Clinical trial NCT02775903
Conditions: Leukemia, Myeloid, Acute Myelodysplastic Syndromes
Keywords: MEDI4736 Durvalumab Myelodysplastic Syndromes Acute Myeloid Leukemia Hematopoietic Stem Cell Transplantation Azacitidine Safety Efficacy PD-L1
Sponsor: Celgene
Start date: 2016-06-03; Completion date: 2021-12-27
Enrollment: 213 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the efficacy of subcutaneous azacitidine in combination with durvalumab as compared with subcutaneous azacitidine alone in adults with previously untreated, higher risk MDS who are not eligible for HSCT or in adults ≥ 65 years old with previously untreated AML who are not eligible for HSCT, with intermediate or poor cytogenetic risk.

Detailed description:

Arms: arm 1: Participants received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met. arm 2: Participants received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.
Interventions: intervention 1: Azacitidine intervention 2: Durvalumab
Intervention descriptions: intervention 1: Administered by subcutaneous injection on Days 1 to 7 of each 4-week treatment cycle. intervention 2: Administered by intravenous infusion on Day 1 of every 4-week treatment cycle.

Protocol documents:
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
1
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
TITLE PAGE
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE 2 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
AZACITIDINE SUBCUTANEOUS IN COMBINATION WITH 
DURVALUMAB (MEDI4736) IN PREVIOUSLY UNTREATED 
SUBJECTS WITH HIGHER-RISK MYELODYSPLASTIC 
SYNDROMES (MDS) OR IN ELDERLY (≥65 YEARS) ACUTE 
MYELOID LEUKEMIA (AML) SUBJECTS NOT ELIGIBLE FOR 
HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)
FUSION HR MDS/ELDERLY AML 001 STUDY
PROTOCOL NUMBER:
MEDI4736-MDS-001 
ORIGINAL DATE FINAL:
17 Nov 2015
AMENDMENT No. 1.0 DATE FINAL:
27 Mar 2017
AMENDMENT No. 2.0 DATE FINAL:
26 Dec 2017
AMENDMENT No. 3.0 DATE FINAL:
05 Mar 2019
EudraCT NUMBER:
2015-003596-30 
IND NUMBER:
127058
SPONSOR NAME/ ADDRESS:
Celgene International II Sàrl
Rue du Pré-Jorat 14
2108 Couvet
Switzerland
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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
2
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION
Contact Information:
Name:
Title:
Address: 
 
Phone:
E-mail:
Contact Information:
Name:
Title:
Address:
86 Morris Avenue, Summit, NJ 07901 USA
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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
3
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be acceptable.  
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be acceptable.  
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
4
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
5
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
6
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
PROTOCOL SUMMARY
Study Title
A Randomized Multicenter, Open-label, Phase 2 Study Evaluating the Efficacy and Safety of 
Azacitidine Subcutaneous in Combination With Durvalumab (MEDI4736) in Previously 
Untreated Subjects with Higher-Risk Myelodysplastic Syndromes (MDS) or in Elderly (≥65 
years) Acute Myeloid Leukemia (AML) Subjects Not Eligible for Hematopoietic Stem Cell 
Transplantation (HSCT).
Indication
Treatment of subjects with untreated myelodysplastic syndromes (MDS), Revised International 
Prognostic Scoring System (IPSS-R) intermediate risk (in combination with more than 10% bone 
marrow (BM) blasts or poor or very poor IPSS-R cytogenetic risk), IPSS-R high and IPSS-R 
very high risk, not eligible for HSCT.
Treatment of previously untreated elderly (≥65 years) acute myeloid leukemia (AML) subjects 
not eligible for HSCT with intermediate or poor cytogenetic risk status.
Objectives
Primary Objective:
Efficacy:
!
Evaluate the efficacy of subcutaneous (sc) azacitidine in combination with 
durvalumab as compared with subcutaneous azacitidine alone in the defined study 
population.
Secondary Objectives:
Safety:
!
Assess the safety and tolerability of subcutaneous (sc) azacitidine in combination 
with durvalumab compared with subcutaneous azacitidine alone in the defined study 
population.
Pharmacokinetics:
!
To assess the pharmacokinetics (PK) of durvalumab when given in combination with 
subcutaneous azacitidine in the defined study population. 
Study Design
This is a randomized, multicenter, open-label, Phase 2 study evaluating the efficacy and safety of 
subcutaneous azacitidine in combination with durvalumab in two separate cohorts. Cohort 1 
comprises subjects with previously untreated MDS IPSS-R intermediate risk (in combination 
with more than 10% bone marrow blasts or poor or very poor IPSS-R cytogenetic risk), IPSS-R 
high and IPSS-R very high risk, who are not eligible for HSCT. Cohort 2 comprises subjects 
with previously untreated AML who are elderly (≥ 65 years) and not eligible for HSCT, with 
intermediate or poor cytogenetic risk.
Subjects will be randomized (1:1 ratio) to receive one of the two treatment arms: 
!
Arm A (subcutaneous azacitidine plus durvalumab)
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
7
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
!
Arm B (subcutaneous azacitidine alone)
The randomization process will aim to balance prognostic factors between study arms. For both 
cohorts (MDS and AML), subjects will be randomized and stratified according to their 
cytogenetic risk: 
!
Intermediate versus poor for AML (Appendix J), 
!
Very good, good and intermediate versus poor and very poor for MDS (Appendix H).
The randomized study will be conducted in 2 stages, with an interim analysis for futility purpose
for each of the 2 disease cohorts as outlined in Section 9. The primary analysis will follow 
completion of Stage 2 (ie after all subjects have completed 6 cycles and had disease assessment) 
with additional analyses conducted approximately 12 months after the last subject is enrolled, as 
described in Section 9. In addition an early safety monitoring will be performed using 
approximately the first 12 subjects randomized.
Study Population
Approximately 182 eligible and evaluable subjects will be included in this study. 
Eligible subjects for the study will require a documented diagnosis of either AML or MDS as 
defined in Section 4, and will be assigned to either the AML or MDS cohort based on the central 
laboratory diagnosis confirmation. Approximately 72 subjects will be included in the 
MDS cohort and approximately 110 subjects in the AML cohort.
Length of Study
The enrollment period for this study is expected to last approximately 15 months. The treatment 
and follow-up periods are expected to conclude approximately 12 months after the last subject is 
randomized. Therefore, the total duration of the study is expected to be approximately 27
months, from first subject enrolled until the last subject last visit. 
Subjects will undergo screening procedures over a period of up to 35 days following the signing 
of their informed consent form (ICF). Eligible subjects will continue to the treatment part of the 
study where they will receive investigational product (IP) for at least six 28-day treatment cycles. 
Those who demonstrate benefit from treatment may continue the IP beyond Cycle 6 until loss of 
that benefit or unacceptable toxicity, or withdrawal of consent (Section 7.2.5).
All subjects will have a Treatment Discontinuation Visit within 7 days after discontinuation of 
study treatment. Subjects are to return to the study site 28 days after the last dose of 
subcutaneous azacitidine and 90 days after the last dose of durvalumab for Safety Follow-up 
Visits. After this visit, subjects will be contacted by telephone every 3 months in the follow-up 
phase of the study.
The End of Trial is defined as either the date of the last subject last visit for the completion of
posttreatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date. See Section 3.3.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
8
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Study Treatments
Subjects will be randomized 1:1 to receive either:
Treatment Arm A: Subcutaneous azacitidine (75 mg/m2 for 7 days every 4 weeks [Q4W]) in 
combination with intravenous (IV) durvalumab at a dose of 1500 mg on Day1 Q4W,
Or 
Treatment Arm B: Subcutaneous azacitidine alone at the dose of 75 mg/m2 for 7 days Q4W.
Early safety monitoring and a comparative safety evaluation will be performed on approximately 
the first 12 subjects randomized to the study (Section 3.2.2.2).
For toxicities 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 7.2.2.2. Dose 
reduction for durvalumab is not permitted. The management of the toxicity due to azacitidine is 
described in Section 7.2.2.1. 
Subjects should receive at least 6 cycles of treatment; however, subjects may be discontinued 
from treatment at the Investigator’s discretion prior to reaching the recommended minimum 
number of cycles. Upon completing 6 cycles, subjects who benefit from treatment may continue 
IP until loss of that benefit, disease progression or other treatment discontinuation criterion is 
met (see Section 7.2.5).
Overview of Key Efficacy Assessments
Subjects’ disease status will be assessed based on available clinical and laboratory assessments 
(bone marrow aspirate [BMA]) at the end of Cycle 3, 6 and every 3rd treatment cycle thereafter.
Subjects who satisfy one of the continuation criteria listed below may continue on to Cycle 7 and 
beyond.
Continuation criteria for MDS cohort:
!
Overall response to treatment: complete remission (CR), marrow complete remission 
(mCR), partial remission (PR) as per the International Working Group (IWG) criteria 
for MDS (Cheson, 2006), or 
!
Red blood cell (RBC) transfusion-independence for at least 56 consecutive days, or
!
Any hematologic improvement (HI) as per the IWG criteria for MDS (Cheson, 2006), 
or
!
Any other clinical benefit, including no evidence of progressive disease (PD).
Continuation criteria for AML cohort:
!
Overall response to treatment: Complete Remission (CR) or Complete Remission 
with incomplete blood count recovery (CRi) per modified IWG response criteria for 
AML (Cheson, 2003), or
!
Any other clinical benefit including no evidence of progressive disease (PD).
Disease diagnosis for all subjects will be confirmed by the central laboratory prior to 
randomization, based on blood samples, bone marrow aspirate and biopsy (at screening only).
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
9
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Bone marrow samples (aspirate and/or biopsy), along with a peripheral blood smear and 
pertinent clinical information will be submitted for review to an independent 
pathologist/cytogeneticist to provide consistency for determination of disease classification, 
assessment, 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 
Section 5 (Table of Events).
 
Overview of Key Safety Assessments
!
Adverse Events(AEs) including adverse events of special interest (AESIs) 
!
Physical examination
!
Vital signs, and body weight measurement
!
Eastern Cooperative Oncology Group (ECOG) performance status
!
Hematology (CBC with differential and platelets)
!
Coagulation parameters
!
Serum chemistry (includes amylase and lipase) 
!
Thyroid function tests
!
Concomitant medications, therapies, and procedures
!
Pregnancy testing (for females of childbearing potential [FCBP] only) 
!
Electrocardiogram (ECG) 
!
Urinalysis
Azacitidine and durvalumab are generally well tolerated without anticipated overlapping 
toxicities. Azacitidine causes well described gastrointestinal and hematologic AEs in the form of 
cytopenias and durvalumab has a low frequency of immune-mediated adverse events similar to 
other immune checkpoint agents (See section 1.4). 
Overview of Pharmacokinetics Assessments
Blood samples for PK assessment of durvalumab will be collected in all subjects receiving 
combination therapy.
 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
10
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
 
Statistical Methods
This is a randomized Phase 2, multicenter, open-label study with 2 separate, parallel disease 
cohorts (MDS and AML).
The study will be conducted in 2 stages for each disease cohort (Section 9.3). Subjects will be 
randomized with 1:1 ratio to receive subcutaneous azacitidine monotherapy or subcutaneous 
azacitidine in combination with durvalumab. 
The randomization procedure will be accomplished by a validated Interactive Response 
Technology (IRT). At randomization, subjects will be stratified by cytogenetic risk, very good, 
good and intermediate versus poor or very poor for MDS cohort, and intermediate versus poor 
for AML cohort. 
In the MDS cohort, the primary efficacy endpoint is the overall response rate (defined as CR, 
mCR, PR, and/or HI) as determined using the IWG 2006 response criteria for MDS. The null 
hypothesis of the response rate (H0 : p ≤ 36%) will be tested against the alternative hypothesis of 
the response rate (H1 : p ≥ 72%) with a type I error rate of 5% and 90% power. A total of 72
subjects will be randomized. An interim analysis for futility purpose will be conducted when 30 
subjects have completed 6 cycles of treatment (See Section 9.3.1). 
In the AML cohort, the primary efficacy endpoint is overall response rate (CR or CRi) based on 
modified IWG 2003 response criteria for AML. The null hypothesis of the response rate (H0 : p 
≤ 25%) will be tested against the alternative hypothesis of the response rate (H1 : p ≥ 50%) with 
a type I error rate of 5% and 80% power. A total of 110 subjects will be randomized. An interim 
analysis for futility purposes will be conducted when 50 subjects have completed 6 cycles of 
treatment (see Section 9.3.2).
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3.2. ).


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
11
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................20
1.1.
Myelodysplastic Syndromes ...................................................................................20
1.2.
Acute Myeloid Leukemia .......................................................................................20
1.3.
Azacitidine .............................................................................................................21
1.3.1.
Clinical Safety Experience with Azacitidine ...........................................................22
1.3.2.
Clinical Experience of Azacitidine in Myelodysplastic Syndromes.........................23
1.3.3.
Clinical Experience of Azacitidine in Acute Myeloid Leukemia .............................24
1.4.
Durvalumab (MEDI4736).......................................................................................25
1.4.1.
Durvalumab Experience in Solid Tumors................................................................26
1.4.2.
Durvalumab Experience in Myelodysplastic Syndromes.........................................28
1.5.
Study Rationale ......................................................................................................29
1.5.1.
Summary/Medical need ..........................................................................................29
1.5.2.
Rationale for Use of PD-1/PD-L1 Inhibition in Myelodysplastic 
Syndromes/Acute Myeloid Leukemia .....................................................................29
1.5.3.
Rationale for the Combination of Durvalumab with Azacitidine in 
Myelodysplastic Syndromes/Acute Myeloid Leukemia...........................................30
1.5.4.
Rationale for Durvalumab and Azacitidine Dosing Regimens.................................31
1.5.5.
Rationale for the Study Design and Choice of Control Arm....................................32
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................35
3.
OVERALL STUDY DESIGN ................................................................................38
3.1.
Study Design ..........................................................................................................38
3.2.
Study Duration for Subjects....................................................................................39
3.2.1.
Screening Phase......................................................................................................39
3.2.2.
Treatment Phase .....................................................................................................40
3.2.2.1.
Scheduled Assessments ..........................................................................................41
3.2.2.2.
Early Safety Monitoring Assessment ......................................................................41
3.2.2.3.
Efficacy Parameters................................................................................................43
3.2.2.4.
Pharmacokinetics 
 Assessment................................................44
3.2.2.5.
Discontinuation from Study Treatment ...................................................................44
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
12
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
3.2.3.
Follow-up Phase .....................................................................................................44
3.2.3.1.
Safety Follow-up Visit(s)........................................................................................44
3.2.3.2.
Survival Follow-up.................................................................................................46
3.2.4.
Discontinuation from Study....................................................................................46
3.3.
End of Trial ............................................................................................................46
4.
STUDY POPULATION.........................................................................................48
4.1.
Number of Subjects ................................................................................................48
4.2.
Eligibility Criteria...................................................................................................48
4.2.1.
Inclusion Criteria....................................................................................................48
4.2.2.
Exclusion Criteria...................................................................................................50
5.
TABLE OF EVENTS.............................................................................................53
6.
PROCEDURES......................................................................................................59
6.1.
Screening................................................................................................................59
6.1.1.
Myelodysplastic Syndromes/Acute Myeloid Leukemia Diagnosis, World 
Health Organization Classifications and Revised International Prognostic 
Scoring System (IPSS-R) Risk Classification..........................................................59
6.1.2.
Demographics and Medical History........................................................................60
6.1.3.
Red Blood Cell and Platelet Transfusion History ....................................................60
6.1.4.
Prior Medications, Procedures and Myelodysplastic Syndromes/Acute 
Myeloid Leukemia Treatments ...............................................................................61
6.1.5.
Clinical Assessments ..............................................................................................61
6.1.5.1.
Physical Examination .............................................................................................61
6.1.5.2.
Vital Signs, Body Weight and Height Measurements..............................................61
6.1.5.3.
Eastern Cooperative Oncology Group Performance Status......................................61
6.1.5.4.
Electrocardiogram ..................................................................................................61
6.1.6.
Laboratory Assessments .........................................................................................61
6.1.6.1.
Coagulation Parameters ..........................................................................................62
6.1.7.
Pregnancy Testing (Female of Child Bearing Potential Only) .................................62
6.1.8.
Bone Marrow Aspirate, Biopsy, and Peripheral Blood Smear .................................62
6.1.9.
Cytogenetics...........................................................................................................63
6.2.
Information to be Collected on Screen Failures.......................................................63
6.3.
Entering a Subject Into the Study............................................................................64
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
13
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
6.4.
Baseline Measurements ..........................................................................................64
6.5.
Durvalumab Infusion Monitoring............................................................................64
6.6.
Safety.....................................................................................................................65
6.6.1.
Adverse Events.......................................................................................................65
6.6.2.
Transformation to Acute Myeloid Leukemia (only for Myelodysplastic 
Syndromes Cohort Subjects)...................................................................................65
6.6.3.
Physical Examination, Vital Signs and Weight .......................................................66
6.6.4.
12-Lead Electrocardiogram.....................................................................................66
6.6.5.
Eastern Cooperative Oncology Group Performance Status......................................66
6.6.6.
Hematology and Serum Chemistry Laboratory Evaluations ....................................66
6.6.6.1.
Hematology............................................................................................................67
6.6.6.2.
Biochemistry Parameters Including Thyroid Function.............................................67
6.6.6.3.
Urinalysis ...............................................................................................................69
6.6.7.
Pregnancy Testing ..................................................................................................69
6.6.8.
Concomitant Medications/Significant Non-drug Therapies/Concomitant 
Procedures..............................................................................................................69
6.7.
Efficacy..................................................................................................................69
6.7.1.
Bone Marrow Aspirate, Biopsy and Peripheral Blood Smear ..................................69
6.7.2.
Cytogenetics...........................................................................................................70
6.7.3.
International Working Group Response Assessment ...............................................70
6.7.4.
General Disease Status Assessment ........................................................................71
6.7.5.
Hematology............................................................................................................72
6.7.6.
Transfusion Assessment..........................................................................................72
6.7.7.
Survival, Transformation to Acute Myeloid Leukemia (only for 
Myelodysplastic Syndromes Cohort Subjects), and Subsequent 
Myelodysplastic Syndromes/Acute Myeloid Leukemia Therapies...........................72
6.9.
Pharmacokinetics....................................................................................................74
6.13.
Unscheduled Visits.................................................................................................75
6.14.
Discontinuation from Study Treatment ...................................................................75
6.15.
Follow-up...............................................................................................................76
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
14
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
7.
DESCRIPTION OF STUDY TREATMENTS........................................................78
7.1.
Description of Investigational Product(s)................................................................78
7.1.1.
Durvalumab............................................................................................................78
7.1.2.
Azacitidine .............................................................................................................78
7.2.
Treatment Administration and Schedule .................................................................78
7.2.1.
Treatment Administration.......................................................................................78
7.2.1.1.
Azacitidine Dispensation and Administration .........................................................79
7.2.1.2.
Durvalumab Dispensation and Administration........................................................79
7.2.1.3.
Monitoring of Durvalumab Dose Administration....................................................80
7.2.1.4.
Missing Doses ........................................................................................................80
7.2.2.
Dose Modifications and Toxicity Management.......................................................81
7.2.2.1.
Azacitidine .............................................................................................................81
7.2.2.2.
Durvalumab............................................................................................................83
7.2.3.
Retreatment Criteria................................................................................................83
7.2.4.
Overdose ................................................................................................................83
7.2.4.1.
Definition of Overdose ...........................................................................................83
7.2.4.2.
Actions Taken in the Event of an Overdose ............................................................84
7.2.5.
Discontinuation ......................................................................................................84
7.3.
Method of Treatment Assignment...........................................................................84
7.4.
Packaging and Labeling..........................................................................................85
7.5.
Investigational Product Accountability and Disposal ..............................................85
7.6.
Investigational Product Compliance........................................................................86
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................87
8.1.
Permitted Concomitant Medications and Procedures...............................................87
8.2.
Prohibited Concomitant Medications and Procedures..............................................88
8.3.
Required Concomitant Medications and Procedures................................................89
9.
STATISTICAL CONSIDERATIONS ....................................................................90
9.1.
Overview................................................................................................................90
9.2.
Study Population Definitions ..................................................................................90
9.2.1.
Intent-to-Treat Population.......................................................................................90
9.2.2.
Efficacy Evaluable Population................................................................................90
9.2.3.
Safety Population....................................................................................................91
9.2.4.
Pharmacokinetic Population....................................................................................91
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
15
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
9.3.
Sample Size and Power Considerations...................................................................91
9.3.1.
Myelodysplastic Cohort..........................................................................................91
9.3.2.
Acute Myeloid Leukemia Cohort............................................................................92
9.4.
Background and Demographic Characteristics........................................................92
9.5.
Subject Disposition.................................................................................................92
9.6.
Efficacy Analysis....................................................................................................92
9.6.1.
Primary Efficacy Analysis ......................................................................................93
9.6.1.1.
Primary Efficacy Endpoint......................................................................................93
9.6.1.2.
Secondary Efficacy Endpoints ................................................................................93
9.7.
Safety Analysis.......................................................................................................94
9.8.
Interim Analysis .....................................................................................................95
9.9.
Other Topics...........................................................................................................95
9.9.1.
Assessment of Pharmacokinetics 
...........................................95
9.9.1.1.
Pharmacokinetic Analysis.......................................................................................95
9.10.
Study Committees ..................................................................................................97
9.10.1.
Data Monitoring Committee (DMC).......................................................................97
9.10.2.
Steering Committee ................................................................................................97
10.
ADVERSE EVENTS..............................................................................................98
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................98
10.2.
Evaluation of Adverse Events.................................................................................99
10.2.1.
Seriousness.............................................................................................................99
10.2.2.
Severity/Intensity..................................................................................................100
10.2.3.
Causality ..............................................................................................................100
10.2.4.
Duration ...............................................................................................................101
10.2.5.
Action Taken........................................................................................................101
10.2.6.
Outcome...............................................................................................................101
10.3.
Abnormal Laboratory Values................................................................................101
10.4.
Pregnancy.............................................................................................................102
10.4.1.
Females of Childbearing Potential: .......................................................................102
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
16
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
10.4.2.
Male Subjects.......................................................................................................102
10.5.
Reporting of Serious Adverse Events....................................................................103
10.5.1.
Safety Queries ......................................................................................................103
10.6.
Expedited Reporting of Adverse Events................................................................103
10.7.
Adverse Events of Special Interest........................................................................104
10.7.1.
Transformation to AML (for MDS Cohort only)...................................................105
11.
DISCONTINUATIONS .......................................................................................106
11.1.
Treatment Discontinuation....................................................................................106
11.2.
Study Discontinuation ..........................................................................................106
12.
EMERGENCY PROCEDURES...........................................................................107
12.1.
Emergency Contact...............................................................................................107
12.2.
Emergency Identification of Investigational Products ...........................................107
13.
REGULATORY CONSIDERATIONS.................................................................108
13.1.
Good Clinical Practice..........................................................................................108
13.2.
Investigator Responsibilities.................................................................................108
13.3.
Subject Information and Informed Consent...........................................................109
13.4.
Confidentiality......................................................................................................109
13.5.
Protocol Amendments...........................................................................................109
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................109
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ..............110
13.8.
Termination of the Study ......................................................................................110
14.
DATA HANDLING AND RECORDKEEPING...................................................111
14.1.
Data/Documents...................................................................................................111
14.2.
Data Management.................................................................................................111
14.3.
Record Retention..................................................................................................111
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................113
15.1.
Study Monitoring and Source Data Verification....................................................113
15.2.
Audits and Inspections..........................................................................................113
16.
PUBLICATIONS .................................................................................................114
17.
REFERENCES.....................................................................................................115
18.
APPENDICES......................................................................................................122
Appendix A:
Table of Abbreviations ....................................................................................122
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16.6


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
17
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Appendix B:
The World Health Organization (WHO) Classification of the Myeloid 
Neoplasms and Leukemia (Vardiman, 2009).........................................................128
Appendix C:
International Prognostic Scoring System for MDS (Greenberg, 1997)..............129
Appendix D:
International Working Group (IWG) Response Criteria in 
Myelodysplasia (Cheson, 2006)............................................................................130
Appendix E:
ECOG Performance Status Scale......................................................................132
Appendix F:
New York Heart Association Classification for Congestive Heart Failure.........133
Appendix G:
National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03................................................................134
Appendix H:
Revised International Prognostic Scoring System for MDS – IPSS-R 
(Greenberg, 2012).................................................................................................135
Appendix I:
The World Health Organization (WHO) Classification of Acute Myeloid 
Leukemia (Swerdlow, 2008).................................................................................137
Appendix J:
Risk Status Based on Cytogenetics for Acute Myeloid Leukemia......................138
Appendix K:
Modified International Working Group AML Response Criteria 
(Cheson, 2003) .....................................................................................................139
Appendix M:
Dosing Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion-related, and Nonimmune–mediated Reactions 
(MEDI4736) 01 Nov 2017 Version.......................................................................143
Appendix N1: Azacitidine Dose Modifications due to Hematologic Toxicity – Subjects 
with Reduced Baseline Blood Counts ...................................................................172
Appendix N2: Azacitidine Dose Modifications due to Hematologic Toxicity – Subjects 
without Reduced Baseline Blood Counts ..............................................................173
Appendix O: Optional Extension Phase...................................................................................174
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
18
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................35
Table 2:
Study Endpoints .....................................................................................................35
Table 3:
Table of Events.......................................................................................................53
Table 4:
Dose Modifications for Subcutaneous Azacitidine in Hematologic Toxicity ...........82
Table 5:
Dose Modifications Based on Bone Marrow Cellularity..........................................82
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82


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
19
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................39
CCI
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
20
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
1.
INTRODUCTION 
1.1.
Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) is an umbrella term that encompasses a heterogeneous 
collection of hematopoietic stem cell disorders primarily affecting older adults. Myelodysplastic 
syndromes is typically characterized by bone marrow (BM) 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.
Allogeneic bone marrow transplantation has been effective, both in subjects 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 
subjects 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 
for MDS (NCCN, 2016).
Higher-risk MDS for this study is defined according to Revised International Scoring System 
(IPSS-R) (Greenberg, 2012): High and Very High with a median survival of 1.6 and 0.8 years 
respectively, and the subpopulation of the Intermediate Risk category with poor and very poor 
cytogenetics with median survival of 1.5 and 0.7 years respectively or a blast count > 10% 
(survival 1.3 years). This is corresponding to the previously used IPSS (Greenberg, 1997) 
intermediate-2 (INT-2) and High-Risk Group with a median survival of 1.1 and 0.4 years, 
respectively.
For subjects diagnosed with, or progressing to, higher-risk disease, the standard of care is 
treatment with a hypomethylating agent (HMA): azacitidine for injection or decitabine. 
Injectable HMAs can produce hematologic response or improvement in approximately half of 
treated subjects, but responses are transient and responding disease will eventually relapse
(Sekeres 2014b, Grinblatt, 2008; Lyons, 2009; Musto, 2010; Silverman, 2002).
1.2.
Acute Myeloid Leukemia 
Acute myeloid leukemia (AML) is an aggressive, clonal myeloid neoplasm with maturation 
arrest of myelopoiesis, leading to an accumulation of myeloblasts in BM and/or blood. Acute 
myeloid leukemia is a life-threatening disease that primarily affects older adults, with a 5-year 
survival rate of 19% (Visser, 2012). More than half of the subjects with newly diagnosed AML 
in developed countries are over 65 years of age, with a median age at diagnosis of 67 to 69 years 
(Colita, 2011; Pollyea, 2011; Smith, 2011). Acute myeloid leukemia is the most frequent form of 
leukemia, accounting for approximately 25% of all leukemias in adults in the Western world 
(Deschler, 2006). Acute myeloid leukemia can arise de novo, through transformation of existing 
myelodysplasia, or be secondary to previous therapy (eg, cytotoxic chemotherapy). It is 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
21
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
estimated that 35% to 40% of subjects with MDS will go on to develop AML, with the disease 
often refractory to current therapy (Silverman, 2002). Pre-existing myelodysplastic or myelo-
proliferative disorders are common in older subjects with AML, occurring in 24% to 40% of 
cases (Gajewski, 1989). Therapy-related AML accounts for about 5% to 10% of all cases 
(Leone, 1999). The prognosis for these subjects is considerably worse than that for subjects with 
primary AML (Löwenberg, 1999). As previously discussed, AML is more common in elderly 
subjects than in younger subjects; furthermore, the prognosis for elderly subjects is far less 
favorable, with only 5% of subjects achieving a 5-year survival compared to 30% in subjects 
aged 30 to 64 years (Visser, 2012). Overall, the elderly subject with AML has a higher incidence 
of unfavorable cytogenetics, molecular mutations, secondary AML (related to previous 
anticancer therapy or prior myelodysplastic diseases), comorbidities, and generally poorer 
performance characteristics. 
Treatment decisions in elderly subjects with AML are complex and often guided by health status, 
consideration of quality of life (QoL) and subject preferences. Once AML has been diagnosed in 
elderly subjects, based upon the factors described above, a decision must be made for intensive 
chemotherapy and/or hematopoietic stem cell transplantation (HSCT), low-intensive 
chemotherapy, a clinical trial, or supportive care alone (Döhner, 2010). Hematopoietic stem cell 
transplantation is rarely used in subjects older than 65 years of age and is reserved for the fit 
subjects with a good prognosis and a matching donor after induction therapy.
Intensive induction chemotherapy is recommended for older subjects with good performance 
status (PS), minimal organ dysfunction or comorbidity, and favorable cytogenetics. Intensive 
induction chemotherapy is the only treatment option that has demonstrated a chance of long-term 
survival in elderly AML subjects with median survivals from 7 to 12 months; however, it also 
carries a high risk of induction-related mortality (10% to 30%) (Burnett, 2007; Deschler, 2006; 
Dombret, 2008; Estey, 2007; Klepin, 2014).
Generally subjects over 75 years old, or those at least 65 years old with PS scores ≥ 2, with 
comorbidities or with complex cytogenetic abnormalities (Milligan, 2006; O’Donnell, 2012) are 
considered to be ineligible for intensive chemotherapy.
Low-dose cytarabine is considered the standard treatment for subjects ineligible for intensive 
chemotherapy and who also have nonadverse cytogenetics. The complete remission (CR) rates 
with low-dose cytarabine are 18% to 22%, with early deaths (within 60 days of the start of 
chemotherapy) reported between 22% to 28% (Yoon, 2013). 
Azacitidine and decitabine are both recommended as alternative treatment options in the 
NCCN guidance for AML (NCCN, 2015) to intensive chemotherapy or low-dose cytarabine and 
best supportive care (BSC) for subjects at least 60 years of age.
1.3.
Azacitidine
Azacitidine is an analog of the naturally occurring pyrimidine nucleoside cytidine and is 
classified as an antimetabolite. Azacitidine has strong in vitro and in vivo antileukemic activity 
and the ability to induce differentiation at lower concentrations in hematopoietic and
nonhematopoietic cell lines. The 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 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
22
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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. 
1.3.1.
Clinical Safety Experience with Azacitidine 
As of 18 May 2016, approximately 19,685 subjects have been treated with azacitidine in clinical 
studies, with 2,049 in the Celgene development program worldwide (1,144 with azacitidine 
injectable, 717 with azacitidine oral, and 192 with injectable and oral azacitidine (please note 
that 3 subjects from AZA PH US 2007 CL005 and 1 subject from AZA PH US 2008 CL008 
enrolled in roll-over protocol CC-486-GEN-001, are counted only once in the overall total), 
8,656 through National Cancer Institute (NCI)-sponsored clinical studies in the US, and an 
estimated 8,980 in non-Celgene-sponsored studies globally. In addition, it is estimated that 
cumulative commercial exposure to azacitidine during marketing experience is 273,411 patients. 
Therefore, overall estimated cumulative exposure to azacitidine during clinical trials and 
commercial experience is 293,096 patients (Azacitidine Development Safety Update Report 
[DSUR] #12, data cut-off 18 May 2016).
The most commonly reported adverse reactions with azacitidine treatment were hematological 
reactions including anemia, thrombocytopenia, neutropenia, febrile neutropenia, and leukopenia, 
gastrointestinal events including nausea, vomiting, abdominal pain, constipation, and diarrhea, 
and injection site reactions (with sc administration).  
For the most frequently reported treatment emergent adverse events (TEAEs) (≥10% of 
subjects), the highest incidence of first occurrence was observed within Cycles 1 and 2, after 
which time the frequencies decreased over subsequent treatment cycles.  Within the cycle, the 
hematological events tended to occur across the first 3 to 4 weeks of the cycle, whereas the 
events associated with the administration of azacitidine tended to occur in the first week.  These 
findings suggested a lack of cumulative toxicity and that adverse events (AEs) of azacitidine 
attenuate over time. 
In general, no clinically relevant differences were seen when the safety data were analyzed for 
age, gender, or MDS subtypes. The most common adverse reactions can be managed through 
delays or dose decrease of azacitidine and/or supportive measures.  
Adult population with MDS, chronic myelomonocytic leukemia (CMML) and AML (20% to 30% 
marrow blasts)
The most commonly reported adverse reactions with azacitidine treatment were hematological 
reactions (71.4 %) including thrombocytopenia, neutropenia and leukopenia (usually Grade 3-4), 
gastrointestinal events (60.6 %) including nausea, vomiting (usually Grade 1-2), or injection site 
reactions (77.1 %; usually Grade 1-2).
The most common serious adverse reactions noted from the pivotal study (AZA PH GL 2003 
CL001) and also reported in the supporting studies (CALGB 9221 and CALGB 8921) included 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
23
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
febrile neutropenia and anemia.  Other serious adverse reactions from these 3 studies included 
neutropenic sepsis and pneumonia (some with fatal outcome), thrombocytopenia, 
hypersensitivity reactions, and hemorrhagic events (eg, cerebral hemorrhage, gastrointestinal 
hemorrhage, and intracranial hemorrhage).
Adult population aged 65 years or older with AML with > 30% marrow blasts 
The most commonly reported (≥ 30%) adverse reactions with azacitidine treatment were 
gastrointestinal events, including constipation (41.9%), nausea (39.8%), and diarrhea (36.9%), 
(usually Grade 1-2), general disorders and administration site conditions including pyrexia 
(37.7%; usually Grade 1-2) and hematological events, including febrile neutropenia (32.2%) and 
neutropenia (30.1%) (usually Grade 3-4). 
The most common serious adverse reactions (≥ 10%) noted from AZA-AML-001 within the 
azacitidine treatment arm included febrile neutropenia (25.0%), pneumonia (20.3%), and pyrexia 
(10.6%). Other less frequently reported serious adverse reactions in the azacitidine treatment arm 
included sepsis (5.1%), anemia (4.2%), neutropenic sepsis (3.0%), urinary tract infection (3.0%), 
thrombocytopenia (2.5%), neutropenia (2.1%), cellulitis (2.1%), dizziness (2.1%), and dyspnea 
(2.1%).Hemorrhagic and infectious events overall were generally reported at percentages that 
were slightly greater in azacitidine subjects than supportive care subjects (most frequent events 
in these categories were epistaxis, hematoma, petechiae, nasopharyngitis, and pneumonia).  
However, adjusting for different lengths of treatment, event rates overall were similar between 
the 2 treatment groups; thus, risks were similar for these types of events occurring in both 
groups.   Hepatic and renal TEAEs were reported in a small number of subjects across treatment 
groups and did not suggest an association of azacitidine treatment with renal or hepatic toxicity.
The safety profile of azacitidine has been well characterized and is based on an extensive amount 
of subject exposure across a wide range of doses and indications, as well as routes of 
administration (sc, intravenous [IV], oral).  The AE profile is remarkably consistent across 
studies, with the most common TEAEs consistent with the known pharmacology of the 
compound, as well as the effects of the underlying disease.
1.3.2.
Clinical Experience of Azacitidine in Myelodysplastic Syndromes
Azacitidine has been studied extensively in MDS. The efficacy and safety of azacitidine were 
studied in an international, multicenter, controlled, open-label, randomized, parallel-group, 
Phase 3 comparative study (AZA PH GL 2003 CL 001) in subjects with INT-2 and high-risk 
MDS according to the International Prognostic Scoring System (IPSS), refractory anemia with 
excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T) and 
modified chronic myelomonocytic leukemia (mCMML) according to the French- American-
British (FAB) classification system. Refractory anemia with excess blasts in transformation
(RAEB-T) subjects (21% to 30% blasts) are now considered to be AML subjects under the 
current WHO classification system. Azacitidine plus best supportive care (BSC) (n = 179) was 
compared to conventional care regimens (CCR). Conventional care regimes consisted of BSC 
alone (n = 105), low-dose cytarabine plus BSC (n = 49) or standard induction chemotherapy plus 
BSC (n = 25). Subjects were preselected by their physician to 1 of the 3 CCR prior to 
randomization. Subjects received this preselected regimen if not randomized to azacitidine. As 
part of the inclusion criteria, subjects were required to have an Eastern Cooperative Oncology 
Group (ECOG) performance status of 0 to 2. The primary endpoint of the study was overall 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
24
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
survival. Azacitidine was administered at a subcutaneous dose of 75 mg/m2 daily for 7 days, 
followed by a rest period of 21 days (28-day treatment cycle) for a median of 9 cycles (range = 1
to 39) and a mean of 10.2 cycles. Within the intent to treat population (ITT), the median age was 
69 years (range 38 to 88 years). In the ITT analysis of 358 subjects (179 azacitidine and 179 
CCR), azacitidine treatment was associated with a median survival of 24.46 months versus 15.02 
months for those receiving CCR treatment, a difference of 9.4 months, with a stratified log-rank 
p-value of 0.0001. The hazard ratio (HR) for the treatment effect was 0.58 (95% confidence 
interval [CI]: 0.43, 0.77). The two-year survival rates were 50.8% in subjects receiving 
azacitidine versus 26.2% in subjects receiving CCR (p < 0.0001) (Fenaux, 2009). In this trial the 
“HI and better” response using IWG 2006 was 36.4% similar to what has been demonstrated in 
Sekeres (2014) with an ORR (CR, mCR, PR, HI) of 36% after four cycles of azacitidine 
monotherapy. Data from the AZA-PH-GL-2003-CL-001 survival study with azacitidine in 
higher-risk MDS subjects found, from analysis of pretreatment bone marrow methylation 
density, that the overall survival (OS) benefit observed with azacitidine versus 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 OS. Subjects with lower levels of methylation treated with azacitidine had 
the best OS, suggesting that they may derive greater benefit from azacitidine.
1.3.3.
Clinical Experience of Azacitidine in Acute Myeloid Leukemia
Azacitidine has been shown to benefit AML subjects with 20% to 30% blasts and multi-lineage 
dysplasia based on the results of a subset of 113 adult subjects in Study AZA PH GL 2003 CL 
001. Azacitidine was administered subcutaneously (sc) at an initial dose of 75 mg/m²/day for 
7 days. The median age was 70 years, 24% of subjects had unfavorable karyotype, and median 
BM blasts was 23%. The median OS was 24.5 months in the azacitidine arm (n = 55) compared 
with 16.0 months in the CCR arm (n = 58) (hazard ratio [HR] = 0.47; p = 0.005) (Fenaux, 2010). 
Additionally, Goldberg et al reported on 33 subjects 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 OS was 13.2 months in the subjects treated with azacitidine compared with 
9.2 months in subjects receiving intensive chemotherapy (Goldberg, 2006).
In addition, the outcome was not significantly different in subjects with an unfavorable 
karyotype, although the sample size was small. Silverman et al, using WHO-defined AML 
criteria for diagnosis, reported a median OS of 19.3 months (n = 27) in subjects treated with 
azacitidine compared with 12.9 months (n = 25) in subjects who received best supportive care 
(Silverman, 2006). 
The efficacy and safety of azacitidine were studied in an international, multicenter, controlled, 
open-label, randomized, parallel-group, Phase 3 comparative study (AZA-AML-001) in older 
subjects (≥ 65 years) with newly diagnosed AML with more than 30% BM blasts. Subjects were 
randomized to azacitidine or CCR. Response was assessed by IWG criteria for AML (Cheson, 
2003) and overall response (OR) was defined as CR plus morphologic CR with incomplete blood 
count recovery (CRi). The median OS was 10.4 months (95% CI = 8.0, 12.7) in the azacitidine 
group (n = 241) compared with 6.5 months (95% CI = 5.0, 8.6) in the CCR group (n = 247), with 
a clinically meaningful difference in OS of 3.8 months with azacitidine treatment. The 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
25
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
azacitidine group had a 15% reduced risk of death compared with subjects in the CCR group 
(HR = 0.85; 95% CI = 0.69,1.03). Although there was a clinically meaningful improvement in 
median OS, the difference between survival curves based on the log-rank test did not reach the 
predefined level of significance (log-rank test, with a stratified p = 0.1009) (Dombret, 2015). In a 
subgroup analysis for subjects with myelodysplasia-related changes the median OS was 12.7 
months (95% CI = 7.2, 14.1) in the azacitidine group (n = 75) compared with 6.3 months (95% 
CI = 4.3, 9.6) in the CCR group (n = 83) log rank p = 0.0357 (Seymour, 2014).
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 subjects (> 70 years of age) 
respond as well as younger subjects, and failure to respond to prior therapy with erythropoiesis 
stimulating agents (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).
In the United States (US), azacitidine (Vidaza®) is approved for the treatment of all 5 FAB 
classification subtypes of MDS: refractory anemia (RA), refractory anemia with ringed 
sideroblasts (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 nonhematopoietic stem cell transplantation-eligible subjects 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).
In October 2015 the European Medicines Agency's (EMA) Committee for Medicinal 
Products for Human Use (CHMP) has approved an expanded indication for the treatment of adult 
subjects aged 65 years or older with AML who are not eligible for HSCT. The expanded 
indication now covers subjects who have > 30% myeloblasts according to the WHO 
classification; previously, the indication covered AML subjects with ≤30% blasts.
1.4.
Durvalumab (MEDI4736)
Durvalumab is a human immunoglobulin G (IgG)1 kappa monoclonal antibody (mAb) directed 
against human programmed death ligand-1 (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 (ADCC) (Oganesyan, 2008).
Refer to the current Investigator’s Brochure for further details.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
26
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
1.4.1.
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
27
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
28
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
Durvalumab half-life is approximately 23 days at doses ≥ 3 mg/kg Q2W (Fairman, 2014).
1.4.2.
Durvalumab Experience in Myelodysplastic Syndromes
Study D4190C00007 is an ongoing Phase 1, multicenter, open-label study to evaluate the safety, 
tolerability, PK, immunogenicity, and antitumor activity of durvalumab in adult subjects with 
MDS after prior treatment with hypomethylating agents. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
29
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
 
