. J. Clin. Oncol. 1982; 5(6):649-55.
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Appendix F: Hematologic Response and Improvement According to the 
International Working Group for MDS – modified
Hematologic Response Modified from IWG Criteria for MDS (Cheson, 2006)
Category 
Response Criteria (responses must last at least 4 weeks)
Complete Remission (CR)
Bone marrow:  ≤ 5% myeloblasts with normal maturation of all cell lines
!
Persistent dysplasia will be noteda,!  
Peripheral blood
!
Hgb ≥ 11 g/dL 
Platelets ≥ 100 X 109/L 
Neutrophils ≥ 1.0 X 109/Lb  
Blasts 0% 
Partial Remission (PR) 
All CR criteria if abnormal before treatment except:  
∀Bone marrow blasts decreased by ≥ 50% over pre-treatment but still > 5% 
∀Cellularity and morphology not relevant 
Marrow CRb  
Bone marrow:  ≤5% myeloblasts and decrease by ≥ 50% over pre-treatmentb
Peripheral blood:  if HI responses, they will be noted in addition to marrow CRb
Stable Disease (SD) 
Failure to achieve any objective response (CR, PR, mCR, or HI), but no evidence of 
disease progression over any 8-week period 
Failure 
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a more 
advanced MDS FAB subtype than pre-treatmentd.
Relapse After CR or PR 
At least 1 of the following demonstrated by ≥ 2 values, separated by ≥ 2 weeks:  
∀Return to pre-treatment bone marrow blast percentage
∀Decrement of ≥ 50% from maximum remission/response levels in 
granulocytes or platelets
∀Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence 
Cytogenetic Response 
Complete:
∀Disappearance of the chromosomal abnormality without appearance of new 
ones 
Partial:
∀At least 50% reduction of the chromosomal abnormality 
Disease Progression 
For subjects with:
∀Less than 5% blasts: ≥100% increase in blasts to ≥8% blasts
∀≥5% blasts:              ≥50% increase to ≥10% blastsd
Any clinical worsening from pre-injectable HMA baseline condition, including:
∀sustained clinically-significant worsening (investigator’s assessment) from 
baseline granulocyte, platelet, or hemoglobin values (≥ 2 values, separated by 
≥ 2 weeks)
o
worsening granulocytes should be ≥ 50% decrease from pre-injectable 
HMA baseline value
o
worsening platelets should be ≥ 50% decrease from pre-injectable HMA 
baseline value
o
worsening hemoglobin should be ≥ 1.5 g/dL decrease from pre-injectable 
HMA baseline value
∀ongoing or worsening RBC or platelet transfusion requirement
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
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Confidential and Proprietary
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Hematologic Response Modified from IWG Criteria for MDS (Cheson, 2006)
Category 
Response Criteria (responses must last at least 4 weeks)
Survival
Endpoints:
∀Overall: death from any cause
∀Event free: failure or death from any cause
∀PFS: disease progression or death from any cause
∀DFS: time to relapse
∀Cause-specific death: death related to MDS
CR = complete remission; DFS = disease-free survival; FAB = French-American-British; Hgb = hemoglobin; HI = hematologic 
improvement; HMA = hypomethylating agentl; IWG = International Working Group; mCR = marrow complete remission; 
MDS = myelodysplastic syndromes; PFS = progression-free survival; PR = partial remission; RBC = red blood cell; SD = 
stable disease; wks = weeks.
a Dysplastic changes should consider the normal range of dysplastic changes (modification).
b Modification to IWG (2000) response criteria.  
c In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, maintenance) before 
the 4-week period.  Such subjects can be included in the response category into which they fit at the time the therapy is started.  
Transient cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of response, as
long as they recover to the improved counts of the previous course.
d 20 – 30% blasts is considered AML according to the WHO classification (Vardiman, 2009).
Notes:  Deletions to the IWG response criteria are not shown.  To convert hemoglobin from grams per deciliter to grams per liter, 
multiply grams per deciliter by 10.  
Source:  Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al.  Clinical application and 
proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia.  Blood. 2006; 108(2):
419-25.
Hematologic Improvement According to IWG Criteria (Cheson, 2006)
Hematologic improvementa
Response criteria (responses must last at least 8 week)b
Erythroid Response (HI-E) 
(pre-treatment, < 11 g/dL) 
∀Hemoglobin increase by ≥ 1.5 g/dL
∀Relevant reduction in units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions/8 wk compared with the pretreatment transfusion 
number in the previous 8 wk
Platelet Response (HI-P)
(pre-treatment, < 100 X 
109/L) 
∀Absolute increase of ≥ 30 X 109/L for subjects starting with > 20 X 109/L 
platelets 
∀Increase from < 20 X 109/L to > 20 X 109/L and by at least 100%b
Neutrophil Response (HI-N)
(pre-treatment, < 1.0 X
109/L) 
∀At least 100% increase and an absolute increase > 0.5 X 109/Lb
Progression or Relapse After 
HIc
At least 1 of the following:
∀At least 50% decrease from maximum response levels in granulocytes or 
platelets
∀Reduction in Hgb by ≥1.5 g/dL
∀Transfusion dependence
KEY:  HI-E = hematologic improvement-erythroid response; HI-N = hematologic improvement-neutrophil response; HI-P =
hematologic improvement-platelet response; IWG = International Working Group; RBC = red blood cell.
a Pre-treatment counts averages of at least 2 measurements (not influenced by transfusions, ie, no RBC transfusions for 2 weeks 
and no platelet transfusions for 1 week) ≥ 1 week apart (modification).  
b Modification to IWG (2000) response criteria.
c In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), 
gastrointestinal bleeding, hemolysis, and so forth.  It is recommended that the 2 kinds of erythroid and platelet responses be 
reported overall as well as by the individual response pattern.  
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tre


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
173
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Note:  Deletions to the IWG response criteria are not shown.  To convert hemoglobin levels from grams per deciliter to grams per 
liter, multiply grams per deciliter by 10.  
Source:  Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al.  Clinical application and 
proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia.  Blood. 2006; 108(2):
419-25.
&&,
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
174
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Appendix G: New York Heart Association Classification for Congestive 
Heart Failure
Functional Capacity
Class I.  Subjects with cardiac disease but without resulting limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II.  Subjects with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III.  Subjects with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV.  Subjects with cardiac disease resulting in inability to carry on any physical activity without 
discomfort.  Symptoms of heart failure or the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort is increased.
Source:  AHA Medical/Scientific Statement: 1994 Revisions to Classification of Functional Capacity and Objective 
Assessment of Patients With Diseases of the Heart. Circulation. 1994;90:644-645.
Available from: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-
Failure_UCM_306328_Article.jsp
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boutHeartFai
outHeartFa


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
175
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Appendix H: Recommendations for Management of Treatment-Induced 
Diarrhea
Published guidelines (Benson, 2004) were modified to be consistent with the clinical protocol.
Key:  CBC = complete blood count; CTC = Common Terminology Criteria for Adverse Events; IV = intravenous; 
NCI = National Cancer Institute; SC = subcutaneous; TID = three times daily.
&&,


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
176
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Appendix I:
List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ADA
Anti-drug antibody
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransaminase (also SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
AR
Accumulation ratio
AST
Aspartate aminotransaminase (also SGOT)
AUC
Area under the concentration-time curve 
AZA
Azacitidine
BID
Twice daily
BLQ
Below the limit of quantification
BM
Bone marrow
BUN
Blood urea nitrogen
C1D1
Cycle 1, Day 1
CBC
Complete blood count
CCR
Conventional care regimen
CD
Cluster of differentiation
CL
Clearance
Cmax
Maximum observed concentration
CMML
Chronic myelomonocytic leukemia
CNS
Central nervous system
CR
Complete remission
CRF
Case report form
CRO
Contract Research Organization
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCO
Data cut-off
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CRO
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&
CT
CT
&


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
177
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Abbreviation
Definition
DCR-24w
Disease control rate at 24 weeks
DLT 
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of response
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EEA
European Economic Area
EMA
European Medicines Agency
EPO
Erythropoietin
ESA
Erythropoiesis stimulating agent
EU
European Union
FAB
French-American-British
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
Fe/TIBC
Serum iron/serum total iron-binding capacity
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GDMS
Global de-methylation score
GGT
Gamma glutamyltransferase
GM-CSF
Granulocyte macrophage colony-stimulating factor
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HgB
Hemoglobin
HI
Hematologic improvement
HI-E
Hematologic improvement-erythroid response
HI-N
Hematologic improvement-neutrophil response
HI-P
Hematologic improvement-platelet response
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HMA
Hypomethylating agent
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HIV
&


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
178
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Abbreviation
Definition
IB
Investigator’s Brochure
ICD
Informed consent document
ICH
International Council for Harmonisation
iHMA
Injectable hypomethylating agent
imAE
Immune-mediated adverse event
IMiD
Immunomodulatory drug
INR
International Normalized Ratio
INT-1
Intermediate-1
INT-2
Intermediate-2
IP
Investigational Product
IPSS
International Prognostic Scoring System
IPSS-R
International Prognostic Scoring System - Revised
IRB
Institutional Review Board
IRTS
Interactive Response Technology System
ITT
Intent-to-treat
IV
Intravenous
IWG
International Working Group
KM
Kaplan-Meier
LDH
Lactate dehydrogenase
MAD
Maximum administered dose
mCR
Marrow complete remission
MCV
Mean corpuscular volume
MDS
Myelodysplastic syndromes
MDS-U
Myelodysplastic syndrome – unclassified
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified intent-to-treat
miRNA
microRNA
MTD
Maximum tolerated dose
NAb
Neutralizing ADA
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
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RNA
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&


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
179
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Abbreviation
Definition
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NYHA
New York Heart Association
ORR
Overall rate of objective response
OS
Overall survival
PBMC
Peripheral blood mononuclear cells
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PFS
Progression-free survival
PK
Pharmacokinetic
PQC
Product Quality Complaint
PR
Partial response 
pRBC
Packed red blood cells
PT
Prothrombin time
Q2W
Once every 2 weeks
Q4W
Once every 4 weeks
QD
Once daily
RA
Refractory anemia
RAEB
Refractory anemia with excess blasts
RAEB-T
Refractory anemia with excess blasts in transformation
RARS
Refractory anemia with ringed sideroblasts
RBC
Red blood cell
RCMD
Refractory cytopenia with multilineage dysplasia
RCUD
Refractory cytopenia with unilineage dysplasia
RDW
Red cell distribution width
RECIST
Response Evaluation Criteria in Solid Tumors
RN
Refractory neutropenia
RNA
Ribonucleic acid
RT
Refractory thrombocytopenia
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
180
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Abbreviation
Definition
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase (also AST)
SGPT
Serum glutamic pyruvate transaminase (also ALT)
SOP
Standard Operating Procedure
SUSAR
Suspected unexpected serious adverse reactions
TIL
Tumor-infiltrating lymphocyte
TNBC
Triple-negative breast cancer
TNF
Tumor-necrosis factor
TNM
Tumor, nodes, metastasis
TSA
Thrombopoiesis-stimulating agent
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
US
United States
USA
United States of America
WBC
White blood cell 
WHO
World Health Organization
WT
Weight
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
181
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
Appendix J: Extension Phase
Upon Protocol Amendment 4 approval at the respective sites, eligible subjects can enter the 
Extension Phase.
Subject Eligibility
At the Investigator’s discretion and following confirmation of eligibility criteria below, subjects 
can enter the Extension Phase:
!
Subjects who have signed the informed consent for the EP of the study;
!
Subjects receiving oral azacitidine and continuing in the Treatment Phase 
demonstrating clinical benefit as assessed by the Investigator are eligible to receive 
oral azacitidine in the EP;
!
Subjects who do not meet any of the criteria for study discontinuation (see 
Section 12).
Treatment Assignment 
Upon approval of Amendment 4, subjects will start the EP at the start of their next regularly 
scheduled dosing cycle for oral azacitidine and align the Cycle X Day 1 visit with the Treatment 
Discontinuation Visit (X= most recent cycle during the treatment phase), so they occur on the 
same day.  The dose and schedule will follow the study treatment administration and schedule
(Section 8.2). Subjects will remain at the same dose levels from the main study during the 
Extension Phase and may decrease dose levels following dose modifications (Section 8.2.4);
however, dose levels will not increase. Any potential dose escalation will be considered a 
treatment failure and the subject will be discontinued.
Cycles should be repeated every 28 days.  Subjects should be monitored locally for hematology 
and chemistry testing, pregnancy testing for FCBP and dose-limiting toxicities before the dosing 
of the next cycle. Dosage delay or reduction as described below may be necessary.
Management of Toxicities and Dose Modifications
Subjects should be monitored for toxicity using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE, Version 4.03), as a guide for the grading of 
severity.  If a certain level of toxicity is observed and considered by the Investigator to be at least 
possibly related to treatment, IP dosing may be interrupted, delayed or modified.  In all cases, the 
reason for dose modification must be recorded in the subject’s medical record and corresponding 
eCRF page.  If the subject discontinues the protocol-prescribed therapy because of an AE, this 
event must be reported in accordance with the procedures outlined in Section 12.
Oral azacitidine dose modifications due to nonhematological and hematological toxicities during 
oral azacitidine treatment should be managed as described in Section 8.2.4 for dose modification 
guidelines due to toxicity.
Any potential dose escalation will be considered a treatment failure and the subject will be 
discontinued.
Adverse Events
Adverse events (non-serious and serious) will continue to be collected in the CRF.  
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
182
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
For subjects entering the EP, ongoing AEs at the time of the Treatment Discontinuation Visit (in 
the main study) should be left as ongoing and should not be recorded again in the EP AE CRF.  
Adverse events with an onset date equal to or after the EP informed consent date should be 
recorded in the EP AE CRF.  If a previously reported AE worsens during the EP, then the AE 
should be recorded as a new AE with a higher grade on the EP AE CRF. All subjects will be 
monitored for AEs for 28 days following the date of last dose of IP. Any SAEs that have not 
resolved upon discontinuation of the subject’s participation in the study must be followed until 
recovered (return to baseline), recovered with sequelae, or death (due to the SAE).  Refer to 
Section 11 Adverse Events for reporting requirements, responsibilities and procedures.
Concomitant Medications
All concomitant medications that are necessary for the subject’s welfare may be given at the 
Investigator’s discretion during the EP and recorded in the CRF.  However, treatment with any 
other investigational medication is not permitted.  Refer to Section 9 for prohibited concomitant 
medications/therapy for subjects on oral azacitidine.
Survival Follow-up
No Survival Follow-up will be required for any subjects in the EP.
Monitoring of Subjects
The monitoring of subjects is to be conducted as per the local standard of care, and include at 
least:
!
Complete blood count with WBC differential and platelet count as required, and at a 
minimum, prior to each dosing cycle
!
For FCBP, pregnancy testing must be done and have a negative result prior to 
initiating a new cycle
!
Bone marrow biopsy and aspirate as clinically indicated
!
Additional tests or more frequent monitoring are at the Investigator’s discretion based 
on the subject’s clinical status.
Investigator’s Responsibility 
!
Obtain subject’s signature of the informed consent form to enter the EP phase
!
Monitoring of subjects (listed above) 
!
Complete Extension Phase case report form pages
!
Document all adverse events (serious and non-serious) on the adverse event log page 
of the Extension Phase CRF as required by the protocol (Section 8.2.4)
!
Report serious adverse events and other immediately reportable events, as required by 
the protocol (see Section 11).  A completed SAE form must be faxed to Celgene Drug 
Safety, as detailed in the Serious Adverse Event Report Form Completion Guidelines, 
immediately (ie, within 24 hours of the Investigator’s knowledge of the event)
!
Dispensing and accountability of drug including patient drug diary cards
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
183
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
!
Report to the sponsor and complete the CRF for Extension Phase termination when 
the subject terminates treatment with oral azacitidine.
!
The subject should stop treatment with oral azacitidine if any of the following occur:
∀
Additional investigational treatment is started;
∀
Subject is no longer receiving clinical benefit, as per the Investigator’s discretion;
∀
Subject has any AE which would result in treatment discontinuation as per the 
Investigator’s discretion
∀
Subject withdraws consent;
∀
A positive pregnancy test in a FCBP, at any time; or
∀
At the specific request of the sponsor or its authorized representative.
!
The Investigator must be available for periodic monitoring visits and allow the 
sponsor access to all medical records.
!
The Investigator will maintain source documents for subjects entering the EP for all 
case report form data points, which include the following:
∀
Informed consent;
∀
Adverse events (including serious adverse events);
∀
Dosing information (date of administration, dose, number of tablets used, and lot 
number); 
∀
Concomitant medications; and
∀
Termination date and reason.
Statistical Methods  
Safety evaluation for the EP will include monitoring for adverse events and recording of 
concomitant medications. Although physical examinations, vital sign measurements and 
laboratory assessments will be performed in the EP, these assessments will not be captured in the 
CRF.  However, clinically significant findings from these assessments which meet the definition 
of an adverse event (see Section 11) will be reported as adverse events.  Adverse events will be 
summarized as per Section 10.7 on the subjects entering the EP.  Exposure to oral azacitidine as 
well as concomitant medications taken during the EP will also be summarized.
&&,
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EDMS Doc. Number: 
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
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the organizations electronic signature policies and procedures.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
3
CC-486-MDS-006 Amendment 4.0 Final: 17 Jun 2019
1.
JUSTIFICATION FOR AMENDMENT
Based on Protocol Section 4.1.7 (Study Closure), the timing for the primary analysis and 
potential closure of the study will be met shortly. Also in line with this section, Celgene is 
adding an Extension Phase for all currently active subjects who are receiving treatment and opt 
to continue with CC-486. 
Study enrollment was closed on 29 Jun 2018. Enrollment in the Phase 1 safety run-in portion for 
CC-486 Monotherapy was completed with 13 subjects in the Phase 1 CC-486 Monotherapy
cohort on 07 Sep 2017. The Phase 1 Combination Therapy Cohort was stopped on 16 Jan 2018 
due to challenges in finding the optimal combination dose. The Phase 2 Monotherapy SD and PD 
cohorts fully enrolled for Stage 1 in December 2017 and June 2018, respectively. However, the 
minimal number of responses required to proceed to Stage 2 was not met and the Phase 2 cohorts 
were closed on 29 Jun 2018. Six subjects are ongoing in the Monotherapy SD/PD cohorts.
Per protocol, the primary analysis will be conducted once all subjects enrolled have completed 
12 months of treatment or have discontinued before reaching 12 months of treatment, whichever 
occurs first.
Significant changes included in this amendment are summarized below:
!
A description of the Extension Phase is presented in Appendix J and mentioned 
throughout the protocol. The overall duration of the study will be extended during the 
Extension Phase.  
∀
Revised sections:  Protocol Summary, Sections 4.1.6 Extension Phase, and 6.15 
Extension Phase, Figure 1, Table 2 (Table of Events) and Appendix J: Extension 
Phase; and other editorial changes in the protocol for the extension phase.
The amendment also includes other minor clarifications and corrections:
!
Protocol Summary and Section 4.1: Information was updated on enrollment closure, 
the Extension Phase, and the number of subjects who are ongoing.
!
Section 4.1.7, 4.4, and 14.8: Language was added on the timing of study closure.
!
Section 4.3: Total study duration was updated to include the Extension Phase.
!
Section 8.1.1: The available CC-486 supply was modified due to current subjects only 
taking 100 mg tablets. “After Amendment 4 approval, the CC-486 supply will be 
limited to 100-mg tablets for oral administration.”
!
Section 8.2.4: Restrictions were added to dose increase modifications during the 
Extension Phase.
!
Section 11.6: The following text was deleted: “Adverse events such as death related 
to disease progression (in the absence of serious IP-related events) and serious events 
due to the relapse of the studied indication will not be subject to expedited reporting 
by the sponsor to regulatory authorities.  These events will be captured as AEs on the 
CRF, reported to Celgene Drug Safety meeting SAE reporting criteria (within 24 
hours) and reported to regulatory authorities in the annual report.” 
The amendment also includes several other minor clarifications and typographical corrections.
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toto


