A Phase IB Rescue Study With Oral Decitabine (AStX727) and Durvalumab (MEDI4736) Combination Therapy in Recurrent and/or Metastatic Head and Neck Cancer Patients Who Have Progressed on Anti-PD-1, Anti-PD-L1, or Anti-CTLA-4 Monotherapy
Phase: PHASE1
Conditions: Head and Neck Cancer
Sponsor: Massachusetts General Hospital

1
Investigational Drug 
Substance(s)
Durvalumab (MEDI4736)  
Azacitidine/Decitabine 
(ASTX727)
Study Number
15-11430
Version Number
13.0
Date
09/20/2024
A Phase Ib Rescue Study With Oral Decitabine (ASTX727) and Durvalumab 
(MEDI4736) Combination Therapy in Recurrent and/or Metastatic SCCHN 
Subjects Who Have Progressed on Anti-PD-1, Anti-PD-L1, and/or Anti-CTLA-
4 Therapy
IND Sponsor: Sara I. Pai, MD, PhD

2
 SCHEDULE OF STUDY ASSESSMENTS
Schedule of study assessments: Screening and Treatment Period (13 months: maximum of 
13 doses, last infusion week 48, last dose week 46)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject.
Screening*
Baseline
Every 2 weeks
Every 4 weeks
Every 
8 weeks
Every 12 weeks
Day
-28 to -1*
1
Day 1 of the week
2, 4, 6, 8, 10, 12, etc.
4, 8, 12, 16, 20, 
etc.
8, 16, 24, 32, 
40, 48
12, 24, 36, 48
Week
-4 to -1
0
(±5 days)
(±7 days)
Written 
informed 
consent/assignment 
of 
 
subject 
identification 
number
X
Demography 
and 
history of tobacco 
and alcohol use
X
Previous treatments 
for head and neck 
cancer
X
Inclusion/Exclusion 
criteria
X
Medicala 
and 
surgical history
X
Urine 
hCG 
or 
serum βhCGb
X
X
X
Durvalumab 
(MEDI4736)  
administration 
X t, u
Tremelimumab 
administration 
Xc, t, u
Oral decitabine
(ASTX 
727) 
or 
Azacitidine
Xd
Xd, u
Physical 
examinatione
X
X
X

3
Schedule of study assessments: Screening and Treatment Period (13 months: maximum of 
13 doses, last infusion week 48, last dose week 46)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject.
Screening*
Baseline
Every 2 weeks
Every 4 weeks
Every 
8 weeks
Every 12 weeks
Day
-28 to -1*
1
Day 1 of the week
2, 4, 6, 8, 10, 12, etc.
4, 8, 12, 16, 20, 
etc.
8, 16, 24, 32, 
40, 48
12, 24, 36, 48
Week
-4 to -1
0
(±5 days)
(±7 days)
Vital signs (pre-, 
during and post-
infusion vital signs 
assessments) f
X
X
X
Weight
X
X
X
Electrocardiogramg
X
X then as 
clinically 
indicated
Adverse 
event/serious 
adverse 
event 
assessment
Xh
X
All visits
Concomitant 
medications
X
X
All visits
Palliative 
radiotherapy
As clinically indicated
ECOG performance 
status
X
X
X
Liver 
enzyme 
paneli
X
X
X
Serum 
chemistry 
(complete 
clin. 
chem. 
panel 
including 
liver 
enzymes) i
X
X
X 
Thyroid 
function 
tests (TSH and fT3 
and fT4) j
X
X
X
Hematologyi
X
X
X