  
 
 
 
 
 
 
1.5.
Study Rationale
1.5.1.
Summary/Medical need
Despite the advances based on the use of HMAs, the overall survival in higher-risk MDS (24.5 
months) is still insufficient (Fenaux, 2009).
Elderly subjects with AML not eligible for HSCT have a very poor prognosis with an overall 
survival of 6.5 months with CCR and 10.5 months with azacitidine (Dombret, 2015).
1.5.2.
Rationale for Use of PD-1/PD-L1 Inhibition in Myelodysplastic 
Syndromes/Acute Myeloid Leukemia
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 
preneoplastic 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 
immune suppressive factors, cells, or messages (Monti, 2005).
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 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
30
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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 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 non-small-cell lung 
cancer (NSCLC) (Brahmer, 2010; Brahmer, 2012; Topalian, 2012; Gordon, 2013), 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 from the US 
Food and Drug Administration (FDA); pembrolizumab for melanoma and metastatic non-small 
cell lung cancer (NSCLC) whose tumors express PD-L1 and nivolumab for melanoma and 
advanced (metastatic) NSCLC whose disease progressed during or after platinum-based 
chemotherapy. 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. Programmed 
death ligand-1 (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 subjects 
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).
Programmed death ligand-1 (PD-L1) and PD-L2 are expressed on many human lymphomas (Li, 
2012; Chen, 2013). Programmed death ligand-1 (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). Programmed death ligand-1 (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). 
1.5.3.
Rationale for the Combination of Durvalumab with Azacitidine in 
Myelodysplastic Syndromes/Acute Myeloid Leukemia
Hypomethylating agents upregulate immune signaling in cancer through the viral defense 
pathway (Chiapinelli, 2015). Myeloid leukemia cell lines that were treated with the 
hypomethylating agent decitabine were shown to have an upregulation of PD-L1 expression 
(Yang, 2014). Upregulation (≥ 2 fold) of PD-L1 has been observed in 25% of AML CD34+ 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
31
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
samples, 33% of PD-L2, and 22% of PD-1 (Yang, 2014). Programmed death-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 (Yang, 2014). 
Programmed death ligand-1 (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. 
1.5.4.
Rationale for Durvalumab and Azacitidine Dosing Regimens
The dose of 75 mg/m2 of subcutaneous azacitidine for 7 days is the established standard dose for 
higher-risk MDS and AML and is going to be used as control arm and for the combination with 
durvalumab as well.
The dose and schedule for durvalumab monotherapy (20 mg/kg every 4 weeks [Q4W]) was 
selected based on 2 sets of data: (1) the safety analysis of doses (0.1, 0.3, 1, 3, and 10 mg/kg 
once 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 
> 40 μg/mL. This trough concentration is supported by 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. Pharmacokinetic simulations indicate that a similar overall exposure as represented by 
AUC (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 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
32
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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 
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 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is the 
recommended dose for the current study.
1.5.5.
Rationale for the Study Design and Choice of Control Arm 
Although historical data with azacitidine in higher-risk MDS and AML is available, these data 
have been generated in a population that varies from that proposed in this study due to the 
differences in the prognostic classification (shift in the MDS/AML definition from 30% to 20% 
blasts) risk classification (move from IPSS to IPSS-R in MDS) and response criteria have 
evolved over time.
This study will be conducted as a randomized Phase 2 study with two separate disease cohorts. 
The randomization will allow having a controlled study design with internal consistency being 
independent from historic control.
Both MDS and AML indications will be assessed in one study. Standard treatment with 
azacitidine will be the same for both cohorts. Potential study subjects will be assigned during 
screening to the MDS or AML cohort according to their percentage of blasts. 
The selection of higher-risk MDS is based on the IPSS-R. Subjects with IPSS-R intermediate 
risk in combination with > 10% bone marrow blasts, poor or very poor cytogenetics are also 
eligible as these risk factors have poor survival rates of less than 1.5 years (Greenberg, 2012).
Both MDS and AML will be analyzed in separate cohorts as assessment of MDS and AML has 
evolved differently with specific response assessment guidelines and specific inclusion criteria. 
In addition, there is a major difference in the outcome for MDS and AML which makes separate 
analysis for MDS and AML required.
Azacitidine is approved globally and is the standard of care for higher-risk MDS. A positive 
opinion by the EMA CHMP for the treatment of elderly AML was obtained in September 2015 
and in October 2015 the European Medicines Agency's (EMA) Committee for Medicinal 
Products for Human Use (CHMP) has approved an expanded indication for the treatment of adult 
subjects aged 65 years or older with AML who are not eligible for HSCT. The expanded 
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Azacit
Azaciti


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
33
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
indication now covers subjects who have > 30% myeloblasts according to the WHO 
classification; previously, the indication covered AML subjects with ≤ 30% blasts.
The primary endpoint ORR was chosen to allow early assessment of activity of the combination 
treatment in comparison to standard treatment. Time-to-event data (OS, PFS and other) will be 
analyzed as secondary endpoints for this Phase 2 trial. 
The interim analysis on futility will support early assessment of efficacy and may minimize the 
number subjects exposed to the investigational regimen in the absence of signs of efficacy.
The combination of azacitidine and durvalumab is currently being evaluated in other studies. 
Currently there is no evidence for drug interactions in terms of dosing or overlapping toxicity. 
The combination of azacitidine with other PD-1 inhibitors (nivolumab, pembrolizumab) and PD-
L1 inhibitors (atezolizumab) are under clinical investigation.
The azacitidine dosing schedule for MDS and AML is identical (as per the EU approved dosing 
regimen). Due to the similar nature of MDS and AML in terms of toxicity, dose regimens will be 
identical in both disease cohorts.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
34
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
35
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the efficacy of subcutaneous azacitidine in 
combination with durvalumab as compared with subcutaneous azacitidine alone in the defined study 
population.
Secondary Objectives
The secondary objectives are to:
!
Assess the safety and tolerability of subcutaneous azacitidine in combination with
durvalumab as compared with subcutaneous azacitidine alone in the defined study 
population
!
Assess the pharmacokinetics (PK) of durvalumab when given in combination with 
subcutaneous azacitidine in the defined study population.
 
 
 
 
Table 2:
Study Endpoints
Endpoint
Name 
Description
MDS Cohort
Primary
Overall response
rate
Overall Response Rate (ORR), (ie, CR, mCR, PR, HI) based on 
IWG 2006 response criteria (Appendix D).
Secondary 
Time to response 
Time from randomization to first documented response according 
to IWG 2006 response criteria (Appendix D).
Secondary 
Relapse-free 
survival
Time from the date CR, PR or mCR is first documented until the 
date of documented relapse, death from any cause, or lost to 
follow-up, whichever occurs first according to IWG 2006 response 
criteria (Appendix D).
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
36
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Table 2:
Study Endpoints (Continued)
Endpoint
Name 
Description
Secondary 
Cytogenetic 
response
Proportion of subjects achieving complete cytogenetic response or 
partial cytogenetic response according to IWG 2006 response 
criteria (Appendix D).
Secondary 
Progression-free 
survival (PFS)
Time from randomization to the first documented PD or death due 
to any cause, whichever occurs first.
Secondary 
Duration of 
response
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 IWG 2006 response criteria 
(Appendix D)
Secondary 
Time to AML 
transformation
Time from randomization to AML transformation.
Secondary 
Transformation 
to AML
Proportion of subjects with disease transformation to AML.
AML Cohort
Primary 
Overall response
rate
Proportion of AML subjects achieving an overall response (CR or 
CRi) based on modified IWG 2003 response criteria for AML
(Appendix K).
Secondary 
Time to response 
Time from randomization to first documented response based on 
modified IWG 2003 response criteria for AML (Appendix K).
Secondary 
Relapse-free 
survival
Relapse-free survival is defined only for subjects who achieve CR 
or CRi and is measured as the interval from the date of first 
documented CR or CRi to the date of documented relapse, death 
from any cause, or lost to follow-up, whichever occurs first
(Appendix K). 
Secondary 
Complete 
cytogenetic 
response (CyCR)
Proportion of subjects with complete cytogenetic response (CyCR) 
based on modified IWG 2003 response criteria for AML 
(Appendix K).
Secondary
Hematologic 
Improvement 
Rate
Rate of HI-NE + HI-P + HI-E according to IWG 2006 response 
criteria (Appendix D).
Secondary
Duration of 
response
Duration of response is defined as the time from the first 
documented CR/CRi to documented morphologic relapse, PD 
based on modified IWG 2003 response criteria for AML 
(Appendix K), or death due to any cause, whichever occurs first.
Phase 2: Both Cohorts
Secondary
Safety
Type, frequency, seriousness and severity of adverse events (AEs), 
and relationship of AEs to study treatment, clinical laboratory 
evaluations. 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
37
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Table 2:
Study Endpoints (Continued)
Endpoint
Name 
Description
Secondary 
Overall survival
Time from randomization to death due to any cause.
Secondary 
One-year 
survival 
The probability of survival at 1 year from randomization.
Secondary 
PK parameters
Typical serum/plasma PK parameters for durvalumab, such as 
maximum observed concentration (Cmax), area under the 
concentration-time curve (AUC), time to maximum concentration 
(Tmax), terminal elimination half-life (t1/2), clearance (CL/F), and 
volume of distribution (Vz/F).
 
 
 
 
 
 
 
 
 
AML = acute myeloid leukemia; CR = complete remission; HI = hematological improvement; HI-E = hematological 
improvement – erythroid response; HI-NE = hematological improvement – neutrophil response; HI-p = 
hematological improvement – platelet response; IWG = International Working Group; mCR = marrow complete 
remission; PD = progressive disease; 
 
; PK = pharmacokinetics.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
38
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 2, multicenter, randomized, parallel-group, open-label study consisting of 3 phases: 
Screening, Treatment, and Follow-up.
To confirm the safety, ie, the absence of overlapping toxicities of the combination treatment 
regimen, an early safety monitoring will be performed based on approximately the first 12 subjects 
randomized. Details are provided in Section 3.2.2.2.
Approximately 72 subjects will be included in the MDS cohort and approximately 110 subjects in 
the AML cohort. 
The enrollment period for this study is expected to last approximately 15 months. The treatment 
and follow-up periods are expected to conclude approximately 12 months after the last subject is 
randomized. Therefore, the total duration of the study is expected to be approximately 27 months, 
from first subject enrolled until the last subject last visit. 
Eligible subjects will be randomized to receive subcutaneous azacitidine alone or in combination 
with durvalumab. The treatment phase will be conducted in 2 stages, with an interim analysis for 
futility purpose, for each of the 2 study cohorts as outlined in Section 9. The primary analysis will 
follow completion of Stage 2 with additional analyses conducted approximately 12 months after 
the last subject is enrolled, as described in Section 9.
Pharmacokinetic 
 sampling will be performed in subjects receiving the 
combination therapy to assess durvalumab PK profile 
.
Details regarding the PK 
 sampling procedure are provided in Section 6.9
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
39
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Figure 1:
Overall Study Design
AML = acute myeloid leukemia; FUP = follow up; HSCT = Hematopoietic Stem Cell Transplant; Int = 
intermediate; IPSS-R = Revised International Prognostic Scoring System; IV = intravenous; MDS = 
myelodysplastic syndromes; Q4W = every 4 weeks; sc = subcutaneous; Tox = toxicity.
3.2.
Study Duration for Subjects
3.2.1.
Screening Phase
Screening procedures are to be conducted within 35 days prior to randomization to ensure that all 
inclusion and exclusion criteria are satisfied. All study-specific screening procedures can only be 
performed after the subjects and the Investigators have signed the informed consent form (ICF). 
During screening, a bone marrow biopsy and an aspirate, peripheral blood smears, blood samples 
and relevant clinical documentation will be obtained and will be sent for centralized review by 
an independent pathologist/cytogeneticist to ensure consistency in determination of diagnosis 
and baseline disease characteristics.
The diagnosis will be done according to the WHO classification for MDS and AML 
(Appendix B and Appendix I, respectively), IPSS-R for MDS (Appendix H), and the risk 
classification and cytogenetic risk category as per NCCN guidelines for AML subjects 
(Appendix J). 
The results from central review must be available prior to the randomization to ensure proper 
stratification and proper cohort allocation.
On a case-by-case basis and after consultation with the medical monitor, it will be determined if 
local pathology reports can be used to support AML subjects’ eligibility. Acute Myeloid 
sc azacitidine on Days 1-7 Q4W
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
40
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Leukemia subjects in the need of an urgent treatment start, may be randomized based on local 
pathology and cytogenetic results. Please note that a biopsy and an aspirate are still required 
prior to randomization for central review, 
 and final diagnosis 
confirmation. Sponsor’s medical monitor will review specific eligibility criteria for all screened 
subjects prior to randomization of subjects via the IRT.
Details on the timing and quantity of material required will be specified in the laboratory manual 
for the study. 
For all subjects, all transfusion records for the 56 days immediately preceding randomization 
should be collected whenever possible. Transfusion data should include the blood product 
transfused, number of units, reason for transfusion, and date of transfusion. Platelet transfusion 
data should include the platelet value for which the transfusion was deemed necessary and RBC 
transfusion data should include the hemoglobin (Hgb) value for which the transfusion was 
administered, if available.
Screening assessments and procedures are described in Section 6.1.
3.2.2.
Treatment Phase
The study will be conducted in 2 stages. Eligible subjects will be randomized 1:1 to one of two 
treatment arms:
Treatment Arm A: Subcutaneous azacitidine (75 mg/m2 for 7 days Q4W) in combination with 
IV durvalumab at a dose of 1500 mg on Day1 Q4W
or
Treatment Arm B: Subcutaneous azacitidine alone at the dose of 75 mg/m2 for 7 days Q4W.
The randomization process will aim to balance prognostic factors between study arms. For both 
cohorts (MDS and AML) subjects will be randomized and stratified according to their 
cytogenetic risk: 
!
Intermediate risk versus poor risk for AML (see Appendix J), 
!
Very good, good and intermediate risk versus poor and very poor risk for MDS (see 
Appendix H, IPSS-R Cytogenetic Risk Groups).
The subject should begin treatment on the day of randomization via integrated response technology 
(IRT) 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. 
On Day 1 of each 28-day treatment cycle, subjects will receive IV infusion of durvalumab prior 
to receiving the first dose of subcutaneous azacitidine. Azacitidine dosing should not begin until 
any immediate toxicities from durvalumab infusion have resolved. 
Azacitidine dose and schedule may be adjusted as described in Section 7.2.2.1 for the 
management of unacceptable toxicity. 
Interruption or delay of treatment with subcutaneous azacitidine for up to 42 days is permitted as 
outlined in Section 7.2.2.1 to enable recovery from investigational product (IP)-related toxicity. 
If there is a delay of more than 42 days (6 weeks) in the start of the next cycle, the sponsor’s
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
41
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
medical monitor must be consulted. When the start of a new treatment cycle with subcutaneous 
azacitidine is delayed for any reason, the infusion of durvalumab will also be delayed (in subjects 
randomized to the combination treatment arm), such that durvalumab and azacitidine continue 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 sponsor’s medical monitor, the subject is experiencing 
clinical benefit.
For toxicity that is thought to be related to treatment with durvalumab, including immune-
mediated adverse events (imAEs) or infusion-type reactions, as well as for nonimmune mediated 
reactions, the infusion of durvalumab may be slowed or interrupted, or a dose may be withheld, 
as described in Section 7.2.2.2. Dose reduction of durvalumab is not permitted.
In the event that a subject assigned to the combination treatment arm discontinues treatment with 
durvalumab or subcutaneous azacitidine because of drug-related toxicity, treatment with 
subcutaneous azacitidine or durvalumab monotherapy may continue until a discontinuation 
criterion is met (see Section 11.1). These subjects will be included in the ITT, safety and EE 
populations if they meet the respective criteria.
3.2.2.1.
Scheduled Assessments 
All screening/baseline assessments and procedures must be performed prior to randomization.
Safety assessments will include: physical examination with vital signs including body weight, 
ECOG performance status, and evaluation for AEs, laboratory evaluations, blood chemistries
including lipase/amylase and thyroid function, complete blood cell count (CBC), pregnancy 
testing, coagulation tests, electrocardiogram (ECG),
pharmacokinetics and 
urinalysis.
Efficacy assessments will include bone marrow aspiration and biopsy, CBC with differential, 
cytogenetics, and transfusion records.
For more details on the evaluations and schedule, refer to the Table of events (Section 5).
3.2.2.2.
Early Safety Monitoring Assessment 
Azacitidine and durvalumab are generally well tolerated without anticipated overlapping 
toxicities. Azacitidine is related to well described gastrointestinal and hematologic AEs, mainly 
in the form of cytopenias. Durvalumab has a low frequency of immune-mediated adverse events 
similar to other immune checkpoint agents (See Section 1.4). 
Safety of the combination therapy of durvalumab and azacitidine in MDS is currently also 
assessed in study MedImmune D4190C00007. The combination of oral azacitidine (CC-486) and 
durvalumab is currently also assessed in study CC-486-MDS-006.
Internal Celgene safety monitoring (safety review) will evaluate all available safety data and will 
assess on an ongoing basis the safety profile of the combination. External reviewers may be 
consulted if needed.
Early safety monitoring and a comparative safety evaluation will be performed on approximately 
the first 12 subjects randomized to the study (in order to analyze at least 6 subjects in the 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
42
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
combination arms). Safety will be evaluated on a real time basis through the electronic case 
report forms (eCRFs).
All available subject data, as well as information from study D4190C00007 as available, will be 
taken into account for the comparative safety evaluation. 
If no major toxicity (eg unacceptable and/or unmanageable toxicities) is observed in the subjects 
randomized to the combination arm enrollment will continue without hold.
As enrollment continues, the first safety monitoring meeting will take place after the first 6 
subjects are enrolled and the first three subjects randomized to combination treatment have 
completed two cycles of treatment. 
At the first safety monitoring meeting, if major toxicity is observed in the first three subjects on 
combination therapy that is not observed in the azacitidine monotherapy arm, the safety review
may conclude: 
!
To continue the randomization and perform a second safety review (see below) based
on the next 6 subjects (3 additional subjects who have completed two cycles of 
combination treatment) as planned.  
!
To continue the randomization and perform a second safety review (see below) based
on the next 6 subjects (3 additional subjects who have completed two cycles of 
combination treatment) and place enrollment on hold until these subjects have been 
observed for at least two cycles of combination treatment and have been reviewed by 
the second safety review meeting.
!
To place enrollment on hold and amend or terminate the study
!
To amend the protocol to place treatment randomization to the durvalumab 
combination arms on hold, but allow enrollment and assignment of subjects to the 
azacitidine monotherapy arms.
A second safety monitoring meeting will take place after approximately 12 subjects are enrolled 
and the first 6 subjects randomized to combination treatment have completed two cycles of 
treatment.
If no major toxicity has been observed in the subjects randomized to the combination arm that is 
not observed in the azacitidine monotherapy arm, the enrollment of the remaining subjects will 
continue.
If major toxicity is observed, the safety review may conclude:
!
To continue the randomization with the early safety monitoring for additional 
subjects
!
To place enrollment on hold and plan for an additional safety review meeting based 
on additional data from ongoing subjects
!
To place enrollment on hold and amend or terminate the study.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
43
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
3.2.2.3.
Efficacy Parameters 
Subjects’ disease status will be assessed based on available clinical and laboratory assessments at 
the end of Cycles 3, 6 (ie, prior to Day 1 procedures of Cycles 4, 7) and at the end of every 3rd 
treatment cycle thereafter. 
Because a hematologic response to treatment with subcutaneous azacitidine and/or durvalumab
may be delayed, subjects will continue on treatment through 6 cycles. Subjects who satisfy one 
of the continuation criteria listed below may continue on to Cycle 7 and beyond.
Continuation criteria for MDS cohort:
!
Overall response to treatment: CR, mCR, PR as per the International Working Group 
(IWG) criteria for MDS (Cheson, 2006), or 
!
Red blood cell (RBC) transfusion-independence for at least 56 consecutive days, or
!
Any hematologic improvement (HI) as per the International Working Group (IWG) 
criteria for MDS (Cheson, 2006), or
!
Any other clinical benefit, including no evidence of progressive disease.
Continuation criteria for AML cohort:
!
Overall response to treatment: CR or CRi per modified IWG response criteria for 
AML (Cheson, 2003), or
!
Any other clinical benefit including no evidence of progressive disease.
Confirmation of a RBC-transfusion-independent response/erythroid response (HI-E; see 
Appendix D) 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, and in respective eCRF. This will 
be compared to the subject’s RBC transfusion history over the 56 days prior to randomization, as 
recorded in the appropriate eCRF during screening. The same will apply with regards to platelet 
transfusions.
Bone marrow samples (aspirate and/or biopsy), along with a peripheral blood smear and 
biological results will be submitted for review to an independent pathologist/cytogeneticist to 
provide consistency for determination of disease classification and response assessment.
Hematologic parameters including hemoglobin, WBC count, differential, and platelets will be 
assessed by the central laboratory at the frequency described in Section 5 (Table of Events).
Subjects who fail to meet one of the above criteria at the end of Cycle 6 and at the end of every 
3rd treatment cycle thereafter will be discontinued from protocol-prescribed therapy and enter 
the Follow-up Phase.
A subject is considered evaluable for response if they have undergone the disease status 
assessment following treatment Cycle 6. A subject who discontinues from the treatment phase 
before the first postbaseline efficacy assessment (following treatment Cycle 3) will be replaced 
unless the subject had a documented progression of their disease or died from their disease or 
died from an IP-related event. An additional subject will be included in that cohort (MDS or 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
44
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
AML cohort). If one postbaseline disease assessment is performed, this assessment would be 
considered for response. 
3.2.2.4.
Pharmacokinetics
 Assessment
All subjects receiving the combination treatment will participate in PK sampling procedures as 
described in Section 6.9. 
 
3.2.2.5.
Discontinuation from Study Treatment 
Prior to discontinuing treatment for a subject, it is recommended that the Investigator contact the 
sponsor’s 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 a Treatment Discontinuation 
Visit within 7 days (Section 6.14) after 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 has been performed within 7 days of the Treatment Discontinuation Visit, it does not 
need to be repeated.
For all subjects, the reason for discontinuing treatment will be recorded in the eCRF and in the 
source document.
3.2.3.
Follow-up Phase
3.2.3.1.
Safety Follow-up Visit(s)
3.2.3.1.1. Safety Follow-up in Subjects Receiving Subcutaneous Azacitidine Alone
All subjects who receive at least one dose of subcutaneous azacitidine and discontinue treatment 
for any reason will be followed for at least 28 days after their last dose of subcutaneous 
azacitidine or after the Treatment Discontinuation Visit, whichever is later, for the assessment of 
safety-related parameters (see Section 6.15). After the 28-day period, any transformation to 
AML (for MDS subjects) and all SAEs made known to the Investigator that are suspected of 
being related to treatment with subcutaneous azacitidine must be reported.
A 28-day follow-up visit will be conducted 28 days following the last dose of subcutaneous 
azacitidine or during the Treatment Discontinuation Visit (whichever date is later) for 
assessment of the following parameters:
!
Survival,
!
Adverse events including AESIs,
!
Physical examination (including vital signs, body weight, ECOG performance status), 
!
Laboratory parameters (hematology, serum biochemistry)
!
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
45
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
!
Urinalysis,
!
Pregnancy test for females of childbearing potential (FCBP) only, 
!
Concomitant medications, therapies, and procedures,
!
Red blood cell and platelet transfusions,
!
Subsequent MDS/AML therapies, 
!
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!
3.2.3.1.2. Safety Follow-up in Subjects Receiving Durvalumab/Subcutaneous Azacitidine 
Combination Therapy
All subjects who receive at least 1 dose of durvalumab 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 6.15). After the 28-day period for subcutaneous 
azacitidine and the 90-day period for durvalumab, any transformation to AML (for MDS 
subjects) and all SAEs made known to the Investigator that are suspected of being related to IP 
must be reported.
Subjects are to return to the study site 28 days after the last dose of subcutaneous azacitidine and 
90 days after the last dose of durvalumab for assessment of the following parameters: 
!
Survival,
!
Adverse events including AESIs (monitored until 28 days after last dose of 
subcutaneous azacitidine and 90 days after last dose of durvalumab),
!
Physical examination (including vital signs, body weight, ECOG performance status), 
!
Laboratory parameters (hematology, serum biochemistry),
!
Thyroid function tests, 
!
Urinalysis,
!
Pregnancy test for FCBP only,
!
Concomitant medications, therapies, and procedures (monitored until 90 days after 
last dose of durvalumab),
!
!
Pharmacokinetics,
!
Red blood cell and platelet transfusions,
!
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!
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
46
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
3.2.3.2.
Survival Follow-up
After completing the Safety Follow-up Visit(s), subjects will be followed and contacted every 
3 months until death, lost to follow-up, withdrawal of consent to further follow-up, or study 
closure to collect information related to: 
!
Survival,
!
Subsequent MDS/AML-related therapies,
!
Disease transformation to AML (for MDS subjects only).
This follow-up will continue until the last active subject completes at least 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 be 
conducted every 3 months by telephone unless special circumstances exist (eg, the subject will 
visit the center for a nonstudy-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.
3.2.4.
Discontinuation from Study
The following events are considered sufficient reasons for study discontinuation:
!
Withdrawal of consent
!
Death
!
Lost to follow-up
!
Study closure
!
Screen failure
!
Other (to be specified on the eCRF).
Subjects not meeting one of these criteria will still be part of the survival follow-up.
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 
whichever is the later date.
The study is expected to close when the last subject completes at least 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 subcutaneous azacitidine and/or durvalumab, without unacceptable toxicities 
and who have met criteria for treatment continuation may continue to receive subcutaneous 
azacitidine plus durvalumab or azaciticine alone provided by the sponsor through an extension to 
this protocol. (See Appendix O).
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
47
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Subjects still on treatment at the end of trial who are not entering the extension phase will 
complete the End of Treatment and End of Study procedures and the appropriate eCRF forms for 
each. This should include the 28-day safety follow-up visit (and 90-day follow-up safety visit for 
patients on durvalumab). Subjects who have ended treatment prior to the End of Trial but are still 
active in the follow-up phase should be discontinued.
CCI
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
48
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
4.
STUDY POPULATION
4.1.
Number of Subjects
Approximately 182 eligible and evaluable subjects will be included in this study. 
Eligible subjects for the study will require a documented diagnosis of either AML or MDS as 
defined in Section 4, and will be assigned to either the AML or MDS cohort based on the central 
laboratory diagnosis confirmation. Approximately 72 subjects will be included in the MDS cohort 
and approximately 110 subjects in the AML cohort.
4.2.
Eligibility Criteria
4.2.1.
Inclusion Criteria 
Subjects must satisfy the following criteria to be enrolled in the study. 
For both cohorts:
1. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted.
2. Have an ECOG performance status of 0, 1, or 2 (Appendix E).
3. Female subjects of childbearing potential1 may participate, providing they meet the 
following conditions: 
a.
Have 2 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 abstinence[2] 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 a highly effective method 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.
                                               