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
3
CC-486-MDS-006 Amendment 3 Final: 28 Dec 2017
1.
JUSTIFICATION FOR AMENDMENT
This protocol was amended as follows:
!
Protocol text was updated to allow the dose escalation of CC-486 after 2 well-tolerated 
cycles (instead of 4 cycles).  The safety assessment observed in the Phase 1 safety run-in 
portion of the trial was based on 2 dosing cycles and most adverse events occurred early 
in these cycles. Thus, it is reasonable that in the absence of unacceptable toxicity, 
subjects who show signs of worsening disease (clinical or hematological), who remain in 
stable disease, or do not experience modified International Working Group (IWG) 2006 
hematologic improvement (HI) or better (partial response [PR], complete response [CR]
or marrow CR – modified IWG 2006) can dose escalate after 2 well-tolerated cycles.
We have also added the text “who remain in stable disease” for clarity that stable disease 
patients may also dose escalate after 2-well tolerated cycles. 
Revised sections include Section 4.1.3 Randomized Treatment Phase, Section 6.5 CC-
486 (Oral Azacitidine), Section 8.2 Treatment Administration and Schedule, and Section 
8.2.4.1 CC-486 (Oral Azacitidine) Dose Modification and Toxicity Management.
!
The dosing modification and Toxicity Management Guidelines have been updated for 
consistency with recommendations in the most recent Durvalumab Investigator’s 
Brochure Edition 12.
Revised sections: Table 5: Durvalumab Treatment Modification and Toxicity 
Management Guidelines for Immune-Mediated Adverse Events, Table 6: Durvalumab 
Treatment Modification and Toxicity Management Guidelines for Infusion-Related 
Reactions, and Table 7:  Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Non-Immune-Mediated Reactions.
!
To be consistent with the Durvalumab Investigator’s Brochure Edition 12, the term 
“immune-related adverse event (abbreviated as irAE) has been changed to “immune-
mediated adverse event” (abbreviated as imAE) throughout the protocol text.
Sections revised include Protocol Summary, Section 4.1.2.2 Durvalumab / CC-486 
Combination Therapy Dose-Limiting Toxicity, Section 4.1.3 Randomized Treatment 
Phase, Section 6.7 Safety, Table 5 Durvalumab Treatment Modification and Toxicity 
Management Guidelines for Immune-Mediated Adverse Events, Section 11.7 Adverse 
Events of Special Interest, Appendix I List of Abbreviations and Definitions of Terms. 
!
 
 
 
 
 
   
 
 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
4
CC-486-MDS-006 Amendment 3 Final: 28 Dec 2017
 