4
Schedule of study assessments: Screening and Treatment Period (13 months: maximum of 
13 doses, last infusion week 48, last dose week 46)
All assessments to be performed pre-infusion unless stated otherwise
Assessments to be 
performed at the 
times stipulated in 
the table and as 
clinically required 
in the management 
of the subject.
Screening*
Baseline
Every 2 weeks
Every 4 weeks
Every 
8 weeks
Every 12 weeks
Day
-28 to -1*
1
Day 1 of the week
2, 4, 6, 8, 10, 12, etc.
4, 8, 12, 16, 20, 
etc.
8, 16, 24, 32, 
40, 48
12, 24, 36, 48
Week
-4 to -1
0
(±5 days)
(±7 days)
Urinalysisl
X
X
X
Coagulation 
parametersm
X
As clinically indicted
Stool 
sample 
collection 
X
Xn
Collection of whole 
blood PBMCs for 
flow cytometry and 
circulating soluble 
factors (cytokines, 
chemokines, 
antibodies 
against 
tumor 
and 
self-
antigens 
in 
circulation)
X
Xo
Tumor 
biopsy 
sample 
Xp
Xq
Tumour assessment 
(CT or MRI) and 
survival updater
X
X
Bone scan(s) 
Xs
*Within 28 days prior to study registration.
a Detailed hepatitis medical history for all subjects
b  Pre-menopausal female subjects of childbearing potential only. Pregnancy test must be done within 72 hours prior to the first 
administration of IP and prior to dosing on Day 1 of every cycle. If the serum screening pregnancy test is performed >72 hours 
before first dose, a urine pregnancy test or a repeat serum pregnancy test should be performed. The subject may not receive IP until 
the Investigator has verified that the result of the pregnancy test is negative.
c For 4 cycles only for those patients receiving azacitidine.
d Refer to Sections 3.1, 6.2, and Table 1 for detailed dose-escalation schedule 
e Full physical examination at baseline; targeted physical examination at other time points