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 in 
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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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
49
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
d. Refrain from egg cell donation while taking durvalumab and for at least 90 days after 
the last dose of durvalumab. 
4. Male subject must:
a.
Either practice true abstinence3 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 childbearing 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.
5. Understand and voluntarily sign a biomarker-specific component of the informed consent 
form prior to any study-related procedures conducted.
6. Willing and able to adhere to the study visit schedule and other protocol requirements.
MDS Cohort:
7. Age ≥ 18 years at the time of signing the informed consent form.
8. Central confirmation of diagnosis of previously untreated primary or secondary MDS as 
per WHO classification (Appendix B). Results of central pathology review are required 
prior to receiving the first dose of IP.
9. Central confirmation of the categorization of the MDS risk classification, as per the IPSS-
R Intermediate risk with >10% blasts or poor or very poor cytogenetics, or IPSS-R High 
or Very High risk (Appendix H) (Results of central pathology review required prior to 
receiving the first dose of IP).
AML Cohort:
10. Age ≥ 65 years at the time of signing the informed consent form (ICF).
11. Central confirmation of diagnosis of one of the following untreated AML as per WHO 
classification (Appendix I):
!
Newly diagnosed, histologically confirmed de novo AML (bone marrow blasts 
≥20%), or
!
AML secondary to prior MDS, or
!
AML secondary to exposure to potentially leukemogenic therapies or agents (eg, 
radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary 
malignancy in remission for at least 2 years.
12. Central confirmation of intermediate or poor risk status, based on Cytogenetics for Acute 
Myeloid Leukemia (Appendix J).
                                               
3 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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12.2. C


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
50
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
4.2.2.
Exclusion Criteria 
The presence of any of the following will exclude a subject from participation in the study.
For both cohorts:
1. Prior hematopoietic stem cell transplant.
2. Considered eligible for hematopoietic stem cell transplant (allogeneic or autologous) at 
the time of signing the ICF.
3. Prior exposure to azacitidine, decitabine or prior exposure to the investigational oral 
formulation of decitabine, or other oral azacitidine derivative.
4. Inaspirable bone marrow.
5. Use of any of the following within 28 days prior to the first dose of IP:
!
Thrombopoiesis-stimulating agents (eg, romiplostim, eltrombopag, Interleukin-11)
!
Any hematopoietic growth factors (ESAs, Granulocyte colony-stimulating factor (G-
CSF) and other RBC hematopoietic growth factors (eg, Interleukin-3)
!
Any investigational agents within 28 days or 5 half-lives (whichever is longer) of 
initiating study treatment 
6. Prior history of malignancies, (except MDS for AML subjects), unless the subject has 
been free of the disease for ≥ 2 years. However, subjects with the following 
history/concurrent conditions are allowed:
!
Basal or squamous cell carcinoma of the skin
!
Carcinoma in situ of the cervix
!
Carcinoma in situ of the breast
!
Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, 
metastasis [TNM] clinical staging system).
7. Pregnant or breast-feeding females or females who intend to become pregnant during 
study participation.
8. Subject has 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 [exclude only if active within the last 6 months prior to signing the ICF], 
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:
!
Subjects with vitiligo or alopecia;
!
Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement for ≥ 3 months prior to signing the ICF; or
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
51
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
!
Subjects with psoriasis not requiring systemic treatment
9. Significant active cardiac disease within the previous 6 months prior to signing the ICF, 
including:
!
New York Heart Association (NYHA) Class III or IV congestive heart failure (see 
Appendix F);
!
Unstable angina or angina requiring surgical or medical intervention; and/or
!
Significant cardiac arrhythmia
!
Myocardial infarction
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic 
fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the 
infection without improvement despite appropriate antibiotics or other treatment), 
uncontrolled hypertension, cardiac arrhythmia, pneumonitis, interstitial lung disease, 
active peptic ulcer disease or gastritis that would limit compliance with study 
requirement. 
11. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or 
evidence of active Hepatitis B Virus (HBV) infection.
12. Known or suspected hypersensitivity to azacitidine, mannitol, or durvalumab, its 
constituents, or to any other humanized monoclonal antibody.
13. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study.
14. Any condition including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study.
15. Prior anti-CTLA-4, PD-1, or PD-L1 or other immune checkpoint mAb exposure.
16. Other investigational mAbs within 6 months prior to first dose of IP.
17. Current or prior use of immunosuppressive medication within 14 days prior to the first 
dose of IP. The following are exceptions to this criterion:
!
Intranasal, inhaled, topical, or local steroid injections (eg, intra-articular injection)
!
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent
!
Steroids as premedication for hypersensitivity reactions (eg, computed tomography 
[CT] scan premedication)
18. History of primary immunodeficiency.
19. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP (NOTE: 
Subjects, if enrolled, should not receive live vaccine during the study and for 30 days 
after the last dose of durvalumab).
20. Unwilling or unable to complete subject reported outcome assessments without assistance 
or with minimal assistance from trained site personnel and/or caregiver.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
52
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
21. Subjects who have had clinical evidence of central nervous system (CNS) or pulmonary 
leukostasis, disseminated intravascular coagulation, or CNS leukemia.
22. Presence of advanced malignant hepatic tumors.
23. Any of the following laboratory abnormalities:
!
Serum aspartate aminotransferase (AST/SGOT) or alanine aminotransferase 
(ALT/SGPT) > 2.5 × upper limit of normal (ULN)
!
Serum total bilirubin > 1.5 × 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
!
Serum creatinine > 2.5 × ULN.
MDS Cohort:
24. Any previous cytotoxic, cytostatic, hormonal, biological or immunological treatment for 
MDS (ESA with or without G-CSF are allowed under certain conditions, see exclusion 
criterion # 5).
25. Any investigational therapy within 28 days prior to the first dose of IP.
26. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample
and prior to first dose of IP.
27. Absolute WBC count ≥ 15 × 109/L.
AML Cohort:
28. Previous cytotoxic, cytostatic, hormonal, biological or immunological treatment (ESA 
with or without G-CSF and iron chelating therapy and hydroxyurea are allowed under 
certain conditions, see exclusion criterion #5) or biologic treatment for AML.
29. Any investigational therapy within 28 days prior to the first dose of IP.
30. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample
and prior to first dose of IP.
31. Prior use of targeted therapy agents (eg, FLT3 inhibitors, other kinase inhibitors).
32. Suspected or proven acute promyelocytic leukemia (FAB M3) based on morphology, 
immunophenotype, molecular assay, or karyotype; AML associated with t(9;22) 
karyotype, biphenotypic acute leukemia or AML with previous hematologic disorder 
such as chronic myelogenous leukemia or myeloproliferative neoplasms.
33. Acute myeloid leukemia associated with inv(16), t(8;21), t(16;16), t(15;17) karyotypes or 
molecular evidence of such translocations if not associated with a c-kit mutation.
34. Absolute WBC count ≥ 15 × 109/L (NOTE: Hydroxyurea is not allowed to attain a WBC 
count ≤ 15 x 109/L).
35. Known history or presence of Sweet Syndrome at screening
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
53
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
5.
TABLE OF EVENTS
Table 3:
Table of Events
Procedure/Assessment
Screening 
Treatment Phase a
Follow-up Phase b
≤ 35 Days 
Prior to 
C1D1
Cycles 1 – 2
Cycles 3 – 6
Cycles 7+
Treatment 
D/C d
Safety 
Follow-up 
Visit(s)w
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
∀
--
--
--
--
--
--
--
--
IRT Registration
∀
--
--
--
--
--
--
--
--
MDS or AML Diagnosis 
∀e
--
--
--
--
--
--
--
--
RBC and Platelet Transfusion History
∀f
--
--
--
--
--
--
--
--
Demographics and Medical History
∀
--
--
--
--
--
--
--
--
Prior Treatment for MDS /AML
∀g
--
--
--
--
--
--
--
--
Prior General Medications and Procedures
∀h
--
--
--
--
--
--
--
--
Examinations
Physical Examination
∀
∀
--
∀
--
∀
∀
∀
--
Vital Signs i
∀
∀
∀
∀
∀
∀
∀
∀
--
Body Weight  
∀
∀
--
∀
--
∀
∀
∀
--
Height
∀
--
--
--
--
--
--
--
--
ECOG Performance Status
∀
∀
--
∀
--
∀
∀
∀
--
Electrocardiogram 12 Lead– Local
∀j
--
--
--
--
--
∀
--
--
Laboratory Assessments
Urinalysisk
∀
--
--
∀
--
∀
∀
∀
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
54
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Table 3:
Table of Events (Continued)
Procedure/Assessment
Screening 
Treatment Phase a
Follow-up Phase b
≤ 35 Days 
Prior to 
C1D1
Cycles 1 – 2
Cycles 3 – 6
Cycles 7+
Treatment 
D/C d
Safety 
Follow-up 
Visit(s)w
Additional 
Follow-up 
Contacts
Day 1c
Days 8, 
15, 22
Day 1
Day 15
Day 1
Hematology l
∀
∀
∀
∀
∀
Day 1 and 
Day 15
∀
∀
--
Coagulation Parameters m
∀
--
--
--
--
--
--
--
--
Serum Chemistry including 
amylase/lipase n
∀
∀
∀
∀
x
Day 1 and 
Day 15
∀
∀
--
Thyroid Function n
∀
∀
--
∀
--
∀
∀
∀
--
Pregnancy Testing (FCBP only) o
∀
∀
--
∀
--
∀
∀
∀
--
Safety Assessments
Assessing Adverse Events including 
AESIs
After signing ICF, until 28 days after the last dose of subcutaneous azacitidine (90 days after the last dose of 
durvalumab) or the Treatment Discontinuation Visit, whichever date is later
--
Monitoring for Transformation to AML
(only for MDS subjects)
After signing ICF and until death, lost to follow-up, withdrawal of consent for further data collection, or end of trial
Concomitant Medications, Therapies, and 
Procedures
From ICF signature until 28 days after the last dose of subcutaneous azacitidine (90 days after the last dose of 
durvalumab) or the Treatment Discontinuation Visit, whichever date is later
--
Disease Assessments
Bone Marrow Aspirate and/or Biopsy p
∀
--
--
End of every 3rd cycle Day 22 p
∀p
--
--
Peripheral Blood Smear p
∀
--
--
End of every 3rd cycle Day 22 p
∀p
--
--
Cytogenetic Testing p
∀
--
--
End of every 3rd cycle Day 22 p
∀p
--
--
 Pharmacokinetic 
Assessments
Bone marrow aspirate and/or biopsy 
sampling for cytogenetics, % plasma cells, 
∀
--
--
End of every 3rd cycle Day 22 p
∀p
--
--
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
55
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Table 3:
Table of Events (Continued)
Procedure/Assessment
Screening 
Treatment Phase a
Follow-up Phase b
≤ 35 Days 
Prior to 
C1D1
Cycles 1 – 2
Cycles 3 – 6
Cycles 7+
Treatment 
D/C d
Safety 
Follow-up 
Visit(s)w
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Contacts
Day 1c
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15, 22
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Day 15
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combination treatment arm only) r
--
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(end of 
infusion), 
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--
C4D1
(pre dose 
and end of 
infusion)
C6D1
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--
--
--
∀
--
IP Administration 
Subcutaneous Azacitidine
Administration s
--
Day 1 to Day 7 of each 28-day treatment cycle 
--
--
--
Durvalumab Administration 1-hour ± 
5min (combination treatment arm only) s
--
Day 1 of each 28-day treatment cycle 
--
--
--
IP Accountability
--
∀
--
∀
--
∀
∀
--
--
Response Assessments
Blood Products Transfusion Assessment t
From Day -56 prior to randomization until 90 days after the last dose of IP or the Treatment Discontinuation 
Visit, whichever occurs later
--
IWG Response Assessment u
--
--
--
∀
--
∀
∀
--
--
General Disease Status Assessment v
--
--
--
∀
--
∀
∀
--
--
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
56
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Table 3:
Table of Events (Continued)
Procedure/Assessment
Screening 
Treatment Phase a
Follow-up Phase b
≤ 35 Days Prior 
to C1D1
Cycles 1 – 2
Cycles 3 – 6
Cycles 7+
Treatment 
D/C d
Safety 
Follow-up 
Visit(s)w
Addition
al 
Follow-
up 
Contacts
Day 1c
Days 8, 
15, 22
Day 1
Day 15
Day 1
Subsequent MDS/AML Therapies 
--
--
--
--
--
--
∀
∀
∀
Survival 
--
--
--
--
--
--
--
∀
∀
; AEs = adverse events; AESIs = adverse events of special interest; AML = acute myeloid leukemia; eCRF = electronic case report form; CxDx = Cycle 
x of Day x; D/C = discontinuation; ECOG = Eastern Cooperative Oncology Group; EPO = erythropoietin; FCBP = female of childbearing potential; Fe/TIBC = serum 
iron/serum total iron-binding capacity; ICF = informed consent form; IP = investigational product; IPSS(-R) = Revised International Prognostic Scoring System; IRT = 
Interactive Response Technology; IWG = International Working Group; MDS = myelodysplastic syndromes; PK = pharmacokinetics; RBC = red blood cell; WBC = white blood 
cell; WHO = World Health Organization.
a. The acceptable study visit window in the treatment phase is ±3 days for Cycles 1 through 6 and; ±7 days for Cycle 7 and beyond, unless otherwise noted for a particular 
assessment. 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 retreatment (see 
Section 7.2.3).
b. The study visit window for the 28-/90-day Safety Follow-Up Visit is ±3 days. If the visit is conducted prior to posttreatment Day 28 (Day 90 for durvalumab), the subject 
should be contacted on or after posttreatment Day 28 to obtain any new or updated information related to survival, AEs, concomitant medications, blood product 
transfusions, additional MDS/AML therapies, and/or disease transformation to AML (for MDS subjects). 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, lost to follow-up, withdrawal of consent to further contact or End of Trial (Section 6.1.5).
c. The first dose of IP in Cycle 1 should be administered on the day of entering the subject in the treatment phase via IRT, 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 eCRF and in the source document for all subjects, even if they never received IP. Reasons for discontinuation are provided in Section 11.1.
e. Documentation supporting MDS diagnosis (WHO classification - Appendix B), and IPSS-R risk classification (Appendix H) will be obtained during screening. 
Documentation supporting AML diagnosis (WHO classification - Appendix I) and cytogenetics risk classification (Appendix J) will be obtained during screening. Diagnosis 
and classification will be confirmed by the central laboratory. Results of central review are required prior to inclusion in the study. Bone marrow aspirate and biopsy 
samples, together with peripheral blood samples and clinical documentation, must be collected during screening, as detailed in Section 6.1.8. 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.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
57
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
f. A comprehensive red blood cell and platelet transfusion history must be available for the 56 days immediately preceding randomization and will be recorded on the 
appropriate eCRF.
g. All prior treatments for MDS/AML, regardless of discontinuation date of treatment, must be recorded as detailed in Section 6.1.4.
h. All nonMDS/AML medications taken in the 4 weeks (28 days) prior to initiation of IP are to be collected on the appropriate eCRF.
i. Vital signs include measurements of blood pressure, pulse, body temperature and respiratory rate and body weight assessment as detailed in Section 6.1.5.2.
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 6.1.5.4.
k. Urinalysis is conducted at the central laboratory. Urine samples will be collected during screening, prior to administration of IP on Day 1 of every 3rd treatment cycle (ie, 
Cycle 3, 6, 9, etc), at the Treatment Discontinuation Visit and 28-day and 90-day Follow-Up Visits (see also Section 6.6.6.3).
l. Hematology includes a complete blood count with WBC differential and platelets as detailed in Section 6.6.6.1. 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, during 
treatment cycles, and at the Treatment Discontinuation and 28-day and 90-day Follow-Up Visits.
m. Coagulation parameters will be assessed during screening only. Retesting of coagulation parameters throughout the study can be performed if clinically indicated. 
Coagulation parameter assessment include: prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT) and fibrinogen.
n. Serum chemistry (to include amylase and lipase) and thyroid function parameters are detailed in Section 6.6.6.2. 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, during
treatment cycles, and at the Treatment Discontinuation Visit and 28-day and 90-day Follow-Up Visits. Assessments do not need to be repeated at Cycle 1 Day 1 (C1D1) if 
screening assessments were performed within 7 days of C1D1. 
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, at the Treatment Discontinuation Visit and 28-day and 90-day Safety Follow-Up visits (Section 6.6.7). The subject 
must 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 aspirate and/or biopsy and peripheral blood samples are required prior to beginning IP and during treatment on Cycle 3 Day 22, and Cycle 6 Day 22 or at the 
latest before starting Cycle 4 or 7. Subjects who continue beyond Cycle 6 will also undergo bone marrow examination every 3 treatment cycles on Day 22 or at the latest 
before starting the next cycle or when necessary to confirm suspected hematologic response or disease progression, and again upon treatment discontinuation (See Section
6.1.8, and 6.7.1). 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. 
 
r. Pharmacokinetic samples will be collected from all subjects receiving the combination treatment. Instructions for IP dosing and PK sample collection timepoints are 
provided in Section 6.9.
s. Investigational product (IP) administration should only start on Day 1 of each treatment cycle after all Day 1 procedures have been completed. For FCBP subjects, a 
negative pregnancy test performed within 72 hours prior to Day 1 IP administration must be documented. It is recommended that an antiemetic medication (eg, ondansetron) 
be taken 30 minutes prior to subcutaneous azacitidine administration during Cycle 1. If nausea/vomiting is not significant, further antiemetic prophylaxis may not be needed.
Durvalumab infusion will be monitored on each Day 1 of all cycles. Monitoring will consist of measuring vital signs 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) postinfusion, 60 minutes 
(± 5 minutes) postinfusion, followed by a 2-hour (± 15 minutes) period of observation.
t. The type of blood product transfused, number of units, reason for transfusion, date of transfusion, and hemoglobin and platelet values are to be collected beginning on C1D1, 
until 90 days after the last dose of IP or the Treatment Discontinuation Visit, whichever occurs later (see Section 6.7.6). 
u. International Working Group Response Assessment based on IWG criteria for MDS (Appendix D) and modified IWG criteria for AML (Appendix K) is to be performed 
every 3 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 4, 7, 10, etc). See Section 6.7.3.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
58
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
v. An assessment of disease status must be performed at the end of Cycle 6, based on available clinical and laboratory evaluations.
!
Subjects who meet continuation criteria (Section 6.7.4) can continue on to Cycle 7 and beyond and disease status will be re-assessed every 3 cycles of treatment.
!
Subjects who fail to meet continuation criteria at the end of Cycle 6 will be discontinued from protocol-prescribed therapy and enter the follow-up phase (Section 6.15).
w. Subjects will be followed for safety-related assessments for 28 days (90 days for durvalumab) posttreatment, or at the Treatment Discontinuation Visit, whichever is later.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
59
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
6.
PROCEDURES
All required study visits are described in the “Table of Events” above 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 Cycle 1 through Cycle 6 must be performed 
± 3 days of the targeted day indicated in the table; all routine assessments of Cycles 7 and 
beyond must be performed ± 7 days of the targeted day; 28 day/90 day safety follow-up visits
must be ± 3 days, posttreatment 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). The written informed consent form must be 
signed before any study-specific procedures are performed and any samples are collected for 
study-specific analysis. 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 receiving the first IP dose. Unless otherwise specified, screening assessments must 
take place, and eligible subjects receive their first dose of IP within 35 days after the date of the 
informed consent form 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.
Subjects who become screen failures can be rescreened once if it is reasonable to believe they 
will meet eligibility criteria during rescreening. If screening assessments are not within the 
allowed screening period, the rescreened subject must reconsent to participation in the study by 
signing a new and current informed consent form.
6.1.1.
Myelodysplastic Syndromes/Acute Myeloid Leukemia Diagnosis, World Health 
Organization Classifications and Revised International Prognostic Scoring 
System (IPSS-R) Risk Classification
Screening procedures are conducted within 35 days prior to randomization to ensure that all 
inclusion and exclusion criteria are satisfied. All study-specific screening procedures can only be 
performed after the subject and the Investigator have signed the ICF. 
During screening, a bone marrow biopsy and an aspirate, peripheral blood smears, blood samples 
and relevant clinical documentation will be obtained and will be sent for centralized review by 
an independent pathologist/cytogeneticist to ensure consistency in determination of diagnosis 
and baseline disease characteristics.
The central determination of the diagnosis will be done according to the WHO classification for 
MDS and AML (Appendix B and Appendix I respectively), IPSS-R (Appendix H), and risk 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
60
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classification and cytogenetic risk category as per NCCN guidelines for AML subjects 
(Appendix J). 
The results from central pathology review will have to be available prior to the randomization to 
ensure proper stratification and proper cohort allocation.
Details on the timing and quantity of material required will be specified in the laboratory manual 
for the study.
All hematology and bone marrow pathology reports generated by central laboratories and used to 
establish subjects’ eligibility will be sent for sponsor review ahead of the planned randomization
to allow for any deficiencies in documentation to be addressed. A checklist will be provided to 
the site to assist in compiling all necessary documentation during screening.
On a case-by-case basis and after consultation with the medical monitor, it will be determined if 
local pathology reports can be used to support AML subjects’ eligibility. Acute Myeloid 
Leukemia subjects in the need of an urgent treatment start, may be randomized based on local 
pathology and cytogenetic results. Please note that a biopsy and an aspirate are still required 
prior to randomization for central review, 
 and final diagnosis 
confirmation. Celgene trial staff will review specific eligibility criteria for all screened subjects 
prior to randomization of subjects via the IRT.
Note: Any time subject-specific documentation is sent to the sponsor, all subject-identifying 
information must be redacted, and the subject’s study-specific Identification 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 eCRF, as 
permitted by local regulations. Relevant medical history and current medical conditions, 
including MDS and AML signs and symptoms, must be recorded on the appropriate eCRF at 
screening.
6.1.3.
Red Blood Cell and Platelet Transfusion History
Documentation of all red blood cell and platelet transfusions received by the subject within 
8 weeks (56 days) prior to randomization should be gathered during the screening period, if 
possible, and recorded on the appropriate eCRF. Transfusion data should include the type of 
transfusion, number of units, reason for, and date of transfusion. Red Blood Cell transfusion data 
should include the hemoglobin concentration prior to transfusion and platelet transfusion data 
should include the pretransfusion platelet value. It is important that all transfusions received by 
the subject during the 56 days prior to randomization are known and recorded, even when not all 
requested data are available.
Confirmation of a RBC-transfusion-independent response/erythroid response (HI-E; see 
Appendix D) requires that the Investigator documents the dates, numbers of units, reason for 
transfusion, and pretransfusion Hgb 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 prior to randomization, as recorded in the appropriate eCRFs 
during screening. The same will apply with regards to platelet transfusions.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
61
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
6.1.4.
Prior Medications, Procedures and Myelodysplastic Syndromes/Acute Myeloid 
Leukemia Treatments
All prior and current medications, including, prescription, over-the-counter, and herbal 
preparations taken for any indication from ICF signature will be recorded on the appropriate 
eCRF.
All prior treatments for MDS/AML as applicable will be recorded on the respective eCRF(s) 
regardless of dates of treatment. 
Note: AML subjects with a past history of MDS are allowed to enter the study providing they 
meet all eligibility criteria. Please refer to Section 4. 
6.1.5.
Clinical Assessments 
6.1.5.1.
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 eCRF.
6.1.5.2.
Vital Signs, Body Weight and Height Measurements  
The routine assessments described Section 6.6.3 must be present in the subject’s source 
documentation and recorded on the appropriate eCRF.
Height is collected during screening only.
6.1.5.3.
Eastern Cooperative Oncology Group Performance Status
Performance status at screening and interval time points will be assessed using ECOG criteria 
provided in Appendix E.
6.1.5.4.
Electrocardiogram 
Electrocardiograms (ECGs) performed during screening, at treatment discontinuation, and if 
clinically indicated during the course of the treatment part of the study, 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 and clinically significant finding(s) on the 
appropriate eCRF. If the ECG is abnormal, the Investigator should consult a cardiologist as 
appropriate. For purposes of this study, ECGs will only be performed during screening and upon 
treatment discontinuation unless additional monitoring is deemed necessary by the Investigator.
6.1.6.
Laboratory Assessments 
Samples for blood hematology, serum biochemistry (including thyroid function and 
amylase/lipase), and urinalysis assessments will be sent to the central laboratory for analysis. 
Refer to Section 6.6.6.1 for timing of required hematology assessments during the study. 
Specific requirements for sample collection, handling, and shipping are provided in the Central 
Laboratory Manual. 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
62
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
6.1.6.1.
Coagulation Parameters 
Coagulation parameters will be assessed during screening. Re-testing of coagulation parameters 
throughout the study is only necessary if clinically indicated.
Coagulation parameter assessment include:
!
Prothrombin time/international normalized ratio (PT/INR)
!
Activated partial thromboplastin time (aPTT)
!
Fibrinogen.
6.1.7.
Pregnancy Testing (Female of Child Bearing Potential Only)
This protocol defines a FCBP as a sexually mature woman who:
!
has not undergone a hysterectomy or bilateral oophorectomy, or 
!
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 eCRF 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. An additional negative serum 
or urine (at Investigator’s discretion) result must be verified by the Investigator prior to 
administration of IP (within 72 hours). Refer to Section 6.6.7 for details regarding pregnancy 
testing during the study and to inclusion criterion number 3 and 4 for contraception requirements 
of the protocol.
6.1.8.
Bone Marrow Aspirate, Biopsy, and Peripheral Blood Smear
During screening, a bone marrow biopsy and an aspirate, peripheral blood smears, blood 
samples, and relevant clinical documentation will be obtained and will be sent for centralized 
review by an independent pathologist/cytogeneticist to ensure consistency in determination of 
diagnosis and baseline disease characteristics.
 
The central determination of the diagnosis will be done according to the WHO classification for 
MDS and AML (Appendix B and Appendix I respectively), IPSS-R (Appendix H), and risk 
classification and cytogenetic risk category as per NCCN guidelines for AML subjects 
(Appendix J). 
The results from central review will have to be available prior to randomization to ensure proper 
stratification and proper cohort allocation.
For AML subjects in the need of an urgent treatment start, recent local pathology and 
cytogenetics reports may be considered for a review of subject eligibility. Please contact the 
medical monitor. This may be considered after the study screening procedures including bone 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
63
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
marrow biopsy and aspirate for central review, 
 and final confirmation 
have been conducted and the respective results are not yet available.
Details on the timing and quantity of material required will be specified in the laboratory manual 
for the study.
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 the informed 
consent form; this will enable resolution of any issues prior to subject’s randomization. 
Therefore, the informed consent process and screening procedures (including bone marrow 
collection) should be planned with careful consideration for the 35-day screening period to avoid 
any potential need for rescreening due to exceeding the 35-day limit. Special handling requests 
such as return of materials to the site will be managed on an individual basis.
6.1.9.
Cytogenetics
Bone marrow cytogenetic testing will be completed by the central laboratory. 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 sign informed consent, but fail to satisfy 
inclusion and exclusion criteria, or for any other reason are not enrolled in the treatment phase of 
the study:
!
Subject Number
!
Informed consent date
!
Demographics
!
Screening Visit Date
!
Reason subject did not qualify for the study
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
64
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
!
All AEs / SAEs during the time period specified by the protocol
!
Investigator’s signature. 
Any AEs 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 eCRF(s). Relevant information will 
also be recorded on a Screening Log. Subjects can be rescreened following discussion with the 
sponsor’s medical monitor. All communications with sponsor’s medical monitor will be 
documented.
6.3.
Entering a Subject Into the Study 
The written informed consent form must be signed by the subject and the Investigator 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 subject’s randomization in the study. 
Randomization will occur via IRT to enable automated tracking and replenishment of IP. 
Specific contact information and instructions will be provided to each study site.
The IRT 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 randomization, 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.
Such approvals must be documented.
Subjects included in the study will be randomly assigned to one of the two treatment arms, either 
subcutaneous azacitidine alone or in combination with durvalumab.
All subjects randomized to combination treatment will participate in PK sampling procedures. 
See Section 6.9 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.
Durvalumab Infusion Monitoring
Subjects will be monitored during and after infusion of durvalumab. Vital signs will be measured
as described in Section 7.2.1.3.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
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6.6.
Safety
Safety assessments include:
!
adverse events including AESIs,
!
postinfusion 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 6.6.6.1)
!
serum chemistry (to include amylase and lipase)
!
Thyroid function tests (see Section 6.6.6.2)
!
concomitant medications, therapies and procedures
!
pregnancy testing (for FCBP subjects)
!
urinalysis 
!
ECG
!
coagulation parameters
6.6.1.
Adverse Events
All subjects will be monitored for AEs including AESIs during the study. Refer to Section 10 for
details regarding monitoring, recording, and reporting of AEs, including SAEs and AESIs.
Information about common side effects already known about azacitidine and durvalumab will be 
included in the subject informed consent form 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.
6.6.2.
Transformation to Acute Myeloid Leukemia (only for Myelodysplastic 
Syndromes Cohort Subjects) 
Transformation to AML will be monitored as an AESI and will be included as part of the safety 
assessment throughout the course of the study. Transformation to AML should be reported if 
documented at any time from signing of informed consent form through death, lost to follow-up, 
withdrawal of consent for further data collection, or study closure (whichever is the later),
whether or not it is thought to be related to treatment with IP.
Events of disease transformation 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 eCRFs and in the subject’s source 
documents. Documentation supporting the diagnosis of transformation to AML (eg, confirmatory 
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riou


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
66
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
histology or cytology results, etc) must be provided at the time of reporting as an SAE. Refer to 
Section 10 for evaluation of AEs.
6.6.3.
Physical Examination, Vital Signs and Weight
The following routine assessments are to be performed as specified below. Significant findings 
must be included on the appropriate eCRF and in the subject’s source documents: 
!
Pulse
!
Blood pressure (systolic and diastolic)
!
Physical examination
!
Body temperature
!
Respiratory rate 
!
Body weight
The above assessments are to be performed during screening, on Day 1 of each cycle before 
administering the study IP, at the Treatment Discontinuation Visit, and at the 28day/90-day
Safety Follow-Up Visits, as applicable. At every visit during treatment phase (Days 8, 15 and 22 
for Cycles 1 and 2 and Days 1 and 15 for Cycle 3 onwards), vital signs that include blood 
pressure, pulse, body temperature and respiratory rate will be assessed.
6.6.4.
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 6.1.5.4.
6.6.5.
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group Performance Status (Appendix E) is to be assessed during 
screening, before IP dosing on Day 1 of each treatment cycle and at Treatment Discontinuation 
and 28-day/90-day Safety Follow-up Visits.
6.6.6.
Hematology and Serum Chemistry Laboratory Evaluations
Hematology including coagulation parameters, serum chemistry including thyroid function and 
urinalyses samples will be processed as detailed in the study laboratory manual and sent to 
central laboratory for analyses and reporting, and are to be performed according to Section
6.6.6.1, Section 6.6.6.2, and Section 6.6.6.3. Any laboratory assessments described below may 
be repeated more frequently as clinically indicated and the results recorded in the appropriate 
eCRF and in the subject’s source documents. 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) and corresponding normal range(s) 
should be recorded in the appropriate eCRF and in the subject’s source documents.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
67
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Refer to Section 10.3 for guidance on the reporting of abnormal laboratory values and test results 
as AEs.
Specific requirements for sample collection, handling, and shipping are provided in the Central 
Laboratory Manual.
6.6.6.1.
Hematology 
Samples for hematology analyses will be collected prior to IP administration on Day 1 of each 
treatment cycle, whenever possible. The schedule of hematology assessments for subjects 
included in the study is as follows:
!
During screening
!
Cycles 1 and 2 – Days 1, 8, 15 and 22
!
Cycles 3 and beyond – Days 1 and 15
!
Treatment Discontinuation Visit
!
28-day Follow-up Visit (After discontinuation of subcutaneous azacitidine treatment)
!
90-day Follow-up Visit (Subjects who received durvalumab)
Complete blood count (CBC) for hematology assessment includes:
!
Red blood cell count
!
Hemoglobin
!
Hematocrit
!
Reticulocyte count
!
Mean corpuscular volume (MCV)
!
Red blood cell distribution width (RDW)
!
Platelet count
!
White blood cell (WBC) count with differential
#
Absolute neutrophils
#
Absolute lymphocytes
#
Absolute monocytes
#
Absolute eosinophils
#
Absolute basophils
#
Percent blasts
6.6.6.2.
Biochemistry Parameters Including Thyroid Function 
Samples for serum chemistry analysis will be collected prior to IP administration on Day 1 of 
each treatment cycle, whenever possible. Based on the mechanism of action of durvalumab
leading to T-cell activation and proliferation, there is the possibility of observing imAEs during 
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6.6.2
6 6 2