 
!
Updated the Therapeutic Area Head on the Celgene Therapeutic Area Head Signature 
Page.
!
Section 16.3 Product Quality Complaint was also added per new language in the protocol 
template. 
!
Appendix I:  List of Abbreviations and Definitions of Terms was also updated to include 
new terms or delete terms that are no longer used within the protocol. 
&&,
CCI
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lude
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
3
CC-486-MDS-006 Amendment 2 Final: 27 Mar 2017
1.
JUSTIFICATION FOR AMENDMENT
This protocol is being amended to address Institutional Review Board (IRB) and Principal
Investigator comments which have been endorsed by the Study Steering Committee.   
Significant changes included in this amendment are summarized below:
!
Primary objective wording was updated to remove the text “the most recent” treatment 
with a prior injectable hypomethylating agent (iHMA) for MDS to provide clarity that 
subjects in this trial need to have failed all prior treatments with iHMA and not just “the 
most recent” treatment.  There is no impact expected regarding study population or 
outcome.  Also, please note that this clarification does not change the overall primary 
objective and no text changes were needed per Section 2.1 Primary Objective.  
Revised sections: Protocol Summary, Section 4.1.3 Randomized Treatment Phase,
Section 6.1.1 MDS Diagnosis, WHO and FAB Classifications and IPSS (-R) Risk 
Classification, and Section 7.2 Inclusion Criteria (criterion number 4).
!
Updates were made to detail that the futility analysis may be performed earlier in Stage 1 
if 3 or more responders are observed prior to the enrollment of 16 subjects.  This update 
will not change what was originally intended for the futility analysis, but is intended to 
expedite subject enrollment in the event we do have early responders. Also, to 
emphasize, we will wait for the last subject’s response result in Stage 2 to perform the 
final overall analysis (rate of response) for that specific cohort.  Each of the 4 cohorts will 
be analyzed separately. 
The protocol language will read as follows:
“The randomized treatment phase will be conducted in 2 stages, with a futility assessment 
planned at the completion of Stage 1 to determine whether the null hypothesis (H0: p 
<12.5%) can be rejected with 3 or more responses in Stage 1.  If 3 or more responses 
have been observed before the end of Stage 1, the planned futility assessment may be 
performed earlier than at the completion of Stage 1 to confirm the finding of responses. 
This earlier analysis will replace the futility analysis planned at the completion of Stage 
1. This earlier futility assessment will have the same integrity as the futility assessment 
planned at the completion of Stage 1. An analysis will be performed at the completion of 
Stage 2 to estimate the overall response rate of treatment of all the subjects in the cohort”.
Revised sections:  Protocol Summary, Section 4.1 Study Design, and Section 10.1 
Overview.
Also, protocol language will read as follows:
“A subject is considered evaluable for response once they have one cycle of treatment 
with a maximum of 6 cycles of treatment”.
Revised section:  Section 4.1.3 Randomized Treatment Phase
!
The enrollment period and total trial duration were extended due to the length of the CC-
486 safety run-in, which required the enrollment and monitoring of additional subjects 
due to gastrointestinal intolerability. Enrollment was extended from “approximately 24 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
4
CC-486-MDS-006 Amendment 2 Final: 27 Mar 2017
months” to “approximately 39 months and the total trial duration was updated to change 
“approximately 36 months” to “approximately 47 months”.  
Revised sections: Protocol Summary and Section 4.3 Study Duration.
!
Updated the section reference from Section 8.2.5 to Section 4.1.3 for those who derive 
benefit from treatment with investigational product (IP) as Section 4.1.3 better defines 
this item.
Revised sections: Protocol Summary and Section 8.2 Treatment Administration and 
Schedule.
!
Updates were made to remove references to specifically defined adverse events of special 
interest (AESIs) and to instead refer to the Durvalumab Investigator’s Brochure, Section 
5.4.2 Summary of Risks. This change was made as durvalumab safety profile is still 
evolving and AESIs are subject to change. 
Protocol Summary, Section 4.1.3 Randomized Treatment Phase, Section 4.1.5.1. Follow-
Up in Subjects Receiving CC-486 Monotherapy, Section 4.1.5.2 Follow-up in Subjects 
Receiving Durvalumab/CC-486 Combination Therapy, Section 6.7 Safety, Section 6.13 
Discontinuation, and Section 6.14 Follow-up.
!
Provided clarity that 16 subjects “per cohort” will be accrued in Stage 1 and not 16 
subjects total and also for 25 additional subjects accrued “per cohort” in Stage 2 for a 
total of 41 subjects “in each cohort”.
Revised sections: Protocol Summary and Section 10.3 Sample Size and Power 
Considerations.
!
Updated to include durvalumab data per the current Durvalumab Investigator’s Brochure, 
Edition 10.
Revised sections: Section 1.3 Durvalumab (MEDI4736), Section 1.3.1 Durvalumab 
Experience in Solid Tumors, and Section 1.3.2 Durvalumab Experience in MDS.
!
Updated to include a timeframe for availability for documentation. If documentation of 
myelodysplastic syndrome (MDS) diagnosis, World Health Organization (WHO)/French-
American-British (FAB) classification and International Prognostic Scoring System 
(IPSS)/IPSS-Revised (-R) risk categorization is available “and within 2 months of 
screening”, results of central review are not required prior to enrollment of the subject in 
the study.
Revised sections: Section 4.1.1. Screening Phase, Table 2 Table of Events, and Section 
6.1.15 Bone Marrow Aspirate, Biopsy, and Peripheral Blood Smear.
!
Based on the outcome of the CC-486 safety run-in, the CC-486 starting dose was lowered 
from 200 mg BID, 21/28 day to 100 mg BID, 21/28 day for the combination safety run-in 
therapy and the Phase 2 CC-486 monotherapy.
The dose levels in Table 1 were updated to “0 to -3” instead of specifically noting a 
“starting dose” of 200 mg BID, 21/28 only. 
Also, clarification is added to state that the safety run-in for CC-486 monotherapy has 
been completed as of December 2016.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
5
CC-486-MDS-006 Amendment 2 Final: 27 Mar 2017
Revised sections: Sections 4.1.2 Safety Run-in, Table 1: CC-486 Dose Levels for Safety 
run-in, and Table 3: Dose Modification Steps.
!
Updated text to include “Please refer to Section 4.1.2.1 for CC-486 related dose-limiting 
toxicity criteria”. Criteria was defined for durvalumab dose-limiting toxicities and wanted 
to guide the reader to the previous section for CC-486 specific dose-limiting toxicities 
(for their reference) as this is combination therapy investigating both CC-486 + 
durvalumab.
Revised section: Section 4.1.2.2 Durvalumab/CC-486 Combination Therapy Dose-
Limiting Toxicity.
!
Additional sample collections are allowed if the site would like to work-up the subject for 
progression. Footnote p was updated to include that unscheduled sample collections are 
also permitted if disease progression is suspected.
Revised section: Table 2: Table of Events
!
The window for inclusion criterion number 5 which was originally 12 weeks was 
increased to 16 weeks due to the difficulty for sites to gather prior subject data with 
regard to prior transfusions, prior iHMA treatments, etc. which potentially would come 
from outside hospitals or other treating institutions.  Alignment was gained with the
Study Steering Committee to extend this window from 12 to 16 weeks. 
Also, the additional text “Given this timeframe, subjects may begin screening after the 
last dose of prior injectable HMA” was added for clarity on when subjects could begin 
screening in relation to their last HMA dose. 
Revised sections: Section 6.1 Screening, Section 6.1.4 Prior Medications and MDS 
Treatments, and Section 7.2 Inclusion Criteria (criterion number 5).
!
Urine collection is not required on Cycle 1 Day -1. This text should have been removed 
in Amendment 1.  Please note that no Cycle 1 Day -1 urine samples have been collected 
to date.
Revised section: Section 6.1.10 Urinalysis
!
Removed reference to collecting “corresponding normal range(s)” in the case report form 
(CRF). Local laboratory ranges will be collected in the electronic CRF (eCRF), however 
the corresponding normal ranges are not collected via CRF.
Section 6.7.7 Hematology and Serum Chemistry Laboratory Evaluations
!
Reference to Section 8.2.2.1 is added for clarity for overnight fasting details and 
correction was made of a typographical error for Cycle 2 blood collections for 
durvalumab as Cycle 1 Day 1 (C1D1) was meant to be C”2”D1.
Revised section: Section 6.10 Pharmacokinetics
!
Electrocardiogram is added in the assessments at discontinuation.
Revised section: Section 6.13 Discontinuation
!
Contraceptive methods for females was updated per IRB recommendations and to remain 
in line with the Clinical Trial Facilitation Group (CTFG) Recommendations related to 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
6
CC-486-MDS-006 Amendment 2 Final: 27 Mar 2017
Contraception and Pregnancy Testing in Clinical Trials (available at the Heads of 
Medicine Agencies [HMA] website).
Revised section: Section 7.2 Inclusion Criteria (criterion number 8)
!
Contraceptive requirements for male participants is updated per the Durvalumab 
Informed Consent Risk language.
Revised section: Section 7.2 Inclusion Criteria (criterion number 9)
!
Included “or” between the two definitions outlined for rapidly-progressing MDS to 
provide clarity that both definitions do not have to be met but instead one definition only 
could constitute rapidly-progressing MDS.
Revised section: Section 7.3 Exclusion Criteria (criterion number 1)
!
Removed “or autologous” stem cell transplant per recommendations from the Study 
Steering Committee and Principal Investigators. Autologous stem cell transplant should 
not apply as low intensity conditioning or post-transplant immunosuppressive therapies 
are not needed as subjects receive their own cells in this type of transplant.
Revised section: Section 7.3 Exclusion Criteria (criterion number 3)
!
Added “at any time in the subject’s prior history” to provide clarity that no time window 
is required and that prior exposure to “oral” decitabine or other “oral” azacitidine, or 
ongoing response (per International Working Group [IWG] 2006) to treatment with 
azacitidine for injection or decitabine can be at any time in the subject’s history.
Revised section: Section 7.3 Exclusion Criteria (criteria numbers 4 and 5)
!
Added “planning to become pregnant” to clarify that females who plan to become 
pregnant will be excluded from this trial.
Revised section: Section 7.3 Exclusion Criteria (criterion number 16)
!
Removed “disseminated intravascular coagulation” (DIC) per the Study Steering 
Committee recommendation that any prior history of DIC should not preclude subjects 
from enrolling into this trial.   DIC is a transient condition and if resolved would not lead 
to any sequelae that would prevent the subject from qualifying for this trial.
Revised section: Section 7.3 Exclusion Criteria (criterion number 21)
!
Added exclusion of myeloproliferative neoplasms (MPN) and chronic myelomonocytic 
leukemia (CMML) to provide clarity that these subjects do not have MDS and should 
explicitly be excluded from the trial.  
Revised section: Section 7.3 Exclusion Criteria (criterion number 26)
!
Updated the list of all discontinuation reasons to align with the current CRFs.
Revised sections: Section 8.2.7 Discontinuation and Section 12 Discontinuations
!
Updated that adverse events (AEs) will be recorded by the investigator from the time the 
subject signs informed consent until 28 days after the last dose of CC-486, 90 days after 
the last dose of durvalumab, “or until the Treatment Discontinuation Visit, whichever is 
later as well as acute myeloid leukemia (AML) cases” to clarify that adverse events also 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
7
CC-486-MDS-006 Amendment 2 Final: 27 Mar 2017
need to be collected until treatment discontinuation as well as the need to report cases of 
AML.
Revised sections: Section 11.1 Monitoring, Recording, and Reporting of Adverse Events 
and Section 11.5 Reporting of Serious Adverse Events
!
Updated language per the current Durvalumab Investigator’s Brochure, Edition 10
regarding AESIs. Sections 11.7.2, 11.7.3, 11.7.4 and 11.7.5 were removed to align with 
the current Durvalumab Investigator’s Brochure, Edition 10 and because the durvalumab 
safety profile is still evolving and AESIs are subject to change. 
Revised section 11.7 Adverse Events of Special Interest
!
Removed 1 reference (Oganesyan, 2008) as data was updated per the current Durvalumab 
Investigator’s Brochure, Edition 10.
Revised section: Section 18 References  
!
Changed the abbreviation for partial response (PR) from partial “remission” to partial 
“response” to align with terminology used in Section 3.1 Primary Endpoint as well as 
added additional abbreviations.  
Revised section: Appendix I: List of Abbreviations and Definitions of Terms
The amendment also includes other minor clarifications and corrections:
!
Change of Medical Monitor 
!
“Patient” has been changed to “subject” in applicable instances throughout the protocol 
amendment
!
All references to “study drug” have been updated to “IP”
!
International Council for Harmonisation definition was updated throughout text
!
Updated the toxicity management guidelines and risk language provided for durvalumab 
from the current Durvalumab Investigator’s Brochure, Edition 10.   
Revised sections: Table 5: Durvalumab Treatment Modification and Toxicity 
Management Guidelines for Immune-related Adverse Events, Table 6: Durvalumab 
Treatment Modification and Toxicity Management Guidelines for Infusion-related 
Reactions, and Table 7: Durvalumab Treatment Modification and Toxicity Management 
Guidelines for Non-immune-mediated Reactions
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
3
CC-486-MDS-006 Amendment 1.0 Final: 08 Sep 2015
1.
JUSTIFICATION FOR AMENDMENT
Rationale for the amendment:
While injectable hypomethylating agents (azacitidine for injection and decitabine) remain the 
standard of care in the treatment of International Prognostic Scoring System (IPSS) higher-risk 
myelodysplastic syndrome (MDS), as many as half of affected patients do not respond to 
treatment, and nearly all those who do respond will eventually relapse.  Upon failure of treatment 
with azacitidine for injection and/or decitabine, the prognosis for patients with higher-risk 
disease is dismal, with median overall survival on the order of 4-6 months. Similarly, injectable 
hypo-methylating agents (iHMAs) are approved for treatment of IPSS lower-risk MDS in some 
countries, and while there are few data to characterize outcomes in lower-risk disease following 
failure of these agents, prognosis is poor and for patients who are not eligible for allogeneic stem 
cell transplant (ASCT), no proven treatment options currently exist.
The goal in treating this population and in evaluating new potentially therapeutic options is to 
capture or recapture hematologic response or hematologic improvement to reduce the rate of 
disease progression and acute myeloid leukemia (AML) transformation, and to prolong survival.  
Despite active interest in the post-HMA setting among researchers, there remains a critical unmet 
medical need.  
Cancer and Immune Function
The importance of the immune system in cancer development and progression has been 
recognized during the past decade.  Failure of immune surveillance of pre-neoplastic lesions and 
micro-metastases is a key step in cancer development. Chronically immunosuppressed 
individuals show higher rates of cancer. This observation led to the hypothesis that sporadic 
cancers among immune-competent individuals are likely to be minimally immunogenic, 
allowing for passive escape from immune surveillance. Recent data suggest that this may be an 
oversimplification. Some sporadic tumors are highly immunogenic, but actively suppress the 
local immune environment through production of immunosuppressive cytokines.  The local 
tumor environment is likely a highly dynamic environment where most tumors grow and 
metastasize through adaptive responses that modulate antitumor immunity. The complexity and 
redundancy of the immune system offers multiple targets that may be manipulated to maximize 
the body’s inherent immune response to a tumor. Immune response may be augmented by 
directly stimulating effector cells, indirectly stimulating effectors by augmenting antigen 
presentation activity or costimulation, or by suppressing immunosuppressive factors, cells, or 
messages.
Immune-checkpoint Inhibition
Tumor-infiltrating lymphocytes (TILs) have the capacity to control the growth of many types of 
cancers.   Most tumors show infiltration by TILs, but tumors modulate the local 
microenvironment through expression of inhibitory molecules. Engagement of  TIL cell-surface 
receptors with these inhibitory ligands leads to a dysfunctional immune response, causes T-cell 
exhaustion, and facilitates tumor progression.   It is increasingly appreciated that cancers are 
recognized by the immune system, and under some circumstances, the immune system may 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
4
CC-486-MDS-006 Amendment 1.0 Final: 08 Sep 2015
control or even eliminate tumors.  Novel monoclonal antibodies (mAbs) that block these 
inhibitory receptors have shown significant clinical activity across a number of tumor types 
Specifically, blockade of immune-checkpoint inhibitors such as cytotoxic T-lymphocyte-
associated antigen 4 (CTLA-4), PD-1, and PD-L1 have shown clinical activity not only in 
conventionally immune-responsive tumors such as melanoma and renal cell carcinoma but also 
in non-small-cell lung cancer (NSCLC), and prostate cancer.  
The PD-1 receptor, in conjunction with receptor ligands PD-L1 and PD-L2, functions to regulate 
the immune system primarily by down regulating signals of the T-cell receptor.  PD-L1 
expressed on tumor cells binds to PD-1 on T-cells which leads to down regulation of T-cell 
activity and allows tumor cells to evade the immune response.
Recent advances in immunotherapy offer promise for improving clinical outcomes in patients 
with MDS or AML. It is increasingly appreciated that cancers are recognized by the immune 
system, and under some circumstances, the immune system may control or even eliminate 
tumors.   Studies in mouse models of transplantable tumors have demonstrated that manipulation 
of costimulatory or co-inhibitory signals can amplify T-cell responses against tumors.  This may
be accomplished by blocking co-inhibitory molecules such as CTLA-4 or PD-1 from binding 
with their ligands, B7 or B7-H1 (PD-L1).
PD-L1 expression is present in MDS and AML, with increased expression observed in advanced 
disease. In addition, there has been evidence to suggest that PD-L1 is upregulated in myeloblasts 
in MDS subtypes.  
In addition, in MDS subtypes, PD-L1 expression on myeloblasts has been associated with MDS 
transformation to AML.  Myeloid leukemia cell lines that were treated with the hypomethylating 
agent decitabine were shown to have an upregulation of PD-L1 expression.  Upregulation (≥ 2 
fold) of PD-L1 has been observed in 25% of AML CD34+ samples, 33% of PD-L2, and 22% of 
PD-1.  PD-1 signaling may be involved in MDS pathogenesis and resistance mechanisms to 
azacitidine; therefore, combined blockade of this pathway can be a potential therapy in MDS and 
AML.
Based on this information, a rationale exists for evaluating durvalumab in combination with 
azacitidine in subjects with MDS and AML. 
Durvalumab is a human immunoglobulin G (IgG)1 kappa mAb directed against human PD-L1.
Durvalumab is expressed in Chinese hamster ovary cells and has an overall molecular weight of 
approximately 149 kDa. Durvalumab selectively binds human PD-L1 with high affinity and 
blocks its ability to bind to PD-1 and cluster of differentiation 80. The fragment crystallizable 
(Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgG1 heavy 
chain that reduces binding to the complement component C1q and the Fc gamma receptors 
responsible for mediating antibody-dependent cell-mediated cytotoxicity.
Study CD-ON-MEDI4736-1108 is a Phase 1, first-time-in-human, multicenter, open-label, dose-
escalation, and dose-expansion study to determine the maximum tolerated dose (MTD) or 
optimal biologic dose, safety, pharmacokinetics (PK), immunogenicity, and antitumor activity of 
durvalumab in adult subjects with advanced solid tumors refractory to standard therapy or for 
which no standard therapy exists. As of 21 Aug 2014, 408 subjects across 8 tumor types 
(NSCLC, squamous cell carcinoma of the head and neck, pancreatic adenocarcinoma, uveal 
melanoma, cutaneous melanoma, gastroesophageal cancer, triple-negative breast cancer, and 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
5
CC-486-MDS-006 Amendment 1.0 Final: 08 Sep 2015
hepatocellular carcinoma [hepatitis B virus and hepatitis C virus positive]) have received 
durvalumab 10 mg/kg every 2 weeks (Q2W) for a median of 6 doses.
Partial efficacy data are available as of 21 Aug 2014.  In this study, 352 of 408 subjects treated 
with durvalumab 10 mg/kg Q2W were evaluable for response analysis, which included subjects 
who had at least 12 weeks of follow-up as of the data cutoff date, measurable disease at baseline, 
and at least 1 follow-up scan (included discontinuations due to progressive disease [PD] or death 
prior to first follow-up scan). Early (5 weeks) and durable (56+ weeks) activity were observed 
across multiple tumor types. Disease control rate at 12 weeks (DCR-12w) was 33% (115/352 
subjects) and objective response rate (ORR) was 10% (36/352 subjects) across the 8 tumor types. 
Greater DCR-12w (47% vs 28%) and ORR (22% vs 5%) were observed in subjects with PD-L1-
positive versus PD-L1-negative tumor. Responses are ongoing in 92% of subjects (33/36) with 
an objective response (OR).
Durvalumab is being evaluated in MDS after iHMA treatment. 
 
 
Despite active interest in the post-HMA setting among researchers, there remains a critical unmet 
medical need.  The current study is being amended to additionally evaluate a new potentially 
therapeutic option, durvalumab in combination with CC-486, in an effort to capture or recapture 
hematologic response or hematologic improvement, to reduce the rate of disease progression and 
AML transformation, and to prolong survival.  
Significant changes included in this amendment are summarized below:
An additional investigational product (IP), anti-PD-L1 monoclonal antibody, durvalumab 
(MEDI4736) in combination with CC-486 (combination therapy), will be evaluated  in this study 
in addition to the evaluation of CC-486 as monotherapy.  The changes in the protocol are being  
made to accommodate this additional arm of combination therapy.
The Introduction (Section 1) now includes a description of durvalumab (Section 1.3) including 
experience in MDS.  Study Rationale (Section 1.4) was changed to include information on 
cancer and immune function, immune checkpoint inhibition 
 and 
durvalumab fixed dosing regimens.
The primary objective of the study (Title Page, Protocol Summary and Section 2.1) remains the 
same except for the addition of combination therapy.  The original secondary objectives  also 
remain the same except for the addition of combination therapy.  An additional secondary 
objective was added  to evaluate the pharmacokinetics of the durvalumab and CC-486 
combination. 
  