5
f Subjects will have their blood pressure and pulse measured before, during, and after each infusion at the following times (based 
on a 60-minute infusion):
•
At the beginning of the infusion (at 0 minutes)
•
At 30 minutes during the infusion (±5 minutes)
•
At the end of the infusion (at 60 minutes ±5 minutes)
•
In the 1 hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 120 minutes from the 
start of the infusion) (±5 minutes) – for the first infusion only and then for subsequent infusions as clinically indicated
If the infusion takes longer than 60 minutes, then blood pressure and pulse measurements should follow the principles 
as described above or more frequently if clinically indicated.
g ECG during screening and at Day1 – baseline. Thereafter as clinically indicated. Baseline and abnormal ECG at any time in 
triplicate others single. 1 ECG is needed while on treatment, and as clinically indicated. ECGs should be taken within an hour 
prior to the start of the infusion and at least one time point 0 to 3 hours after the infusion.  
h For  history of AEs/SAEs reported during prescreening additional information such as prior immunotherapy, medical history 
and concomitant medications may be needed.
iIf screening laboratory assessments are performed within 3 days prior to Day 1 of protocol treatment they do not need to be 
repeated at Day 1. Results for safety bloods must be available and reviewed before commencing an infusion. Gamma 
glutamyltransferase tested at Screening, Day 1 and as clinically indicated.   
j Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an 
adverse event related to the endocrine system.
l Urinalysis performed at Screening, Day 1, every 4 weeks and as clinically indicated.
mCoagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated.
n Sample to be collected on Day 1 of Week 8 (+/- 7 days)
o The peripheral blood for flow cytometry will be obtained at the time of the tumor biopsy.  Please refer to q
p Archival FFPE sample or fresh tissue wil be submitted for the screening or pre-dose Cycle Day 1 timepoint.  HPV testing will 
be performed if indicated based on an oropharyngeal or unknown primary if HPV testing has not been previously done.
q A biopsy will be obtained on week 8 for the phase 1b portion of the study
r Timing of CT scans and survival update: default is every 8 weeks for the first 48 weeks and then every 12 weeks until 
confirmed PD, start of a new anticancer treatment, or withdrawal of consent. Tumor assessments are to be done up to and 
including the assessment which shows first disease progression. If a patient discontinues protocol treatment due to reasons other 
than disease progression, tumor assessments should be performed until first disease progression until 24 months from study 
registration. All patients including those who discontinue protocol therapy early, will be followed for response until first disease 
progression and survival until 24 months from study registration. 
s Bone scans will be repeated only if symptomatic or with known bone metastasis, per standard of care
t For patients receiving azacitidine, the durvalumab and tremelimumab will start Day 1 Week 4 (Cycle 2). For patients receiving 
decitabine, the durvalumab will start Day 1 Week 4 (Cycle 2).
u In  Cycle 1, subjects will receive azacitidine or decitabine only. For those patients receiving azacitidine, starting in Cycle 2, 
patients will continue with azacitidine, durvalumab, and tremelimumab combination therapy for Cycles 3-5 and and azacitidine 
and durvalumab for Cycles 6-12. For those patients receiving decitabine, starting in Cycle 2,  patients will continue with 
decatibine and durvalumab combination therapy for Cycles 3-12. 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
6
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS.........................................................................................6
ABBREVIATIONS AND DEFINITION OF TERMS..........................................12
1.
INTRODUCTION..................................................................................................17
1.1.1
Head and Neck Squamous Cell Carcinoma Background.......................................17
1.1.2
Immunotherapies....................................................................................................18
1.1.3
Durvalumab (MEDI4736)......................................................................................19
1.1.4
Tremelimumab .......................................................................................................20
1.1.5
Durvalumab (MEDI4736) in combination with tremelimumab ............................21
1.1.6
Azacitidine/Oral Decitabine (ASTX727)...............................................................22
1.1.7
DNA Methyltrasnferase Inhibitor Experience in Solid Tumors ............................24
1.1.8
DNA Methyltransferase Inhibitors in Head and Neck Cancer...............................26
1.2
Research Hypothesis ..............................................................................................27
1.3
Rationale for conducting this study........................................................................27
1.3.1
Durvalumab (MEDI4736) + tremelimumab combination therapy dose 
rationale..................................................................................................................29
1.3.2
Rationale for 4 cycles of combination therapy followed by durvalumab 
(MEDI4736) monotherapy.....................................................................................35
1.3.3
Rationale for study design......................................................................................36
1.4
Benefit/risk and ethical assessment........................................................................36
1.4.1
Potential benefits....................................................................................................36
1.4.1.1
Durvalumab (MEDI4736)......................................................................................36
1.4.1.2
Tremelimumab .......................................................................................................37
1.4.1.3
Durvalumab (MEDI4736) + tremelimumab ..........................................................37
1.4.1.4
Azaciditine/Oral Decitabine (ASTX727)...............................................................38
1.4.2
Potential risks.........................................................................................................39
1.4.2.1
Durvalumab (MEDI4736)......................................................................................39
1.4.2.2
Tremelimumab .......................................................................................................41
1.4.2.3
Durvalumab (MEDI4736)  + tremelimumab .........................................................42
1.4.2.4
Fixed Dosing for durvalumab (MEDI4736) and tremelimumab ...........................43
1.4.2.5
Azacitidine/Oral Decitabine (ASTX727)...............................................................44
1.4.3
Overall benefit-risk and ethical assessment ...........................................................46
2.
STUDY OBJECTIVE ............................................................................................47
2.1.1
Primary objective(s)...............................................................................................47
2.1.2
Secondary Objective: .............................................................................................48
3.
STUDY DESIGN...................................................................................................48
3.1
Overview of study design.......................................................................................48