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
68
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
the conduct of this study. Potential imAEs may be similar to those seen with the use of other 
checkpoint inhibitors and may include immune-mediated enterocolitis, dermatitis, hepatitis, and 
endocrinopathies (Hodi, 2010; Brahmer, 2012; Topalian, 2013). Subjects should be monitored 
for signs and symptoms of imAEs. In the absence of an alternate etiology (eg, infection or PD), 
an immune-mediated etiology should be considered for signs or symptoms of enterocolitis, 
dermatitis, hepatitis, and endocrinopathy. Please refer to Appendix M for the management of
imAEs. 
The schedule of serum chemistry assessments for enrolled subjects is as follows: 
!
During screening
!
Cycles 1 and 2 – Days 1, 8, 15 and 22
!
Cycles 3 and beyond – Days 1 and 15
!
Treatment Discontinuation Visit
!
28-day Follow-up Visit (After discontinuation of subcutaneous azacitidine treatment)
!
90-day Follow-up Visit (Subjects who received durvalumab)
Serum chemistry assessments include:
!
sodium
!
potassium
!
chloride
!
bicarbonate
!
calcium
!
magnesium
!
phosphorus
!
uric acid
!
total and direct/indirect bilirubin
!
aspartate aminotransferase 
(AST/SGOT)
!
blood urea nitrogen (BUN)
!
creatinine
!
glucose
!
albumin
!
total protein
!
alkaline phosphatase
!
lactate dehydrogenase (LDH)
!
alanine aminotransaminase 
(ALT)/SGPT)
!
*thyroid stimulating hormone 
(TSH), free T4, free T3
!
amylase
!
lipase
*The schedule of thyroid function testing is as follows:
! During screening
! Day 1 of each cycle
! Treatment Discontinuation Visit
! 28-day Follow-up Visit (After discontinuation of subcutaneous azacitidine treatment)
! 90-day Follow-up Visit (Subjects who received durvalumab)
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
69
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
6.6.6.3.
Urinalysis 
Urine samples should be obtained during screening and at the frequency specified below prior to 
IP administration as follows: 
!
During screening
!
Day 1 of every 3rd cycle (eg, Cycles 3, 6, 9 etc)
!
Treatment Discontinuation Visit
!
28-day Follow-up Visit (After discontinuation of subcutaneous azacitidine treatment)
!
90-day Follow-up Visit (Subjects who received durvalumab)
Urinalysis includes examination for glucose, ketones, blood, pH, and protein, and microscopic 
analysis if indicated.
6.6.7.
Pregnancy Testing
For all female subjects of childbearing potential (FCBP – see Section 6.1.7), a screening serum
pregnancy test is required.
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 the pregnancy 
test is negative.
Guidance for pregnancy testing during screening is provided in Section 6.1.7.
6.6.8.
Concomitant Medications/Significant Non-drug Therapies/Concomitant 
Procedures
All prescription, over-the-counter, or herbal medications and therapeutic procedures received 
from the date of signature of ICF until 28 days after the last dose of subcutaneous azacitidine and 
90 days after the last dose of durvalumab (or until the Treatment Discontinuation Visit, 
whichever period is longer) must be recorded on the appropriate eCRF page. Concomitant 
medications, therapies, and procedures are those that are received by the subject during their 
participation in the study as described above. 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 8 for details regarding concomitant 
medications and procedures.
6.7.
Efficacy
6.7.1.
Bone Marrow Aspirate, Biopsy and Peripheral Blood Smear
Samples will be processed as described in the Central Laboratory Manual and submitted for 
central review along with any pertinent clinical information. Determination of disease status as 
per the IWG 2006 criteria for MDS and IPSS-R for MDS or Modified IWG 2003 and 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
70
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
cytogenetic risk category as per NCCN guidelines for AML subjects will be done centrally. 
Results of central review will be utilized for determination of subjects’ responses.
During study treatment, bone marrow aspirate (or biopsy if adequate aspirate cannot be obtained) 
is collected:
!
At the end of every 3rd treatment cycle (before starting the next cycle, ideally on Day 
22) to confirm suspected disease response or progression, and
!
Upon treatment discontinuation.
This bone marrow sample, along with peripheral blood and blood smear slide(s) must be 
collected at the end of that cycle, but before Day 1 of the next cycle; early enough in order to 
allow sufficient time to obtain central laboratory results. Samples will be processed according to 
instructions provided in the Central Laboratory Manual and sent for:
!
Central pathology review,
!
Central laboratory assessments,
!
Central cytogenetics review, and
!
Results from central pathology/cytogenetic review of blood and bone marrow samples will be 
used for:
!
Response assessment,
!
General disease status assessment, and
!
Monitoring for transformation to AML (only for MDS cohort subjects).
Central laboratory results will be used to programmatically derive the subject’s response.
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.
6.7.2.
Cytogenetics
Bone marrow cytogenetic testing is to be completed by the central cytogenetic laboratory 
whenever a bone marrow aspirate or biopsy is collected for disease assessment. Note: specific 
handling of the biopsy/aspirate is required in order to be used for cytogenetics testing. See the 
Central Laboratory Manual for handling instructions.
6.7.3.
International Working Group Response Assessment
Hematologic response or improvement according to criteria from that of the International 
Working Group response criteria for MDS (Cheson 2006), and the modified International 
Working Group response criteria for AML (Cheson 2003) is to be assessed following every 3 
treatment cycles prior to Day 1 procedures of subsequent cycles (ie, Cycles 4, 7, 10, etc) and at 
treatment discontinuation.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
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MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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.
6.7.4.
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 may continue on to Cycle 7 and beyond, and 
will have disease status re-assessed prior to beginning each 3rd treatment cycle thereafter based 
on available clinical and laboratory evaluations and at Treatment Discontinuation Visit. Bone 
marrow and peripheral blood smear examinations will only be performed after Cycles 3, 6 and 
every 3rd cycle thereafter, unless additional bone marrow examination is deemed necessary by 
the Investigator.
For MDS subjects the continuation criteria are:
!
Overall response to treatment: CR, mCR, PR as per the IWG criteria for MDS 
(Cheson, 2006), or 
!
Red blood cell transfusion-independence for at least 56 consecutive days, or
!
Any HI as per the IWG criteria for MDS (Cheson, 2006) or
!
Any other clinical benefit, including no evidence of progressive disease.
For AML subjects the continuation criteria are:
!
Overall response to treatment: CR or CRi as per modified IWG response criteria for 
AML (Cheson 2003), or
!
Any other clinical benefit, including no evidence of progressive disease.
Subjects who fail to meet one of the above 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 sponsor’s 
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/erythroid response (See Appendix D)
requires that the Investigator documents the dates, numbers of units, reason for transfusion, and 
pretransfusion 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 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
72
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
history over the 56 days prior to randomization, as recorded in the appropriate eCRFs during 
screening.
6.7.5.
Hematology
Hematology results obtained from the central lab will be used to 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 6.6.6.1 for a list of hematology parameters being assessed by the central laboratory 
for this study.
6.7.6.
Transfusion Assessment
The following will be recorded for all transfusions the subject received within 56 days (8 weeks) 
prior to randomization, until 90 days after the last dose of subcutaneous azacitidine or 
durvalumab or the Treatment Discontinuation Visit, whichever occurs later:
!
Type of transfusion (eg, RBC 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.
Red blood cell 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.
Red blood cell transfusion-independent response or improvement will be assessed according to 
criteria from that of the IWG criteria for MDS (Cheson 2006) (Appendix D).
6.7.7.
Survival, Transformation to Acute Myeloid Leukemia (only for Myelodysplastic 
Syndromes Cohort Subjects), and Subsequent Myelodysplastic 
Syndromes/Acute Myeloid Leukemia Therapies
All subjects discontinued from protocol-prescribed therapy for any reason should undergo 
treatment discontinuation procedures (Section 6.14) and be followed for survival, disease 
transformation to AML, and subsequent MDS/AML therapies (Section 6.15). Data regarding 
subsequent therapies, determination of disease progression, and date and cause of death will be 
recorded in the appropriate eCRF and in the subject’source documents.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
73
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
74
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
 
 
  
6.9.
Pharmacokinetics 
All subjects receiving the combination therapy will participate in the PK procedures. 
Durvalumab PK sample collection:
Blood samples for durvalumab PK analysis will be collected, processed, and analyzed. Samples 
will be collected at the following timepoints:
!
Cycle 1 Day 1: end of infusion (EOI).
!
Cycle 2 Day 1: preinfusion (-90 to -5 minutes prior to dose).
!
Cycle 4 Day 1: preinfusion (-90 to -5 minutes prior to dose) and end of infusion.
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Cycle 6 Day 1: preinfusion (-90 to -5 minutes prior to dose).
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
75
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
 
 
 
 
 
 
6.13.
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 eCRF. These evaluations should also appear in the subject’s chart and/or other 
source documentation.
6.14.
Discontinuation from Study Treatment 
Prior to discontinuing a subject from study treatment, it is recommended that the Investigator
contact the sponsor’s 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 the Treatment 
Discontinuation Visit within 7 days of the treatment discontinuation, where the following 
procedures will be performed: including: 
!
AEs including AESI
!
Physical examination
!
Vital signs
!
Body weight 
!
ECOG performance status
!
Electrocardiogram
!
Hematology 
!
Serum chemistry (to include amylase and lipase)
!
Thyroid function tests
!
Urinalysis
!
Pregnancy test (FCBP only)
!
Concomitant medications, therapies and procedures
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
76
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
!
Transfusion assessment
!
Bone marrow aspirate/biopsy and peripheral blood smear
!
!
Cytogenetics
!
IWG response assessment
!
General disease status assessment
!
!
 
!
Disease transformation to AML (MDS subjects only)
!
Subsequent MDS/AML 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 on the eCRF and in source documents for all 
randomized subjects. 
In the event that a subject assigned to the combination treatment arm discontinues treatment with 
durvalumab or subcutaneous azacitidine because of drug-related toxicity, treatment with single-
agent durvalumab or subcutaneous azacitidine may continue until any discontinuation criterion is 
met.
6.15.
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 subcutaneous azacitidine and 90 days after the last dose of 
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 subcutaneous 
azacitidine or 90 days after last dose of durvalumab)
!
physical examination
!
vital signs
!
body weight 
!
ECOG performance status
!
hematology
!
serum chemistry (to include amylase and lipase)
!
thyroid function tests
!
pregnancy testing (FCBP only) 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
77
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
!
urinalysis
!
concomitant medications, therapies and procedures
!
transfusion assessment
!
subsequent MDS/AML therapies
!
survival
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.
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 Safety Follow-up Visit(s) until 
the last active subject reaches 12 months of treatment, unless additional follow-up is needed to 
evaluate time-to-event endpoints (eg, PFS and survival), or until death, lost to follow-up, 
withdrawal of consent to further follow-up, or study closure to collect information related to: 
!
survival
!
subsequent MDS/AML therapies
!
disease transformation to AML (only for MDS cohort subjects).
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).
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
78
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
7.1.1.
Durvalumab
Durvalumab will be supplied by Celgene 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 durvalumab at a 
concentration of 50 mg/mL. Durvalumab is stored at 2∃C to 8∃C (36∃F to 46∃F) and must be used 
before the individually assigned expiry date on the label.
Site to supply the following:
!
Intravenous 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.
!
Since the compatibility of durvalumab with other IV medications and solutions, other 
than normal saline is not known, the durvalumab solution must not be infused through 
an IV line in which other solutions or medications are being administered.
Refer to the current durvalumab IB for detailed information about the physical properties of 
durvalumab and to the pharmacy manual for additional preparation, administration, or storage 
information.
7.1.2.
Azacitidine 
Azacitidine will be supplied by Celgene as a sterile lyophilized powder containing 100 mg of 
azacitidine and 100 mg of mannitol per vial. Each single-use vial will be supplied in single-count 
cartons. 
Refer to the current azacitidine IB for detailed information about the physical properties of 
azacitidine and to the pharmacy manual for additional preparation, administration, or storage 
information.
7.2.
Treatment Administration and Schedule
7.2.1.
Treatment Administration 
Subjects will receive treatment in 28-day cycles as described in the section below and may 
continue to receive the protocol therapy for as long as they benefit from the treatment or until 
treatment is discontinued for reasons detailed in Section 6.14.
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 AE). For additional information on preparation and storage please 
refer to the pharmacy manual.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
79
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
7.2.1.1.
Azacitidine Dispensation and Administration
Azacitidine will be administered on Days 1 to 7 of each treatment cycle. The subject may not 
receive IP for each treatment cycle until all Day 1 procedures have been completed.
Vials/syringes should be used for the specific subjects to whom they are assigned, and must not 
be shared between subjects.
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.
Subjects will receive azacitidine 75 mg/m2/day subcutaneous for 7 days (Days 1 to 7) every 28 
days. In the event 2 or fewer doses are missed during the 7-day dosing period, dosing should 
continue so the subject receives the full 7 days of therapy. If 3 or more days are missed during 
the 7-day dosing period, the Investigator should contact the sponsor and a decision on dosing 
will be made on a case-by-case basis. 
Subjects assigned to the combination treatment arm will have azacitidine administered on Day 1 
of each treatment cycle approximately one hour after completion of the durvalumab infusion, 
after resolution of any related AE immediately after durvalumab infusion, if any.
If the dose of azacitidine is modified during the course of the study (Section 7.2.2.1) and benefit 
is demonstrated at a dose lower than 75 mg/m2, that dose should be maintained during 
subsequent cycles that are given (unless toxicity develops). 
7.2.1.2.
Durvalumab Dispensation and Administration
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. Durvalumab 
does not contain preservatives and any unused portion must be discarded.
Sites should follow standard and local aseptic procedures and instructions from the pharmacy 
manual 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. 
The preparation of infusion bags should be done under aseptic conditions by trained personnel; 
they should not be prepared on the ward.
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. 
Subjects will receive durvalumab, 1500 mg intravenously on Day 1 of each 28-day treatment 
cycle by IV infusion over approximately 1 hour (± 5 minutes). Infusions of durvalumab may be 
interrupted, slowed, or discontinued in order to address toxicity, but dose reduction of 
durvalumab is not permitted (see Section 7.2.2.2). 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
80
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Refer to the current durvalumab IB for detailed information about the physical properties of 
durvalumab and to the pharmacy manual for additional preparation, administration, or storage 
information.
7.2.1.3.
Monitoring of Durvalumab 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, at the end of the durvalumab infusion (± 5 minutes), and at 
30 minutes (± 5 minutes) and 60 minutes (± 5 minutes) postinfusion 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 in severity, IP will be discontinued.
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. 
7.2.1.4.
Missing Doses 
Subjects will receive subcutaneous azacitidine 75 mg/m2/day for 7 days every 28 days until the 
end of the study, unless they are discontinued from the treatment. In the event 2 or less doses are 
missed during the 7-day dosing period, dosing should continue so the subject receives the full 7 
days of therapy. If 3 or more days are missed during the 7-day dosing period, the Investigator
should contact the sponsor and a decision on dosing will be made on a case-by-case basis.
In order to optimally benefit from the azacitidine treatment, Investigators should aim to treat 
subjects for at least 6 cycles. However, subjects may be discontinued from the treatment per 
Investigator discretion, even during the first 6 cycles, for any of the reasons detailed in 
Section 11.1. If the dose of subcutaneous azacitidine is modified during the course of the study 
(Section 7.2.2.1) and benefit is demonstrated at a dose lower than 75 mg/m2, that dose should be 
maintained during subsequent cycles that are given (unless toxicity develops). All subjects 
discontinued regardless of the reason will be followed for a period of 28 days following the date 
of the last dose of subcutaneous azacitidine or the date of the Treatment Discontinuation Visit
(whichever date is later) for collection of AEs and will also be followed for survival until the end 
of the study.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
81
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
7.2.2.
Dose Modifications and Toxicity Management
7.2.2.1.
Azacitidine
The first cycle of subcutaneous azacitidine should always be given at 100% of the dose, 
regardless of the subject’s laboratory values (provided that the subject is allowed to enter the 
study based on the inclusion and exclusion criteria).
Subjects should be monitored for hematologic and renal toxicity; a delay in starting the next 
cycle or dose reduction as described by the guidance below may be necessary and followed at the 
investigator’s discretion. Assessment to modify the dose should be made taking into 
consideration the subject’s clinical condition including all adverse events (eg, bleeding or 
infections) and the subject’s underlying disease status.
The Investigator should contact the sponsor’s medical monitor for guidance on subcutaneous 
azacitidine dose modification, if needed. 
Dose Modifications due to Nonhematological Toxicity
Following receipt of any dose of subcutaneous azacitidine, subsequent cycles may be delayed if 
a certain level of toxicity occurs after the previous dose. Any subject who experiences a 
nonhematological AE with Common Terminology Criteria for Adverse Events (CTCAE Version 
4.03) toxicity Grade 3 or 4 that is an escalation from his or her status at baseline (prior to the first 
dose) should have subcutaneous azacitidine temporarily discontinued until the toxicity grade 
returns to less than Grade 3. Subcutaneous azacitidine should be permanently discontinued if 
nonhematological toxicity persists at Grade 3 or 4 for more than 21 days, despite the temporary 
interruption of subcutaneous azacitidine.
Dose Modifications due to Hematological Toxicity
Treatment with subcutaneous azacitidine is associated with anemia, neutropenia, and 
thrombocytopenia, particularly during the first 2 cycles. Complete blood counts should be 
performed as specified in Section 6.6.6.1 and as needed to monitor response and toxicity. 
Recovery is defined as an increase of cell line(s) where hematological toxicity was observed of 
at least half of the difference of nadir and the baseline count plus the nadir count (ie, blood count 
at recovery ≥ Nadir Count + (0.5 × [Baseline count – Nadir count]).
Subjects without reduced baseline blood counts (ie, WBC ≥ 3.0 × 109/L and absolute 
neutrophil count [ANC] ≥ 1.5 × 109/L and platelets ≥ 75.0 × 109/L) prior to first treatment
If hematological toxicity is observed following subcutaneous azacitidine treatment, the next 
cycle of subcutaneous azacitidine therapy should be delayed until platelet count and ANC have 
recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. However, if 
recovery has not been achieved within 14 days, the dose should be reduced according to Table 4.
Following dose modifications, the cycle duration should return to 28 days. The reduced dose 
should be maintained during subsequent cycles that are given (unless toxicity develops). A flow 
diagram for the determination of subcutaneous azacitidine dose adjustment in subjects without 
reduced baseline blood counts is provided in Appendix N2.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
82
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Table 4:
Dose Modifications for Subcutaneous Azacitidine in Hematologic Toxicity
Nadir Counts
% Dose in the Next Cycle if 
recoverya is not achieved in next 
14 days
ANC (× 109/L) 
≤ 1.0
> 1.0
Platelets (× 109/L)
≤ 50.0
> 50.0
50%
100%
ANC = absolute neutrophil count
a Recovery = counts ≥ nadir count + (0.5 × [baseline count – nadir count]).
Subjects with reduced baseline blood counts (ie, WBC < 3.0 × 109/L or ANC < 1.5 × 109/L 
or platelets < 75.0 × 109/L) prior to treatment
Following subcutaneous azacitidine treatment, if the decrease in ANC or platelets from that prior 
to treatment is less than 50%, or greater than 50% but with an improvement in any cell line 
differentiation, the next cycle should not be delayed and no dose adjustment made.
If the decrease in ANC or platelets is greater than 50% from that prior to treatment, with no 
improvement in cell line differentiation, the next cycle of subcutaneous azacitidine therapy 
should be delayed until the platelet count and the ANC have recovered. If recovery is achieved 
within 14 days, no dose adjustment is necessary. However, if recovery has not been achieved 
within 14 days, bone marrow cellularity should be determined. If the bone marrow cellularity is> 
50%, no dose adjustments should be made. If bone marrow cellularity is ≤ 50%, treatment should 
be delayed and the dose reduced according to Table 5.
Table 5:
Dose Modifications Based on Bone Marrow Cellularity
Bone Marrow Cellularity
% Dose in the Next Course if recoverya is not achieved in next 
14 days
Recovery ≤ 21 days a
Recovery > 21 days a
15 – 50%
< 15%
100%
100%
50%
33%
a Recovery = counts ≥ nadir count + (0.5 × [baseline count – nadir count])
Following dose modifications, the cycle duration should return to 28 days. The reduced dose 
should be maintained during subsequent cycles that are given (unless toxicity develops). A flow 
diagram for the determination of subcutaneous azacitidine dose adjustment in subjects with 
reduced baseline blood counts is provided in Appendix N1.
Renal Dysfunction During Subcutaneous Azacitidine Therapy
Renal abnormalities ranging from elevated serum creatinine to renal failure and death were 
reported rarely in subjects treated with intravenous azacitidine in combination with other 
chemotherapeutic agents. In addition, renal tubular acidosis, defined as a fall in serum 
bicarbonate to < 20 mmol/L in association with an alkaline urine and hypokalemia (serum 
potassium < 3 mmol/L) developed in 5 subjects with chronic myelogenous leukemia (CML) 
treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
83
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
(< 20 mmol/L) occur, the dose should be reduced by 50% on the next cycle. Similarly, if 
unexplained elevations in serum creatinine or BUN to ≥ 2-fold above baseline values and above 
ULN occur, the next cycle should be delayed until values return to normal or baseline and the 
dose should be reduced by 50% on the next treatment cycle. The reduced dose should be 
maintained during subsequent cycles that are given (unless toxicity develops).
7.2.2.2.
Durvalumab
Please refer to Appendix M for detailed instructions for dose modifications and toxicity 
management.
7.2.3.
Retreatment Criteria 
In order to proceed to the next cycle, subjects must continue to meet entry criteria regarding 
renal and hepatic function (AST/SGOT or ALT/SGPT ≤ 2.5 × ULN, serum total bilirubin ≤1.5 × 
ULN, serum creatinine ≤ 2.5 × ULN). 
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 sponsor’s 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 sponsor’s medical monitor, the subject is 
experiencing clinical benefit. Justification of the subject continuing in the study must be recorded 
in the source documents. Subjects assigned to the combination treatment arm will have 
azacitidine administered on Day 1 of each treatment cycle approximately one hour after 
completion of the durvalumab infusion, after resolution of any related AE immediately after 
durvalumab infusion, if any.
Prior to discontinuing a subject from study treatment, it is recommended that the investigator 
contact the sponsor’s 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.
7.2.4.
Overdose 
7.2.4.1.
Definition of Overdose
Overdose, as defined for this protocol, refers to azacitidine and durvalumab dosing only.
On a per dose basis, an overdose is defined as any amount over the protocol-specified dose of 
subcutaneous azacitidine or intravenous durvalumab assigned to a given subject, regardless of 
any associated AEs or sequelae.
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2.4.1.
D
Overdos
Overdo


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
84
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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 subcutaneous azacitidine, any amount over the protocol-specified dose
!
For IV durvalumab, 10% over the protocol-specified dose.
7.2.4.2.
Actions Taken in the Event of an Overdose 
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form. See 
Section 10.1 for the reporting of AEs associated with overdose.
Use of IP in doses in excess of that specified in the protocol is considered to be an overdose. 
There is currently no specific treatment in the event of overdose of IP, and possible symptoms of 
overdose are not established. 
An overdose with associated AEs will be recorded as the AE diagnosis or symptoms in the 
relevant AE modules of the eCRF and in the Overdose eCRF module.
An overdose without associated symptoms will only be reported in the Overdose eCRF module. 
If an overdose of durvalumab occurs in the course of the study, then the Investigator or other site 
personnel will inform appropriate Celgene representatives immediately, or no later than 24 hours 
of when he or she becomes aware of it. The designated Celgene representative will work with the 
Investigator to ensure that all relevant information is provided to Celgene.
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 10.5.
For other overdoses, reporting must occur within 30 days.
7.2.5.
Discontinuation
Reasons for discontinuing a subject from the investigational product and/or from the study are 
listed in Sections 11.1 and 11.2.
Because a hematologic response to treatment with subcutaneous azacitidine 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 subject’s eCRF and source documents. 
7.3.
Method of Treatment Assignment
Subjects will be enrolled via IRT to ensure timely registration and to facilitate subject tracking 
and IP resupply needs.
Investigator or designated site staff will be assigned password protected, identification numbers 
that give them authorization to call into the IRT to enroll a subject. At screening, the Investigator
or designated staff will call into the IRT and provide the requested identifying information for 
the subject. The IRT will then confirm the assignment of a unique subject number. If a subject is 
screened but not enrolled, the screen-failure must be registered using the IRT. During the 
CCI
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nvestigat
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hat giv
at giv


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
85
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
treatment phase, calls will be placed to the IRT 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 IRT are found in the IRT User Manual.
7.4.
Packaging and Labeling
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
No blinding is applied in this study.
7.5.
Investigational Product Accountability and Disposal 
The Investigator(s) or designee is responsible for taking an inventory of each shipment of 
investigational product received and comparing it with the accompanying shipping 
order/packaging slip. The investigator(s) will verify the accuracy of the information on the 
shipping order/packaging slip and call IRT to register receipt at the site of the investigational 
product.
At the study site, investigational product will be stored in a locked, safe area to prevent 
unauthorized access and should be stored as directed on the product label.
An accurate accounting of the dispensing and return of investigational product for each study 
subject will be maintained in source documents on an ongoing basis by a member of the study 
site staff. Additionally, if any investigational product is lost or damaged or if the study subject 
misses a dose, this information should be documented in the study subject’s eCRF and source 
documents.
Investigational product accountability will be assessed by the Investigator or designee. 
Applicable information such as lot number, vial count, and expiration date should be collected.
The investigator(s) or designee(s) is responsible for accounting for all IP during the course of the 
study according to applicable regulatory requirements. Any unused IP must be 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. 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 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 
CCI
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unit dos
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
86
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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).
7.6.
Investigational Product Compliance
Subjects will receive azacitidine and durvalumab at the investigation site during the study. 
Administration of all IP will be recorded by the Investigator on the subject’s eCRF, including 
dispensing, dosing, and any changes in dosage administration such as interruption or reduction in 
dosing due to an AE. 
CCI
&(/*(1(35235,(7$5<,1)250$7,21
uding
uding
reduction i
reduction 


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
87
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
8.
CONCOMITANT MEDICATIONS AND PROCEDURES
All prior and concomitant medications (prescription and nonprescription), treatments, and 
therapies taken from signing of the ICF up to 28 days after the last dose of subcutaneous 
azacitidine or up to 90 days after the last dose of for durvalumab, or up to the Treatment 
Discontinuation Visit, whichever date is later, must be recorded on the appropriate subject’s 
eCRF. 
All prior treatments for MDS, including ESAs, thrombopoiesis-stimulating agents (TSAs), iron-
chelating agents, or other medications considered supportive care for MDS should be recorded 
on the respective subject’s eCRF(s) regardless of the date of these treatments. All prior 
treatments for AML, as applicable, should also be recorded on the appropriate subject’s eCRF(s).
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.
8.1.
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 granulocyte colony stimulating factor [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. Red blood cell and platelet transfusions will be considered concomitant procedures 
and should be collected on the appropriate subject’s eCRF.
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 randomization. Initiation, modification, and/or 
discontinuation of iron-chelating agents during the treatment phase of the study is discouraged 
and should be discussed with the sponsor’s 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. If 
nausea/vomiting is not significant, further antiemetic prophylaxis may not be needed. 
Pretreatment or posttreatment 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 subject’s eCRF.
Treatment with antidiarrheal medications is recommended at the first sign of diarrhea.
Premedication with antidiarrheal medication for subsequent doses of subcutaneous azacitidine 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
88
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
and/or durvalumab may be appropriate. Pre and posttreatment with an antidiarrheal must be 
recorded in the subject’s eCRF as concomitant medication.
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 × 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 subject’s eCRF. 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 7.2.2 remain applicable. Discontinuation of secondary prophylaxis with myeloid growth 
factors should be considered by the Investigator as clinically appropriate.
Concurrent systemic corticosteroids for non-cancer-related conditions are allowed (eg, insulin 
for diabetes and hormone replacement therapy), provided the subject is on a stable or decreasing 
dose for ≥ 1 week prior to the first dose of IP, and provided the exclusion criteria #17 is met. 
Initiation, modification, and/or discontinuation of corticosteroids during the treatment phase of 
the study is discouraged and should be discussed with the sponsor’s medical monitor first 
whenever possible.
For AML subjects, the use of hydroxyurea is permitted up to 2 weeks prior to the screening 
hematology sample and is prohibited during the whole study participation.
8.2.
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 IV injection, decitabine, or other demethylating agents
!
Lenalidomide, thalidomide, and a proprietary series of drugs with immunomodulatory 
and other properties (IMiDs®)
!
Erythropoiesis stimulating agents and other hematopoietic growth factors (eg, 
interleukin-3)
!
Romiplostim and other TSAs (eg, interleukin-11, eltrombopag)
!
Hydroxyurea for MDS subjects only (for AML subjects, see Section 8.1), 
!
Androgens, unless to treat hypogonadism
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
89
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
!
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, 
azathioprine, and tumor necrosis factor – alpha (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 
sponsor’s medical monitor. 
!
Live attenuated vaccines during the study through 30 days after the last dose of 
durvalumab.
Refer to Section 4.2.2 for exclusion criteria pertaining to prohibited concomitant medications.
8.3.
Required Concomitant Medications and Procedures
There are no required concomitant medications, although prophylactic treatment with an 
antiemetic and/or antidiarrheal medication may be considered and is recommended during the 
first cycle. 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
90
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 2 randomized, multicenter, open-label, study evaluating the efficacy of 
subcutaneous azacitidine in combination with durvalumab in the defined study population (see 
Section 4).
The study will be run in two separate, parallel cohorts with separate inclusion and exclusion 
criteria as well as separate response criteria (MDS and AML).
Subjects in each cohort will be randomized into a monotherapy arm and a combination therapy 
arm with 1:1 allocation ratio using dynamic randomization method. At randomization, subjects 
will be stratified by cytogenetic risk (Intermediate risk versus poor risk for AML cohort, very 
good, good and intermediate risk versus poor and very poor risk for MDS Cohort). In each 
cohort, the study will be conducted in two stages, with an interim analysis for futility purposes 
following completion of the first stage and the primary analysis following completion of second 
stage. The interim analysis for futility will be performed independently in each cohort, and there 
will not be any recruitment hold between stages within each cohort.
The primary objective is to evaluate the efficacy of subcutaneous azacitidine in combination with 
durvalumab as compared with subcutaneous azacitidine alone in the defined study population 
(see Section 4). The secondary objectives are to assess the safety and tolerability of subcutaneous
azacitidine in combination with durvalumab; to assess overall survival, and additional secondary 
efficacy criteria including but not limited to time to response, duration of response, cytogenetic 
responses, proportion of MDS subjects transforming to AML and time to AML transformation, 
and duration of remission in AML subjects; to evaluate the PK profile of durvalumab in 
combination with subcutaneous azacitidine; 
 
This section defines the subject populations for the statistical data analyses, the justifications of 
sample sizes for each cohort, 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.
9.2.
Study Population Definitions
For the purpose of statistical analyses and data presentation, the study populations are defined as 
follows.
9.2.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population will include all randomized subjects. The primary efficacy 
analyses will be performed on the ITT population.
9.2.2.
Efficacy Evaluable Population
The supportive efficacy analyses will be performed on the efficacy evaluable (EE) population, 
which will include all ITT subjects who completed 6 cycles of treatment, unless they have 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
91
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
established an earlier response or who discontinued the study due to death or disease 
progression. 
Subjects who do not have an on-treatment disease assessment and discontinue due to death or
disease progression without postbaseline response assessment will be considered as 
nonresponders.
9.2.3.
Safety Population 
The safety population will include all subjects who take at least 1 dose of IP.
9.2.4.
Pharmacokinetic Population 
The PK population includes all subjects who received at least one dose of study treatment and 
who have at least 1 measurable durvalumab concentration datum. For subjects who are 
determined to be noncompliant with respect to administration of durvalumab, or for subjects with 
incomplete data, a decision as to their inclusion in the population will be made on a case-by-case 
basis prior to the analysis.
9.3.
Sample Size and Power Considerations
9.3.1.
Myelodysplastic Cohort 
Sekeres et al. (Sekeres, 2014) demonstrated that treating subjects with higher-risk MDS resulted 
in an ORR (CR, mCR, PR, HI) of 36% after four cycles of azacitidine monotherapy. This 
number is consistent with the “HI and better” rate from the AZA-MDS-001 trial of 36.4%. 
Assuming a treatment effect of 100% relative improvement of ORR (from 36% to 72% ORR), a 
sample size of 72 subjects will provide a power of 90% to detect such an effect at the 5% level of 
statistical significance.
An interim analysis for futility purpose will be conducted on the first 30 subjects who have 
completed 6 cycles of treatment unless they have established an earlier response (i.e. for arm A, 
6 cycles of durvalumab and azacitidine, arm B, 6 cycles of azacitidine) or discontinued due to 
death or disease progression. The MDS cohort will be completed to include a total of 72 efficacy 
evaluable MDS subjects if one of the below conditions is met: 
!
If the overall response rate (considering the composite score of CR + PR + mCR + 
HI) in the combination arm is numerically higher than or equal to the control group 
(azacitidine alone) or,
!
If the response rate of one of the components of this composite score (in particular 
CR rate) in the combination arm is numerically higher than or equal to the control 
group (azacitidine alone) or,
!
If evidence of a clinical meaningful difference in favor of the combination arm in a 
secondary endpoint (eg, duration of response) is provided.
If none of these conditions is met, then the cohort might be terminated. The DMC will review the 
data at the time of interim analysis and will provide recommendation/advice to Celgene.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
92
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
9.3.2.
Acute Myeloid Leukemia Cohort
Dombret and Fenaux (Dombret, [2015]; Fenaux, [2010]) showed the response (CR + CRi) rate is 
25% in AML subjects treated with azacitidine. Assuming a treatment effect of 100% relative 
improvement of CR (from 25% to 50% absolute CR rates), a sample size of 110 subjects will 
provide a power of 80% to detect such an effect at the 5% level of statistical significance.
An interim analysis for futility purpose will be conducted on the first 50 subjects who have 
completed 6 cycles of treatment unless they have established an earlier response (i.e. for arm A, 
6 cycles of durvalumab and azacitidine, arm B, 6 cycles of azacitidine) or discontinued due to 
death or disease progression. The AML cohort will be completed to include a total of 110 
efficacy evaluable AML subjects if one of the below conditions is met: 
!
If the overall response rate (considering the composite score of CR + CRi) in the 
combination arm is numerically higher than or equal to the control group (azacitidine 
alone) or,
!
If the response rate of one of the components of this composite score (in particular 
CR rate) in the combination arm is numerically higher than or equal to the control 
group (azacitidine alone) or,
!
If evidence of a clinical meaningful difference in favor of the combination arm in a 
secondary endpoint (eg, duration of response) is provided. 
If none of these conditions are met, then the cohort might be terminated. The DMC will review 
the data at the time of interim analysis and will provide recommendation/advice to Celgene.
9.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations. Medical history data will be summarized using frequency tabulations by system 
organ class (SOC) and preferred term (PT).
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for treatment discontinuation and primary reason for study discontinuation) will be 
summarized by disease cohort and treatment arm using frequency and percent for both treatment 
and follow-up phases. A summary of subjects enrolled by site will be provided. Protocol 
deviations/violations will be summarized using frequency tabulations.
9.6.
Efficacy Analysis
Primary efficacy analyses will be performed on the ITT population. Supportive efficacy analyses 
will also be performed using the EE population.
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will also b