 
 
 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
6
CC-486-MDS-006 Amendment 1.0 Final: 08 Sep 2015
 
 
 
The study design (Protocol Summary, Section 4) and study design rationale (Section 4.2)  has 
been changed to accommodate the addition of the combination therapy.  The study design now 
includes a safety run-in:  a 3+3 design for CC-486 monotherapy followed by a 3+3  design with 
combination therapy to evaluate safety and tolerability.  Dose limiting toxicity was defined for 
monotherapy and for combination therapy.  The previous randomized treatment phase was 
changed to add the additional arm of combination therapy.   Section 4.1.3 was updated to state 
that once the CC-486 dose and schedule in the safety-run in of a treatment arm is identified, 
enrollment for Stage 1 of the treatment phase may begin. A pharmacokinetic sub-study (Section 
4.1.4 and 6.10) was added that will collect samples from 10-12 evaluable subjects randomized to 
the combination treatment arm.  Subjects participating in the pharmacokinetic sub-study will 
receive CC-486 on Day -1 of Cycle 1 (Section 6.3, Section 6.10, Section 8.2).
The previous study design (Figure 1) and the amended study design including the run-in phase 
(Figure 2 and 3) are attached.  The follow-up phase is extended from 28 days to 90 days for the 
combination therapy.
Study populations (Protocol Summary, Section 7.1) has been amended to include additional 
subjects for treatment in the safety run-in and in the combination arm.  At least 6 subjects  will 
be treated in the safety run-in phase, utilizing the  standard 3+3 design for the monotherapy and 
then for the combination therapy.  The Stage 1 randomized treatment will include 64 subjects: 
approximately 32 with stable disease and 32 with progressive disease.  If there are 3 or more 
responses in any arm, that arm with enroll 25 additional subjects in Stage 2.  The total number of 
subjects  in the randomized treatment phase will range from 64 to 164 subjects.  
The enrollment period (Protocol Summary, Section 4.3) for this study has been increased and is 
expected to last approximately 24 months.  The treatment and follow-up phases of study are 
expected to conclude approximately 12 months after the last subject is enrolled.  Therefore, the 
total duration of the study is expected to be approximately 36 months.  
Inclusion criteria was amended to include the signing of an additional 
 
 and the exclusion criteria (Section 7.3) was amended to add exclusions 
appropriate to ensure safety and exclusions of conditions that would confound the ability to 
interpret the data of subjects receiving durvalumab including subjects who received previous 
treatments similar to durvalumab.  
Study treatment (Title Page, Protocol Summary, Section 6.5 now Section 6.6, Section 8, Section 
7.3, and Section 9.2) was amended to add the following information for durvalumab:  
description, dosing and administration, IP dispensation and guidelines for toxicity management 
and overdose.  Prohibited medications was expanded to add immunosuppressive agents and live 
attenuated vaccines.
Statistical analysis  (Protocol Summary, Section 10) now refers to the 2-arm study with the 
addition of the combination treatment.   Sample size and power considerations, primary efficacy 
analysis, 
 
were changed to reflect the addition of the combination therapy arm.   
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
7
CC-486-MDS-006 Amendment 1.0 Final: 08 Sep 2015
Safety assessments and  adverse events (Protocol Summary, Table of Events, Section 6.6 now 
Section 6.7 and Section 11), and adverse events of special interest were added primarily to 
reflect those additional events that are specific to durvalumab, e.g., hepatic function abnormality, 
pneumonitis, infusion reactions and hypersensitivity.  Appropriate safety assessments were 
added including infusion monitoring and 12-lead ECG at study discontinuation. 
Other significant changes and rationale for those changes:
Concomitant medications (Section 6.1.4, Section 6.6.7 now 6.7.9, Section 9, Table 1 footnote) 
All prescription, over-the-counter, or herbal medications and therapeutic procedures received 
within 12  4 weeks (28 84 days) prior to the first dose of IP, until 28 days after the last dose of 
the IP (or until the treatment discontinuation visit, whichever period is longer) must be recorded 
on the appropriate CRF page.
Rationale:  Medications discontinued more than 28 days prior to the first dose of IP will be 
unlikely to impact the study.  Treatments for MDS are gathered outside of that time frame.
Coagulation parameters will be collected at baseline (Table 1 now Table 2: Table of Events and 
Section 6.1.5).
Rationale:  Collection of coagulation parameters has been added as an additional safety 
measure.
Amylase and lipase will now be added to serum chemistries as well as thyroid function tests 
(Protocol Summary, Section 4.1.3, Table of Events, Section 6.1.13, Section 6.7, Section 6.14) 
Rationale:  Collection of amylase, lipase and thyroid function tests have been added as
additional safety measures. 
A urine sample should be collected prior to IP administration on Day 1 of every 3rd treatment 
cycle (i.e. Cycles 3, 6, 9, etc), treatment discontinuation and safety follow-up, and sent to central 
lab for analysis (Protocol Summary, Section 4.1.3, Table of Events, Section 6.1.10, Section 6.7, 
Section 6.13 and Section 6.14). 
Rationale:  Urine monitoring time points have been added as an additional safety measure.
IVRS (Interactive Voice Response System) was changed to IRTS (Interactive Response 
Technology System).
Rationale: This change was provided by Endpoint, our IRTS vendor.
 
 
 
 
 
 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
8
CC-486-MDS-006 Amendment 1.0 Final: 08 Sep 2015
Figure 1: Overall Study Design Prior to Amendment 
Key: AML = acute myeloid leukemia; Cum = cumulative; ECOG PS = Eastern Cooperative Oncology Group 
Performance Status; HMA = hypomethylating agent; mo = month; ORR = overall response rate; PD = progressive 
disease; SD = stable disease
Figure 2:  Safety Run-in Phase Study Design in Protocol Amendment
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
Summary of Changes CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
9
CC-486-MDS-006 Amendment 1.0 Final: 08 Sep 2015
Figure 3:  Randomized Treatment Phase Study Design in Protocol Amendment
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
1
3/30/2020
STATISTICAL ANALYSIS PLAN
A Phase 2, International, Multicenter, Randomized, Open-Label, Parallel Group Study to Evaluate the 
Efficacy and Safety of CC-486 (Oral Azacitidine) Alone and in Combination with Durvalumab 
(Medi4736) in Subjects with Myelodysplastic Syndromes who fail to achieve an objective response to 
treatment with Azacitidine for injection or Decitabine
INVESTIGATIONAL PRODUCT (IP):
CC-486 (oral azacitidine)
Durvalumab (MEDI4736)
PROTOCOL NUMBER:
CC-486-MDS-006
DATE FINAL:
30 June 2014
DATE AMENDMENT #1.0 FINAL
08 Sep 2015
EudraCT NUMBER:
2014-002675-29
IND NUMBER:
074618
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue, Summit, NJ 07901
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
2
3/30/2020
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................5
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION..................................................................................................10
3.
OBJECTIVES ........................................................................................................11
3.1.
Primary Objective...................................................................................................11
3.2.
Secondary Objectives .............................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................12
4.1.
Overall Study Design and Plan ...............................................................................12
4.2.
Study Endpoints .....................................................................................................13
4.2.1
Primary Endpoint...................................................................................................13
4.2.2
Secondary Endpoint(s)............................................................................................13
4.3.
Sample Size............................................................................................................14
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................16
5.1.
Reporting Conventions ...........................................................................................16
5.1.1.
Calculation Using dates ..........................................................................................16
5.1.2.
Calculation of Cycles..............................................................................................17
5.2.
Analysis Populations ..............................................................................................17
5.2.1.
Intent-to-Treat Population.......................................................................................17
5.2.2.
Modified Intent-to-Treat Population .......................................................................17
5.2.3.
Safety Population....................................................................................................17
5.2.4.
Evaluable Population..............................................................................................17
5.2.5.
PK Population ........................................................................................................17
5.2.6.
Immunogenicity Population....................................................................................18
6.
SUBJECT DISPOSITION......................................................................................19
7.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................20
7.1.
Demographics.........................................................................................................20
7.2.
Baseline Clinical Characteristics.............................................................................20
7.3.
Medical History......................................................................................................21
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
3
3/30/2020
7.4.
Prior MDS Treatment .............................................................................................21
7.5.
RBC and Platelet Transfusion History ....................................................................21
7.6.
Pregnancy...............................................................................................................21
8.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................22
9.
PRIOR/CONCOMITANT MEDICATIONS AND PROCEDURES .......................24
10.
EFFICACY ANALYSIS ........................................................................................25
10.1.
Primary Efficacy Analysis ......................................................................................25
10.2.
Secondary Efficacy Analyses..................................................................................25
10.2.1.
Overall Survival .....................................................................................................25
10.2.2.
Time to Onset of Response .....................................................................................26
10.2.3.
Duration of Response .............................................................................................26
10.2.4.
Progression-free Survival........................................................................................26
10.2.5.
Stable Disease ........................................................................................................27
10.2.6.
Disease Progression to AML ..................................................................................27
11.
SAFETY ANALYSIS ............................................................................................28
11.1.
Adverse Events.......................................................................................................28
11.2.
Clinical Laboratory Evaluations..............................................................................31
11.3.
Vital Sign Measurements........................................................................................32
11.4.
ECOG Performance Status......................................................................................32
11.5.
Bone Marrow Aspirate, Biopsy, and Peripheral Blood Smear .................................32
11.6.
Electrocardiogram ..................................................................................................32
12.
INTERIM ANALYSIS...........................................................................................33
13.
PHARMACOKINECTIC ANALYSES ..................................................................34
13.1.
CC-486...................................................................................................................34
13.1.1.
Plasma concentrations.............................................................................................34
13.1.2.
PK Parameter..........................................................................................................35
13.1.3.
PK Analyses...........................................................................................................36
13.2.
Durvalumab............................................................................................................36
13.2.1.
Plasma concentrations.............................................................................................36
13.2.2.
PK Parameter..........................................................................................................37
13.2.3.
PK Analyses...........................................................................................................39
13.3.
Immunogenicity......................................................................................................39
14.
REFERENCES.......................................................................................................40
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
4
3/30/2020
15.
APPENDICES........................................................................................................41
15.1.
Appendix A: Date Imputation Guideline.................................................................41
15.1.1.
Impute Missing AE start day and month [namely, dd & mm in dd-mm-yyyy 
are missing] ............................................................................................................41
15.2.
Appendix B: Myelodysplastic Syndromes World Health Organization 
Classification System..............................................................................................44
15.3.
Appendix C:  International Prognostic Scoring System Score .................................46
15.4.
Appendix D:  ECOG Performance Status................................................................47
15.5.
Appendix E:  Hematologic Response According to the IWG Criteria for 
MDS.......................................................................................................................48
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
7
3/30/2020
HISTORY OF AMENDMENTS
Amendment 
number
Date of 
amendment
Rationale of 
amendment
Impact to statistical 
analysis and descriptions
#1
June, 2019
The PK analyses were planned 
but not conducted in the 
combination arm which was 
stopped since the optimal 
combination dose could not be 
determined. Only a few 
subjects were enrolled in the 
combination arm who agreed 
to PK sample collection and 
due to the limited samples 
collected, the PK TLGs will 
not be generated. 
The PK TLG will not be 
produced.
#2
Mar 19, 2020
The AESI list had been 
updated to reflect the new 
search paths.
The AESI related tables 
and listings will be 
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
8
3/30/2020
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
AE
adverse event
AML
acute myelogenous leukemia
ATC
Anatomical Therapeutic Chemical
BMI
body mass index
BSA
body surface area
CI
confidence interval
CR
complete remission
CRF
case report form
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data management committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ESA
erythropoiesis-stimulating agents
FCBP
female of child-bearing potential
HI
hematologic improvement
HI-E
hematologic improvement erythroid
HI-N
hematologic improvement neutrophil
HI-P
hematologic improvement platelet
HRQoL
health-related quality-of-life 
IC
informed consent
INT-1
intermediate-1
IP
Investigational Product
IPSS
International Prognostic Scoring System
ITT
Intent to treat
IVRS
Interactive Voice Response System
IWG
International Working Group
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
9
3/30/2020
KM
Kaplan-Meier
mCR
Marrow CR
MDS
myelodysplastic syndromes
MedDRA®
Medical Dictionary for Regulatory Activities
mITT
modified intent to treat
NCI
National Cancer Institute
OS
overall survival
PD
pharmacodynamic/pharmacodynamic
PK
pharmacokinetics/pharmacokinetic
PR
partial remission
pRBC
packed red blood cell
QD
once daily
RBC
red blood cell 
ROW
rest of world
SAP
statistical analysis plan
SAS
Statistical Analysis Software
SC
subcutaneously/subcutaneous
SD
stable disease
SOC
system organ class
TEAE
treatment emergent adverse event
WBC
white blood cell 
WHO
World Health Organization
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
10
3/30/2020
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the scope and methodologies of statistical data 
analyses and presentations of the analytical results for Celgene protocol CC-486-MDS-006: “A 
Phase 2, International, Multicenter, Randomized, Open-label, Parallel Group Study to Evaluate 
the Efficacy and Safety of CC-486 (Oral Azacitidine) Alone and in Combination With 
Durvalumab (MEDI4736) in Subjects With Myelodysplastic Syndromes Who Fail to Achieve an 
Objective Response to Treatment With Azacitidine for Injection or Decitabine.” 
This SAP contains brief descriptions of the investigational plan, study subject disposition, 
demographics and baseline characteristics of study subjects, treatment exposure analysis, 
concomitant medication analysis, and general statistical considerations for the analysis of 
efficacy and safety data.
The study consists of four study phases: Screening, Safety Run-in, Randomized Treatment, and Follow-
up. The objective of the safety run-in phase is to determine the dose regimen for the monotherapy with 
CC-486 and the combination therapy with CC-486 + durvalumab using the 3+3 experimental design. 
After the determination of dose regimen for monotherapy or combination therapy, the study will enter the
randomization treatment phase utilizes the Simon’s two-stage design method for four patient cohorts, 
namely, the stable disease (SD) cohort treated with CC-486, the progressive disease (PD) cohort treated 
with CC-486, the SD cohort treated with CC-486 + durvalumab, and the PD cohort treated with CC-486 + 
durvalumab. 
The analysis will be performed for the first stage initially to determine whether a cohort should continue 
to the second stage. Further analysis at the end of second stage will be conducted for the cohorts which 
enter the second stage of the study. Subjects will be followed for potential safety issues after they leave 
the safety run-in or treatment phase. The analytical results of efficacy and safety data for all cohorts will 
be presented together in a report with tables and listings.
This SAP will be finalized and signed-off prior to the clinical database is locked for the interim analysis 
or the first stage clinical data analysis, whichever occurs sooner, of any patient cohort. All statistical
analyses detailed in this SAP will be conducted using Statistical Analysis Software (SAS)® Version 9.3 or 
higher.  
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
11
3/30/2020
3.
OBJECTIVES
3.1.
Primary Objective
The primary objective of this study is to investigate the efficacy of CC-486 as monotherapy, and in 
combination with anti-PD-L1 monoclonal antibody, durvalumab (MEDI4736), in subjects with MDS that 
did not respond to the most recent treatment with an injectable hypomethylating agent (HMA –
azacitidine for injection or decitabine), or were unable to tolerate treatment with an injectable HMA.
3.2.
Secondary Objectives
The secondary objectives of the study are to:
!
Assess the safety and tolerability of CC-486 alone and in combination with durvalumab, 
as treatment for MDS.
!
Describe the clinical relevance of objective hematologic and/or biologic responses 
associated with treatment with CC-486 alone and in combination with durvalumab.
!
Evaluate the impact (if any) of durvalumab on the pharmacokinetics of CC-486 and CC-
486 on durvalumab in subjects with MDS.
 