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
7
3.2
Study schema .........................................................................................................50
4.
PATIENT 
SELECTION, 
ENROLLMENT, 
RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................51
4.1
Inclusion criteria.....................................................................................................51
4.2
Exclusion criteria ...................................................................................................54
4.3
Withdrawal of Subjects from Study Treatment and/or Study................................56
5.
INVESTIGATIONAL PRODUCT(S)...................................................................58
5.1
Durvalumab (MEDI4736) and tremelimumab.......................................................58
5.1.1
Formulation/packaging/storage..............................................................................58
5.1.2
Treatment regimens................................................................................................58
5.1.3
Duration of treatment and criteria for retreatment .................................................59
5.1.4
Study drug preparation of durvalumab (MEDI4736) and tremelimumab .............60
5.1.5
Monitoring of dose administration.........................................................................63
5.1.6
Accountability and dispensation ............................................................................64
5.1.7
Disposition of unused investigational study drug ..................................................64
5.2
Azacitidine/Oral Decitabine (ASTX727)...............................................................64
5.2.1
Formulation/packaging/preparation/storage ..........................................................66
5.2.2
Doses and treatment regimens ...............................................................................68
5.2.3
Dose administration ...............................................................................................68
5.2.4
Accountability and dispensation ............................................................................68
5.2.5
Disposition of unused investigational study drug ..................................................68
6.
TREATMENT PLAN ............................................................................................69
6.1
Subject enrollment .................................................................................................69
6.1.1
Assignment of screening number...........................................................................69
6.1.2
Procedures for randomization ................................................................................69
6.1.3
Procedures for handling subjects incorrectly enrolled...........................................69
6.2
Dosage and Administration....................................................................................70
6.3
Dose Escalation Decision Rules.............................................................................72
6.3.1
Definition of BED..................................................................................................73
6.4
Definition of DLT ..................................................................................................73
6.5
Dose Modification and Toxicity Management ......................................................75
6.5.1
Durvalumab (MEDI4736) and tremelimumab.......................................................75
6.5.2
Azacitidine/Oral decitabine (ASTX727)................................................................75
7. 
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S)...................................................................................................79
7.1
Restrictions during the study..................................................................................79

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
8
7.2
Concomitant treatment(s).......................................................................................81
7.2.1
Permitted concomitant medications .......................................................................81
7.2.2
Excluded Concomitant Medications ......................................................................82
8.
STUDY PROCEDURES .......................................................................................84
8.1
Schedule of study procedures.................................................................................84
8.1.1
Screening Phase .....................................................................................................84
8.1.2
Treatment Phase.....................................................................................................85
8.1.3
End of Treatment....................................................................................................86
8.2
Description of study procedures.............................................................................87
8.2.1
Medical history and physical examination, electrocardiogram, weight and 
vital signs ...............................................................................................................87
8.2.2
Physical examination .............................................................................................87
8.2.3
Electrocardiograms ................................................................................................87
8.2.4
Vital signs...............................................................................................................88
8.2.5
Clinical laboratory tests..........................................................................................89
8.3
Biological sampling procedures.............................................................................90
8.3.1
Biomarker sampling and evaluation methods........................................................90
8.3.2
Estimate of volume of blood to be collected..........................................................92
8.3.3
Archival tumor samples and fresh tumor biopsies.................................................92
8.3.3.1
Archival tumor samples .........................................................................................92
8.3.3.2
Fresh tumor biopsies ..............................................................................................92
8.3.4
Stool Collection......................................................................................................93
8.3.5
Withdrawal of informed consent for donated biological samples .........................93
9.
DISEASE EVALUATION AND METHODS ......................................................94
9.1.1
Response Assessments...........................................................................................95
10.
ASSESSMENT OF SAFETY................................................................................96
10.1.1
Safety Parameters...................................................................................................96
10.1.1.1
Definition of adverse events...................................................................................96
10.1.2
Definition of serious adverse events ......................................................................97
10.1.3
Durvalumab (MEDI4736) + tremelimumab adverse events of special 
interest....................................................................................................................97
10.1.4
Immune-related adverse events..............................................................................98
10.2
Assessment of safety parameters .........................................................................100
10.2.1
Assessment of severity.........................................................................................100
10.2.2
Assessment of relationship...................................................................................101
10.3
Recording of adverse events and serious adverse events.....................................101
10.3.1
Study recording period and follow-up for adverse events and serious adverse 
events....................................................................................................................102
10.3.2
Reporting of serious adverse events.....................................................................103
10.3.2.1
Reporting of deaths ..............................................................................................104