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
93
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
9.6.1.
Primary Efficacy Analysis
9.6.1.1.
Primary Efficacy Endpoint
The primary efficacy endpoint will be programmatically derived using the results/assessments 
generated by the central morphologic/cytogenetic and hematology laboratories. This analysis 
will be conducted after completion of the Stage 1 and Stage 2 portions of the study. A subject is 
considered evaluable for response if they have undergone the disease status assessment following 
treatment Cycle 6. Subjects who discontinue from the treatment phase before the first 
postbaseline efficacy assessment (following treatment Cycle 3) and will be replaced unless the 
subject had a documented progression of their disease or died will be considered as 
nonresponders. If one postbaseline disease assessment is performed, this assessment would be 
considered for response.
The primary efficacy analysis will be based on the ITT population. Analysis based on the EE 
population will be confirmative and supportive. Test statistics on the difference of proportion of 
overall response between monotherapy arm and combination therapy arm using unpooled 
estimate of variance will be used for the primary efficacy endpoint analysis along with 
confidence intervals.
9.6.1.1.1. Myelodysplastic Syndromes Cohort
For the MDS cohort, the primary efficacy endpoint is the overall response rate (defined as CR, 
PR, mCR and/or HI) as determined using the IWG 2006 response criteria for MDS. The ORR 
will be summarized together with 95% CI. Subjects discontinued before 6-cycle treatment 
without achieving overall response will be counted as nonresponders.
9.6.1.1.2. Acute Myeloid Leukemia Cohort
For AML cohort, the primary efficacy endpoint is the overall response rate (CR or CRi) based on 
modified IWG 2003 response criteria for AML. The ORR will be summarized together with 95% 
CI. Subjects discontinued before 6-cycle treatment without achieving overall response will be 
counted as nonresponders.
9.6.1.2.
Secondary Efficacy Endpoints
Secondary endpoints are listed in Section 2.
Overall survival is defined as the time between randomization and death/censored date. Subjects 
who die, regardless of the cause of death, will be considered to have had an event. Subjects who 
are alive at the time of clinical data cut-off date will be censored at the last assessment date at 
which the subject was known to be alive. All subjects who were lost to follow-up prior to the 
clinical data cut-off date will also be censored at the time of last contact. The OS curve and OS at 
12 months will be estimated using Kaplan-Meier (KM) method.
Rate of hematological improvement – erythroid response (HI-E), hematological improvement –
platelet response (HI-P) and hematological improvement – neutrophil response (HI-N) according 
to IWG 2006 response criteria (Appendix D), will be assessed for AML subjects as secondary 
efficacy endpoint.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
94
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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 for MDS Cohort, CR or CRi for AML Cohort) is 
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 for the treatment group will be estimated using the KM method.
Duration of response will be calculated only for subjects who achieve CR, mCR, PR or HI for
the MDS Cohort, CR or CRi for the AML Cohort. Duration of response is defined as the time 
from first response observed until relapse or PD. Duration of response will be censored at the last 
date that the subject is known to be progression-free for: 
1. subjects who have not progressed at the time of analysis; 
2. subjects who have withdrawn consent or are lost to follow-up prior to documentation of 
progression. 
Duration of response will be analyzed using the KM method. Median duration of response along 
with two-sided CI will be provided for each cohort.
Relapse-free survival is defined only for subjects who achieve CR, PR or mCR for MDS 
subjects, CR and CRi and for AML subjects, and is measured as the interval from the date of first 
documented response to the date of disease relapse, death from any cause, or lost to follow-up, 
whichever occurs first, censoring for subjects alive in continuous response. The RFS curve will 
be estimated using KM method.
External central pathology/cytogenetic reviewers will review the morphologic/cytogenetic data 
from bone marrow aspirate (BMA), bone marrow biopsies (if performed), and/or peripheral 
blood smears to determine whether a subject achieved a cytogenetic response (complete or 
partial cytogenetic responses for MDS subjects and cytogenetic complete response for AML 
subjects). For cytogenetic response evaluable subjects, the number and percentage of subjects 
who achieve the responses will be summarized.
MDS Cohort:
Progression-free survival is calculated as the time from randomization to the first documented 
progression or death due to any cause during or after the treatment period, whichever occurs 
first. Subjects who are still alive and progression free will be censored at the date of their last 
response assessment. The PFS curve will be estimated using KM method.
For the MDS cohort, transformation to AML and time to transformation to AML will be 
summarized. Time to transformation to AML is defined as the time from the date of 
randomization until the date the subject has documented transformation to AML. Subjects who 
do not transform to AML will be censored at the date of last follow-up, the date of death, or the 
date of study termination. Time to transformation to AML will be estimated using KM method.
9.7.
Safety Analysis
All subjects in the safety population who receive at least one dose of any assigned IP, will be 
included in the safety analyses. Adverse events, vital sign measurements, physical exam 
findings, clinical laboratory data, ECG interpretations, pregnancy tests for FCBP, concomitant
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9.7.
9.7


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
95
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
medications and procedures will be tabulated and summarized by treatment arm, and cohort, as 
appropriate.
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 graded according to CTCAE Version 4.03 criteria (Appendix G). 
The frequency of AEs will be tabulated by MedDRA SOC and PT. In the by-subject analysis, a
subject having the same event more than once will be counted only once. Adverse events leading
to discontinuation from treatment, events leading to dose reduction/interruption/delay, events 
classified as CTCAE Version 4.03 Grade 3 or higher, IP-related events, AESI, imAEs and 
serious AEs will be tabulated and listed separately. By-subject listings of all AEs, and AESIs, 
serious AEs, and their attributes will be provided.
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. Laboratory data 
will be graded according to CTCAE Version 4.03 criteria for select analytes unless otherwise 
specified. The frequencies of the worst severity grade observed during treatment will be 
displayed in cross-tabulations by screening status. Clinically significant hematologic and 
nonhematologic laboratory abnormalities that meet Grade 3 or Grade 4 criteria according to 
CTCAE Version 4.03 will be listed and summarized.
Vital signs and ECG data will be summarized by cross-tabulations presenting normal and 
abnormal values by number of subjects at pre-and post-IP initiation. 
Graphical displays will be provided where useful in the interpretation of results.
9.8.
Interim Analysis
Interim analyses for futility purposes are planned for each cohort as described in Section 9.3. and 
will be based on the EE population.
9.9.
Other Topics
9.9.1.
Assessment of Pharmacokinetics
9.9.1.1.
Pharmacokinetic Analysis
Pharmacokinetic concentration data and summary statistics will be tabulated. Individual and 
mean concentration-time profiles will be generated. The following PK parameters will be 
determined after the first and steady-state doses: peak and trough concentration (as data allow). 
The PK, pharmacodynamics, demographic, safety, and efficacy data collected in this study may 
also be combined with similar data from other studies and explored using population PK and/or 
PK-pharmacodynamic methods. The results of such an analysis will be reported in a separate 
report.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
96
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
97
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
9.10.
Study Committees
9.10.1.
Data Monitoring Committee (DMC)
An external and independent DMC with multidisciplinary representation will be established to 
evaluate the results of the study.
The DMC will review the safety and the efficacy data of the study subjects after completion of 
Stage 1 of each cohort of the study.
The DMC chairman may convene formal DMC meetings if there are any unusual safety/efficacy 
concerns (eg, higher than expected transformation to AML rate observed in the study). The 
sponsor can also request a DMC review of the safety data if other events occur at a higher than 
expected rate. The DMC responsibilities, authorities, and procedures will be detailed in the DMC 
charter.
9.10.2.
Steering Committee
A Steering Committee (SC) will be established by charter. The SC will be comprised of Study 
Investigators, and representatives of Celgene, and may include additional ad hoc members. The 
SC, separate from the DMC, will serve in an advisory capacity to the sponsor and recommend:
!
Changes to the protocol or conduct of the study based upon emerging clinical or 
scientific data from this and/or other studies.
!
Procedures to ensure the safety of subjects and integrity of study data.
!
Procedures to meet the overall goals and objectives of the study.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
98
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE. A diagnosis or syndrome should be recorded on 
the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose eCRF (see Section 7.2.4 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 eCRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on an SAE report form and on the AE eCRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and eCRF but should not be reported 
as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for durvalumab or 
subcutaneous azacitidine 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 
form until 28 days after the last dose of subcutaneous azacitidine (90 days after the last dose of
durvalumab), or until the Treatment Discontinuation Visit, whichever is later as well as AML 
cases and those SAEs made known to the Investigator at any time thereafter that are suspected of 
being related to study treatment (durvalumab, subcutaneous azacitidine).
Adverse events and SAEs will be recorded on the AE page of the eCRF and in the subject’s 
source documents. All SAEs must be reported to Celgene Drug Safety within 24 hours of the 
Investigator’s knowledge of the event by facsimile, or other appropriate method, using the SAE 
Report Form, or approved equivalent form.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
99
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to:
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:
!
a standard procedure for protocol therapy administration. However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
!
routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
the administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling). However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.
!
hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
100
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
!
an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 
!
emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the study treatment (durvalumab, subcutaneous azacitidine), action taken 
regarding the study treatment (durvalumab, subcutaneous azacitidine), and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the CTCAE, Version 4.03; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
Adverse events that are not defined in CTCAE Version 4.03 should be evaluated for 
severity/intensity according to the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death - the event results in death]
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This criterion is not the same as “serious” which is based 
on subject/event outcome or action criteria associated with events that pose a threat to a subject’s 
life or functioning.
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP
(durvalumab, subcutaneous azacitidine) and the occurrence of an AE/SAE as Not Suspected or 
Suspected as defined below:
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
101
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Not suspected:
a causal relationship of the adverse event to study treatment 
(durvalumab, subcutaneous azacitidine) administration is unlikely or 
remote, or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of study 
treatment (durvalumab, subcutaneous azacitidine) caused the adverse 
event. ‘Reasonable possibility’ means there is evidence to suggest a 
causal relationship between the study treatment (durvalumab, 
subcutaneous azacitidine) and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with study treatment (durvalumab, subcutaneous 
azacitidine) as a result of an AE or SAE, as applicable (eg, discontinuation, interruption, or dose 
reduction of study treatment, as appropriate) and report if concomitant and/or additional 
treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from IP;
!
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
!
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
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res
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!


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
102
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as an SAE.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF. If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events. 
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated beta-human chorionic gonadotropin 
[β-hCG] or positive pregnancy test in a female subject of childbearing potential regardless of 
disease state) occurring while the subject is on study treatment, or within 90 days after last dose 
of study treatment (durvalumab, subcutaneous azacitidine), are considered immediately 
reportable events. Investigational product is to be discontinued immediately. The pregnancy, 
suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by email, phone or facsimile, or other appropriate method, using the Pregnancy 
Initial Report Form, or approved equivalent form.
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or 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 study treatment (durvalumab, subcutaneous azacitidine)
should also be reported to Celgene Drug Safety by facsimile, or other appropriate method, within 
24 hours of the Investigator’s knowledge of the event using the SAE Report Form, or approved 
equivalent form.
10.4.2.
Male Subjects
If a female partner of a male subject taking study treatment (durvalumab, subcutaneous
azacitidine) 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 study treatment (durvalumab, subcutaneous 
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0.4.2.
f


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
103
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
azacitidine) should notify the Investigator, and the pregnant female partner should be advised to 
call their healthcare provider immediately.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF. All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form. This instruction pertains to initial SAE reports as well as any follow-up reports.
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 study treatment (durvalumab, 
subcutaneous azacitidine) that occur during the study (from the time the subject signs informed 
consent form until 28 days after the last dose of subcutaneous azacitidine (90 days after the last 
dose of durvalumab), whichever is later or any transformation to AML cases (MDS subjects) and 
those SAE made known to the Investigator at any time thereafter that are suspected of being 
related to study treatment (durvalumab, subcutaneous azacitidine). Serious adverse events 
occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents. If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available. Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety. 
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail. The response time is expected to be no more than five (5) business 
days. Urgent queries (eg, missing causality assessment) may be handled by phone.
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to durvalumab and subcutaneous azacitidine based on the 
Investigator’s Brochures.
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 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
104
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
clinical trials on investigational products for human use (ENTR/CT3) and also in accordance 
with country-specific requirements.
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 eCRF, reported to Celgene Drug Safety if meeting SAE reporting criteria (within 24 
hours) and reported to regulatory authorities in the annual report.
Celgene or its authorized representative shall notify the Investigator of the following 
information:
!
Any AE suspected of being related to the use of study treatment (durvalumab, 
subcutaneous azacitidine) in this study or in other studies that is both serious and 
unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC (see Section 14.3 for record retention 
information).
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.
10.7.
Adverse Events of Special Interest
An Adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and may require close monitoring and rapid 
communication by the Investigator to the sponsor. An AESI may be serious or nonserious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product.
Adverse events of special interest 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 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 aetiology. 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 AE being an imAE, the Investigator should 
promptly contact the Medical Monitor.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
105
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Further information on risks (eg, presenting symptoms) can be found in the current version of the 
Investigator Brochure including guidelines for their evaluation and treatment.
10.7.1.
Transformation to AML (for MDS Cohort only)
Transformation to AML will be monitored as an AESI 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 ICF until death, lost to follow-up, withdrawal of consent for further data 
collection, or study closure, whichever is later.
CCI
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
106
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):
!
Adverse Event
!
Progressive disease
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Pregnancy
!
Other (to be specified on the eCRF).
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor. However, prior to discontinuing 
a subject, the Investigator may contact the sponsor’s medical monitor and forward appropriate 
supporting documents for review and discussion.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
!
Adverse event
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Study Closure
!
Other (to be specified on the eCRF).
The reason for study discontinuation should be recorded in the subject’s eCRF and in the source 
documents.
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cum
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ents.


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
107
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible sponsor’s Clinical 
Research Physician (CRP)/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 sponsor’s CRP/Medical Monitor or designee cannot be reached, 
please contact the global Emergency Call Center by telephone at the number listed on the 
Emergency Contact Information page of the protocol (after title page). This global Emergency 
Call Center is available 24 hours a day and 7 days a week. The representatives are responsible 
for obtaining your call-back information and contacting the on-call Celgene/contract research 
organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the sponsor’s CRP(s) or Medical Monitor or designee for emergency calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
108
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International Council 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.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for GCP and in the local 
regulations. Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an ICF and are 
screened for entry into the study. Subjects who fail screening must have the reason(s) recorded in 
the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records 
(eg, medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information. Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement. Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene. Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 
5 business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
109
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date. The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject. In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised. Study 
subjects participating in the study when the amended protocol is implemented must be 
reconsented with the revised version of the ICF. The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene CRP/Medical Monitor. 
Amendments will be submitted to the IRB/EC for written approval. Written approval must be 
obtained before implementation of the amended version occurs. The written signed approval 
from the IRB/EC should specifically reference the Investigator name, protocol number, study 
title and amendment number(s) that is applicable. Amendments that are administrative in nature 
do not require IRB/EC approval but will be submitted to the IRB/EC for information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
Investigational product can only be supplied to an Investigator by Celgene or its authorized 
representative after documentation on all ethical and legal requirements for starting the study has 
been received by Celgene or its authorized representative. This documentation must also include 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
110
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
a list of the members of the IRB/EC and their occupation and qualifications. If the IRB/EC will 
not disclose the names, occupations and qualifications of the committee members, it should be 
asked to issue a statement confirming that the composition of the committee is in accordance 
with GCP. For example, the IRB General Assurance Number may be accepted as a substitute for 
this list. Formal approval by the IRB/EC should mention the protocol title, number, amendment 
number (if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected AEs as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In 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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
111
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained. Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM. There will be no analysis of data 
generated after the final data cut-off date. As such, any data generated after the final data cut-off 
date will be maintained in the source documents but will not need to be entered into the eCRF.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene SOPs. This 
data will be electronically verified through use of programmed edit checks specified by the 
clinical team. Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary. Resolutions to these issues will be reflected in the 
database. An audit trail within the system will track all changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:
!
Signed ICFs for all subjects;
!
Subject identification code list, screening log (if applicable), and enrollment log;
!
Record of all communications between the Investigator and the IRB/EC;
!
Composition of the IRB/EC;
!
Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);
!
List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
112
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
!
All other source documents (subject records, hospital records, laboratory records, 
etc); 
!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period. 
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
113
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study. All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting. Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator. Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone. During monitoring visits, the facilities, 
investigational product storage area, eCRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs against the appropriate source documentation. Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff. Any necessary 
corrections will be made directly to the eCRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified. Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene. Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives. The Investigator should make every effort to be available 
for the audits and/or inspections. If the Investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene immediately.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
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Confidential and Proprietary
114
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications. Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance. This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes. Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
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MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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EDMS Doc. Number:
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Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
116
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
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Confidential and Proprietary
117
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
118
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
 
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Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
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Confidential and Proprietary
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MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
120
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
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Xerri L, Chetaille B, Seriari N, Attias C, Guillaume Y, Arnoulet C, et al. Programmed death-1 is 
a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic 
lymphoma/chronic lymphocytic leukemia. Human Pathol 2008;39(7):1050-8.
Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng QR, et al.  Expression of 
PD-L1, PD-L2, PD-1, and CTLA4 in myelodysplastic syndromes is enhanced by treatment with 
hypomethylating agent. Leukemia 2014;28(6):1280-8.
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Yoon JH, Cho BS, Kim HJ, Kim JH, Shin SH, Yahng SA, et al,. Outcomes of elderly de novo 
acute myeloid leukemia treated by a risk-adapted approach based on age, comorbidity, and 
performance status. Am J Hematol. 2013;88(12):1074-81.
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of 
therapeutic peptides and proteins in adults. J Clin Pharmacol 2012;52(1):18–28.
Zingg JM, Jones PA. Genetic and epigenetic aspects of DNA methylation on genome expression, 
evolution, mutation and carcinogenesis. Carcinogenesis 1997;18(5):869-82.
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18.
APPENDICES
Appendix A:
Table of Abbreviations
Abbreviation or 
Specialist Term
Explanation
ADL
Activity of daily living
AE
Adverse event
AESI
Adverse event of special interest 
ALT
Alanine aminotransferase (SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time 
ASCT
Allogeneic stem cell transplantation
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the curve
BM
Bone marrow 
BMA
Bone marrow aspirate 
BSC
Best supportive care 
BUN
Blood urea nitrogen
CBC
Complete blood count
CCR
Conventional care regimen 
CHMP
Committee for medicinal products for human use
CI
Confidence interval 
CL
Clearance
Cmax
Maximum observed concentration
CMML
Chronic myelomonocytic leukemia
CML
Chronic myelogenous leukemia
CNS
Central nervous system
CR
Complete remission 
CRi
Complete remission with incomplete blood recovery 
CRP
Clinical Research Physician
CRS
Clinical Research Scientist
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Abbreviation or 
Specialist Term
Explanation
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4 
Ctrough
Trough concentration
DLT
Dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DSUR
Development Safety Update Report
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
eCRF
Electronic case report form
EMA
European Medicines Agency
EOI
End of infusion
 
EOT
End of treatment
ESA
Erythropoietin-stimulating agent 
EU
European Union 
FAB
French-American-British 
Fc
Fragment crystallizable 
FCBP
Female of child-bearing potential 
FDA
Food and Drug Administration
FT3/Free T3
Free Triiodothyronine
FT4/Free T4
Free Thyroxine
GCP
Good Clinical Practice
GGT
Gamma Glutamyltransferase
GM-CSF
Granulocyte macrophage colony-stimulating factor 
G-CSF
Granulocyte colony-stimulating factor 
HBV
Hepatitis B virus 
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Abbreviation or 
Specialist Term
Explanation
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus 
Hgb
Hemoglobin 
HI
Hematological improvement 
HI-E
Hematological improvement – Erythroid response 
HI-NE
Hematological improvement – Neutrophil response
HI-P
Hematological improvement – Platelet response
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen 
HMA
Hypomethylating agent 
HR
Hazard ratio 
 
HSCT
Hematopoietic stem cell transplantation 
IB
Investigator’s brochure 
ICF
Informed consent form
ICH
International Council for Harmonization
IFN-γ
Interferon-gamma
IgE
Immunoglobulin E
IgG
Immunoglobulin G
imAE
Immune-mediated adverse event
IMiD®
A proprietary series of drugs with immunomodulatory and other 
properties
IND
Investigational New Drug
INR
International normalized ratio 
INT-1
Intermediate-1 
INT-2
Intermediate-2
IP
Investigational Product
IPSS
International prognostic scoring system
IPSS-R
Revised - International prognostic scoring system
IRB
Institutional Review Board
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Abbreviation or 
Specialist Term
Explanation
IRT
Integrated Response Technology
ITT
Intent to treat 
IV
Intravenous
IVIG
Intravenous immunoglobulin
IWG
International working group 
KM
Kaplan-Meier 
LDH
Lactate dehydrogenase 
LFTs
Liver Function Tests
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody 
mCR
marrow complete remission
MCV
Mean corpuscular volume 
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCCN
National comprehensive cancer network 
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer 
NYHA
New York Heart Association 
ORR
Objective response rate
OR
Overall response
OS
Overall survival
PCP
Pneumocystis pneumonia
PD
Progressive disease
PD-1
Programmed death-1
PD-L1
Programmed death ligand-1
PD-L2
Programmed death ligand-2
PFS
Progression-free survival
PK
Pharmacokinetics
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Abbreviation or 
Specialist Term
Explanation
PR
Partial remission 
 
PS
Performance status 
PT
Preferred term 
PT/INR
Prothrombin time/international normalized ratio
QoL
Quality of life 
Q2W
Every 2 weeks 
Q3W
Every 3 weeks
Q4W
Every 4 weeks 
RA
Refractory anemia
RARS
Refractory anemia with ring sideroblasts 
RAEB 
Refractory anemia with excess blasts
RAEB-T
Refractory anemia with excess blasts in transformation
RBC
Red blood cell 
RFS
Relapse free survival 
RNA 
Ribonucleic acid
SAE
Serious adverse event
SC
Steering committee
sc
Subcutaneous 
SD
Stable disease 
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOC
System organ class 
SOP
Standard operating procedure
sPD-L1
Soluble program death ligand-1
SUSAR
Suspected unexpected serious adverse reaction
TB
Total bilirubin
TCR
T cell receptor
TEAE
Treatment emergent adverse event
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Abbreviation or 
Specialist Term
Explanation
TIL
Tumor infiltrating lymphocyte 
TNF-α
Tumor necrosis factor-alpha 
TNM
Tumor, node, metastases
TSA
Thrombopoiesis-stimulating agent 
TSH
Thyroid-stimulating hormone 
ULN
Upper limit of normal
US
United States
WBC
White blood cell 
WHO
World Health Organization 
WT
(Body) Weight 
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Appendix B: The World Health Organization (WHO) Classification of the 
Myeloid Neoplasms and Leukemia (Vardiman, 2009)
CMML = chronic myelomonocytic leukemia; MPN-U = myeloproliferative neoplasms unclassified
* For this study CMML subjects will be excluded.
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.
Category
Peripheral Blood
Bone Marrow
Refractory anemia (RA)
Anemia
< 1% blasts
< 1 × 109 monocytes
Erythroid dysplasia
< 10 % myeloid or megakaryocytic dysplasia
< 5% blasts
< 15% sideroblasts 
Refractory anemia with ring 
sideroblasts (RARS)
Anemia
< 1% blasts 
< 1 × 109 monocytes
Erythroid dysplasia
< 10 % myeloid or megakaryocytic dysplasia
< 5% blasts
> 15% sideroblasts
Refractory cytopenia with 
multilineage dysplasia 
(RCMD)
Bi-or pancytopenia
< 1% blasts
< 1 × 109 monocytes
Dysplasia in > 10% of the cells in 2 or more cell lines
< 5% blasts
< 15% sideroblasts
Refractory anemia with 
multilineage dysplasia and 
ring sideroblasts (RCMD-RS)
Bi-or pancytopenia
< 1% blasts
< 1 × 109 monocytes
Dysplasia in > 10% of the cells in 2 or more cell lines
< 5% blasts 
> 15% sideroblasts
Refractory anemia with excess 
blasts type I & II (RAEB-1 & 
RAEB II)
Cytopenia
Type I: 1-5% blasts
Type II: 5-19% blasts 
Uni- or multilineage dysplasia
Type I 5-9% blasts
Type II 10-19% blasts
5q- syndrome
Anemia
Normal or elevated 
platelets
< 5% blasts
Normal or increased megakaryocytes
< 5% blasts
MDS unclassified (MDS-U)
Cytopenia
< 1% blasts
Unilineage dysplasia of myeloid or megakaryocytic 
line
< 5% blasts
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Appendix C: International Prognostic Scoring System for MDS 
(Greenberg, 1997)
Survival and AML Evolution Score Value
Prognostic Variable
0
0.5
1.0
1.5
2.0
Marrow Blasts (%)
< 5
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n/a
11 to 20
21 to 30
Karyotype
Good
Normal or 
any 1 of:
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Intermediate
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chromosome 
anomaly
Poor
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7 anomalies;
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% 3 
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anomalies
n/a
n/a
Cytopenias:
Neutrophil count 
< 1800/&L
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Hb < 10 g/dL
0 or 1
2 or 3
n/a
n/a
n/a
AML = acute myeloid leukemia; Hb = hemoglobin
The total IPSS score and IPSS risk category are calculated as the sum of three individual scores 
based on the marrow blast percentage, the karyotype, and the number of cytopenias.
Risk Category
Combined Score = Sum of Marrow blast + Karyotype + Cytopenia Score
Low
0
Intermediate-1
0.5 to 1.0
Intermediate-2
1.5 to 2.0
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 Working Group (IWG) Response Criteria in 
Myelodysplasia (Cheson, 2006)
Altering Disease Natural History
Complete remission (CR)
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines
Persistent dysplasia will be noted a
Peripheral blood:
-
Hemoglobin ≥ 11 g/dL
-
Platelets ≥ 100 × 109/L
-
Neutrophils ≥ 1.0 × 109/L
-
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 CR
Bone marrow:  ≤ 5% myeloblasts and decrease by ≥ 50% over 
pretreatment
Peripheral blood: if HI responses, they will be noted in addition to 
marrow CR
Stable disease (SD)
Failure to achieve at least PR, but no evidence of progression for
> 8 weeks
Failure
Death during treatment
Disease progression characterized by worsening of cytopenias, increase 
in % of bone marrow blasts, or progression to a more advanced MDS 
FAB subtype than pretreatment
Disease Progression (PD)
For patients with:
! Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts
! 5% - 10% blasts: ≥ 50% increase in blasts to > 10% blasts
! 10% - 20% blasts: ≥ 50% increase in blasts to > 20% blasts
! 20% - 30% blasts: ≥ 50% increase in blasts to > 30% blasts
Any of the following:
! At least 50% decrement from maximum remission/response levels in 
granulocytes or platelets
! Reduction in Hgb concentration by ≥ 2 g/dL 
! Transfusion dependence
a Dysplastic changes should consider the normal range of dysplastic changes (modification).
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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Appendix D: International Working Group (IWG) Response Criteria in 
Myelodysplasia (Cheson, 2006) (Continued)
Altering Disease Natural History
Disease transformation
Transformation to AML (30% or more blasts)
Relapse after CR or PR
At least one of the following:
! Return to pretreatment bone marrow blast %
! 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
Hematological Improvement (HI)
Erythroid response (HI-E)
(Pretreatment < 11 g/dL) 
Hgb 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 Hgb of ≤ 9.0 g/dL pretreatment will count in 
the RBC transfusion evaluation
Platelet response (HI-P)
(Pretreatment < 100 × 109/L)
Absolute increase of ≥ 30 × 109/L for patients starting with > 20 ×
109/L
Increase from < 20 × 109/L to > 20 × 109/L and by at least 100%
Neutrophil response (HI-N)
(Pretreatment < 1.0 × 109/L)
At least 100% increase and an absolute increase of > 0.5 × 109/L
Progression/relapse after HI 
At least one of the following:
! At least 50% decrement from maximum response levels in 
granulocytes or platelets 
! Reduction in Hgb by ≥ 1.5 g/dL
! Transfusion dependence
AML = acute myeloid leukemia; Hgb = hemoglobin; RBC = red blood cell
Source: Cheson BD, Greenberg PL, Bennett JM, Löwenberg 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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Appendix E:
ECOG Performance Status Scale
The ECOG Performance Status Scale is used to score a subject’s quality of life through 
evaluation, by a health professional, of daily activities and how those activities are affected by 
the disease of the subject.
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead
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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Fadden ET, 
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n. Oncol. 198
. Oncol. 19


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Appendix F: New York Heart Association Classification for Congestive 
Heart Failure
Classification of Heart Failure
Class
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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94;90:644
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HeartFailure/A
eartFailure/A


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Appendix G: National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03
Currently active minor version of NCI CTCAE, Version 4.03:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
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Appendix H: Revised International Prognostic Scoring System for MDS –
IPSS-R (Greenberg, 2012)
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
-
Inter-
mediate
Poor
Very Poor
Bone Marrow Blast 
(%)
≤2
-
> 2 - < 5
-
5 - 10
> 10
-
Hemoglobin (g/dL)
≥10
-
8 - < 10
<8
-
-
-
Platelets (× 109/L)
≥100
50 - < 100
< 50
-
-
-
-
ANC (× 109/L)
≥0.8
< 0.8
-
-
-
-
-
ANC = absolute neutrophil count
The total IPSS-R score is calculated as the sum of the cytogenetics, bone marrow blast 
percentage, hemoglobin, platelets and ANC individual scores.
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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
IPSS-R: Prognostic Risk Category Clinical Outcomes
Prognostic variable
No. pts
Very 
Low
Low
Intermediat
e
High
Very 
High
Patients (%)
7012
19%
38%
20%
13%
10%
Median Overall Survival 
(years)
-
8.8
5.3
3.0
1.6
0.8
Median time to 25% AML 
evolution
-
Not 
reached
10.8
3.2
1.4
0.7
Source: Greenberg, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic 
scoring system for myelodysplastic syndromes. 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.
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Appendix I:
The World Health Organization (WHO) Classification of Acute 
Myeloid Leukemia (Swerdlow, 2008)
Acute myeloid leukemia with recurrent genetic abnormalities
Acute myeloid leukemia with t(8;21)(q22;q22); (RUNX1-RUNX1T1)
Acute myeloid leukemia with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); (CBFB-MYH11)
Acute promyelocytic leukemia with t(15;17)(q22;q12); (PML-RARA)
Acute myeloid leukemia with t(9;11)(p22;q23); MLLT3-MLL
Acute myeloid leukemia with t(6;9)(p23q34); DEK-NUP214
Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q26.2); RPN1-EVI1
Acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
Acute myeloid leukemia with gene mutations
Acute myeloid leukemia with myelodysplasia-related changes
Therapy-related myeloid neoplasms
Acute myeloid leukemia, not otherwise categorized
Acute myeloid leukemia with minimal differentiation
Acute myeloid leukemia without maturation
Acute myeloid leukemia with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia)
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
IARC = International Agency for Research on Cancer; WHO = World Health Organization
Source: Swerdlow SH, Campo E, Harris HL, et al. eds. WHO Classification of Tumors of Haematopoietic and 
Lymphoid Tissues. Lyon, France: IARC Press: 2008; 109-139.
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Appendix J:
Risk Status Based on Cytogenetics for Acute Myeloid Leukemia
Risk Groups
Risk Status
Cytogenetics
Molecular Abnormalitiesa
Better-risk
inv(16)b,c
t(16;16)b
t(8;21)b
t(15;17)
Normal cytogenetics:
NPM1 mutation in the absence of 
FLT3-ITD or isolated biallelic 
CEBPA mutation 
Intermediate-risk
Normal cytogenetics
+8
t(9;11)
Other non-defined
t(8;21), inv(16), t(16;16):
with c-KIT d mutation
Poor-risk
Complex (≥ 3 clonal chromosomal 
abnormalities)
Monosomal karyotype
-5, 5q-, -7, 7q-
11q23 - non t(9;11)
inv(3), t(3;3)
t(6;9)
t(9;22)e
Normal cytogenetics:
with FLT3-ITD mutation f
a The molecular abnormalities included in this table reflect those for which validated assays are available in 
standardized commercial laboratories.  Given the rapidly evolving field, risk stratification should be modified 
based on continuous evaluation of research data.  Other novel genetic mutations have been identified that may 
have prognostic significance.  
b Other cytogenetic abnormalities in addition to these finding do not alter risk status.
c Paschka P, Du J, Schlenk RF, Gaidzik VI, Bullinger L, Corbacioglu A, et al. Secondary genetic lesions in acute 
myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML study group (AMLSG). 
Blood 2013; 121:170-177.
d Emerging data indicates the presence of c-KIT mutation in subjects with t(8;21), and to a lesser extent, inv(16), 
confers a high risk of relapse.  These subjects should be considered for clinical trials, if available.
e For Philadelphia+ acute myeloid leukemia (AML) t(9;22), manage as myeloid blast crisis in chronic myeloid 
leukemia (CML), with addition of tyrosine kinase inhibitors.  These subjects are excluded from study entry.
f FLT3-ITD mutations are considered to confer a significant poor outcome in subjects with normal karyotype, and 
these subjects should be considered for clinical trials where available.  There is controversy as whether FLT3-TKD 
mutations carry equally poor prognosis
Source:  
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Acute Myeloid Leukemia. 
National Comprehensive Cancer Network website.  Available at 
http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf.  Accessed 05 Aug 2015.
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Appendix K: Modified International Working Group AML Response 
Criteria (Cheson, 2003)
Hematologic Response According to IWG Criteria for AML
Category 
Definition 
Morphologic Complete 
Remission (CR)
The following conditions should be met:
!
ANC ≥ 1,000/μLb;
!
Platelet count ≥ 100,000/μL; 
!
The bone marrow should contain less than 5% blast cells; 
!
Auer rods should not be detectable;
!
Independent of transfusions
Morphologic Complete 
Remission with Incomplete 
Blood Count Recovery 
(CRi)
Defined as a morphologic complete remission but the ANC count may be 
< 1,000/μL and/or the platelet count may be < 100,000/μL.
Cytogenetic Complete 
Remission (CRc)
Defined as morphologic complete remission with a reversion to a normal 
karyotype.
Partial Remission (PR)
Defined as an ANC ≥ 1,000/μL and platelet count ≥ 100,000/μL with a > 50% 
decrease in the percentage of bone marrow blasts to 5% to 25% (a blast count 
value of  ≤ 5% may also be considered a partial remission if Auer rods are 
present).a, b
Relapse after CR or CRi
Defined as 
1) the reappearance of > 5% blasts in the peripheral blood, or 
2) a single finding of > 15% blasts in the bone marrow.
All of the above occurrences should be attributed to relapse following CR or 
CRi and not attributable to another cause (eg, bone marrow regeneration after 
consolidation therapy)b.
Treatment Failure
Aplasia: Subject survives ≥ 7 days post chemotherapy; death while cytopenic, 
with aplastic bone marrow.
Indeterminate Cause: 
!
Subjects who die < 7 days posttherapy
!
Subjects who die ≥7 days posttherapy with no peripheral blood 
blasts, but no bone marrow examination b
!
Subjects who die without completing the first course of therapy
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Category 
Definition 
Progressive Diseaseb
Defined as: 
1) a > 50% increase in bone marrow blast count percentage from the baseline 
bone marrow blast count that persists for at least 2 bone marrow assessments 
separated by at least 1 month, unless the baseline bone marrow blast count is > 
70%, in which case, a finding of > 70% blasts that persists for 2 postbaseline 
bone marrow assessments separated by at least 1 month would be considered 
progression, or
2) a doubling of the baseline absolute peripheral blood blast count that persists 
for at least 7 days and the final absolute peripheral blood blast count is > 10 ×
109/L. The date of progressive disease is defined as the first date that there was 
either a > 50% increase in bone marrow blast count from baseline, a persistence 
of bone marrow blasts > 70% in subjects with a baseline bone marrow blast 
count of > 70%, or a doubling of the peripheral blood blast count.
ANC = absolute neutrophil count
a If the pretreatment bone marrow blast percentage was 50% to 100%, the percentage of blasts must decrease to a value between 
5% and 25%; if the pretreatment blast percentage was 20% to less than 49%, they must decrease by at least half to a value of 
more than 5%.
b Modification to IWG response criteria.
Notes: Deletions to the IWG response criteria are not shown.
Source: Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the International Working Group for 
diagnosis, Standardization of response Criteria, Treatment Outcomes, and reporting Standards for Therapeutic Trials in Acute 
Myeloid Leukemia. J Clin Oncol 2003;21:4642-9.
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CCI
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CCI
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Appendix M: Dosing Modification and Toxicity Management Guidelines for Immune-mediated, Infusion-
related, and Nonimmune–mediated Reactions (MEDI4736) 01 Nov 2017 Version
General Considerations
Dose Modifications
Toxicity Management
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 regimen 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.
3.
Doses of prednisone are at ≤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.
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold IP/study 
regimen, and if complete work up shows no evidence of pancreatitis, IP/study 
regimen may be continued or resumed.
It is recommended that management of immune-mediated adverse events 
(imAEs) follows 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 (e.g., disease progression, concomitant medications, and 
infections) 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 (>3 to 5 days) low-grade (Grade 2) or severe (Grade 
≥3) events, promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.
−
Some events with high likelihood for morbidity and/or mortality –
e.g., 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 [e.g., up 
to 2 to 4 mg/kg/day PO or IV 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 
(e.g., infliximab) (also refer to the individual sections of the imAEs 
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General Considerations
Dose Modifications
Toxicity Management
IP Note: IP/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., 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 – e.g., 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 (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes 
mellitus).
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 – e.g., 
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/study regimen is not mandated for Grade 3/Grade 4 
inflammatory reactions attributed to local tumor response (e.g., inflammatory 
reaction at sites of metastatic disease and lymph nodes). Continuation of 
IP/study regimen 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; IV 
intravenous; NCI National Cancer Institute; PO By mouth.
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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 (e.g., 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 
(e.g., 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, 
CCI
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
146
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 [e.g., 
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 (e.g., 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 (e.g., 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 
CCI
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Promptly
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
147
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
alternative etiology (e.g., 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 (e.g., 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 (e.g., 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 
CCI
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
148
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., 
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
CCI
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aution: it is
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
149
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., 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 (e.g., 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 (i.e., 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
CCI
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1.1.
reat as
reat as
s to Grade 
s to Grade ≤1
≤1
me IP/study
me IP/study
completion o
completi
er.
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aluate liver fu
aluate liver f
B.
for alternativ
for alternativ
e progression
progres
50
1:
1:
Continue LF
Continue L
1)
For Gra
For G
$5
7$