 
 
 
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
12
3/30/2020
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 2, international, multicenter, randomized, parallel group, open-label study consisting of 4 
study phases: Screening, Safety Run-in, Randomized Treatment, and Follow-up.
Safety Run-In Phase:
Safety Run-in will use the 3+3 design to explore the possible dose regimen for the monotherapy and 
combination therapy as well as the corresponding safety and tolerability profiles. Safety run-in will be 
conducted in sequential order with monotherapy first and then the combination therapy.  The number of 
subjects needed for this phase will depend on the safety and tolerability findings
Randomized Treatment Phase:
The randomized treatment phase of the study will be conducted in 2 stages using Simon’s two-stages 
design. Following identification of dose and schedule in the safety run-in of a treatment arm, enrollment 
for Stage 1 of the treatment phase may begin. 
Eligible subjects will be randomized to one of two open treatment arms. In the event that combination 
therapy cohorts are not ready to enroll for this phase, the available subjects will be enrolled into the 
monotherapy cohorts. The randomization with 1:1 ratio will start when safety run-in phase is finished for 
both monotherapy and combination therapy arms. In the event that one arm has completed enrollment, all 
available subjects thereafter will be enrolled into the other arm. The randomization will be stratified 
according to subject’s disease status, namely, Stable Disease (SD) or Progressive Disease (PD), at study 
entry.
Based on subject’s disease status and the treatments, there will be four cohorts: (1) SD with Monotherapy, 
(2) PD with Monotherapy, (3) SD with Combination therapy, and (4) PD with Combination therapy.
During Stage 1, if a cohort is awaiting the decision to continue to Stage 2 pending on the response 
evaluation while the other cohort of the same patient classification is open for enrollment, available 
patients will be assigned to the cohort with open enrollment without randomization. If both cohorts of the 
same patient classification are waiting for response evaluations, enrollment of that patient classification 
will be temporarily halted.
The total number of subjects for the randomized treatment phase will range from approximately 64 (at 
Stage 1) to 164 (Stage 1 plus Stage 2) for the four subject cohorts. More subjects can potentially be 
recruited for replacement of non-evaluable subjects, if needed. Details can be found in the Sample Size 
section.
PK Sampling: 
Blood samples for pharmacokinetic analysis will be collected from approximately 10-12 evaluable 
subjects received the combination treatment arm at selected sites. This will enable assessment of drug-
drug interactions.
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
13
3/30/2020
All subjects who receive at least one dose of CC-486 (durvalumab) in the safety run-in or randomized 
treatment phase and discontinue treatment for any reason will be followed for at least 28(90) days after 
their last dose of CC-486 (durvalumab) for the assessment of safety-related parameters. After the 28(90)-
day period for CC-486 (durvalumab), only SAEs made known to the investigator that are suspected of 
being related to treatment with CC-486 (durvalumab) need to be reported.
A 28(90)-day follow-up visit will be conducted 28(90) (±3) days following the last dose of CC-486 
(durvalumab) or during the final treatment phase study visit (whichever date is later) for assessment of the 
safety-related parameters.
Subjects in follow-up will then be contacted every 3 months from the date of the 28(90)-day follow up 
visit for CC-486 (durvalumab) until death, loss-to follow-up, withdrawal of consent to further follow-up, 
or study closure to collect information related to survival, subsequent MDS-related therapies, and disease 
progression to AML. This will continue until the last active subject completes approximately 12 months 
of treatment and/or follow-up unless additional follow-up is needed to evaluate time-to-event endpoints. 
Follow-up contacts will routinely be conducted by telephone unless special circumstances exist.
Study Closure
The study is expected to close when the last subject completes approximately 12 months of treatment 
and/or follow-up, unless additional follow-up is needed to analyze time-to-event endpoints.
4.2.
Study Endpoints
4.2.1
Primary Endpoint
The primary endpoint of this study is the overall rate of objective response (ORR) to treatment with CC-
486 as the monotherapy and treatment with CC-486 and durvalumab as combination therapy. The ORR is 
defined as the proportion of subjects achieving an objective response (HI, PR, CR, or marrow CR) based 
on modified International Working Group (IWG) 2006 criteria.
4.2.2
Secondary Endpoint(s)
The secondary endpoints of this study are:
!
Overall survival;
!
Time to onset of responses;
!
Duration of responses;
!
Progression free survival (time to disease progression or death from any cause);
!
Proportion of subjects with progressive disease at baseline achieving Stable Disease, as 
well as time to achieving stable disease and duration of stable disease;
!
The proportion of subjects progressing to AML and time to AML progression;
!
Safety and tolerability (type, frequency, severity of AEs and relationship of AEs to CC-
486 and/or durvalumab; monitoring for disease progression to AML, as well as immune-
and infusion-type reactions); 
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!
Serum/plasma PK parameters for durvalumab and CC-486, such as maximum observed 
concentration (Cmax), area under the concentration-time curve (AUC), time to maximum 
concentration (Tmax), terminal half-life (
2
/
1t
), clearance (CL/F) and volume of
distribution (Vz/F).
 
 
 
 
 
 
 
4.3.
Sample Size
The sample size required will be identical for each treatment arm in each cohort and is estimated 
using the optimal design of the Simon's two-stage design method (Simon, 1989). The null 
hypothesis of the response rate will be tested against a one-sided alternative. 
For each cohort, the null hypothesis of the response rate (H0 : p ≤ 0.125) will be tested against 
the alternative hypothesis of the response rate (H1 : p ≥ 0.27) with a type I error rate of 10% and 
80% power. During the first stage, 16 subjects will be accrued. If there are 2 or fewer responses 
in these 16 subjects, the cohort will be stopped, and no further recruitment will be needed. 
Otherwise, 25 additional subjects will be accrued for a total of 41 subjects per cohort. If 8 or 
more responses are observed in these 41 subjects, the null hypothesis will be rejected. 
For each cohort, in addition to the evaluation of treatment responses based on objective response 
criteria, the quality of responses will also be considered for the decision whether to continue the 
cohort to the second stage of the study. Quality of response will be assessed based on the 
CCI
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 null hypot
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magnitude of hematologic and biologic responses observed in individual subjects, with special 
consideration for response duration.
&(/*(1(35235,(7$5<,1)250$7,21


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5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
Summary tables, listings, and any supportive SAS output will include a “footer” of explanatory 
notes that will indicate, at a minimum, the program source (e.g., SAS program name, including 
the path, that generates the output) and data extraction date (e.g., the database lock date, run 
date). The purpose of the data extraction date is to link the output to a final database, either 
active or archived, that is write-protected for replication and future reference. An output date will 
also appear on each output page and will indicate the date the output was generated by the 
analysis program. Individual source listing will display all the relative values supporting 
corresponding tables and figures.
Descriptive summaries for continuous data will include the following statistics: N, mean, standard 
deviation (SD), minimum, median, and maximum, unless specified otherwise.  Categorical summaries for 
discrete data will include the frequency (count) and percentage at each discrete value (category), unless 
specified otherwise.
5.1.1.
Calculation Using dates
Calculations using dates (e.g., subject’s age or relative day after the first dose of study 
medication) will adhere to the following conventions: 
!
Study days after the start day of study drug will be calculated as the difference between 
the date of interest and the first date of dosing of study medication (dstart) plus 1 day. 
o
The generalized calculation algorithm for relative day is defined as: 
a.
study day = [(target date – dstart) + 1], if (target date >= dstart).
b. study day = [(target date – dstart)], if (target date < dstart).
o
Note: Study Day 1 is the first day of treatment of study drug.  Negative study days 
indicate the observations were obtained before the first dose of study drug.  
o
Partial date for the first study drug dosing will be imputed according to the 
criterion in Appendix A of section 14.1. All effort should be tried to avoid 
incomplete start date of study drug. 
!
Age (in years) is defined as: [Age = date of consent – date of birth + 1]/365.25 with 
rounding.
o
Calculation of age should base on the dates in clinical database, otherwise, the 
calculation will base on dates from CRF or IVRS. 
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date will
ate wil
y the
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porting
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N, mean, sta
N, mean, sta
.  C
.  Categoric
tegor
crete value 
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e day after t
day after t
ns:
ns:
drug will b
drug will b
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of dosing
ation algori
ation algori
= [(target da
= [(target 
day
day = [
= [(targ
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ay 1
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arti
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date f
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ter
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ro
r und
nd


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o
Partial birth date will be imputed as follows: impute missing day as 15th of the 
month; impute missing month as July. If birth year is missing, age will be 
recorded as missing.
!
Algorithm to convert DAYS to WEEKS: WEEKS = DAYS /7.
!
Algorithm to convert DAYS to MONTHS: MONTHS = DAYS /30.4167.
5.1.2.
Calculation of Cycles
The start date of each treatment cycle will be calculated based on study drug exposure records 
for each patient. The start date of the first cycle will be the date when the subject receives the 
first dose of study drug. Once the start date is calculated, the end date of each cycle is calculated 
as the day before the start date of the following cycle. For the last cycle, the end date will be 
calculated as the start date plus prescribed cycle length, or the death date, whichever is earlier. 
The cycle number will be calculated based on the cycle window set by their start and end dates. 
5.2.
Analysis Populations
5.2.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population will include all enrolled subjects who received at least one dose of IP.
5.2.2.
Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population includes all ITT subjects who have at least one post-
baseline efficacy assessment performed, met all inclusion/exclusion criteria, and received a minimum of 
one cycle of treatment.
5.2.3.
Safety Population
The safety population includes all enrolled subjects who have received at least 1 dose of IP and had at 
least 1 post-dose safety assessment.
5.2.4.
Evaluable Population
The evaluable population includes all ITT subjects who have at least one post-baseline efficacy 
assessment performed, experienced no major protocol deviations during the study, and have received a 
minimum of one cycle of treatment are considered to be in the evaluable population. 
5.2.5.
PK Population
The PK Population includes all subjects who receive at least one dose of study treatment and have at least
one measureable plasma/serum exposure. If any subjects are found to be noncompliant with respect to 
dosing, have incomplete data, or encounter other circumstances that would affect the evaluation of the 
PK, a decision will be made on a case-by-case basis as to the inclusion of his PK data in the statistical 
analysis.
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ves 
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w
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hichever is
hichever i
eieir st
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i
art and
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ubjects who 
bjects who 
udes all ITT 
udes all ITT
nclusion/exc
nclusion/ex
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nrolled subj
ent
ent.
Population
Population
ion includes
on include
med, experie
med, experie
e cycle of tr
cycle of 
PK Pop
PK Po
K Populatio
K Populat
e measureab
e measureab
dosing, hav
dosing, hav
K, a d
K, a d


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5.2.6.
Immunogenicity Population
The immunogenicity Population includes all subjects who receive at least one dose of durvalumab and 
have at least one measureable PK and/or ADA concentration. If any subjects are found to be 
noncompliant with respect to dosing, have incomplete data, or encounter other circumstances that would 
affect the evaluation of the PK and/or ADA, a decision will be made on a case-by-case basis as to the 
inclusion in the analysis.
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6.
SUBJECT DISPOSITION
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation from study as stated in the study CRF) will be summarized using 
frequency and percentage for both cohort and follow-up phases. 
This will be provided for both ITT and Safety populations. A summary of subjects enrolled by 
site will be provided. Protocol deviations will be summarized using frequency tabulations. The 
details will be provided in the study Tables and Listings.
&(/*(1(35235,(7$5<,1)250$7,21
e


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7.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Data on the demographics and baseline clinical characteristics will be summarized for the Safety
population, as well as the ITT. Summary for mITT population will be presented only if there is a 
substantial difference between ITT and mITT populations.  
7.1.
Demographics
Demographic characteristics consist of age, gender, race, ethnicity, etc., will be summarized for the ITT 
population and safety population.  Age is defined as the integer part of (informed consent date – birth date
+ 1)/365.25.  
7.2.
Baseline Clinical Characteristics
Baseline values are defined as the last assessment of a particular parameter (e.g., vital signs, weight, or 
laboratory assessments) prior to administration of the first dose of IP in the treatment phase of the study, 
unless noted otherwise for a particular assessment. In most cases, baseline assessments are those
performed before dosing on Day 1 of Cycle 1. When there are retested values, the retest values will be 
used for the analysis. 
Data collected in the CRF, including medical history, prior treatments, disease diagnosis, etc., will be 
summarized using frequency tabulations by system organ class and preferred term.
A similar summary will be generated for the currently active abnormalities only, per body system. 
Individual subject listings will be provided to support the tables. 
The following baseline of clinical characteristics will also be summarized:
!
The WHO classification, IPSS classification, and FAB classification of MDS.
!
The Eastern Cooperative Oncology Group (ECOG) performance status, and time since initial 
diagnosis of MDS, which is defined as the number of months from the date of initial diagnosis to 
the date of informed consent.
!
The MDS diagnosis classification at study entry by WHO, IPSS, and FAB criteria, and ECOG 
performance status, will be summarized categorically. Time since initial diagnosis will be 
summarized descriptively. 
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the
th ITT
ITT
e – birth
birth dat
dat
g., vital sign
vital s
treatment p
eatment 
line assessm
line assessm
sted values
sted values
ior treatmen
ior treatme
organ class 
organ clas
urrently act
urrently act
d to support
d to support
aracteristic
aracteristic
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on, IPSS cla
IPSS c
operative On
perative On
f MDS, whic
MDS, whic
of 
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inform
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MDS dia
performan
perform
summ
summ


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7.3.
Medical History
!
Medical history data, including any prior or concomitant diseases and the status of 
diagnosis if available, will be summarized using frequency tabulations by system organ 
class and preferred term according to (MedDRA) version 19, or higher.
7.4.
Prior MDS Treatment
!
A frequency table by Anatomical Therapeutic Chemical (ATC) class and preferred name
will be provided according to the coding scheme of the latest version of WHO drug 
dictionary for all prior treatments of MDS recorded on the CRF, which includes all 
medications taken for any indication within the 4 weeks (28 days) prior to the first dose 
of IP. The start date and end date of the treatment if available, the dose and frequency 
will also be summarized.
7.5.
RBC and Platelet Transfusion History
!
Documentation of all red blood cell and platelet transfusions received by the subject 
within 8 weeks (56 days) prior to the first dose of IP will be reported in a listing if 
recorded on the appropriate CRF. The transfusion data may include the type of 
transfusion, number of units, reason for, and date of transfusion.
7.6.
Pregnancy
!
A by-subject listing of status of childbearing potential, pregnancy tests and results as well 
as menstrual cycles regularity, will be provided for all female patients of childbearing 
potential if recorded in CRF. For female patients without childbearing potential, the 
status of hysterectomy, the status of bilateral oophorectomy, and the status of consecutive 
naturally post-menopausal will also be reported.
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8.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Following variables regarding the extent of study drug exposure are defined and will be 
summarized.
!
Treatment Duration: 
o
Definition: (study treatment end date – first study drug start date + 1)/30.4167. 
o
Descriptive summary statistics will be provided. An additional table will be 
created for all treated subjects, displaying number of subjects by cycle. A by-
subject listing of all exposure information collected on the CRF will be provided. 
!
Number of Treatment Cycles: 
o
Descriptive summary statistics will be provided for safety population.
!
Duration of exposure: 
o
Definition: total number of days on the study drug during the treatment period 
(excluding the periods of dose break per protocol or dose interruptions). 
o
Descriptive summary statistics will be provided for safety population.
!
Average Length of Cycle: 
o
Definition: the number of days on treatment divided by the number of cycles. 
o
Descriptive summary statistics will be provided for safety population.
!
Average Number of Days Dosed Per Cycle: 
o
Definition: the number of days a subject is dosed divided by the number of cycles 
the subject had. 
o
Descriptive summary statistics will be provided for safety population.
!
Cumulative Dose: 
o
Definition: the sum of all doses taken during the treatment period (in milligrams). 
o
Descriptive summary statistics will be provided for safety population by cohort
and overall.  
!
Average Daily Dose: 
o
Definition: the cumulative dose of the study drug divided by the number of days 
dosed (received a non-zero dose).   
o
Descriptive summary statistics will be provided for safety population.  
!
Dose Intensity: 
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during the 
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vided for sa
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treatment 
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Averag


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o
Definition: the cumulative dose of the study drug divided by treatment duration of 
the study drug.   
o
Descriptive summary statistics will be provided for safety population.  
!
Dose Modification: 
o
Descriptive summary statistics will be provided for safety population, including

subjects who have at least one dose reduction/interruption, 

time to first dose reduction/interruption,

first dose reduction/interruption due to AE,

duration of first dose reduction/interruption due to AE.
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9.
PRIOR/CONCOMITANT MEDICATIONS AND PROCEDURES
Prior medications are defined as medications that were started before the date of first dose of IP (whether 
or not ended before the date of first dose). Prior medications that continue into study treatment period will 
be also reported as concomitant medication. Prior medications will be coded in the latest version of the 
WHO drug dictionary. Medication not in the WHO drug dictionary will be classified as “Not Coded” in 
the analysis. A frequency table by Anatomical Therapeutic Chemical (ATC) class and preferred term will 
be provided. A listing of prior medications documented on the CRF will also be provided. All prior and 
concomitant medications (prescription and non-prescription), treatments, and therapies taken from 84 
days (12 weeks) prior to the first dose of IP, up to 28 days after the last dose of IP or up to the last study 
visit, whichever date is later, will be analyzed. All prior treatments for MDS, including ESAs, 
thrombopoiesis-stimulating agents (TSAs), iron-chelating agents, chemotherapy, cytotoxic therapy, 
investigational agents, or other medications considered supportive care for MDS should be recorded on 
the respective CRF(s) regardless of discontinuation date of treatment.
Concomitant medication is defined as all medications taken from the date of first dose until 28 days after 
the last dose of IP or until the last study visit, whichever period is longer. Concomitant medications will 
be coded in the latest version of the WHO drug dictionary. Medication not in the WHO drug dictionary 
will be classified as “Not Coded” in the analysis. The Anatomical Therapeutic Chemical (ATC) coding 
scheme of the WHO will be used to group medications into relevant categories. A frequency table by 
ATC class and preferred term will be provided. All concomitant medications documented on the CRF will 
be listed for the safety population. 
The total number of prior and concomitant medications and the number and percentages of patients with 
at least one prior and one concomitant medication will be summarized. The number and percentages of all 
prior and concomitant medications will be summarized and listed by drug class and preferred term.
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10.
EFFICACY ANALYSIS
All efficacy analyses will be performed on the ITT population. Supportive efficacy analyses will 
also be performed using the evaluable population.
10.1.
Primary Efficacy Analysis
The primary assessment of efficacy will be the overall rate of response (defined as CR, PR, or 
mCR), and HI as determined using the modified IWG 2006 response criteria for MDS. 
Hematologic response (CR, PR, mCR, and HI) will be determined by investigator assessment and 
responses will also be derived, summarized and analyzed separately. The percentage of these responses 
will be estimated separately, and the corresponding 95% confidence interval will also be provided. The 
percentage of subjects with other response outcomes of stable disease, failure, relapse after CR or PR, and 
disease progression will also be presented. 
!
Hematologic Response (including CR, PR, mCR, SD, Failure, Relapse after CR or PR, and 
Cytogenetic Response) is defined according to modified IWG 2006 criteria. Subjects will be 
classified according to their best response achieved during treatment for the response categories 
of CR, PR, mCR, SD, and failure. Only subjects who achieve CR or PR will be included in the 
Relapse after CR or PR category. Subjects will be evaluated for cytogenetic response regardless 
of their response status in other categories. Hematologic response will be presented descriptively 
using counts and percentages.
!
Cytogenetic Response Subjects will be classified as having a complete or partial response based 
on the best response achieved during treatment. Responses will be presented descriptively using 
counts and percentages.
!
The response rates at the end of Stage 2 and the associated 90% confidence interval will be 
estimated for each cohort which completes Stage 2. Similar estimates for Stage 1 will be provided 
for any cohort which does not continue to Stage 2. 
!
The response rates at the end of Stage 2 will be compared between cohorts of SD and PD subjects 
(if both cohorts finished Stage 2) using the relative risk ratio or other appropriate methods. 
Specifically, if relative risk method is used, the ratio of response rates for both cohorts and the 
associated 90% confidence interval will be estimated.
10.2.
Secondary Efficacy Analyses
10.2.1.
Overall Survival
!
Overall survival (OS), time to death from any cause, will be calculated using date of first 
dose and date of death, or date of last follow-up for censored subjects. Time to death 
from any cause is defined as the time between first dose and death from any cause. 
!
All subjects will be followed until drop-out, death, or study termination. Drop-out may be 
due to withdrawal of consent from further data collection or loss to follow-up. Subjects 
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dose
dose
f


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who drop-out or are alive at study termination will have their OS times censored at the 
time of last contact, as appropriate.  
!
The OS will be estimated using Kaplan-Meier (KM) method.  
10.2.2.
Time to Onset of Response
!
Time to onset of first response is defined as the time between the date of first IP dose and 
the earliest date any response (CR, PR, mCR, or HI) is first observed.  
!
Subjects who do not achieve any defined response during the treatment period will be 
censored at the date of treatment discontinuation, disease progression, or death, 
whichever occurs first.  
!
Time to onset of best response will be defined in a similar manner. 
!
Time to onset of first response and best response will be estimated using KM method.  
10.2.3.
Duration of Response
!
Duration of hematologic response/improvement will be determined only for subjects who 
achieve a response on treatment.  
!
Duration of hematologic response/improvement is defined as the time from the date 
response/improvement is first observed until the date the subject has a subsequently 
documented relapse or disease progression as defined by the modified IWG 2006 criteria.  
!
Subjects who maintain hematologic response/improvement through the end of the 
treatment period will be censored at the date of treatment discontinuation or death, 
whichever occurs first.  
!
Duration of response will be assessed for both first response and best response.  
!
Duration of hematologic response/improvement will be estimated using KM method.
10.2.4.
Progression-free Survival
!
Progression-free survival (PFS), time to disease progression or death from any cause, will 
be calculated using date of first dose and the earliest of date of disease progression or 
date of death, or date of last follow-up for censored subjects. 
!
Time to disease progression or death from any cause is defined as the time between first 
dose and the earliest of disease progression or death from any cause. 
!
All subjects will be followed until drop-out, death, or study termination. Drop-out may be 
due to withdrawal of consent from further data collection or loss to follow-up. Subjects 
who drop-out or are alive without disease progression at study termination will have their 
PFS times censored at the time of last contact, as appropriate.  
!
The PFS will be estimated using Kaplan-Meier (KM) method.
&(/*(1(35235,(7$5<,1)250$7,21
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using KM 
determined
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is defined a
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the date th
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n as defined
n as define
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at the date 
at the date
be assessed
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free Sur
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e survi
urvi
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ulated using
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of death, o
Time to di
Time to di
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dose an
!
Al
Al


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10.2.5.
Stable Disease
!
A subject will be considered as having a stable disease if the disease neither responded 
nor progressed during or after the treatment. 
!
The duration of stable disease will be defined as the time between any two observations
of objective disease progression (modified IWG criteria), starting from the first day of 
dosing with IP.  Note, objective disease progression requires two observations 
demonstrating progressive disease, at least 8 weeks apart.  The date of disease 
progression will be that of the earliest observation that is not followed by a discordant 
observation within the subsequent 8 weeks.  
!
Subjects who maintain stable disease through the end of the treatment period will be 
censored at the date of study termination. 
!
Duration of stable disease will be estimated using KM method.
10.2.6.
Disease Progression to AML
!
Time to AML progression is defined as the time from the date of first dose of IP until the 
date the subject has documented progression to AML. 
!
Subjects who do not progress to AML will be censored at the date of last follow-up, the 
date of death, or the date of study termination. 
!
Time to AML progression will be estimated using KM method.
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
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11.
SAFETY ANALYSIS
The purpose of this section is to define the safety analysis for the study. All summaries of safety 
data will be conducted using the safety population. Descriptive statistics will be provided by 
disease cohort and treatment arm.
11.1.
Adverse Events
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) of 
Version 22. Adverse event listings will include the verbatim term and the MedDRA preferred 
term.  The intensity of AEs will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03 or higher. For any AE not listed in the CTCAE grading 
system, the intensity of these events will be assessed by the Investigator using a 5-point scale as 
described in protocol.
If a subject experiences multiple AEs under the same PT (SOC), the subject will be counted only 
once for that PT (SOC). If a subject experiences the same AE more than once with a different 
intensity grade, the event with the highest grade will be tabulated in “by grade” tables. In 
addition, AEs with a missing intensity will be presented in the summary table as an intensity 
category of “Missing” and will not be imputed.
Treatment emergent adverse events (TEAEs) are defined as AEs occurring or worsening on or 
after the date of the first dose of the study treatment (CC-486 or durvalumab) and within 28 days 
after last dose of CC-486 or 90 days after last dose of durvalumab. A treatment-related TEAE is 
defined as a TEAE where the causal relationship was assessed by the investigator as 
“Suspected”. If the relationship between a TEAE and a study drug is missing, the TEAE will be 
considered to be related to the study treatment.
Summary tables for the incidence of TEAEs will be summarized by disease cohort, treatment 
arm, SOC, and PT within SOC. They will be sorted by alphabetically order of SOC and PT, and
then sorted by decreasing frequencies, unless otherwise specified. Following tables will be 
generated:
!
TEAEs;
!
TEAEs related to CC-486 only, durvalumab only, or CC-486 or durvalumab; 
!
TEAEs of CTCAE grade 3 or 4; 
!
TEAEs related to CC-486 only, durvalumab only, or CC-486 or durvalumab with 
CTCAE grade 3 or 4; 
!
TEAEs with death outcome;
!
TEAEs with death outcome related to CC-486 only, durvalumab only, or CC-486 or
durvalumab;
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TEAE
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CT
CT
!


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
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!
Serious TEAEs; 
!
Serious TEAEs related to CC-486 only, durvalumab only, or CC-486 or durvalumab;
!
TEAEs leading to discontinuation of CC-486 only, durvalumab only, or CC-486 or
durvalumab; 
!
TEAEs leading to dose reduction of CC-486;
!
TEAEs leading to dose interruption of CC-486 only, durvalumab only, or CC-486 or
durvalumab; 
!
TEAEs leading to infusion interruption of durvalumab. 
As well as
!
TEAEs by cycle of onset as well as the safety run-in period; 
!
TEAEs related to CC-486 only, durvalumab only, or CC-486 or durvalumab, by cycle of
onset;
!
TEAEs by maximum CTCAE grade;
!
TEAEs related to CC-486 only, durvalumab only, or CC-486 or durvalumab, by 
maximum CTCAE grade;
!
Common (>=10%) TEAEs; 
!
Common (>=10%) TEAEs related to CC-486 only, durvalumab only, or CC-486 or
durvalumab;
!
By age category: <65, 65-74, ≥75;
!
By gender.
All deaths, on treatment deaths, off treatment deaths and causes of death will be summarized
from the Death form in the CRF. Deaths within or 28 days after last dose of CC-486 or 90 days 
after the last dose of durvalumab will be summarized separately.
Individual subject listing of AEs will be presented. In addition, the following listings will be 
provided:
!
Listing of SAE;
!
Listing of TEAEs leading to permanent withdrawal of any study drug 
!
Listing of all TEAEs with outcome of death
!
Listing of all subjects who died 
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. 
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!
List
Listing
ing
!
L


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
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The AEs 
 
 
The following TEAEs
 
!
Myelosuppression (neutropenia, thrombocytopenia, anemia, general myelosuppression) 
!
Gastrointestinal disorders 
!
Hemorrhagic events
!
Infections
!
Renal failure
!
Hepatic failure
!
Ischemic colitis
!
Interstitial lung disease
!
Cardiac events (cardiac failure, cardiac arrhythmias, myocardial infarction)
!
Anxiety, Confusional state, Insomnia
!
Other psychiatric disorders
!
Tumour lysis syndrome
Although not determined as an important risk in the Vidaza RMP, gastrointestinal events as 
defined by System Organ Class Gastrointestinal disorders will also be summarized as an adverse 
event of special interest for this study. 
For durvalumab, following are the AESIs for Ongoing Surveillance Activities based on pre-
defined search criteria as provided by Astrazeneca/MedImmune:
!
Diarrhoea
!
Colitis
!
Intestinal perforations
!
Pneumonitis
!
Hepatitis
!
Hepatic laboratory parameters reported as AEs
!
Adrenal insufficiency
!
Type 1 diabetes mellitus
!
Hypophysitis
!
Thyroiditis
CCI
CCI
CCI
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esti
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the AESIs
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ovi
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Hepatititi
i s
!
Hepa
Hepa
!
A


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
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31
3/30/2020
!
Hyperthyroidism
!
Thyroid laboratory parameters reported as AEs (increased thyroid activity))
!
Hypothyroidism
!
Thyroid laboratory parameters reported as AEs (decreased thyroid activity))
!
Rash 
!
Dermatitis
!
Nephritis
!
Renal laboratory investigations reported as AEs
!
Pancreatitis
!
Pancreatic laboratory investigations reported as AEs
!
Myocarditis
!
Myositis
!
Myasthenia gravis
!
Guillain-Barré syndrome
!
Other rare/miscellaneous
!
Hypersensitivity / Anaphylactic reactions
!
Infusion related reaction
After review of the data, there may be other AEs of special interest identified. For summaries 
based on selected MedDRA preferred terms, the final selection of inclusive preferred terms will 
be performed based on review of final data to ensure all relevant terms are captured. Summary 
table will be provided for all TEAEs included in the above-mentioned AEs of special interest.
!
All TEAEs 
!
TEAEs of Grade 3 or 4 
!
Serious TEAEs 
!
TEAEs leading to study drug withdrawal 
!
TEAEs leading to study drug dose reduction 
!
TEAEs leading to study drug dose interruption
!
TEAEs leading to death
The incidence rate per 100 person-years will also be derived for each AESI. 
11.2.
Clinical Laboratory Evaluations
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other AEs o
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de 3 or 4
de 3 o
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TEAEs 
TEAEs
!
TEA
TEA
he inc
he inc


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
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3/30/2020
Clinical laboratory test results in SI units will be summarized descriptively and will include a display of 
change from baseline to each post-dose scheduled time point.  Baseline values for all lab tests will be the 
last non-missing value on or before date of first treatment.
Laboratory values outside of the normal ranges will be identified.  Clinically significant hematologic and 
non-hematologic laboratory abnormalities that meet Grade 3 or Grade 4 criteria according to the CTCAE 
will be listed and summarized. Clinical laboratory values will be presented using the reported units.
11.3.
Vital Sign Measurements
Vital sign measurements reported in CRF and physical examinations will be summarized 
descriptively, and listed for each subject at baseline and each visit after, and change from 
baseline will be summarized. A listing of vital signs will be provided.
11.4.
ECOG Performance Status
ECOG performance will be summarized categorically with a shift from baseline by cycle, end of study 
and maximum shift by treatment. Individual subject data will be listed. The last ECOG performance score 
prior to and including the date of the first dose of study drug will be used as the baseline value.
11.5.
Bone Marrow Aspirate, Biopsy, and Peripheral Blood Smear
Bone marrow and peripheral blood samples will be collected at screening and following every 2 cycles of 
treatment during the first 6 treatment cycles (i.e., Cycle Day 28 [± 14 days]). Subjects who continue 
beyond Cycle 6 will undergo bone marrow examination following every 3 treatment cycles or when 
necessary to confirm suspected hematologic response or disease progression, and again upon treatment 
discontinuation. The data collected in CRF will be summarized in table and listing.
11.6.
Electrocardiogram
An electrocardiograms (ECG) will be conducted and analyzed locally at screening and at treatment 
discontinuation by the local laboratory.  The ECG is to be performed using the internationally recognized 
12-leads.  The investigator will review the results and assess as normal, abnormal - not clinically 
significant, or abnormal - clinically significant, and will report abnormal finding(s) on the respective 
CRF.  If the ECG is abnormal, the investigator should consult a cardiologist if deemed appropriate. The 
ECG data from CRF will be summarized.
   