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
150
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (i.e., 
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 (i.e., 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
CCI
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t 
nases 
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s in bilirubin
s in bilirubin
nue IP/study 
ue IP/study
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discontin
r any case m
any case m
eria (AST an
eria (AST an
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itial findings
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Management
Managemen
7,2
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Inflixim
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50
7$


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
151
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., viral hepatitis, 
disease progression, concomitant medications, 
worsening of liver cirrhosis [e.g., 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
CCI
&(/
pri
prietet
(/*(1(
1(
1(
ether 
(1(
vated at 
*(1
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Management
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
152
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., 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 (i.e., liver ultrasound), and consider starting 
immunosuppressives (i.e., 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 (e.g., 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 
CCI
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
153
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., 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
CCI
&(/
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
154
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., 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 (e.g., 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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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
155
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
156
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., diphenhydramine or hydroxyzine) and 
topical therapy (e.g., 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 (e.g., diphenhydramine or hydroxyzine) and 
topical therapy (e.g., 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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
157
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., 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 
(e.g., 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 (e.g., thyroiditis, 
pancreatitis, hypophysitis, or diabetes insipidus), the 
investigator should send a blood sample for appropriate 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
158
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., 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 (e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt 
initiation of treatment with relevant hormone 
replacement (e.g., 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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
159
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., 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 
(e.g., 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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
160
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., disease progression, infections, metabolic 
syndromes, or medications).
−
Monitor subject for general symptoms (headache, 
nausea, vertigo, behavior change, or weakness).
−
Consider appropriate diagnostic testing 
(e.g., 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 (e.g., 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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
161
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., IV IG).
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 
(e.g., IV IG).
−
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 (e.g., 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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
162
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 
(e.g., 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 IV IG and followed by 
plasmapheresis if not responsive to IV IG.
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 (e.g., gabapentin or 
duloxetine).
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
163
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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
Subjects unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or 
IV IG. 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 IV IG and followed by plasmapheresis if 
not responsive to IV IG.
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:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
164
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 
IV IG.
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 IV IG and followed by plasmapheresis if 
not responsive to IV IG.
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 (e.g., 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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1(


EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
165
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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 (e.g., disease progression, other 
medications, or infections)
Grade 1
(asymptomatic with 
laboratory (e.g., 
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-
- 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 (e.g., 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 
(e.g., 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, 
CCI
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
166
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
threatening 
consequences; urgent
intervention 
indicated (e.g., 
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.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
167
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 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, 
creatine kinase, aldolase, LDH, BUN/creatinine, 
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 (i.e., 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 (e.g., 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 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
168
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Neurology consultant 
−
If clinical course is not rapidly progressive, start 
systemic steroids (e.g., 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 (e.g., 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 (e.g., 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 
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
169
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of 
the Event (NCI 
CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
using infliximab.
−
Consider whether subject may require IV IG, 
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
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.
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate 
aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung 
disease; imAE immune-mediated adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; 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.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
170
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Infusion-Related Reactions
Severity Grade of the 
Event (NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:
−
Manage per institutional standard at the discretion of 
investigator.
−
Monitor subjects for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or 
itching, alterations in heart rate and blood pressure, dyspnea 
or chest discomfort, or skin rashes) and anaphylaxis 
(e.g., generalized urticaria, angioedema, wheezing, 
hypotension, or tachycardia).
Grade 1 or 2
For Grade 1:
The infusion rate of IP/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the 
event.
For 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.
For Grade 1 or 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 3 or 4
For Grade 3 or 4:
Permanently discontinue IP/study regimen.
For Grade 3 or 4:
−
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV 
diphenhydramine and ranitidine, and IV glucocorticoid).
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute.
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EDMS Doc. Number:
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
171
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Non–Immune-Mediated Reactions
Severity Grade of the Event 
(NCI CTCAE version 4.03)
Dose Modifications
Toxicity Management
Any Grade
Note: Dose modifications are not required for AEs 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 modifications.
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, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the Sponsor.).
Treat accordingly, as per institutional standard.
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.
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: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
172
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Appendix N1: Azacitidine Dose Modifications due to Hematologic Toxicity –
Subjects with Reduced Baseline Blood Counts
CCI
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
173
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Appendix N2: Azacitidine Dose Modifications due to Hematologic Toxicity –
Subjects without Reduced Baseline Blood Counts
CCI
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
174
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Appendix O: Optional Extension Phase 
Subject Eligibility
At the end of trial (Section 3.3), at the Investigator’s discretion, subjects who continue to benefit 
from treatment with subcutaneous azacitidine and/or durvalumab, without unacceptable toxicities 
and who have met criteria for treatment continuation may continue to receive subcutaneous 
azacitidine and/or durvalumab provided by the sponsor through this protocol. (See Safety 
Review and Update, below)
At the Investigator’s discretion, subjects meeting all the following continuation criteria are 
eligible to enter the optional extension phase: 
1. Subjects who have signed the addendum informed consent for the extension phase of the 
study.
2. Subjects who do not meet any of the following treatment discontinuation criteria (see 
Section 11):
!
Adverse Event
!
Progressive disease
!
Withdrawal by subject
!
Lost to follow-up
!
Pregnancy.
3. Subjects who continue to show clinical benefit from study treatment as per the 
Investigator’s assessment (See Section 6.7.4 for MDS and AML continuation criteria).
Subjects will start the extension phase at the time of the next regularly scheduled dosing cycle 
for study drug azacitidine or azacitidine and durvalumab.
Safety Review and Update
The study has been closely monitored by the independent Data Monitoring Committee (DMC) as 
described in the protocol. Following a planned and recent review (December 2018) of both 
safety and efficacy data, the DMC noted that that there may not be an added benefit of 
durvalumab plus azacitidine in terms of efficacy, and there exists a potential for late events such 
as cytopenias and immune mediated adverse events (ImAEs). Accordingly, the DMC advised to 
discontinue administration of durvalumab and continue only azacitidine for all ongoing study 
subjects.  Before implementing DMC recommendation, a thorough review of safety and efficacy 
data of all ongoing subjects was conducted along with a literature review of long-term safety on 
Durvalumab. No new safety concerns were identified. This was presented to the DMC in January 
2019. 
The DMC assessed individual safety and efficacy data for all ongoing subjects on long-term 
therapy (≥ 12 cycles). Upon review of the additional data, the DMC recognized that individual 
subjects may be impacted by indiscriminate discontinuation of durvalumab. In their 
recommendation following the second meeting, the DMC noted that Celgene may continue 
treatment with durvalumab in subjects who are actively being treated on the combination arm 
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
175
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
and wish to continue following careful review of the efficacy and toxicity data and the DMC’s 
report for the study.
Celgene, upon careful review of all safety and efficacy data and risk benefit ratio, which remains 
acceptable, decided to allow the continuation of durvalumab and azacitidine for those subjects 
who wish to continue the combination treatment based on a discussion with their investigator or 
continue on azacitidine alone. Subjects on azacitidine monotherapy who continue to receive 
clinical benefit will be allowed to continue treatment as planned. Celgene will continue to 
monitor safety including late events in subjects who are actively receiving durvalumab in the 
combination treatment arm of both MDS and AML cohorts.
Dosage and Regimen During the Extension Phase
The dosing and schedule in the extension phase should follow the same treatment administration 
and schedule as outlined in the protocol (Section 7.2).  The dose for the first treatment cycle in 
the extension phase should be the same dose the subject received during the final treatment cycle 
prior to the extension.
Extension Phase Treatment Cycles
Cycles should be repeated every 28 days. For subjects on combination therapy, durvalumab is 
administered Day 1 of each cycle. Azacitidine is administered Days 1 to 7 of each cycle. 
Azacitidine is to be administered one hour after completion of the durvalumab dose on Day 1.
Dosage delay or reduction may be necessary as described below.
Dose Modification and Toxicity Management
Please follow the Dose Modification and Toxicity Management guidance as outlined in the 
protocol (Section 7.2.2, Appendix N1, and Appendix N2).  
Adverse Event Reporting
Only SAEs should be reported (see Section 10.5 of the protocol for SAE reporting guidance). All 
SAEs must be reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge 
of the event by facsimile, or other appropriate method (eg, via email), using the SAE Report 
Form, or approved equivalent form. This instruction pertains to initial SAE reports as well as any 
follow-up reports. Serious Adverse Events will NOT be entered into an eCRF.
Concomitant Medications
All concomitant medications that are necessary for the subject’s welfare and are unlikely to 
interfere with azacitidine or durvalumab may be given at the Investigator’s discretion during the 
extension phase.  However, treatment with another investigational medication is not permitted. 
Monitoring of Subjects
The subjects included in the extension phase will be monitored according to the standard of care 
at the site. Source documentation (medical records, laboratory reports, investigator notes, disease 
assessments, etc) needs to be complete and accessible for review as required. Data collection in 
the eCRF will stop, but the IRT system remains to track study visits and IP accountability.
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
176
MEDI4736-MDS-001 Amendment 3.0 Final: 05 Mar 2019
Investigator’s Responsibility
1. Document and report only serious adverse events and pregnancies as required by the 
protocol. A completed SAE and/or pregnancy form must be faxed to Celgene Drug 
Safety, as detailed in the Serious Adverse Event Report Form Completion Guidelines or
Pregnancy Report Form Completion Guidelines, immediately (ie, within 24 hours of the 
Investigator’s knowledge of the event). (see Section 10.5).  
2. The subject should stop treatment if any of the following occur:
a.
Additional investigational treatment is started
b. Subject is no longer receiving clinical benefit, as per Investigator discretion
c.
Subject withdraws consent
d. At the specific request of the sponsor or its authorized representative.
3. The Investigator must be available for a monitoring visit (if necessary) and allow the 
sponsor access to all medical records.
4. The Investigator will maintain documentation in the subjects’ medical chart for the 
following:
a.
Informed consent
b. Adverse events and Serious Adverse Events to allow for monitoring of possible late 
events
c.
Dosing information (date of administration, dose administered) 
d. Extension Phase termination date and reason.
Note: There will not be an eCRF for data collection in the extension phase of this study. The 
only data collection for reporting to the sponsor is for SAEs. These will be reported to the 
sponsor Safety department as outlined in the protocol (See Section 10.5). Therefore, any 
reference to eCRF entries in the protocol are no longer applicable after the final analysis cut-off 
date.
End of the Extension Phase
The extension phase will be considered complete when the last subject included in this phase 
completes their last treatment cycle and has been followed-up as per the site standard of care. 
Subjects should be followed for safety up to 28 days for azacitidine and up to 90 days for 
durvalumab after the last dose of corresponding study drug.
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EDMS Doc. Number: 
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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EDMS Doc. Number: 
Durvalumab
Summary of Changes MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
3
MEDI4736-MDS-001 Amendment #3.0 Final: 05 Mar 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
The primary update via this amendment is the addition of Appendix O that describes the 
extension phase. The purpose of this amendment is to provide an extension to the study to allow 
patients who were benefiting from treatment to continue treatment with either azacitidine alone 
or azacitidine and durvalumab (depending on their randomization in the main study) now that the 
study is ending. The only change to the body of the protocol is in Section 3.3.
Subjects who enter the extension phase will continue to be seen and treated by the investigator. 
The amendment does not require any laboratory work, testing or assessment other than 
investigator reporting of serious adverse events SAEs as stipulated under the full protocol. 
Subjects will be receiving standard of care for their condition.
In addition, the independent data monitoring committee (DMC) reviewed the safety and efficacy 
results as described in the protocol in December 2018 and January 2019. Their initial
recommendation was to stop on-study durvalumab treatment for all patients and to continue with 
AZA alone in both arms. However, they recognized that individual patients may be impacted by 
indiscriminate drug discontinuation, both in a positive direction and in a negative direction due 
to the chance of serious adverse events when continuing with durvalumab. Therefore, they noted 
that Celgene may wish to continue treatment with durvalumab in patients who are actively being 
treated on the combination arm and wish to continue following careful review of the efficacy and 
toxicity data and the DMC’s report on the MEDI4736-MDS-001study.
Title Page (updated)
1. Sponsor address updated.
Section 3.3 (updated)
2. Includes a reference to Appendix O.
3. Procedural directions for subjects not entering the extension.
Section 14.1 (updated)
1. Statement to clarify that data analysis will not be conducted on data generated after the 
final data cut-off date and therefore this data to be recorded in the source documents and 
not in the electronic case report form (eCRF).
Appendix O (new)
1. Defines eligibility for subject enrollment into the extension based on the investigator
assessment. 
2. Places subjects in a standard of care situation. Celgene will provide the investigational 
product (IP), but the office visits and all other procedures (laboratory assessments, bone 
marrow biopsy/aspirate, etc) are at the discretion of the investigator and are not part of 
the protocol.
3. Establishes the documentation that is required in the subjects’ medical chart. 
a.
There will not be a clinical database; no data collected in an eCRF
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EDMS Doc. Number: 
Durvalumab
Summary of Changes MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
4
MEDI4736-MDS-001 Amendment #3.0 Final: 05 Mar 2019
b. Investigator will document all adverse events and report to the sponsor only the 
serious adverse events and pregnancies as required by the main protocol.
4. The Extension phase will end when the last subject included in this phase completes their 
last treatment cycle and has been followed-up as per the site standard of care. 
5. In addition, Appendix O details the following:
a.
Dosing, dose modification and treatment cycles
b. Adverse event reporting
c.
Investigator’s responsibilities
d. Safety Review and Update – includes the DMC reviews, Celgene review of safety 
in long-term treatment (≥12 cycles), and the decision to continue treating subjects 
with durvalumab plus azacitidine for those subjects who wish to continue the 
combination treatment based on a discussion with their investigator or continue 
on azacitidine alone.
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
3
MEDI4736-MDS-001 Amendment 2.0 Final: 26 Dec 2017
1.
JUSTIFICATION FOR AMENDMENT
This protocol was amended as follows:
 
 
 
 
 
   
 
 
 
 
2. Update of the Therapeutic Area Head on the Celgene Therapeutic Area Head Signature 
Page
3. The dosing modification and toxicity management guidelines (Appendix M of the 
protocol) have been updated following a durvalumab investigator’s brochure (IB) update.
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(abbreviated as imAE), and the term, “immune-related etiology”, has been changed to 
“immune-mediated etiology” throughout the protocol text and in Appendix A, Table of 
Abbreviations.
5. Editorial updates were made throughout the protocol to correct superscript formatting 
(updating “109” to “109”).
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
3
MEDI4736-MDS-001 Amendment 1 Final: 27 Mar 2017
1.
JUSTIFICATION FOR AMENDMENT
Protocol Amendment 1.0 was written to provide clarification language and ensure the protocol is 
more precise on certain aspects.
Significant changes included in this amendment are summarized below:
!
Clarification on the cytogenetic risk stratification:
By opposing intermediate versus poor and very poor, it was misleading in the very few 
occasions where subjects with good/very good cytogenetic risk were enrolled. This 
modification will have no impact on stratification in Interactive Response Technology 
(IRT), and no impact on study population. Revised wording: “Very good, good and 
intermediate versus poor and very poor for MDS (Appendix H)”.
Revised sections:  Protocol Summary, Section 3.2.2 “Treatment Phase”, Section 9.1 
“Overview”.
!
Clarification on good cytogenetic risk AML patients. As per National Comprehensive 
Cancer Network (NCCN) guidelines, document that is used for reference, Good 
cytogenetic risk patients are to be excluded from this protocol, unless associated with c-
kit mutation. Clarification has been added to allow recruitment of such patients.
Revised section:  Section 4.2.2 “Exclusion criteria No. 33”.
!
Addition of an extra exclusion criteria, based on Investigator feedback. There has been 
one case of worsening Sweet Syndrome while on study treatment. As this is a rare 
condition, this should not affect patient population and recruitment.
Revised section:  Section 4.2.2 “Exclusion criteria No. 35”.
!
Table of events has been updated to reflect the following modifications:
Vital signs will be required at each visit. The Clinical team wants to reinforce patients’ 
monitoring, so everytime a patient will come for a visit (eg, for blood draw), patients will 
have their vital signs checked (blood pressure, pulse, body temperature and respiratory 
rate) by the principal investigator (PI)/nurse.
Chemistry tests frequency increased from cycle 3 onwards. Starting cycle 3 onwards the 
chemistry test was scheduled on Day 1 of each cycle. In order to increase patients’ 
monitoring the decision was made to perform chemistry tests on Day 1 and Day 15 of all 
cycles.
Bone marrow aspirate for disease assessment. The window for bone marrow collection 
has been extended to allow more flexibility. Instead of collecting bone marrow aspirate 
on Day 22 of the concerned cycles +/- 3 days, it will be required to perform the bone 
marrow aspirate prior to the next cycle.
Revised sections:  Section 5 “Table of events”, Footnote p of the Table of events, Section 
6.6.3 “Physical examination, Vital signs and Weight”, Section 6.6.6.2 “Biochemistry 
parameters” and Section 6.7.1 “Bone Marrow aspirate”.
!
Patient population in the statistical section has been made more precise, to clarify that the 
efficacy evaluable population is the intent to treat (ITT) population who completed 6 
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
4
MEDI4736-MDS-001 Amendment 1 Final: 27 Mar 2017
cycles of treatment, unless they have established an earlier response or who discontinued 
study due to death or disease progression. Precision has also been made for the interim 
analyses for both cohorts. The subjects part of these interim analyses will be subjects who 
have completed 6 cycles of assigned treatment (ie, for arm A, 6 cycles of durvalumab and 
azacitidine, arm B, 6 cycles of azacitidine), unless they have established an earlier 
response or discontinued due to death or disease progression.
This clarification has been made to ensure that interim conclusions are made based on 
subjects who have received 6 cycles of the assigned study treatment and were sufficiently 
exposed.
Revised sections:  Section 9.2.2 “Efficacy Evaluable Population”, Section 9.3.1
“Myelodysplastic Cohort”, Section 9.3.2 “Acute Myeloid Leukemia Cohort”.
!
Adverse events of special interest (AESI) definition has been further defined to include 
Astra Zenecca-Medimmune recommended language for durvalumab AESIs and
harmonized with other durvalumab protocols.
Revised section:  Section 10.7 “Adverse Events of Special Interest”.
The amendment also includes several other updates, clarifications and corrections:
!
Clinical Research Physician (CRP) name change:
 has been replaced by 
Revised sections:  Medical Monitor/Emergency Contact Information.
!
Wherever possible, the term “patient” has been replaced by “subjects”
!
Change in contraception wordings under Inclusion Criteria to comply with Clinical Trial 
Facilitation Group Recommendations related to contraception and pregnancy testing in 
clinical trials.
Revised section:  Section 4.2.1 “Inclusion criteria No. 3b and No. 4”.
!
Modification of the wording describing the 2 stages of recruitment. The sentence 
“determining whether that cohort proceeds to Stage 2” has been removed. The reason is 
that given the actual recruitment, it is likely that stage 2 of the cohort will be already 
completed at the time of interim analysis conclusions.
Revised sections:  Protocol Summary, Section 3.1 “Study design”, Section 9.1 
“Overview”.
!
Clarification on sample size: Addition of the word “evaluable” patients. This will allow 
for a slight over recruitment to replace those not evaluable patients.
Revised sections:  Protocol Summary, Section 4.1 “Number of subjects”, Section 9.3.1 
“Myelodysplastic Cohort”, Section 9.3.2 “Acute Myeloid Leukemia Cohort”.
!
Revision of the introduction to reflect Azacitidine Investigator Brochure updates.
Revised section:  Section 1.3.1 “Clinical Safety Experience with Azacitidine”.
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EDMS Doc. Number: 
Durvalumab (MEDI4736)
Summary of Changes MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
5
MEDI4736-MDS-001 Amendment 1 Final: 27 Mar 2017
!
Revision of the introduction to reflect Durvalumab Investigator Brochure updates.
Revised sections:  Section 1.4.1 “Durvalumab Experience in Solid Tumors”, Section 
1.4.2 “Durvalumab Experience in Myelodysplastic Syndromes.
!
Clarification on the granulocyte colony-stimulating factor (G-CSF) use prior to study 
entry. It is allowed providing a wash-out period of 28 days is respected.
Revised section:  Section 4.2.2 “Exclusion criteria No. 5”.
!
Clarification on Hydroxyurea use prior to study entry. It is prohibited within the 2 weeks 
prior to obtaining the screening hematology sample and also prior to the first dose of 
investigational product (IP).
Revised section:  Section 4.2.2 “Exclusion criteria No. 26 and No. 30”.
!
Dose modification and toxicity management wording for azacitidine has been revised. 
Flexible language has been added to let the investigator decide on dose modification 
taking into consideration the patient’s condition. Wording must be considered more as a 
guidance and is to be followed at the investigator’s discretion.
Revised section:  Section 7.2.2.1 “Azacitidine”.
!
Update to Durvalumab Treatment Modification and Toxicity Management Guidelines 
(Appendix M).   
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE 2 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
AZACITIDINE SUBCUTANEOUS IN COMBINATION WITH 
DURVALUMAB (MEDI4736) IN PREVIOUSLY UNTREATED 
SUBJECTS WITH HIGHER-RISK MYELODYSPLASTIC
SYNDROMES (MDS) OR IN ELDERLY (≥ 65 YEARS) ACUTE 
MYELOID LEUKEMIA (AML) SUBJECTS NOT ELIGIBLE FOR 
HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)
FUSION HR MDS/ELDERLY AML 001 STUDY
STUDY DRUG:
Durvalumab (MEDI4736) + Azacitidine
PROTOCOL NUMBER:
MEDI4736-MDS-001
DATE DRAFTED:
23 Oct 2017
Prepared by:
On behalf of 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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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ............................................................................................1
TABLE OF CONTENTS............................................................................................................2
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION..................................................................................................10
3.
OBJECTIVES ........................................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................12
4.1.
Overall Study Design and Plan ...............................................................................12
4.2.
Stratification, Randomization, and Blinding............................................................17
4.3.
Sample Size............................................................................................................19
4.3.1.
MDS Cohort...........................................................................................................19
4.3.2.
AML Cohort...........................................................................................................20
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................22
5.1.
Reporting Conventions ...........................................................................................22
5.1.1.
Dates Handling.......................................................................................................22
5.1.2.
Calculations Using Dates........................................................................................23
5.1.3.
Calculation of Cycles..............................................................................................23
5.1.4.
Descriptive Statistics ..............................................................................................24
5.2.
Analysis Populations ..............................................................................................24
5.2.1.
Intent to Treat Population .......................................................................................24
5.2.2.
Efficacy Evaluable Population................................................................................24
5.2.3.
Safety Population....................................................................................................24
5.2.4.
Pharmacokinetic Population....................................................................................24
5.3.
Definitions..............................................................................................................25
5.3.1.
Date of First Administration of Study Treatment ....................................................25
5.3.2.
Date of Last Administration of Study Treatment.....................................................25
5.3.3.
Study Day...............................................................................................................25
5.3.4.
Baseline..................................................................................................................25
6.
SUBJECT DISPOSITION......................................................................................26
7.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................28
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
3
7.1.
Background and Demographic Characteristics........................................................28
7.2.
Baseline Characteristics..........................................................................................28
7.3.
Medical History......................................................................................................29
7.4.
Prior Medications ...................................................................................................29
7.5.
Prior Anticancer Therapy........................................................................................29
8.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................30
8.1.
Treatment Exposure and Duration...........................................................................30
8.2.
Cumulative Dose: ...................................................................................................31
8.3.
Average Daily Dose................................................................................................31
8.4.
Treatment Compliance............................................................................................31
8.5.
Dose Intensity.........................................................................................................31
8.6.
Relative Dose Intensity...........................................................................................31
8.7.
Dose Modification..................................................................................................32
9.
CONCOMITANT MEDICATIONS/PROCEDURES AND SUBSEQUENT 
THERAPY .............................................................................................................33
9.1.
Concomitant Medications .......................................................................................33
9.2.
Concomitant Procedures.........................................................................................33
9.3.
Subsequent Therapy ...............................................................................................33
10.
EFFICACY ANALYSIS ........................................................................................34
10.1.
Primary Efficacy Endpoint......................................................................................34
10.2.
Secondary Efficacy Endpoints ................................................................................36
10.3.
Eastern Cooperative Oncology Group Performance Status......................................40
11.
PHARMACOKINETIC ANALYSIS......................................................................42
12.
SAFETY ANALYSIS ............................................................................................43
12.1.
Adverse Events.......................................................................................................43
The incidence rate per 100 person-years will also be derived for each AESI..............................47
12.2.
Clinical Laboratory Evaluations..............................................................................47
12.4.
Vital Sign Measurements........................................................................................47
12.5.
Electrocardiogram ..................................................................................................47
14.
INTERIM ANALYSIS...........................................................................................50
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
4
14.1.
General Information................................................................................................50
14.2.
Statistical Approaches for Control of Alpha............................................................50
15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................51
16.
REFERENCES.......................................................................................................52
17.
APPENDICES........................................................................................................53
17.1.
Date Imputation Guideline......................................................................................53
17.1.1.
Impute Missing AE/Prior or Concomitant Medications Start Dates.........................53
17.1.2.
Impute Missing AE/ Prior or Concomitant Medications Stop Dates ........................53
17.1.3.
Impute Missing Disease Diagnosis Dates................................................................54
17.1.4.
Impute Missing Dates in Prior Cancer Regimen......................................................54
17.1.5.
Impute Missing Dates in Subsequent Cancer Therapy.............................................54
17.2.
International Working Group (IWG) Response Criteria in Myelodysplasia 
(Cheson, 2006) .......................................................................................................55
17.3.
Modified International Working Group AML Response Criteria 
(Cheson, 2003) .......................................................................................................59
17.4.
Revised International Prognostic Scoring System for MDS – IPSS-R 
(Greenberg, 2012)...................................................................................................62
17.5.
Risk Status Based on Cytogenetics for Acute Myeloid Leukemia ...........................64
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Study Endpoints .....................................................................................................15
Table 3:
Number of days to be covered by the last dose........................................................31
Table 4:
Event and Censoring Rules for Progression-free Survival, Duration of 
Response, Time-to-Response and Relapse-free Survival.........................................39
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................13
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
AML
Acute myeloid leukemia
AST
Aspartate aminotransferase (SGOT)
ATC
Anatomical therapeutical chemical
BM
Bone marrow
BMA
Bone marrow aspirate
BMI
Body mass index 
BSA
Body surface area
CrCL
Creatinine clearance
CyCR
Cytogenetic response
CI
Confidence interval
CKD
chronic kidney disease
CR
Complete response/Complete remission
CRc
Cytogenetic complete remission
CRi
Complete remission with incomplete blood recovery 
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
DoR
Duration of response
DBP
Diastolic blood pressure
DMC
Data monitoring committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EE 
Efficacy evaluable
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
8
Abbreviation or 
Specialist Term
Explanation
 
EOT
End of treatment
Hgb
Hemoglobin 
HI
Hematological improvement
HI-E
Hematological improvement – erythroid
HI-N
Hematological improvement – neutrophil
HI-P
Hematological improvement – platelet
 
HSCT
Hematopoietic stem cell transplantation
ICF
Informed consent form
IP
Investigational product
IPSS-R
Revised - International prognostic scoring system
IRT
Interactive Response Technology
ITT
Intent to treat
IV
Intravenous
IVRS
Interactive voice response system
IWG
International working group
KM
Kaplan-Meier
mCR
Marrow complete remission
MedDRA
Medical Dictionary for Regulatory Activities
MDS
Myelodysplastic syndromes
ORR
Overall response rate
OS
Overall survival
Pd
Pharmacodynamics
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
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Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
9
Abbreviation or 
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Explanation
PR
Partial response/remission
PT
Preferred term 
Q4W
Every 4 weeks
RBC
Red blood cell
RMP
Risk management plan
RFS
Relapse free survival
sc
Steering committee
SAP
Statistical analysis plan
SAS®
Statistical Analysis System
SBP
Systolic blood pressure
SD
Stable disease
SMQ
Standardized MedDRA Query
SOC
System organ class
STD
Standard Deviation
TEAE
Treatment emergent adverse event
TTR
Time to response 
WBC
White blood cell
WHO
World Health Organization
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
10
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations to be performed 
for Celgene’s protocol MEDI4736-MDS-001 “A randomized, multicenter, open-label, Phase 2
study evaluating the efficacy and safety of azacitidine subcutaneous in combination with 
durvalumab (MEDI4736) in previously untreated subjects with higher-risk MDS or in elderly (≥
65 years) AML subjects not eligible for hematopoietic stem cell transplantation (HSCT) 
(MEDI4736-MDS-001)” which was issued on 17 Nov 2015 and amended on 27 Mar 2017. The 
SAP contains definitions of analysis populations, derived variables, and statistical methods for 
the analysis of efficacy and safety.
These analyses include interim analysis, final analysis (after 6 cycles) and additional analysis 
(after 12 months). Throughout this SAP, the treatment arms will be referred to as subcutaneous 
azacitidine plus durvalumab and subcutaneous azacitidine alone. The purpose of the SAP is to 
ensure the credibility of the study findings by prespecifying the statistical approaches to the 
analyses of study data prior to database lock for the study. This SAP provides a description of the 
strategy, rationale, and statistical techniques to be used to achieve the objectives of the study.
The SAP will be finalized and signed off prior to the clinical database lock for the interim
analysis. All statistical analyses detailed in the SAP will be conducted using SAS® Version 9.3 
or higher. 
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
11
3.
OBJECTIVES
Primary objectives 
!
To evaluate the efficacy of subcutaneous azacitidine in combination with durvalumab 
as compared to subcutaneous azacitidine alone in the defined study population.
Secondary objectives
!
To assess the safety and tolerability of subcutaneous azacitidine in combination with 
durvalumab as compared to subcutaneous azacitidine alone in the defined study 
population.
!
To assess the pharmacokinetics (PK) of durvalumab when given in combination with 
subcutaneous azacitidine in the defined study population. 
 
 
 
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
12
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 2, multicenter, randomized, parallel-group, open-label study evaluating the 
efficacy and safety of subcutaneous azacitidine either alone or in combination with durvalumab 
in two separate cohorts. Cohort 1 comprises subjects with previously untreated myelodysplastic 
syndrome (MDS) Revised International Prognostic Scoring System (IPSS-R) intermediate risk 
(in combination with more than 10% bone marrow (BM) blasts or poor or very poor IPSS-R 
cytogenetic risk), or IPSS-R high or IPSS-R very high risk, who are not eligible for HSCT. 
Cohort 2 comprises subjects with previously untreated acute myeloid leukemia (AML) (de novo 
AML with ≥20% blasts) or secondary AML, as per WHO classification, who are elderly (≥ 65 
years) and not eligible for HSCT, with intermediate or poor cytogenetic risk.
Subjects will be randomized (1:1 ratio) to receive one of the two treatment arms:
!
Arm A (subcutaneous azacitidine plus durvalumab)
!
Arm B (subcutaneous azacitidine alone)
The randomization process will aim to balance prognostic factors between study arms. For both 
cohorts (MDS and AML), subjects will be randomized and stratified according to their 
cytogenetic risk:
!
Intermediate versus poor for AML (Appendix 17.5),
!
Very good, good and intermediate versus poor and very poor for MDS (Appendix 
17.4).
The randomized study will be conducted in 2 stages, with an interim analysis for futility purpose 
for each of the 2 disease cohorts determining whether that cohort proceeds to Stage 2. The 
interim analysis will be conducted in the MDS cohort when the first 30 subjects have completed 
6 cycles of treatment unless they have established an earlier response (CR. mCR, PR or HI) or 
discontinued due to death or disease progression while the interim analysis in the AML cohort 
will be conducted when the first 50 subjects have completed 6 cycles of treatment unless they 
have established an earlier response (CR or CRi) or discontinued due to death or disease 
progression. Subjects assigned to Arm A, who received less than 3 cycles of durvalumab and 
continued under azacitidine monotherapy are to be excluded from the interim analysis.
The primary analysis will follow completion of Stage 2 (ie, after all subjects have completed 6 
cycles and had disease assessment) with additional analyses conducted approximately 12 months 
after the last subject is enrolled, as described in Section 9 of the protocol. In addition, early
safety monitoring meetings will be performed after 6 subjects and after 12 subjects have 
completed 2 treatment cycles.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
13
Figure 1:
Overall Study Design
AML = acute myeloid leukemia; Int = intermediate; IPSS-R = Revised International Prognostic Scoring System; 
MDS = myelodysplastic syndrome; Q4W = every 4 weeks; sc = subcutaneous.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
14
Study Population
A total of approximately 182 eligible subjects will be included in this study. 
Eligible subjects for the study will require a documented diagnosis of either AML or MDS as 
defined in Section 4 of the protocol, and will be assigned to either the AML or MDS cohort 
based on the central laboratory diagnosis confirmation. Approximately 72 subjects will be 
included in the MDS cohort and 110 subjects in the AML cohort.
Length of Study
The enrollment period for this study is expected to last approximately 15 months. The treatment 
and follow-up periods are expected to conclude approximately 12 months after the last subject is 
randomized. Therefore, the total duration of the study is expected to be approximately 
27 months, from first subject enrolled until the last subject last visit.
Subjects will undergo screening procedures over a period of up to 35 days following the signing 
of their informed consent form (ICF). Eligible subjects will continue to the treatment part of the 
study where they will receive investigational product (IP) for at least six 28-day treatment cycles. 
Those who demonstrate benefit from treatment may continue the IP beyond Cycle 6 until loss of 
that benefit or unacceptable toxicity, or withdrawal of consent (Section 7.2.5 of the protocol).
All subjects will have a Treatment Discontinuation Visit within 7 days after discontinuation of 
study treatment. Subjects are to return to the study site 28 days after the last dose of 
subcutaneous azacitidine and 90 days after the last dose of durvalumab for Safety Follow-up 
Visits. After this visit, subjects will be contacted by telephone every 3 months in the follow-up 
phase of the study.
The End of Trial is defined as either the date of the last subject last visit for the completion of 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analyses, whichever is the later date. See 
Section 3.3 of the protocol.
Study Treatments
Subjects will be randomized 1:1 to receive either:
Treatment Arm A: Subcutaneous azacitidine (75 mg/m2 daily for 7 days every 4 weeks 
[Q4W]) in combination with intravenous (IV) durvalumab at a dose of 1500 mg on Day1 
Q4W,
Or
Treatment Arm B: Subcutaneous azacitidine alone at the dose of 75 mg/m2 daily for 7 days 
Q4W.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
15
Table 2:
Study Endpoints
Endpoint
Name
Description
MDS Cohort
Primary
Overall response 
rate
Proportion of MDS subjects achieving an overall response
(CR, mCR, PR or HI), based on IWG 2006 response criteria 
(Appendix 17.2).
Secondary
Time to response 
Time from randomization to first documented response according 
to IWG 2006 response criteria (Appendix 17.2).
Relapse-free 
survival
Time from the date CR or PR is first documented until the date of 
documented relapse, death from any cause, or lost to follow-up, 
whichever occurs first according to IWG 2006 response criteria
(Appendix 17.2).
Cytogenetic 
response (CyCR)
Proportion of subjects achieving complete cytogenetic response 
or partial cytogenetic response according to IWG 2006 response 
criteria (Appendix 17.2).
Progression-free 
survival (PFS)
Time from randomization to the first documented PD, relapse or 
death due to any cause, whichever occurs first.
Duration of 
response
Duration of response is defined as the time from first response 
observed (CR, mCR, PR or HI) until relapse, PD or death as 
defined by the IWG 2006 criteria (Appendix 17.2).
Time to AML 
transformation
Time from randomization to AML transformation defined by at 
least 30% of myeloblasts either in the bone marrow or the 
peripheral blood.
Transformation to 
AML
Proportion of subjects with disease transformation to AML.
AML 
Cohort
Primary
Overall response 
rate
Proportion of AML subjects achieving an overall response (CR or 
CRi) based on modified IWG 2003 response criteria for AML. 
(Appendix 17.3).
Secondary
Time to response 
Time from randomization to first documented response based on 
modified IWG 2003 response criteria for AML (Appendix 17.3).
Relapse-free 
survival
Relapse-free survival is defined only for subjects who achieve CR 
or CRi and is measured as the interval from the date of first 
documented CR or CRi to the date of documented relapse, death 
from any cause, or lost to follow-up, whichever occurs first.
Complete 
cytogenetic 
Response (CyCR)
Proportion of subjects with complete cytogenetic response 
(CyCR) based on modified IWG 2003 response criteria for AML 
(Appendix 17.3).
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
16
Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Duration of 
response
Duration of response is defined as the time from the first 
documented CR/CRi to documented morphologic relapse, PD 
based on modified IWG 2003 response criteria for AML 
(Appendix 17.3) or death due to any cause, whichever occurs 
first.
Hematologic 
Improvement Rate
Proportion of subjects achieving a hematological improvement 
(HI-N + HI-P + HI-E) according to IWG 2006 response criteria 
(Appendix 17.2).
Both 
Cohorts
Secondary
Safety
Type, frequency, seriousness and severity of adverse events 
(AEs), and relationship of AEs to study treatment, clinical 
laboratory evaluations.
Overall survival
(OS)
Time from randomization to death due to any cause.
One-year survival 
The probability of survival at 1 year from randomization.
PK
Durvalumab concentration.
 
 
 
 
 
 
 
 
 
 
 = hematological improvement; HI-E = hematological 
improvement – erythroid response; HI-NE = hematological improvement – neutrophil response; HI-
p = hematological improvement – platelet response; IWG = International Working Group; mCR = marrow 
complete remission; OS = overall survival; PD = progressive disease; 
 
 PK = pharmacokinetics; PR = partial 
remission.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
17
4.2.
Stratification, Randomization, and Blinding
The study will be conducted in 2 stages for each disease cohort (Section 9.3 of the protocol). 
Subjects will be randomized with 1:1 ratio to receive subcutaneous azacitidine alone or 
subcutaneous azacitidine in combination with durvalumab.
The randomization procedure will be accomplished by a validated Interactive Response 
Technology (IRT). At randomization, subjects will be stratified by cytogenetic risk: very good, 
good, intermediate versus poor or very poor for the MDS cohort (Appendix 17.4, IPSS-R 
Cytogenetic Risk Groups), and intermediate versus poor for the AML cohort (Appendix 17.5).
This study will employ dynamic randomization based on two stratification factors (defined 
above) to achieve an even treatment balance between (A) Combination and (B) Monotherapy.
Step 1: Determine Primary (Disease Type) and Secondary (Cytogenetic Risk Factor) 
Stratification Factors
Subjects will first be stratified based on the disease type of either MDS or AML, as the 
secondary stratification factor variable depends on this information. Once disease type has been 
identified, the secondary stratification factor of cytogenetic risk factor can be identified. 
Cytogenetic risk factor options for each disease type are as follows:
!
MDS: Very good, good and intermediate vs. Poor and Very Poor
!
AML: Intermediate vs. Poor
Step 2: Determine Evaluable Subjects
Only evaluable subjects will be considered when dynamic randomization is performed.
Evaluable subjects are those who have been randomized and NOT been marked as replacement 
eligible via the Replacement Eligibility Review admin module.
Step 3: Determine Set of Ranges
To achieve treatment balance the measure of variability needs to be defined and is a quantitative 
way to describe the imbalance of patients amongst the treatment arms. Specifically, the measure 
of variability for this procedure is the Range which is the difference between the number of 
patients in the treatment arm with the most patients and the number of patients in the treatment 
arm with the least patients. For example, if treatment A has 4 patients and treatment B has 3 
patients, the Range is 1, ie, 4 (maximum) – 3 (minimum). When a new subject is to be 
randomized, the potential Ranges will be calculated for each possible treatment assignment. This 
will provide a Set of Ranges that measures the potential imbalance resulting from assigning a 
patient to the different treatments.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
18
For example, the current enrollment (of evaluable subjects) for the MDS disease type is:
Treatment A
Treatment B
Total Randomized
6
5
Level/Stratum Balance
Intermediate
4
3
Poor and Very Poor
2
2
The next subject to be randomized has disease type MDS and is Intermediate cytogenetic risk. 
First step is to calculate the Set of Ranges for the Intermediate level. 
If the subject were to be assigned to treatment A the totals would become 5 and 3 and the 
intermediate level range would be 2, as calculated by Treatment A – Treatment B = 2.
Treatment A
Treatment B
Intermediate
5
3
If the subject were to be assigned Treatment B the Range would be 4 – 4 = 0 for the strata.
Treatment A
Treatment B
Intermediate
4
4
Step 4: Determine the Rank
Continuing with the above example, since Treatment B has the lowest Range, it receives Rank 1 
and Rank 2 would be assigned to Treatment A.
Step 5: Determine the Appropriate Cumulative Representation
Using the tables below and considering that in the scenario above, Rank 1 <> Rank 2 we would 
reference Rank Scenario 4 to determine the appropriate Cumulative probabilities. Ultimately 
based on this Rank Scenario the probability to randomize the patient to treatment A or B will be 
1/1 if there is no difference in Rank (Rank Scenario 1 below). Otherwise, the probability will be 
9/1 – with the treatment defined as Rank 1 above receiving the higher probability (Rand Scenario 
2 below).
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
19
Rank Scenario 1: Rank 1 = Rank 2
Rank
Probability
Decimal Probability
Cumulative Probability
Rank 1
1/2
0.5
0.5
Rank 2
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0.5
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Rank
Probability
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Cumulative Probability
Rank 1
9/10
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Rank 2
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Step 6: Query the Random Number table
A table is required that contains a sequence of random numbers between 0.0000 and 1.0000. This 
list should be uniformly distributed. Based on the next unassigned random number on the list. If 
the number is <= Rank 1 cumulative probability, then the treatment in Rank 1 gets the 
assignment. If the number is > Rank 1 cumulative probability then the treatment in Rank 2 gets 
the assignment.
Blinding : not applicable for this study. 
4.3.
Sample Size
A total of approximately 182 eligible subjects will be enrolled in the study, with a total of 72 
subjects in the MDS cohort and 110 subjects in the AML cohort.
A subject who discontinues from the treatment phase before the first postbaseline efficacy 
assessment (following treatment Cycle 3) will be replaced unless the subject had a documented 
progression of their disease or died from their disease or died from an IP-related event. An 
additional subject will be included in that cohort (MDS or AML cohort).
4.3.1.
MDS Cohort 
Sekeres et al (Sekeres, 2014) demonstrated that treating subjects with higher-risk MDS resulted 
in an overall response rate (ORR) (complete remission [CR], marrow complete remission 
[mCR], partial remission [PR], hematological improvement [HI]) of 36% after four cycles of 
azacitidine alone. This number is consistent with the “HI and better” rate from the AZA-MDS-
001 trial of 36.4%.
Assuming a treatment effect of 100% relative improvement of ORR (from 36% to 72% ORR), a 
sample size of 72 subjects will provide a power of 90% to detect such an effect at the 5% level of 
statistical significance.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
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An interim analysis for futility purpose will be conducted on the first 30 subjects who have 
completed 6 cycles of treatment unless they have established an earlier response (CR. mCR, PR
or HI) or discontinued due to death or disease progression. Subjects assigned to Arm A, who 
received less than 3 cycles of durvalumab and continued under azacitidine monotherapy are to be 
excluded from the interim analysis. 
The MDS cohort will continue to enroll a total of 72 MDS subjects if one of the below 
conditions is met at the interim analysis:
!
If the ORR (considering the composite score of CR + PR + mCR + HI) in the 
combination arm is numerically higher than or equal to the control group (azacitidine 
alone) or,
!
If the response rate of one of the components of this composite score (in particular 
CR rate) in the combination arm is numerically higher than or equal to the control 
group (azacitidine alone) or,
!
If evidence of a clinically meaningful difference in favor of the combination arm in a 
secondary endpoint (eg, duration of response) is provided.
If none of these conditions is met, then the cohort might be terminated. The data monitoring 
committee (DMC) will review the data at the time of interim analysis and will provide 
recommendation/advice to Celgene.
4.3.2.
AML Cohort
Studies conducted by Dombret et al and Fenaux et al (Dombret, 2015; Fenaux, 2010) showed a 
response (CR + complete remission with incomplete blood recovery [CRi]) rate of 25% in AML 
subjects treated with azacitidine. Assuming a treatment effect of 100% relative improvement of 
CR and CRi (from 25% to 50% absolute CR and CRi rates), a sample size of 110 subjects will 
provide a power of 80% to detect such an effect at the 5% level of statistical significance.
An interim analysis for futility purpose will be conducted on the first 50 subjects who have 
completed 6 cycles of treatment unless they have established an earlier response (CR or CRi) or 
discontinued due to death or disease progression. Subjects assigned to Arm A, who received less 
than 3 cycles of durvalumab and continued under azacitidine monotherapy are to be excluded 
from the interim analysis.
The AML cohort will continue to enroll a total of 110 AML subjects if one of the below 
conditions is met at the interim analysis:
!
If the ORR (considering the composite score of CR + CRi) in the combination arm is 
numerically higher than or equal to the control group (azacitidine alone) or,
!
If the response rate of one of the components of this composite score (in particular 
CR rate) in the combination arm is numerically higher than or equal to the control 
group (azacitidine alone) or,
!
If evidence of a clinical meaningful difference in favor of the combination arm in a 
secondary endpoint (eg, duration of response) is provided.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
21
If none of these conditions are met, then the cohort might be terminated. The DMC will review 
the data at the time of interim analysis and will provide recommendation/advice to Celgene.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
22
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 following: 
!
Program source (eg, SAS program name, including the path, that generates the 
output) and
!
Data extraction date (eg, 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 listings will display all the relative values supporting corresponding 
table and figure.
5.1.1.
Dates Handling
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (ie, the Date9 datetime format in SAS). Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, bone 
marrow aspirates or biopsies, etc. They should be present whenever data for a 
protocol-specified procedure is present and should only be missing when a procedure 
is marked as NOT DONE in the database. Procedure dates will not be imputed.
!
Log Dates are dates recorded in the case report form (CRF) data logs. Specifically, 
they are the start and end dates for adverse events and concomitant 
medications/procedures. They should not be missing unless an event or medication is 
marked as ongoing in the database. Otherwise, incomplete log dates will be imputed 
according to the rules in Appendix 17.1 (eg, for duration or cycle assignment etc). 
However, in listings, log dates will be shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study termination, etc. They should not be missing if the milestone occurs 
for a subject. They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc. In most cases they are derived either from a milestone (eg, the 
survival date is derived from the death date), or a procedure date (eg, the progression 
date is derived from the date of the tumor scan that was used to determine 
progression). They may be subject to endpoint-specific censoring rules if the outcome 
did not occur, but are not otherwise subject to imputation.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
23
!
Special Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules 
(see Section 5.1.2 below). 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
5.1.2.
Calculations Using Dates
Calculations using dates (eg, 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 plus 1 
day. The generalized calculation algorithm for relative day calculations will be [date 
of interest – treatment start date + (date of interest >= treatment start date)]. This 
calculation will result in dates prior to the treatment start date being presented as 
negative days, and those occurring on or after the treatment start date as Day 1 or 
later, ie, there will be no Day 0. Note: Partial date for the first study drug is not 
imputed in general. All effort should be made to avoid incomplete study drug start 
date. 
!
Age (expressed in days) is calculated: 
AGE = DATE of informed consent – DATE of BIRTH + 1. In practice, age will be 
transformed into years by dividing the difference by 365.25 days, then truncating.
o
Using calculated age from the clinical database is preferred. When not 
available, the calculated/reported age from the CRFs or interactive voice 
response system (IVRS) may be used
o
Partial birth date: impute missing day as 15th of the month; impute missing 
month as July; set age as missing if missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS / 7.
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS / 30.4375.
5.1.3.
Calculation of Cycles
The start date of each treatment cycle will be calculated based on study drug exposure records 
for each subject. The start date of the first cycle will be the date when the subject receives any 
dose of study drug. First dose date of Durvalumab infusion or azacitidine injection in each cycle 
will be considered as the start of the cycle.
Once the start dates, eg, S1, S2, S3… are calculated, the end date of each cycle is calculated as the 
day before the start date of the following cycle, ie, Ei = Si+1 -1. The last cycle in the treatment 
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
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24
phase is defined as the cycle with the last dose of any study drug. For the last cycle, the end date 
will be the last dose date plus 28 days or the death date, whichever is earlier. 
The cycle number for each date of interest, eg, AE or lab, will be calculated based on the cycle 
window set by their start and end dates. If a date is on or after Si and before Si+1, the 
corresponding cycle number will be i.
5.1.4.
Descriptive Statistics
By default, descriptive statistics for continuous variable include: n, Mean, Standard Deviation 
(STD), Q1 and Q3, Median, Minimum (Min), and Maximum (Max). Unless specified in the 
actual table shells, the mean, median, Q1 and Q3 should be displayed to the one more decimal 
place than the original data (derived analysis data). Standard deviation should be displayed to the 
two more decimal places than the original data (derived analysis data). The minimum and 
maximum should be displayed to the same number of decimal places as the original data.
5.2.
Analysis Populations 
5.2.1.
Intent to Treat Population
The intent to treat (ITT) Population will include all randomized subjects. The primary efficacy 
analyses will be performed on the ITT Population.
5.2.2.
Efficacy Evaluable Population
The supportive efficacy analyses will be performed on the efficacy evaluable (EE) population, 
which will include all ITT subjects who completed 6 cycles of treatment, unless they have 
established an earlier response or who discontinued the study due to death or disease 
progression. Subjects assigned to Arm A, who received less than 3 cycles of durvalumab and 
continued under azacitidine monotherapy are to be excluded from the EE population.
An earlier response is defined as CR, mCR, PR or HI before the end of cycle 6 for the MDS 
cohort or CR and CRi before the end of cycle 6 for the AML cohort.
Subjects who do not have an on-treatment disease assessment and discontinue due to death or 
disease progression without post baseline response assessment will be considered as 
nonresponders.
5.2.3.
Safety Population
The Safety Population will include all subjects who take at least 1 dose of any study drug.
5.2.4.
Pharmacokinetic Population
Not applicable. The PK analyses will be performed by the Celgene TD group.
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Pharm
harm
ot applicabl
applicabl


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
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25
5.3.
Definitions
5.3.1.
Date of First Administration of Study Treatment
The date of first administration of study treatment is derived as the first date that durvalumab, or 
azacitidine was administered.
For simplicity, the date of first administration of study treatment will also be referred as the start 
date of study treatment.
5.3.2.
Date of Last Administration of Study Treatment
The date of last administration of study treatment is the last date that durvalumab or azacitidine 
was administered.
5.3.3.
Study Day
The study day will be calculated as specified in Section 5.1.2 and will be displayed in the data 
listings.
5.3.4.
Baseline
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 any study 
drug, unless noted otherwise for a particular assessment. In most cases, baseline assessments are 
those performed before dosing on Cycle 1, Day 1. However, the last measurement on or prior to 
the randomization date will be used as the baseline value for subjects who did not take any study 
drug. Unless otherwise specified in the derived data set specification, the baseline disease 
characteristics, baseline laboratory value and vital sign that are used in the safety analyses will be 
derived using this method.
Since the hemoglobin value can be influenced by a red blood cell (RBC) transfusion, the
hemoglobin (Hgb) values used in some efficacy analyses are required to satisfy the 7/3-day rule 
below:
!
7/3-day rule: Only hemoglobin values that are at least 7 days after a transfusion may 
be used unless there is another transfusion within 3 days after the hemoglobin 
assessment.
In efficacy analyses, after applying above 7/3-day rule, the baseline hemoglobin value is defined 
as the last hemoglobin value in 56-days on or prior to randomization.
&(/*(1(35235,(7$5<,1)250$7,21
acit
acitidine
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displayed in
displayed in
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er
moglo
oglobin
bin v


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
26
6.
SUBJECT DISPOSITION
Reasons for screen failure will be summarized and listed. Enrollment by country and sites will be 
summarized by treatment arm within each disease cohort.
A summary of subject disposition (analysis population allocation, subjects randomized, subjects 
discontinued, along with primary reason for treatment discontinuation and study discontinuation) 
will be presented for the ITT Population and for the Safety Population and will be summarized 
using frequencies for both Treatment and Follow-up Periods.
Reasons for discontinuing study treatment will be collected on the CRF and will be summarized 
for all randomized subjects with the following categories:
!
Completed
!
Death
!
Adverse event
!
Progressive disease
!
Lack of efficacy
!
Withdrawal by subject
!
Lost to follow-up
!
Protocol violation
!
Other
Reasons for discontinuing the study (ie, no follow-up visit and no longer participating in the 
study) will be collected on the CRF and will be summarized for all randomized subjects with the 
following categories:
!
Completed (per protocol) 
!
Death
!
Adverse event
!
Withdrawal by subject
!
Lost to follow-up
!
Other
Protocol violations / deviations will be summarized and listed by disease cohort and treatment 
arm for the ITT Population. Protocol violation / deviation will be reported and monitored 
throughout the study. Data of protocol violation / deviation will be finalized prior to database 
lock. 
The following by-subject listing of subjects with demographic information will be provided:
!
Subject listing of discontinuation. 
&(/*(1(35235,(7$5<,1)250$7,21
marized 
arized
o fo
follo
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d will be su
will be s
ocol)
ocol)
entnt
awal by sub
awal by sub
st to follow
t to follow
Other
Other
colol vivi
l
olatatioi
m fofor th
the IT
IT
throughout
roughout
h
ock.
ck.


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
27
!
Subject listing of screen failures.
!
Subject listing of protocol violations and protocol deviations.
!
Subject listing of being excluded from ITT, EE, Safety or PK Population.
&(/*(1(35235,(7$5<,1)250$7,21


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
28
7.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries using descriptive statistics for the demographics and baseline characteristics will be 
carried out by disease cohort and treatment arm for each analysis population defined in Section 
5.2. Listings will be presented for the ITT Population. Continuous variables will be summarized 
using descriptive statistics and categorical variables will be summarized with frequency counts 
and percentages.
7.1.
Background and Demographic Characteristics
Age at time of consent (years), weight (kg), height (cm), body mass index (BMI), body surface 
area (BSA) and other continuous demographic will be summarized using descriptive statistics 
(eg, mean, standard deviation [STD], median, minimum [Min] and maximum [Max]), while age 
category (<65 ; ≥ 65 - <75; ≥75), gender, race and other categorical variables will be summarized 
with frequency counts and percentages.
The below formulas will be used:
BMI (kg/m2) = weight (kg) / (height * height (m2)).
BSA (m2) = (weight (kg)^0.425) * (height (cm)^0.725)*0.007184.
7.2.
Baseline Characteristics
Baseline clinical characteristics include temperature (°C), systolic blood pressure (SBP, mmHg), 
diastolic blood pressure (DBP, mmHg), pulse (bpm), respiratory rate, Eastern Cooperative 
Oncology Group (ECOG) performance status (PS) and baseline electrocardiograms (ECGs) will 
be summarized.
Coagulation test performed at screening will be summarized. Overall interpretation from 
coagulation test will be summarized along with prothrombin time/international normalized ratio, 
activated partial thromboplastin time, and thrombin time.
Baseline laboratory assessments from central laboratory will be summarized for Hgb, platelet 
count, absolute neutrophil count (ANC), white blood cell (WBC) count, creatinine, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and total bilirubin.
Creatinine clearance (CrCl) will be assessed at screening by the central laboratory. Creatinine 
clearance is estimated using the Cockcroft-Gault formula where CrCl(mL/min) = (140 – age) 
(weight [kg]) / 72 (serum creatinine [mg/dL]; for females, the formula is multiplied by 0.85 
(Cockcroft, 1976). The CrCl will be summarized as continuous variable. The creatinine 
clearance will be normalized to an average surface area (size) of 1.73m2. The corrected CrCl will 
be summarized as continuous variable and category variable defined as chronic kidney disease 
(CKD) stages (Stage 1, 90+; Stage 2, 60-89; Stage 3, 30-59; Stage 4, 15-29; Stage 5, <15).
Cytogenetic risk classifications (Appendix 17.4 and 17.5) will be summarized with frequency 
counts and percentages. For MDS cohort, IPSS-R will be summarized along with hemoglobin,
platelet and absolute neutrophil count used in the derivation. Bone marrow blast will be 
summarized as continuous variable and category variable as defined in IPSS-R (≤ 2%; > 2% -
< 5%; ≥5% - ≤ 10%; >10%).
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dy surface
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whil
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7184.
7184.
(°C
°C), 
), systo
s
pm),
m), respi
espiri
(PS) and
(PS) and b
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will be s
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along wi
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and t
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ft, 1976). T
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Cytytogen
oge


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
29
Baseline RBC transfusion burden and platelet transfusion burden will be summarized. The 
baseline transfusion burden is defined the total number of units of transfusion received before or 
on the first dose date. Only RBC transfusions given for hemoglobin of ≤ 9.0 g/dL before or on 
the first dose date will count in the baseline RBC transfusion burden.
The time from initial diagnosis to randomization will also be summarized.
7.3.
Medical History
Medical history will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) Version 19.0, or higher. Individual subject listings will be provided. System organ 
class (SOC) and preferred term (PT) will be summarized by frequency and percentage. Tables 
will be provided for subjects in the ITT Population and the Safety Population.
7.4.
Prior Medications
Prior medications are defined as medications that were started before the start of study treatment 
(regardless of whether or not they are stopped before the start of the study treatment). Prior 
medications that are ongoing at the start date of study treatment will also be reported as 
concomitant medications. 
The Anatomical Therapeutical Chemical (ATC) coding scheme of the World Health 
Organization (WHO) (September 2016 version, or higher) will be used to group medications into 
relevant categories. All prior medications will be summarized by ATC level 1, ATC 3 term term 
and preferred name in frequency tabulations for the ITT Population and the Safety Population.
7.5.
Prior Anticancer Therapy
Whether subject had prior cancer surgery, prior radiation therapy, prior systemic anticancer 
therapy, prior stem cell transplantation, and prior hormonal anticancer therapy will be 
summarized with frequency counts and percentages in the ITT population. The number of prior 
systemic anticancer regimens will be summarized descriptively. In addition, prior exposure to 
anticancer systemic therapies will also be summarized by ATC level 1 term, ATC 3 term and 
preferred name with frequency counts and percentages in the ITT Population and the Safety
Population.
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rgan 
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udy
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prior 
or radiat
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and 
and pri
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nc
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count


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
30
8.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Study treatment and extent of exposure summaries will be provided based on the Safety 
Population. Descriptive statistics will be provided for treatment exposure, cumulative dose, 
average daily dose, treatment compliance, dose intensity, relative dose intensity and dose 
modifications by disease cohort and treatment arm. Related summary will be provided for each 
treatment arm across the two disease cohorts. Individual subject listings will be provided to 
support the tables.
8.1.
Treatment Exposure and Duration
Treatment exposure and number of days dosed will be summarized. Total treatment exposure 
(days) for each study drug is defined as follows:
!
Azacitidine: date of first dose through date of last dose + 28 days;
!
Durvalumab: date of first dose through date of last dose + 90 days.
Treatment exposure for subjects in the azacitidine alone arm is same as the treatment exposure of 
azacitidine. Treatment exposure for subjects in the combination arm is defined as date of first 
dose of any study drug through later one of date of last dose azacitidine + 28 days and date of 
last dose durvalumab + 90 days. Duration of exposure will be summarized for each arm. 
Total number of days dosed is defined as the total number of days with a nonmissing dosing 
date.
See Section 5.1.3 for cycle definition. Average cycle length (days) and number of treatment 
cycles will be summarized for each study drug. For azacitidine, average number of days dosed 
per cycle will be summarized. The number of days dosed per cycle is defined as the number of 
days with a nonmissing dosing date within that cycle. For average cycle length and average 
number of days dosed per cycle, a single average value will be computed for each subject and 
then the descriptive statistics will be provided. Additionally, the count and percent of subjects by 
number of cycles of treatment will be provided for each treatment.
For each study drug, duration of treatment (days) is defined as:
!
(study drug end date) – (date of Cycle 1 Day 1) + 1.
Study drug end date is defined as Min [last non-zero/non-missing dose date + number of days to 
be covered by the last dose, death date].
The number of days to be covered by the last dose is defined in the table 3.
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nt exposure
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0 days.
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e as the tre
s the t
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cycle leng
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er of days d
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ithin that cy
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the last do
he last d
ber of days 
r of days 


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
31
Table 3:
Number of days to be covered by the last dose
IP
Schedule
n = days to be covered by the actual last dose (if schedule 
respected) *
Durvalumab
CxD1
n=27
Azacitidine
CxD1 to CxD7
n=21
* if schedule is not respected the number of days to be covered by the actual last dose will be adapted accordingly so 
that the last dose date + n corresponds to the study day 28 of the cycle.
8.2.
Cumulative Dose: 
The cumulative dose during the treatment is defined as the sum of all doses taken across the 
treatment period (in mg). Cumulative dose will be calculated separately for azacitidine and 
durvalumab. 
8.3.
Average Daily Dose
For each drug, average daily dose (mg/day), defined as the cumulative dose divided by number 
of days dosed, will be calculated. A single average value will be computed for each subject, 
overall and within each cycle, and then the descriptive statistics will be computed for each 
treatment group.
8.4.
Treatment Compliance
For each drug, treatment compliance (%) will be calculated for each subject for each cycle of 
treatment and overall. The compliance is defined as the ratio of the average total daily dose 
(mg/day) to the average calculated daily dose (mg/day). Calculated daily dose is the prescribed 
daily dose (mg/m2) multiplied by the subject’s BSA (m2). Average calculated daily dose is 
defined as the sum of each calculated daily dose divided by the number of days of scheduled 
dosing (eg, 7 days / cycle for azacitidine). Compliance for each drug will be summarized using 
descriptive statistics overall and by cycle.
8.5.
Dose Intensity 
For each cycle, dose intensity for a study drug is defined as the cumulative dose of the study 
drug in the cycle divided by the cycle length. The overall dose intensity for each study drug is 
defined as the cumulative dose divided by the total length of cycles in treatment duration. A 
single average value will be computed for each subject, overall and within each cycle, and then 
the descriptive statistics will be computed for each treatment group.
8.6.
Relative Dose Intensity
Relative dose intensity is defined as the actual dose intensity divided by the planned dose 
intensity;
!
For durvalumab, the planned dose intensity (mg/day) is 1500 mg / 28 days.
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8.6.
.6.
R
Relativ
Relativ


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
32
!
For azacitidine, the planned dose intensity (mg/day) is 75 mg/m2* 7 multiplied by the 
subject’s BSA (m2) / 28 days.
Descriptive statistics of overall and by cycle relative dose intensity will be summarized. 
Additionally, the number and percentage of subjects will be summarized by category such as
≤85% and > 85% for relative total dose intensity of azacitidine, durvalumab, the actual category 
can be data driven.
8.7.
Dose Modification
Dose modifications are permitted in any cycle for appropriate management of AEs or 
hematological toxicity. Dose reductions are only allowed for azacitidine. 
Dose reduction is defined as a nonzero dose administered after the Cycle 1 Day 1 (C1D1) dose 
which is at a lower dose level than the dose the subject received at the previous dosing day. Dose 
interruption occurs if the record of actual administered dose is zero except as required by the 
protocol. If an interruption happens at the start of cycle and causes the cycle to be postponed, it is 
also called dose delay. Consecutive zeros are counted as one interruption.
Dose reduction or dose interruption will be summarized separately for azacitidine. Summaries 
include number of subjects who had at least 1 dose reduction (or interruption), time to first dose 
reduction( or interruption), number of subjects who had at least 1 dose reduction (or interruption)
due to AE and time to first dose reduction (or interruption) due to AE will be provided. 
Dose interruption as well as infusion interruption will be summarized for durvalumab. Dose 
delays are summarized for durvalumab only. Number of subjects who had at least 1 interruption, 
time to the first interruption, number of subjects who had at least 1 interruption due to AE and 
time to first interruption due to AE will be summarized.
An infusion interruption refers to an interruption of an infusion that actually started.
&(/*(1(35235,(7$5<,1)250$7,21
C1D1)
C1D1) dos
dos
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required b
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on
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be summar
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
33
9.
CONCOMITANT MEDICATIONS/PROCEDURES AND 
SUBSEQUENT THERAPY
9.1.
Concomitant Medications
Concomitant mediations are defined as non-study medications that are started during the study 
treatment exposure period, or started before the start of the study treatment and ended or were 
ongoing during the study treatment exposure period. The study treatment exposure period is 
defined as the interval between the date of first administration of any study treatment and the 
later of 28 days after the last dose of azacitidine and 90 days after the last dose of durvalumab.
All concomitant treatments documented during the study treatment exposure period will be 
summarized in frequency tabulations by disease cohort for the ITT and Safety Populations. The 
ATC coding scheme of the WHO (September 2016 version, or higher) will be used to group 
medications into relevant categories for these tabulations.
Listings of concomitant medications by subject will be provided.
9.2.
Concomitant Procedures
The CRF page records procedure, date, and indication. These procedures will be coded using 
MedDRA Version 19.0 or higher. A frequency summary of subjects by concomitant procedures 
summarized in frequency tabulations by SOC and preferred term by disease cohort for the ITT 
Population.
Concomitant procedures will be identified as procedures or surgeries that occurred after or on the 
date of first dose of durvalumab or azacitidine until 28 days after the last dose of subcutaneous 
azacitidine and 90 days after the last dose of durvalumab.
9.3.
Subsequent Therapy
Whether subject had subsequent radiation therapy, cancer surgery, stem cell transplantation and 
hormonal anticancer therapy for this disease will be summarized with frequency counts and 
percentages. In addition, subsequent hormonal anticancer and systemic anticancer therapies will 
be summarized by ATC level 1 term, ATC 3 term and preferred name for the Safety Population.
Details of subsequent therapies will be presented in subjects’ data listings.
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ne
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until 28
e of durvalu
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nt radiat
radiatioion
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subsequen
subsequ
TC level
TC level 1 t
ent therapie
ent therapie


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
34
10.
EFFICACY ANALYSIS
All efficacy analyses will be carried out on the ITT Population. Supportive efficacy analyses will 
also be performed using EE Population. 
All efficacy endpoints will be summarized by disease cohort and treatment arm.
All confidence intervals (CIs) will be provided at a level of 95% and between-group comparisons
will be provided as appropriate as described below.
10.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the ORR and will be programmatically derived using the 
results/assessments generated by the central morphologic/cytogenetic and hematology 
laboratories. In case no central hematology results are available within +/- 8 days of bone 
marrow samples, local hematology results might be used if available. This analysis will be 
conducted after completion of the Stage 1 and Stage 2 portions of the study. A subject is 
considered evaluable for response if they have undergone at least one disease status assessment 
following treatment Cycle 6. Subjects who discontinue from the treatment phase before the first 
post baseline efficacy assessment (following treatment Cycle 3) will be replaced unless the 
subject had a documented progression of their disease or died and will be considered as non-
responders. If one post baseline disease assessment is performed, this assessment would be 
considered for response. 
The difference of the proportions for overall response between the azacitidine alone and 
combination therapy arms will be tested using a standard Wald asymptotic two-sided test with 
unpooled estimate of variance and presented along with corresponding two-sided 95% CIs.
The hypothesis tested will be:
:  = 0
versus

:  ≠0,
Where  =  − is difference in overall response rate in the combination therapy arm (p1) 
versus the overall response rate in the monotherapy arm (p2). 
The test statistic is
 = /()
Where, the standard error is computed from the sample proportions as 
 = ̂(1 −̂)

+ ̂(1 −̂)

Where ̂ (respectively ̂) is the estimated response rate in the combination therapy arm 
(respectively monotherapy arm) and is derived as the observed response rates in respective arms.
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ns
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day
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
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
35
Myelodysplastic Syndromes Cohort
For the MDS cohort, the primary efficacy endpoint is the proportion of subjects achieving an 
overall response rate (defined as CR, PR, mCR, and/or HI)) as determined using the International 
Working Group (IWG) 2006 response criteria for MDS (Appendix 17.2). The ORR will be 
summarized together with two-sided 95% CI. Subjects discontinued before 6-cycle treatment 
without achieving overall response will be counted as nonresponders.
The number and percentage of subjects who achieve each component of the overall response
(CR, PR, mCR, HI-E, HI-P, HI-N) will be summarized together with associated two-sided 95% 
CI. 
The best overall response per IWG 2006 response criteria will be summarized. The best overall 
response is defined as the best response prior to progressive disease and first subsequent therapy.
The below order will be considered for the definition of best response:
1. CR
2. PR
3. mCR
4. SD
5. PD
6. Disease transformation
7. Failure due to death
8. Not Evaluable/Missing
Acute Myeloid Leukemia Cohort
For the AML cohort, the primary efficacy endpoint is the proportion of subjects achieving an 
overall response rate (CR or CRi) based on modified IWG 2003 response criteria for AML 
(Appendix 17.3). The ORR will be summarized together with two-sided 95% CI. Subjects 
discontinued before 6-cycle treatment without achieving overall response will be counted as 
nonresponders.
The number and percentage of subjects who achieve CR, PR, CRi, HI-E, HI-P and HI-N will be 
summarized together with associated two-sided 95% CI
The best overall response per modified IWG response criteria will be summarized. The best 
overall response is defined as the best response prior to progressive disease and first subsequent 
therapy.
The below order will be considered for the definition of best response:
1. CR
2. CRi
3. CRc
&(/*(1(35235,(7$5<,1)250$7,21
% 
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st overall
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based
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percentage
percentage
ogether wit
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overall resp
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response i
response i
apy
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The
The below
below
1.1