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CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
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12.
INTERIM ANALYSIS
An Independent Data Monitoring Committee will review the safety data during the safety run-in 
phase. The committee will also review the efficacy and safety data during the randomized phase 
of the study, in addition to the recommendation for any cohort to continue to stage-2 of the 
study. The details of the data monitoring plan will be provided in a separate charter document.
&(/*(1(35235,(7$5<,1)250$7,21


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
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13.
PHARMACOKINECTIC ANALYSES
The following PK analyses were planned but not conducted in the combination arm which was 
stopped since the optimal combination dose could not be determined. Only a few subjects were 
enrolled in the combination arm who agreed to PK sample collection and due to the limited 
samples collected, the PK TLGs will not be generated. 
13.1 CC-486
13.1.1 Plasma concentrations
By-subject listing of pharmacokinetic blood sample collection times as well as derived sampling 
time deviations will be provided.  CC-486 plasma concentrations will be summarized using 
descriptive statistics (N, arithmetic mean, standard deviation, standard error, minimum, median, 
maximum, percent coefficient of variation, geometric mean, and geometric percent coefficient of 
variation). 
Concentrations that are below the limit of quantitation (BLQ) will be treated as zero for the 
computation of descriptive statistics. Missing concentrations and concentrations from blood 
samples collected more than ± 10% of nominal time will be omitted from the calculation of 
descriptive statistics.
Individual subject concentration-time data and mean concentration-time data for each cycle will be 
graphically presented on linear and semi-logarithmic scales.
Following dose administration, pre-dose samples that are BLQ or missing will be assigned a 
numerical value of zero for the calculation of AUC.  Following the first administration, any 
anomalous concentration values observed at pre-dose will be identified in the study report and 
used for the computation of AUC.  Pharmacokinetic parameters will be computed if the
anomalous value is not greater than 5% of the Cmax.  If the anomalous value is greater than 5% of 
Cmax, the computed PK parameters for the given subject will be dropped from the PK analysis.  
Any other BLQ concentrations will be assigned a value of zero if they precede quantifiable 
samples in the initial portion of the profile.  A BLQ value that occurs between quantifiable data 
points, especially prior to Cmax, will be evaluated to determine if an assigned concentration of 
zero makes sense, or if reanalysis or exclusion of the data is warranted. Following Cmax, BLQ 
values embedded between two quantifiable data points will be treated as missing when 
calculating AUC.  Values below the quantifiable limit, occurring at the end of the collection 
interval (after the last quantifiable concentration), will be treated as missing data.  If consecutive 
BLQ concentrations are followed by quantifiable concentrations in the terminal portion of the 
concentration curve, these quantified values will be excluded from the PK analysis by assigning 
them a value of missing, unless otherwise warranted by the concentration-time profile.  For the 
purpose of analysis, these trailing BLQ values may be designated as zero in the dataset if the PK 
program used to do the analysis (such as WinNonlin®) will treat trailing zero values as missing 
when calculating AUC.
Actual sampling times will be used in the calculations of pharmacokinetic parameters that will be 
derived using non-compartmental (NCA) methods with Phoenix™ WinNonlin® Professional 
ved sampli
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purpose o
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rogram
rogram


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
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3/30/2020
Version 6.4, or higher, (Pharsight®, a Certara™ company, St. Louis, Missouri).  Graphics may
be prepared with SAS Version 9.3, or higher; or Excel 2007, or higher; Phoenix™ WinNonlin®
Professional 6.4, or higher.
13.1.2 PK Parameter
The following PK parameters will be calculated for CC-486:
AUC0-∞
Area under the plasma concentration-time curve from Time 0 extrapolated to 
infinity, calculated as [AUC0-t + Ct/∀z].  Ct is the last quantifiable concentration. 
No AUC extrapolation will be performed with unreliable ∀z. If %AUCextrap is 
≥25%, AUC0-∞will not be reported.
AUC0-t
Area under the plasma concentration-time curve from Time 0 to the time of the 
last quantifiable concentration, calculated by linear trapezoidal method when 
concentrations are increasing and the logarithmic trapezoidal method when 
concentrations are decreasing.
Cmax
Maximum observed plasma concentration, obtained directly from the observed 
concentration versus time data.
Tmax
Time to Cmax, obtained directly from the observed concentration versus time data.
t1/2
Terminal phase half-life in plasma, calculated as [(ln 2)/∀z].  t1/2 will only be 
calculated when a reliable estimate for ∀z can be obtained.  
CL/F
Apparent total clearance, calculated as [Dose/ AUC0-∞]. 
Vz/F
Apparent volume of distribution, calculated as [(CL/F)/∀z]. 
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alculated a
alculated 
distribut
tributioion


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
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3/30/2020
The following PK parameters will be calculated for diagnostic purposes and listed, but they will 
not be summarized:
∀z
Apparent terminal rate constant, calculated by linear regression of the 
terminal portion of the log-concentration versus time curve in plasma.  
Visual assessment will be used to identify the terminal linear phase of the 
concentration versus time profile.  A minimum of three data points will be 
used for calculation.  ∀z will not be estimated if the terminal phase of the 
log-concentration versus time profile does not exhibit a linear decline 
phase, or if the regression coefficient < 0.8.  
∀z lower
Lower limit of time (h) included in the calculation of ∀z. 
∀z N
Number of data points used in the calculation of ∀z.
∀z upper
Upper limit of time (h) included in the calculation of ∀z.
Rsq
Regression coefficient for calculation of ∀z.  
%AUCextrap
Percentage of AUC0-∞due to extrapolation from the last quantifiable time 
point to infinity.
13.1.3 PK Analyses
By-subject listing of pharmacokinetic parameters will be provided.  The values of the 
pharmacokinetic parameters will also be summarized using descriptive statistics (N, arithmetic 
mean, standard deviation, standard error, minimum, median, maximum, percent coefficient of 
variation, geometric mean, and geometric percent coefficient of variation) for each cycle.  Also, 
when appropriate, graphical representations (i.e., scatter plots, box plots, etc.) may be used to 
visualize the results.
The effect of durvalumab on the PK of CC-486 will be assessed using graphic comparison and 
descriptive stats.
 
13.2Durvalumab
13.2.1 Plasma concentrations
By-subject listing of pharmacokinetic blood sample collection times as well as derived sampling 
time deviations will be provided.  Durvalumab serum concentrations will be summarized using 
descriptive statistics (N, arithmetic mean, standard deviation, standard error, minimum, median, 
maximum, percent coefficient of variation, geometric mean, and geometric percent coefficient of 
variation). 
Concentrations that are below the limit of quantitation (BLQ) will be treated as zero for the 
computation of descriptive statistics. Missing concentrations and concentrations from blood 
CCI
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1


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
Confidential and Proprietary
37
3/30/2020
samples collected more than ± 10% of nominal time will be omitted from the calculation of 
descriptive statistics.
Individual subject concentration-time data and mean concentration-time data for each cycle will be 
graphically presented on linear and semi-logarithmic scales.
Following dose administration, pre-dose samples that are BLQ or missing will be assigned a 
numerical value of zero for the calculation of AUC.  Following the first administration, any 
anomalous concentration values observed at pre-dose will be identified in the study report and 
used for the computation of AUC.  Pharmacokinetic parameters will be computed if the 
anomalous value is not greater than 5% of the Cmax.  If the anomalous value is greater than 5% of 
Cmax, the computed PK parameters for the given subject will be dropped from the PK analysis.  
Any other BLQ concentrations will be assigned a value of zero if they precede quantifiable 
samples in the initial portion of the profile.  A BLQ value that occurs between quantifiable data 
points, especially prior to Cmax, will be evaluated to determine if an assigned concentration of 
zero makes sense, or if reanalysis or exclusion of the data is warranted.  Following Cmax, BLQ 
values embedded between two quantifiable data points will be treated as missing when 
calculating AUC.  Values below the quantifiable limit, occurring at the end of the collection 
interval (after the last quantifiable concentration), will be treated as missing data.  If consecutive 
BLQ concentrations are followed by quantifiable concentrations in the terminal portion of the 
concentration curve, these quantified values will be excluded from the PK analysis by assigning 
them a value of missing, unless otherwise warranted by the concentration-time profile.  For the 
purpose of analysis, these trailing BLQ values may be designated as zero in the dataset if the PK 
program used to do the analysis (such as WinNonlin®) will treat trailing zero values as missing 
when calculating AUC.
Actual sampling times will be used in the calculations of pharmacokinetic parameters that will be 
derived using non-compartmental (NCA) methods with Phoenix™ WinNonlin® Professional 
Version 6.4, or higher, (Pharsight®, a Certara™ company, St. Louis, Missouri).  Graphics may 
be prepared with SAS Version 9.3, or higher; or Excel 2007, or higher; Phoenix™ WinNonlin®
Professional 6.4, or higher.
13.2.2 PK Parameter
The following PK parameters will be calculated for durvalumab on Cycle 1:
AUC0-∞
Area under the serum concentration-time curve from Time 0 extrapolated to 
infinity, calculated as [AUC0-t + Ct/∀z].  Ct is the last quantifiable concentration. 
No AUC extrapolation will be performed with unreliable ∀z.  If %AUCextrap is 
≥25%, AUC0-∞will not be reported.
AUC0-t
Area under the serum concentration-time curve from Time 0 to the time of the 
last quantifiable concentration, calculated by linear trapezoidal method when 
concentrations are increasing and the logarithmic trapezoidal method when
concentrations are decreasing.
Cmax
Maximum observed serum concentration, obtained directly from the observed 
concentration versus time data.
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A


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
Celgene Corporation
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Tmax
Time to Cmax, obtained directly from the observed concentration versus time data.
t1/2
Terminal phase half-life in serum, calculated as [(ln 2)/∀z].  t1/2 will only be 
calculated when a reliable estimate for ∀z can be obtained.  
CL
Total clearance, calculated as [Dose/AUC0-∞]. 
Vz
Volume of distribution, calculated as [(CL)/∀z]. 
The following PK parameters will be calculated for diagnostic purposes and listed, but they will 
not be summarized:
∀z
Apparent terminal rate constant, calculated by linear regression of the 
terminal portion of the log-concentration versus time curve in serum.  
Visual assessment will be used to identify the terminal linear phase of the 
concentration versus time profile.  A minimum of three data points will be 
used for calculation.  ∀z will not be estimated if the terminal phase of the 
log-concentration versus time profile does not exhibit a linear decline 
phase, or if the regression coefficient < 0.8.  
∀z lower
Lower limit of time (h) included in the calculation of ∀z. 
∀z N
Number of data points used in the calculation of ∀z.
∀z upper
Upper limit of time (h) included in the calculation of ∀z.
Rsq
Regression coefficient for calculation of ∀z.  
%AUCextrap
Percentage of AUC0-∞due to extrapolation from the last quantifiable time 
point to infinity.
The following PK parameters will be calculated for durvalumab on Cycle 2:
AUC0-t
Area under the serum concentration-time curve from Time 0 to the time of the 
last quantifiable concentration, calculated by linear trapezoidal method when 
concentrations are increasing and the logarithmic trapezoidal method when 
concentrations are decreasing.
Cmax
Maximum observed serum concentration obtained directly from the observed 
concentration versus time data.
Tmax
Time to Cmax, obtained directly from the observed concentration versus time data.
Note: only the 3 PK parameters listed above will be calculated as durvalumab is expected to not 
be at BLQ level at the start of Cycle 2.
&(/*(1(35235,(7$5<,1)250$7,21
ey will
will
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concentrat
concentra
concen
concen
max
M
max


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
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3/30/2020
13.2.3 PK Analyses
By-subject listing of pharmacokinetic parameters will be provided.  The values of the 
pharmacokinetic parameters will also be summarized using descriptive statistics (N, arithmetic 
mean, standard deviation, standard error, minimum, median, maximum, percent coefficient of 
variation, geometric mean, and geometric percent coefficient of variation) for each cycle.  Also, 
when appropriate, graphical representations (i.e., scatter plots, box plots, etc.) may be used to 
visualize the results.
The effect of CC-486 on the PK of durvalumab will be assessed using graphic comparison and 
descriptive stats.
 
 
13.3Immunogenicity
From all subjects dosed with durvalumab, 6 PK and 6 immunogenicity predose samples (Cycle 
1, 2, 4, 6, 10, and 14 Day 1), Anti-Drug Antibody (ADA), should have been collected.  
By-subject listing of pharmacokinetic and ADA blood sample collection times will be provided.  
Durvalumab serum concentrations and ADA will be summarized using descriptive statistics (N, 
arithmetic mean, standard deviation, standard error, minimum, median, maximum, percent 
coefficient of variation, geometric mean, and geometric percent coefficient of variation). 
 
.
CCI
CCI
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CC


CC-486 (oral azacitidine), Durvalumab (MEDI4736)
Statistical Analysis Plan. Protocol CC-486-MDS-006
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3/30/2020
14 REFERENCES
1.
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials. 1989; 
10:1-10.
&(/*(1(35235,(7$5<,1)250$7,21


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Celgene Corporation
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41
15 APPENDICES 
15.1Appendix A: Date Imputation Guideline
15.1.1 Impute Missing AE start day and month [namely, dd & mm in dd-mm-yyyy are 
missing]
!
If yyyy(AE) = yyyy(1st day of study medication), then
o
dd(AE) = dd(1st day of study medication)
o
mm(AE) = mm(1st day of study medication)
!
If yyyy(AE) < yyyy(1st day of study medication), then
o
dd(AE) = 31
o
mm(AE) = December
!
If yyyy(AE) > yyyy(1st day of study medication), then
o
dd(AE) = 1
o
mm(AE) = January
14.1.2
Missing AE start month only [namely, mm in dd-mm-yyyy is missing]
!
If yyyy(AE) = yyyy(1st day of study medication), then
o
mm(AE) = mm(1st day of study medication)
!
If yyyy(AE) < yyyy(1st day of study medication), then
o
mm(AE) = December
!
If yyyy(AE) > yyyy(1st day of study medication), then
o
mm(AE) = January
14.1.3 Missing AE start day only [namely, dd in dd-mm-yyyy is missing]
!
If yyyy(AE) = yyyy(1st day of study medication), then
o
If mm(AE) = mm(1st day of study medication), then

dd(AE) = dd(1st day of study medication)
o
If mm(AE) > mm(1st day of study medication), then

dd(AE) = 1
o
If mm(AE) < mm(1st day of study medication), then
&(/*(1(35235,(7$5<,1)250$7,21
hen
hen
mely, mm i
ely, mm 
tudy
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day
day of
of
y
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stud
f
day
day of
y
 stu
 s
f
= Decemb
= Decembe
> yyyy(1
> yyyy(1st
mm(
m(AE) = 
AE) = 
ng AE star
g AE sta
If 
If yyyy(A
yyy(A


Azacitidine (Oral)
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Celgene Corporation
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42

dd(AE) = last day of mm(AE)
!
If yyyy(AE) < yyyy(1st day of study medication), then
o
If AE stop date exists and is complete, then 

dd(AE) = dd(AE stop);
o
if AE stop date does not exist or is incomplete, then

dd(AE) = last day of mm(AE)
!
If yyyy(AE) > yyyy(1st day of study medication), then
o
dd(AE) = first day of mm(AE)
14.2.1 Missing AE stop day and month [namely, dd & mm in dd-mm-yyyy are missing]
!
If yyyy(AE) = yyyy(last day of study medication), then
o
dd(AE) = dd(last day of study medication)
o
mm(AE) = mm(last day of study medication)
!
If yyyy(AE) < yyyy(last day of study medication), then
o
dd(AE) = 31
o
mm(AE) = December
!
If yyyy(AE) > yyyy(last day of study medication), then
o
dd(AE) = 1
o
mm(AE) = January
14.2.2 Missing AE stop month only [namely, mm in dd-mm-yyyy is missing]
!
If yyyy(AE) = yyyy(last day of study medication), then
o
mm(AE) = mm(last day of study medication)
!
If yyyy(AE) < yyyy(last day of study medication), then
o
mm(AE) = December
!
If yyyy(AE) > yyyy(last day of study medication), then
o
mm(AE) = January
14.2.3 Missing AE stop day only [namely, dd in dd-mm-yyyy is missing]
!
If yyyy(AE) = yyyy(last day of study medication), then 
o
If mm(AE) = mm(last day of study medication), then
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y are missi
are mis
), then
), then
dy
dy m
y
edicat
edicat
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h only [nam
h only [nam
yyyy(last da
yyy(last d
(AE) = mm
AE) = mm
y(AE) < yy
y(AE) < yy
o
mm(
mm(A
IfIf yyyy(
yyyy
2


Azacitidine (Oral)
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Celgene Corporation
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
dd(AE) = dd(last day of study medication)
o
If mm(AE) > mm(last day of study medication), then

If AE start date exists and is complete, then 
!
dd(AE) = dd(AE start);

if AE start date does not exist or is incomplete, then
!
dd(AE) = first day of mm(AE)
o
If mm(AE) < mm(last day of study medication), then

dd(AE) = last day of mm(AE)
!
If yyyy(AE) < yyyy(last day of study medication), then
o
dd(AE) = last day of mm(AE)
!
If yyyy(AE) > yyyy(last day of study medication), then
o
If AE start date exists and is complete, then 

dd(AE) = dd(AE start);
o
if AE stop date does not exist or is incomplete, then

dd(AE) = first day of mm(AE)
&(/*(1(35235,(7$5<,1)250$7,21
comp
mplete, th
lete,
(A
(AE)
E)


Azacitidine (Oral)
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Celgene Corporation
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44
15.2Appendix B: Myelodysplastic Syndromes World Health Organization 
Classification System
Myelodysplastic Syndromes WHO Classification System
Category
Definition
Peripheral Blood Smear 
Evaluation
Bone Marrow Evaluation
Refractory cytopenia with unilineage
dysplasia (RCUD): (refractory anemia
[RA]; refractory neutropenia [RN];
refractory thrombocytopenia [RT])
Unicytopenia or bicytopeniaa
No or rare blasts (< 1%)b
Unilineage dysplasia: ≥ 10% of the cells
in one myeloid lineage
< 5% blasts
< 15% of erythroid precursors are ringed
sideroblasts
Refractory Anemia With Ringed 
Sideroblasts (RARS)
Anemia
No blasts
≥ 15% of erythroid precursors are ringed
sideroblasts
Erythroid dysplasia only
< 5% blasts
Refractory Cytopenia With
Multilineage Dysplasia (RCMD)
Cytopenia(s)
No or rare blasts (< 1%)b
No Auer rods
< 1x109/L monocytes
Dysplasia in ≥ 10% of the cells in ≥ 2 
myeloid lineages (neutrophil and/or 
erythroid precursors and/or 
megakaryocytes)
< 5% blasts in marrow
No Auer rods
± 15% ringed sideroblasts
Refractory Anemia With Excess
Blasts-1 (RAEB-1)
Cytopenias
< 5% blastsb
No Auer rods
< 1x109/L monocytes
Unilineage or multilineage
dysplasia
5%-9% blastsb
No Auer rods
Refractory Anemia With Excess
Blasts-2 (RAEB-2)
Cytopenias
5%-19% blastsc
Auer rodsc
< 1x109/L monocytes
Unilineage or multilineage
dysplasia
10%-19% blastsc
Auer rods ±c
Myelodysplastic Syndrome -
Unclassified (MDS-U)
Cytopenias
< 1% blastsb
Unequivocal dysplasia in < 10% of cells
in one or more myeloid lineages when
accompanied by a cytogenetic
abnormality considered as presumptive
evidence for a diagnosis of MDSd
MDS Associated With Isolated
del(5q)
Anemia
Usually normal or increased platelet 
count
No or rare blasts (< 1%)
Normal to increased
megakaryocytes with
hypolobated nuclei
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< 5% blasts
Isolated del(5q) cytogenetic
abnormality
No Auer rods
a Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U.
b If the marrow myeloblast percentage is < 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic 
classification is RAEB-1. Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as
MDS-U.
c Cases with Auer rods and < 5% myeloblasts in the blood and less than 10% in the marrow should be classified as 
RAEB-2. Although the finding of 5% to 19% blasts in the blood is, in itself, diagnostic of RAEB-2, cases of RAEB-
2 may have 5% blasts in the blood if they have Auer rods or 10% to 19% blasts in the marrow or both. Similarly, 
cases of RAEB-2 may have < 10% blasts in the marrow but may be diagnosed by the other 2 findings,
Auer rods + and/or 5% to 19% blasts in the blood.
d Includes unbalanced abnormalities -7 or del(7q), -5 or del(5q), i(17q) or t(17p), -13 or del(13q), del(11q), del(12p)
or t(12p), del(9q), idic(X)(q13), balanced abnormalities t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1),
t(1;3)(p36.3;q21.1), T2;11)(p21;q23), inv(3)(q21q26.2), and t(6;9)(p23;q34), and complex karyotype (3 or more
chromosomal abnormalities) involving one of more of the listed abnormalities.
Sources: 
1.
Brunning RD, Bennett JM, Flandrin G, Matutes E, Head D, Vardiman JW, et al. Pathology and genetics of
tumors of hematopoietic and lympoid tissues. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World
Health Organization Classification of Tumors. Lyon (France). IARC Press, 2001:63-73.
2.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World 
Health Organization (WHO) classification of myeloid neoplasms and acute myeloid leukemia: rationale and 
important changes. Blood 2009; 114(5):937-51.
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classified as
classified as
, cases of RA
cases of R
or both. Simil
r both. Sim
2 findings,
2 findings,
13 or del(13q
3 or del(13q
t(3;21)(q26.2
t(3;21)(q26.
q34), and com
q34), and co
normalities.
normalities
E, Head D, V
E, Head D, V
In: Jaffe
n: Jaffe ES,
ES
ors. Lyon (F
rs. Lyon (F
running RD, 
nning RD,
fication of m
fication of m
; 114(5):937
; 114(5):937


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15.3Appendix C:  International Prognostic Scoring System Score
International Prognostic Scoring System for MDS
Prognostic Variable
Score Value
0
0.5
1.0
1.5
2.0
Bone Marrow Blasts (%)
< 5
5-10
-
11-20
21-30
Karyotypea
Good
Intermediate
Poor
Cytopeniasb
0 or 1
2 or 3
a Good:  normal, -Y, del(5q), del(20q); Poor:  complex (# 3 abnormalities) or chromosome 7 anomalies; 
Intermediate:  other abnormalities.
b Defined as:  Hemoglobin < 100 g/L, absolute neutrophil count < 1.5 x 109/L, and platelet count < 100 x 109/L.
Note:  Scores for risk groups are as follows:  Low = 0; INT-1 = 0.5-1.0; INT-2 = 1.5-2.0; and High:  # 2.5
Source:  
1.Greenberg, P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al.  International scoring system for 
evaluating prognosis in myelodysplastic syndromes.  Blood 1997;89:2079-88.
&(/*(1(35235,(7$5<,1)250$7,21
0$
0$
0$
s; 
< 100 x 10
100 x 109/
High:  
High:  # 2.5
2.5
scoring syste
scoring syst


Azacitidine (Oral)
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15.4Appendix D:  ECOG Performance Status
ECOG Performance Status
Grade
ECOG
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, e.g., light house work, 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.
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity and response 
criteria of the Eastern Cooperative Oncology Group.  Am. J. Clin. Oncol. 1982;5(6):649-55.
$
ut 
$
0$
rs.
rs.
0$
0$
0$
ir.
ir.
50
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)2
Toxicity and
Toxicity
6):649
):649-55.
-55.


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15.5Appendix E:  Hematologic Response According to the IWG Criteria for 
MDS
Modified Hematologic Response According to IWG Criteria for MDS
Category 
Response criteria (responses must last at least 4 weeks) 
Complete Remission (CR)
Bone marrow:  ≤ 5% myeloblasts with normal maturation of all cell linesa
Persistent dysplasia will be noteda,b  
Peripheral bloodc
     Hgb ≥ 11 g/dL 
     Platelets ≥ 100 X 109/L 
     Neutrophils ≥ 1.0 X 109/Lb  
     Blasts 0% 
Partial Remission (PR) 
All CR criteria if abnormal before treatment except:  
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
Cellularity and morphology not relevant 
Marrow CRb  
Bone marrow:  ≤5% myeloblasts and decrease by ≥ 50% over pretreatmentb  
Peripheral blood:  if HI responses, they will be noted in addition to marrow CRb  
Stable Disease (SD) 
Failure to achieve at least PR, but no evidence of progression for > 8 wks 
Failure 
Death during treatment or disease progression characterized by worsening of cytopenias, 
increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB 
subcancer than pretreatment 
Relapse After CR or PR 
At least 1 of the following:  
     Return to pretreatment bone marrow blast percentage 
     Decrement of ≥ 50% from maximum remission/response levels in granulocytes or platelets 
Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence 
Cytogenetic Response 
Complete - Disappearance of the chromosomal abnormality without appearance of new ones 
Partial - At least 50% reduction of the chromosomal abnormality 
Disease Progression 
For subjects with:  
     Less than 5% blasts:  ≥ 50% increase in blasts to > 5% blasts 
     5%-10% blasts:  ≥ 50% increase to > 10% blasts 
     10%-20% blasts:  ≥ 50% increase to > 20% blasts 
     20%-30% blasts:  ≥ 50% increase to > 30% blasts 
Any of the following:  
     At least 50% decrement from maximum remission/response in granulocytes or platelets 
     Reduction in Hgb by ≥ 2 g/dL 
Transfusion dependence 
KEY:  CR = complete remission; DFS = disease-free survival; FAB = French-American-British; Hgb = hemoglobin; HI = 
hematologic improvement; IWG = International Working Group; MDS = myelodysplastic syndromes; PFS = progression free 
survival; PR = partial remission  
a Dysplastic changes should consider the normal range of dysplastic changes (modification).
b Modification to IWG response criteria.  
d In some circumstances, protocol therapy may require the initiation of further treatment (e.g., consolidation, maintenance) 
before the 4-week period.  Such subjects can be included in the response category into which they fit at the time the therapy is 
started.  Transient cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of 
response, as long as they recover to the improved counts of the previous course.  
Notes:  Subjects with CMML will be assessed for response using the IWG criteria for MDS.  Deletions to IWG response criteria 
are not shown.  To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.  
Source:  Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al.  Clinical application and 
proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia.  Blood 2006; 108 (2): 
419-25.
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Modified Hematologic Improvement According to IWG Criteria
Hematologic improvementa
Response criteria (responses must last at least 8 week)b
Erythroid Response (HI-E) 
(pretreatment, <11 g/dL) 
Hemoglobin increase by ≥ 1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC 
transfusions/8 weeks compared with the pretreatment transfusion number in the previous 
8 weeks.  Only RBC transfusions given for a hemoglobin of ≤ 9.0 g/dL pretreatment will 
count in the RBC transfusion response evaluationb  
Platelet Response  (HI-P)
(pretreatment, <100 X 109/L) 
Absolute increase of ≥ 30 X 109/L for subjects starting with > 20 X 109/L platelets 
Increase from < 20 X 109/L to > 20 X 109/L and by at least 100%b  
Neutrophil Response (HI-N)
(pretreatment, <1.0 X 109/L) 
At least 100% increase and an absolute increase > 0.5 X 109/Lb  
Progression or Relapse After HIc
At least 1 of the following:  
     At least 50% decrement from maximum response levels in granulocytes or platelets 
     Reduction in hemoglobin by ≥ 1.5 g/dL 
     Transfusion dependence 
KEY:  HI = hematologic improvement; HI-E = hematologic improvement erythroid response; HI-N = hematologic 
improvement neutrophil response; HI-P = hematologic improvement platelet response; IWG = International 
Working Group; MDS = myelodysplastic syndromes; RBC = red blood cell
a Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥ 1 week apart 
(modification).  
b Modification to IWG response criteria.  
c In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), 
gastrointestinal bleeding, hemolysis, and so forth.  It is recommended that the 2 kinds of erythroid and platelet 
responses be reported overall as well as by the individual response pattern.  
Note:  Deletions to the IWG response criteria are not shown.  To convert hemoglobin levels from grams per deciliter 
to grams per liter, multiply grams per deciliter by 10.  
Source:  Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al.  Clinical 
application and proposal for modification of the International Working Group (IWG) response criteria in 
myelodysplasia.  Blood 2006; 108 (2): 419-25.
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