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
36
4. PR
5. SD
6. PD
7. Treatment failure
8. Not Evaluable/Missing
10.2.
Secondary Efficacy Endpoints
Overall response rate and best overall response will also be provided according to the 
investigator assessment. Of note a response reported as Cytogenetic Complete Remission (CRc)
in the eCRF would also be considered as CR in the summaries, CRc being a subset of CR.
Time to event data will be compared between treatment arms within each cohort using a log-rank 
test stratified according to their cytogenetic risk at time of randomization (intermediate vs poor 
and very poor for MDS and intermediate vs poor for AML).
Response rates will be compared between treatment groups using the same methodology for the 
primary endpoint.
Overall Survival 
Overall survival is defined as the time between randomization and death/censored date. Subjects
who die, regardless of the cause of death, will be considered to have had an event. Subjects who 
are alive at the time of clinical data cut-off date will be censored at the earlier between last 
assessment at which the subject was known to be alive and cut-off date will be used. All subjects 
who were lost to follow-up prior to the clinical data cut-off date will also be censored at the time
of last contact. The stratified log rank test will be used to compare the time-to-event curves 
between Arm A and Arm B. The OS curve and OS at 6 and 12 months will be estimated and 
compared using Kaplan-Meier (KM) method.
Time-to-Response (TTR)
Time to onset of first response is defined as the time between the date of randomization and the 
earliest date any response (CR, PR, mCR, or HI for MDS Cohort, CR or CRi for AML Cohort
whichever is the 1st) is observed. Subjects who do not achieve any defined response during the 
treatment period will be censored at the date of last adequate response assessment, disease 
progression, or death, whichever occurs first. Median time to onset of first response and 
associated two-sided 95% CI for the treatment group will be estimated using the KM method.
A sensitivity analysis of TTR will be performed for subjects who had responded. Summaries 
using descriptive statistics n, Mean, Standard Deviation (STD), Q1 and Q3, Median, Minimum 
(Min), and Maximum (Max) will be provided.
Duration of Response (DoR)
Duration of response will be calculated only for subjects who achieve CR, mCR, PR or HI for 
the MDS Cohort, CR or CRi for the AML Cohort. Duration of response is defined as the time 
from first response observed until relapse, PD or death. Duration of response will be censored at 
the last response assessment date that the subject is known to be progression-free for: 
&(/*(1(35235,(7$5<,1)250$7,21
on (CRc)
n (CRc)
of CR.
of CR.
rt using a lo
t using a
term
ermediate
ediat
same meth
same meth
tion and de
n and d
dered to ha
dered to ha
be censore
be censo
alive and c
alive and 
data cut
data cut-o
will be used
ill be use
ve and OS 
ve and O
method.
method
se is defined
e is define
(CR, PR, m
CR, PR, m
observed. S
observed. 
be censor
be censo
eath, which
eath, which
sided 
sided 95%
95
ty analysis
y analysis
escript
escriptive
ive
n), and Max
n), and Ma
Duration o
Duration o
Durati
Durati


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
37
!
Subjects who have not relapsed, progressed or died at the time of analysis.
!
Subjects who have withdrawn consent or are lost to follow-up prior to documentation 
of progression.
Censoring rules are defined in Table 4.
Duration of response will be analyzed using the KM method. Median duration of response along 
with two-sided 95% CI will be provided for each cohort and treatment group. 
In addition, the duration of each specific subcategory of response in the MDS Cohort (CR, mCR, 
PR or HI) and in the AML Cohort (CR) will be summarized using standard descriptive statistics.
Relapse-free Survival (RFS)
Relapse-free survival is defined only for subjects who achieve CR or PR for MDS subjects, CR 
and CRi for AML subjects, and is measured as the interval from the date of first documented 
response to the date of disease relapse or death from any cause, whichever occurs first. Subjects 
who are still alive and relapse-free will be censored at the date of their last response assessment. 
The RFS curve will be estimated using KM method.
Median RFS along with two-sided 95% CI will be provided for each cohort and treatment group.
The RFS at 6 and 12 months will be estimated and compared using Kaplan-Meier (KM) method.
Censoring rules are defined in Table 4.
Cytogenetic Response 
External central pathology/cytogenetic reviewers will review the morphologic/cytogenetic data 
from bone marrow aspirate (BMA), bone marrow biopsies (if performed) to determine whether a 
subject achieved a cytogenetic response (complete or partial cytogenetic responses for MDS 
subjects and cytogenetic complete response for AML subjects). For cytogenetic response
evaluable subjects (ie subjects with baseline cytogenetic abnormalities), the number and 
percentage of subjects who achieve the cytogenetic responses will be summarized together with 
associated two-sided 95% CI.
MDS Cohort:
Progression-free Survival (PFS)
Progression-free survival is calculated as the time from randomization to the first documented 
progression, relapse or death due to any cause during or after the treatment period, whichever 
occurs first. Subjects who are still alive and progression-free will be censored at the date of their 
last response assessment. The PFS curve will be estimated using KM method. 
Median PFS along with two-sided 95% CI will be provided for each cohort and treatment group.
The PFS at 6 and 12 months will be estimated and compared using Kaplan-Meier (KM) method.
A sensitivity analysis of PFS will be performed, censoring PFS at the time of subsequent 
systemic anticancer therapy if the subject did not progress before that time.
Transformation to AML and Time to AML Transformation
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CR,
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subjects, 
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will review 
w biopsies
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ponse asses
ponse asses
dian PFS a
dian PFS a
The PFS 
The PFS atat
A sensi
A sens


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
38
Number of subjects with transformation to AML and time to transformation to AML will be 
summarized. Time to transformation to AML is defined as the time from the date of 
randomization until the date the subject has documented transformation to AML (at least 30% of 
BM blats). Subjects who do not transform to AML will be censored at the date last disease 
assessment date. Median time to transformation to AML and associated two-sided 95% CI will 
be estimated using KM method. 
AML Cohort:
HI
Rate of HI – erythroid response (HI-E), hematological improvement – platelet response (HI-P) 
and hematological improvement – neutrophil response (HI-N) according to IWG 2006 response 
criteria for MDS (Appendix 17.2), will be provided together with Wald asymptotic two-sided 
95% CIs.
&(/*(1(35235,(7$5<,1)250$7,21
nse (HI
nse (HI-P) 
P) 
2006 respo
06 respo
toti
otic two
c two-si


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
39
Table 4:
Event and Censoring Rules for Progression-free Survival, Duration of 
Response, Time-to-Response and Relapse-free Survival
Situation
Date of Progression or Censoring
Situation 
Outcome
Censoring Rules for PFS and DoR 
Progression
If the first PD is a scheduled assessment then Date of 
first PD;
If the first PD is an unscheduled assessment and no 
previous assessment, then Date of PD;
If the first PD is an unscheduled assessment and has 
previous assessment, then Date of previous assessment 
(regardless of the response type).
Event
Death between scheduled 
assessments or within the 
first two missed scheduled 
assessments
Date of death
Event
No progression
Date of last adequate assessment with evidence of no 
PD
Censored
Death or progression after 
two or more missed 
scheduled assessments
Date of last adequate assessment with evidence of no 
PD; if no adequate assessment exists then censored at 
date of first dose
Censored
Censoring Rules for RFS
Relapse
If the first relapse is a scheduled assessment then Date 
of first relapse;
If the first relapse is an unscheduled assessment and no 
previous assessment, then Date of relapse;
If the first relapse is an unscheduled assessment and has 
previous assessment, then Date of previous assessment 
(regardless of the response type).
Event
Death between scheduled 
assessments or within the 
first two missed scheduled 
assessments
Date of death
Event
No relapse
Date of last adequate assessment with evidence of no 
relapse
Censored
Death or progression after 
two or more missed 
scheduled assessments
Date of last adequate assessment with evidence of no 
relapse; if no adequate assessment exists then censored 
at date of first dose
Censored
Censoring Rules for PFS (sensitivity analysis), DoR and RFS
Additional therapy received 
prior to progression or death
Date of additional systemic anticancer therapy
Censored
&
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ensor
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scheduled a
cheduled a
/*
&


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
40
Censoring Rules for TTR
Subject responded before 
PD 
First documented response date (CR, PR, mCr, or HI
for mDS Cohort, CR or CRi for AML Cohort )
Event
Subject responded after PD
Date of last adequate disease assessment at PD date or 
death date
Censored
Other case
Date of last adequate disease assessment; if no adequate 
assessment exists, then censored at date of first dose
Censored
10.3.
Eastern Cooperative Oncology Group Performance Status
Shift tables from baseline to best post baseline in ECOG performance score will be displayed by 
disease cohort and treatment arm for the ITT Population.
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$7
$7
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be displaye
be display


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
41
 
 
CCI
&(/*(1(35235,(7$5<,1)250$7,21


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
42
11.
PHARMACOKINETIC ANALYSIS
Pharmacokinetic concentration data and summary statistics will be tabulated. The PK, 
pharmacodynamics, demographic, safety, and efficacy data collected in this study may be 
combined with similar data from other studies and explored using population PK and/or PK-
pharmacodynamic methods. A separate SAP will provide the details of the statistical methods 
used to analyze PK data. The results of such an analysis will be reported in a separate report.
&(/*(1(35235,(7$5<,1)250$7,21


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
43
12.
SAFETY ANALYSIS
This section defines the safety parameters 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.
12.1.
Adverse Events
All safety analyses will be conducted using the Safety Population. All analyses will be presented 
by disease cohort and treatment arm within each disease cohort. Adverse events will be coded 
according to the MedDRA Version 19.0 or higher. The intensity of AEs will be graded according 
to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 or higher.
If a subject experiences multiple AEs under the same PT (SOC), then 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, then 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 (durvalumab or azacitidine) and within 90 
days after last dose of durvalumab or 28 days after last dose of azacitidine, as well as those 
serious TEAEs made known to the investigator at any time thereafter that are suspected of being 
related to study treatment. 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.
Tables summarizing the incidence of TEAEs by disease cohort and treatment arm will be 
generated with the following:
!
TEAEs;
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab; 
!
TEAEs of CTCAE grade 3
!
TEAEs of CTCAE grade 4
!
TEAEs of CTCAE grade 3 or 4; 
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab with 
CTCAE grade 3
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab with 
CTCAE grade 4
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab with 
CTCAE grade 3 or 4; 
!
TEAEs with CTCAE grade 5;
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ented 
nted 
oded 
ded 
d according
accordin
r hi
r higher.
gher.
ect will be c
ct will be
an once wit
n once wi
bulated in “
ulated 
he summary
he summar
Es occurrin
occu
umab
umab or az
az
ose of azac
se of azac
time therea
time there
E is define
E is defin
“Suspected
“Suspected
e considere
e considere
AEs by
AEs by dise
dise
azacit
azacitididine
ine
CAE grade
CAE gr
f CTCAE g
CTCAE 
Es of CTCA
Es of CTCA
EAEs relat
EAEs rela
CTCAE g
CTCAE 
!
TEA
EA
C
!


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
44
!
TEAEs with CTCAE grade 5 related to azacitidine, durvalumab and azacitidine
and/or durvalumab;
!
Serious TEAEs;
!
Serious TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab;
!
TEAEs leading to discontinuation of azacitidine, durvalumab and azacitidine and/or
durvalumab; 
!
TEAEs leading to dose reduction of azacitidine;
!
TEAEs leading to dose interruption of azacitidine, durvalumab and azacitidine and/or
durvalumab;
!
TEAEs leading to infusion interruption of durvalumab. 
As well as
!
TEAEs by cycle of onset; 
!
Serious TEAEs by cycle of onset;
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab, by 
cycle of onset;
!
TEAEs of CTCAE grade 3 by cycle of onset
!
TEAEs of CTCAE grade 4 by cycle of onset;
!
TEAEs of CTCAE grade 3 or 4 by cycle of onset; 
!
TEAEs by maximum CTCAE grade; 
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab, by 
maximum CTCAE grade;
!
Common (>=10%) TEAEs; 
!
Common (>=10%) TEAEs related to azacitidine, durvalumab and azacitidine and/or
durvalumab;
!
By age category: <65, 65-74, ≥75
!
By gender
Unless otherwise stated, TEAEs will be presented by MedDRA SOC and PT. To facilitate 
clinical study report writing the following tables will be produced
!
TEAEs by PTs
!
TEAEs by SOCs 
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab by PTs
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab by SOCs
!
TEAEs of CTCAE Grade 3 or 4 by PTs, by Grade (3 and 4 separately) and combined (3 
or 4 combined)
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e and/or
and/or
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ycle of onse
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ade;
, durvalum
durvalu
;
EAEs;
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%) TEAEs 
%) TEAE
ategory
egory: <6
<
ender
ender
rwise stated
rwise state
tudy
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eport
y
TEAEs b
EAEs
!
TEA
EA
!


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
45
!
TEAEs of CTCAE Grade 3 or 4 by SOCs, by Grade (3 and 4 separately) and combined (3 
or 4 combined)
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab of CTCAE 
Grade 3 or 4 by PTs, by Grade (3 and 4 separately) and combined (3 or 4 combined)
!
TEAEs related to azacitidine, durvalumab and azacitidine and/or durvalumab of CTCAE 
Grade 3 or 4 by SOCs, by Grade (3 and 4 separately) and combined (3 or 4 combined)
All deaths, on treatment deaths, off treatment deaths and causes of death will be summarized. On 
treatment deaths are defined as deaths occurring within 90 days after the last dose of durvalumab 
or 28 days after last dose of azacitidine. Off treatment death are defined as deaths occurring after 
that period. These summaries will be based on the death eCRF page.
Individual subject listing of AEs will be presented. In addition, the following tabulated lists 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 
Adverse events of special interests (AESI)
The adverse events of special interest (AESI) refer to a group of PTs from one or more SOCs
relating to a defined medical condition or area of interest. Unless an AESI is defined by a single 
PT the AESI generally refers to a group of PTs, rather than the individual PTs.
AESIs will be summarized separately for azacitidine and durvalumab, The AESI summary for 
each study treatment will be summarized by AESIs, which will be referred as AESI categories in 
tables and listings, and by PT.
The following AESIs for azacitidine based on risk definitions (search criteria) as outlined in the 
Vidaza risk management plan (RMP) currently approved at the time of data cut-off will be 
summarized: 
!
Myelosuppression (Neutropenia, thrombocytopenia, anemia, general 
myelosuppression) 
!
Hemorrhagic events
!
Infections
!
Renal failure
!
Hepatic failure
!
Ischemic colitis
!
Interstitial lung disease
!
Cardiac events (cardiac failure, cardiac arrhythmias, myocardial infarction)
!
Anxiety, confusional state, insomnia
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(RMP
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orrhagic e
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nfections
!
Renal 
Renal
!
H
!


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
46
!
Other psychiatric disorders
!
Tumour lysis syndrome
!
Gastrointestinal disorders as defined by MedDRA SOC
Below are the AESIs for durvalumab for regulatory purposes:
!
Adrenal insufficiency
!
Colitis
!
Dermatitis
!
Diarrhoea
!
Diabetes Mellitus Type 1
!
Hyperthyroidism
!
Hypophysitis
!
Hypothyroidism
!
Infusion related/Hypersensitivity/Anaphylactic reactions
!
Select renal events
!
Select pancreatic events
!
Pneumonitis
!
Rash
!
Select hepatic events
!
Other rare/miscellaneous
After review of the data, there may be other AESIs identified. The following summaries will be 
provided for TEAEs included in the above-mentioned AEs of special interest: 
!
All TEAEs 
!
All TEAEs by cycle of onset
!
TEAEs of Grade 3
!
TEAEs of Grade 4
!
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
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eactions
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may
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EAEs
EAEs by cy
by cy
EAEs of G
EAEs of G
TEAEs 
TEAEs
!
TEA
TEA
!


Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
47
!
TEAEs leading to death
The incidence rate per 100 person-years will also be derived for each AESI. 
12.2.
Clinical Laboratory Evaluations
Descriptive statistics of observed and change from baseline values will be presented.
Clinical laboratory values will be graded according to CTCAE Version 4.03 or higher for 
applicable tests. Baseline grade and worst grade during treatment for selected laboratory results 
will be summarized. Shifts from baseline to the worst grade observed during the treatment for 
selected laboratory results will also be provided.
Clinically significant hematologic and nonhematologic laboratory abnormalities that meet 
Grade 3 or Grade 4 criteria according to CTCAE Version 4.03 will be listed and summarized.
Listings of clinical laboratory data from central laboratory with abnormal flags will be provided 
by subjects and tests.
Listings of clinical laboratory data from central laboratory with abnormal flags will be provided 
by subjects and tests. Listings will also be provided for the local laboratory data. 
 
 
 
12.4.
Vital Sign Measurements 
For vital signs with shifts from baseline to worst during treatment (below, within, and above the 
normal ranges) will be displayed in cross–tabulations. Summary statistics (N, Mean, STD, 
median, Q1, Q3 Min, and Max) of observed and change from baseline values will be presented.
Normal ranges are defined as follows:
!
Systolic blood pressure (SBP)  Normal (100 – 140 mm Hg, inclusive)
!
Diastolic blood pressure (DBP)  Normal (60 – 90 mm Hg, inclusive)
!
Body temperature  Normal (35 – 38°C, inclusive)
!
Pulse  Normal (60 – 100 bpm, inclusive)
!
Respiration  Normal (12 – 20 BPM, inclusive).
12.5.
Electrocardiogram
The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with “Normal”, “Abnormal, not clinically significant, and “Abnormal, clinically 
significant”. Baseline and end of treatment (EOT) in the overall ECG interpretation will be 
displayed in cross-tabulations.
CCI
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
48
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
49
 
 
 
CCI
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
50
14.
INTERIM ANALYSIS 
14.1.
General Information
The interim analysis on futility will support early assessment of efficacy and may minimize the 
number of subjects exposed to the investigational regimen in the absence of signs of efficacy.
An interim analysis for futility purposes following the completion of first stage will be 
conducted. The primary analysis will be conducted following the completion of second stage. 
The decision to proceed to Stage 2 after completion of Stage 1 will be performed independently 
in each cohort as mentioned below.
The DMC will review the safety data on a regular basis.
Myelodysplastic Cohort 
An interim analysis for futility purpose will be conducted on the first 30 subjects who have 
completed 6 cycles of treatment unless they have established an earlier response (CR. mCR, PR
or HI) or discontinued due to death or disease progression. Subjects assigned to Arm A, who 
received less than 3 cycles of durvalumab and continued under azacitidine monotherapy are to be 
excluded from the interim analysis.
The MDS cohort will be completed to include a total of 72 MDS subjects. Details of futility rules 
are given in section 4.3.1.
Acute Myeloid Leukemia Cohort
An interim analysis for futility purpose will be conducted on the first 50 subjects who have 
completed 6 cycles of treatment unless they have established an earlier response (CR or CRi) or 
discontinued due to death or disease progression. Subjects assigned to Arm A, who received less 
than 3 cycles of durvalumab and continued under azacitidine monotherapy are to be excluded 
from the interim analysis.
The AML cohort will be completed to include a total of 110 AML subjects. Details of futility 
rules are given in section 4.3.2.
Interim analyses for futility purposes are planned for each cohort as described above and will be 
based on the EE population.
14.2.
Statistical Approaches for Control of Alpha
The interim analysis is for futility purposes, type I error will be well controlled.
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15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
Response derivations have been updated for consistency with IWG Response Criteria in 
Myelodysplasia (Cheson, 2006) and Modified IWG AML Response Criteria (Cheson, 2003).
IA requirements and definition of EE population have been detailed in order to specify that 
subjects assigned to Arm A, who received less than 3 cycles of durvalumab and continued under 
azacitidine monotherapy are to be excluded from interim analysis and/or in the EE population.
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Durvalumab (MEDI4736)
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52
16.
REFERENCES
Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux 
P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, 
Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European LeukemiaNet. Diagnosis and 
management of acute myeloid leukemia in adults: recommendations from an international expert 
panel, on behalf of the European LeukemiaNet.Blood. 2010;115:453-474.
Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH et al. International 
phase 3 study of azacitidine vs conventional care regimens in older patients with newly 
diagnosed AML with >30% blasts. Blood. 2015;126(3).
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 
FDA/CDER/CBER May 2007.
 
Sekeres MA and Cutler C. How we treat higher-risk myelodysplastic syndromes. Blood. 
2014;123:829-836.
CCI
CCI
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Durvalumab (MEDI4736)
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17.
APPENDICES 
17.1.
Date Imputation Guideline
17.1.1.
Impute Missing AE/Prior or Concomitant Medications Start Dates
If the stop date is nonmissing and the imputed start date is after the stop date, the start date will 
be imputed by the stop date.
Missing day and month
!
If the year is same as the year of first day on study medication, then the day and 
month of the start date of study medication will be assigned to the missing fields
!
If the year is prior to the year of first day on study medication, then December 31 
will be assigned to the missing fields.
!
If the year is after the year of first day on study medication, then January 1 will be 
assigned to the missing fields.
Missing day only 
!
If the month and year are same as the year and month of first day on study 
medication, then the start date of study medication will be assigned to the missing 
day.
!
If the month and year are before the year and month of first day on study medication, 
then the last day of the month will be assigned to the missing day.
!
If the month and year are after the year and month of first day on study medication, 
then the first day of the month will be assigned to the missing day.
Missing day, month, and year
!
Included as TEAE
17.1.2.
Impute Missing AE/ Prior or Concomitant Medications Stop Dates 
If the imputed stop date is before the start date then the imputed stop date will be equal to the 
start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dose date of 
study medication, then the day and month of the last dose date will be assigned to the 
missing fields.
!
If the year of the incomplete stop date is prior to the year of the last dose date, then 
December 31 will be assigned to the missing fields.
!
If the year of the incomplete stop date is after the year of the last dose date of study 
medication, then January 1 will be assigned to the missing fields.
Missing day only 
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!
If the month and year of the incomplete stop date are the same as the month and year 
of the last dose date of study medication, then the day of the last dose date will be 
assigned to the missing day.
!
If the month and year of the incomplete stop date are before the month and year of 
the last dose date of the study medication, then the last day of the month will be 
assigned to the missing day.
!
If the month and year of the incomplete stop date are after the month and year of the 
last dose date of study medication, then the first day of the month will be assigned to 
the missing day.
17.1.3.
Impute Missing Disease Diagnosis Dates
For partial diagnosis dates, January will be assigned to the missing month; and the first day of 
the month will be assigned to the missing day.
17.1.4.
Impute Missing Dates in Prior Cancer Regimen
For each prior cancer regimen, the regimen start/stop date, disease progression date, best 
response date, and date of first response for PR or better, will be collected. If the day of any date 
is missing, then the first day the nonmissing month will be assigned to the missing day; if month 
or year of the date is missing, the date will not be imputed and treated as missing.
17.1.5.
Impute Missing Dates in Subsequent Cancer Therapy 
Subject will allow take other antimyeloma therapy after discontinued from the study. The cancer 
therapy start/stop date will be collected. If the day of any date is missing, then the last day the 
nonmissing month will be assigned to the missing day; if day and month are both missing, then 
the December 31 of the nonmissing year will be assigned to the missing day.
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will be ass
will be 


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17.2.
International Working Group (IWG) Response Criteria in 
Myelodysplasia (Cheson, 2006)
Altering Disease Natural History
Complete remission (CR)

BM Blasts ≤ 5% 
AND

All of the following peripheral blood values met:

Hemoglobin ≥ 11 g/dL 

Platelets ≥ 100 x109/L

ANC ≥ 1.0 x109/L

Peripheral Blasts=0% 
Labs must meet criterion for at least 28 consecutive days. If not 
confirmed for 28 days then response should be mCR.
In addition

The 7/3 rule should be applied to Hemoglobin. 

Platelets collected 3 days period following Platelet transfusion will 
not be used
-
ANC values that must be at least 14 days following a G-CSF 
application
Partial remission (PR)

BM Blasts decreased by ≥ 50% over pretreatment but still > 5% 
AND

All of the following peripheral blood values met:

Hemoglobin ≥ 11 g/dL 

Platelets ≥ 100 x109/L

ANC ≥ 1.0 x109/L

Peripheral Blasts=0%
Labs Must meet criterion for at least 28 consecutive days. 
In addition

The 7/3 rule should be applied to Hemoglobin.  

Platelets collected 3 days period following Platelet transfusion will 
not be used
ANC values that must be at least 14 days following a G-CSF application
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Marrow CR

Bone marrow:  ≤ 5% myeloblasts and decrease by ≥ 50% over 
pretreatment with baseline BM blast >5%
AND

Not all of the following peripheral blood values met or none are met:

Hemoglobin ≥ 11 g/dL 

Platelets ≥ 100 x109/L

ANC ≥ 1.0 x109/L

Peripheral Blasts=0% 
Peripheral blood: if HI responses, they will be noted in addition to 
marrow CR
Stable disease (SD)
Any evaluable time point where criteria for all other response categories 
(i.e., CR, PR, PD, Failure due to death, Not Assessable) are not met
Failure
Death during treatment
Disease Progression (PD)

If condition for Transformation to AML and relapse after CR/PR are 
not verified

For patients with:

Nadir value less than 5% blasts: ≥ 50% increase in blasts to > 
5% blasts

Nadir value 5% - 10% blasts: ≥ 50% increase in blasts to > 
10% blasts

Nadir value 10% - 20% blasts: ≥ 50% increase in blasts to > 
20% blasts
AND ANY OF THE FOLLOWING

≥ 50% decrement from max level of ANC and ANC < 1.0 GI/L
OR

≥ 50% decrement from max level of Platelets and Platelets < 100 
GI/L
OR

Reduction  from max level of Hgb ≥ 20 g/L and Hgb < 110 g/L 
OR
!
Transfusion dependence (apply to baseline TI subjects only)
a Dysplastic changes should consider the normal range of dysplastic changes (modification).
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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Altering Disease Natural History
Disease transformation
Transformation to AML (30% or more blasts)
Relapse after CR or PR
!
BM % blast >= baseline % blast and BM % blast >= 5%
OR
!
≥ 50% decrement from max level of ANC and ANC < 1.0 GI/L
OR
!
≥ 50% decrement from max level of Platelets and Platelets < 100 
GI/L
OR
!
Reduction  from max level of Hgb ≥ 20 g/L and Hgb < 110 g/L
OR
!
RBC/platelet transfusion is given after CR/PR
Cytogenetic Response
Complete
Disappearance of the chromosomal abnormality without appearance 
of new ones
Partial
At least 50% reduction of the chromosomal abnormality
Hematological Improvement (HI)
Erythroid response (HI-E)
(Pretreatment < 11 g/dL) 

Hgb increase by ≥ 1.5 g/dL in >=8 weeks
OR

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 Hgb of ≤ 9.0 g/dL pretreatment 
will count in the RBC transfusion evaluation

For Hgb, 7/3 rule should be applied first
Platelet response (HI-P)
(Pretreatment < 100 × 109/L)

in >=8 weeks Absolute increase of ≥ 30 × 109/L for patients 
starting with > 20 × 109/L
OR

Increase from <= 20 × 109/L to > 20 × 109/L and by at least 100%
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Neutrophil response (HI-N)
(Pretreatment < 1.0 × 109/L)

in >=8 weeks At least 100% increase and an absolute increase 
from mean of pre-dose of > 0.5 × 109/L
AML = acute myeloid leukemia; Hgb = hemoglobin; RBC = red blood cell
Source: Cheson BD, Greenberg PL, Bennett JM, Löwenberg 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


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17.3.
Modified International Working Group AML Response Criteria 
(Cheson, 2003)
Hematologic Response According to IWG Criteria for AML
Category 
Definition 
Morphologic Complete 
Remission (CR)
!
BM Blasts < 5% 
AND
!
All of the following peripheral blood values met:
o
Platelets ≥ 100 x109/L
o
ANC ≥ 1.0 x109/L
Where the date of the hematology assessment used is 
within the window -8 and +8 days of BM date. If multiple 
hematology assessments within this window, the closest 
to BM date should be used. If multiple on same distance to 
BM date, the one before BM date should be used
AND
!
No  platelet, or whole blood transfusions for 1 week (7days) prior 
to the date of the hematology assessment used for the response 
evaluation
Morphologic Complete 
Remission with 
Incomplete Blood Count 
Recovery (CRi)

BM Blasts < 5% 
AND

One or both of the following peripheral blood values met:

Platelets < 100 x109/L 

ANC < 1.0 x109/L
Where the date of the hematology assessment used is within the 
window -8 and +8 days of BM date. If multiple hematology 
assessments within this window, the closest to BM date should be used. 
If multiple on same distance to BM date, the one before BM date 
should be used
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Category 
Definition 
Cytogenetic Complete 
Remission (CRc)

CR criteria met 
AND

Abnormal karyotype present at baseline 
AND
Reversion to normal karyotype at time of CR (based on ≥ 10 
metaphases), where date of cytogenetic sample = date of BM sample 
used for the CR assessment
Partial Remission (PR)

One of the following BM Blasts values met:

BM blasts of 5% to 25% (inclusive) when baseline BM 
blasts is 50% to 100% (inclusive)

BM blasts ≥ 5% and 50% decrease from baseline when 
baseline BM blasts is <= 49% (inclusive) 
AND

All of the following peripheral blood values met:

Platelets ≥ 100 x109/L

ANC ≥ 1.0 x109/L
Where the date of the hematology assessment used is within the 
window -8 and +8 days of BM date. If multiple hematology 
assessments within this window, the closest to BM date should be used. 
If multiple on same distance to BM date, the one before BM date 
should be used
Relapse after CR or CRi

> 5% blast in peripheral blood following CR or CRi 
OR
> 15% BM blast following CR or CRi
Treatment Failure

Death w/death date  during Cycle 1
OR
!
Death w/death date ≤ 28 days after last dose date and prior to 
C2D1
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Category 
Definition 
Progressive Diseaseb

If the lowest/best response %BM blast is <= 70%, PD is defined 
when there’s an increase of %BM blast of at least 50%. 
If the lowest/best response %BM blast is > 70% instead, PD is defined 
when there’s an increase of %BM blast of at least 10% (absolute 
increase). If %BM blast doesn’t increase more than 10%, PD is defined 
as an increase of at least 2x in %PB blast from the lowest/best response 
with %PB blast > 10%.
Stable disease

Any evaluable time point where criteria for all other response 
categories (i.e., CR, CRi, PR, PD, Treatment failure, Not Assessable) 
are not met
ANC = absolute neutrophil count
a If the pretreatment bone marrow blast percentage was 50% to 100%, the percentage of blasts must decrease to a 
value between 5% and 25%; if the pretreatment blast percentage was 20% to less than 49%, they must decrease by 
at least half to a value of more than 5%.
b Modification to IWG response criteria.
Notes: Deletions to the IWG response criteria are not shown.
Source: Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the International Working Group 
for diagnosis, Standardization of response Criteria, Treatment Outcomes, and reporting Standards for Therapeutic 
Trials in Acute Myeloid Leukemia. J Clin Oncol 2003;21:4642-9
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17.4.
Revised International Prognostic Scoring System for MDS – IPSS-R 
(Greenberg, 2012)
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
-
Inter-
mediate
Poor
Very 
Poor
Bone Marrow 
Blast (%)
≤ 2
-
> 2 - < 5
-
5 - 10
> 10
-
Hemoglobin 
(g/dL)
≥10
-
8 - < 10
<8
-
-
-
Platelets 
(× 109/L)
≥100
50 -
< 100
< 50
-
-
-
-
ANC (× 109/L)
≥0.8
< 0.8
-
-
-
-
-
ANC = absolute neutrophil count
The total IPSS-R score is calculated as the sum of the cytogenetics, bone marrow blast percentage, 
hemoglobin, platelets and ANC individual scores.
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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
IPSS-R: Prognostic Risk Category Clinical Outcomes
Prognostic variable
No. pts
Very 
Low
Low
Intermedia
te
High
Very 
High
Patients (%)
7012
19%
38%
20%
13%
10%
Median Overall Survival 
(years)
-
8.8
5.3
3.0
1.6
0.8
Median time to 25% AML 
evolution
-
Not 
reached
10.8
3.2
1.4
0.7
Source: 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.
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17.5.
Risk Status Based on Cytogenetics for Acute Myeloid Leukemia
Risk Groups
Risk Status
Cytogenetics
Molecular Abnormalities a
Better-risk
inv(16)b, c
t(16;16)b
t(8;21)b
t(15;17)
Normal cytogenetics:
NPM1 mutation in the absence of 
FLT3-ITD or isolated biallelic 
CEBPA mutation 
Intermediate-risk
Normal cytogenetics
+8
t(9;11)
Other non-defined
t(8;21), inv(16), t(16;16):
with c-KIT d mutation
Poor-risk
Complex (≥ 3 clonal chromosomal 
abnormalities)
Monosomal karyotype
-5, 5q-, -7, 7q-
11q23 - non t(9;11)
inv(3), t(3;3)
t(6;9)
t(9;22)e
Normal cytogenetics:
with FLT3-ITD mutation f
a The molecular abnormalities included in this table reflect those for which validated assays are available in 
standardized commercial laboratories.  Given the rapidly evolving field, risk stratification should be modified 
based on continuous evaluation of research data.  Other novel genetic mutations have been identified that may 
have prognostic significance.
b Other cytogenetic abnormalities in addition to these finding do not alter risk status.
c Paschka P, Du J, Schlenk RF, Gaidzik VI, Bullinger L, Corbacioglu A, et al. Secondary genetic lesions in acute 
myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML study group (AMLSG). 
Blood 2013; 121:170-177.
d Emerging data indicates the presence of c-KIT mutation in subjects with t(8;21), and to a lesser extent, inv(16), 
confers a high risk of relapse.  These subjects should be considered for clinical trials, if available.
e For Philadelphia+ acute myeloid leukemia (AML) t(9;22), manage as myeloid blast crisis in chronic myeloid 
leukemia (CML), with addition of tyrosine kinase inhibitors.  These subjects are excluded from study entry.
f FLT3-ITD mutations are considered to confer a significant poor outcome in subjects with normal karyotype, and 
these subjects should be considered for clinical trials where available.  There is controversy as whether FLT3-TKD 
mutations carry equally poor prognosis
Source:  National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Acute Myeloid 
Leukemia. National Comprehensive Cancer Network website.  Available at 
http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf.  Accessed 05 Aug 2015.
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
65
CCI
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Durvalumab (MEDI4736)
Statistical Analysis Plan: Protocol MEDI4736-MDS-001
Celgene Corporation
Confidential and Proprietary
66
CCI
,21
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