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
9
10.3.3
Other events requiring reporting ..........................................................................105
10.3.3.1
Overdose ..............................................................................................................105
10.3.3.2
Hepatic function abnormality...............................................................................106
10.3.3.3
Pregnancy.............................................................................................................106
10.3.3.3.1Maternal exposure................................................................................................106
10.3.3.3.2Paternal exposure .................................................................................................108
11
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ..........108
12
ETHICAL AND REGULATORY REQUIREMENTS.......................................110
12.1 
Ethical conduct of the study.................................................................................110
12.2 
Ethics and regulatory review................................................................................111
12.3
Informed consent..................................................................................................111
12.4
Changes to the protocol and informed consent form ...........................................111
12.5
Audits and inspections .........................................................................................111
13
STUDY MANAGEMENT...................................................................................112
14.
DATA MANAGEMENT.....................................................................................114
15.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ..................114
16.
LIST OF REFERENCES .....................................................................................115

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
10
LIST OF TABLES
 Table 1: Treatment-Emergent Adverse Events with Severity > Grade 3 by System Organ 
Class and Preferred Term…………………………………………………………………….32
Table 2: Subjects with at Least One Serious Related Event…………………………….…….33
Table 3: Adverse Events of Special Interest (Investigator Selection)…………………….…..34
Table 4: Nomenclature and Properties: Cedazuridine and Decitabine......................................65
Table 5. Cohort size and dose escalation increments for Azacitide/Decitabine .......................71
Table 6. Dose Adjustments and Dose Delays for Toxicity.......................................................76
Table 7. Effective methods of contraception (2 methods must be used) .............................. ...80
Table 8. Prohibited and Rescue Medications ...........................................................................83
Table 9. Trial Treatment............................................................................................................86
Table 10. Hematology Laboratory Tests...................................................................................89
Table 11. Clinical chemistry (Serum or Plasma) Laboratory Tests..........................................90
Table 12. Urinalysis Test...........................................................................................................90
Table 13. Volume of blood to be drawn from each subject......................................................92
Table 14. List of investigational products for this study.........................................................114
LIST OF FIGURES
Figure 1          Study flow chart.............................................................................................50
Figure 2
Chemical Structure of Azacitidine/Decitabine..............................................64 
Figure 3
ASTX727 Tablet ...........................................................................................67

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
11
LIST OF APPENDICES
Appendix 1. Dose modification and toxicity management guidelines for immune-mediated, 
infusion-related, and non immuned-mediated reactions (MEDI4736 
monotherapy or combination therapy with tremelimumab or 
tremelimumab monotherapy) ............................................................................128
Appendix 2. Schedule of study procedures: follow-up for subjects who have completed 
durvalumab (MEDI4736) and tremelimumab treatment and achieved 
disease control (until confirmed progression of disease) and subjects 
who have discontinued durvalumab (MEDI4736) or tremelimumab due 
to toxicity in the absence of confirmed progression of disease ........................158
Appendix 3. Schedule of study procedures: follow-up for subjects who have discontinue 
durvalumab (MEDI4736)  and tremelimumab treatment due to 
confirmed progression of disease at the investigator discretion .......................160
Appendix 4. Durvalumab (MEDI4736)  DOSE CALCULATIONS ................................................162
Appendix 5. Durvalumab (MEDI4736)  DOSE VOLUME CALCULATIONS.............................. 163
Appendix 6. Tremelimumab DOSE CALCULATIONS ..................................................................164
Appendix 7. Tremelimumab DOSE VOLUME CALCULATIONS ................................................165
Appendix 8. Participant Self-Administration Drug Diary (ASTX727) .............................................167

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
12
ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation 
or 
special term
Explanation
AChE
Acetylcholine esterase
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
APF12
Proportion of patients alive and progression free at 12 months from 
randomization
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC0-28day
Area under the plasma drug concentration-time curve from time zero to Day 
28 post-dose
AUCss
Area under the plasma drug concentration-time curve at steady state
BICR
Blinded Independent Central Review
BoR
Best objective response
BP
Blood pressure
C
Cycle
CD
Cluster of differentiation
CI
Confidence interval
CL
Clearance
Cmax
Maximum plasma concentration
Cmax,ss
Maximum plasma concentration at steady state
CR
Complete response
CSA
Clinical study agreement
CSR
Clinical study report

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
13
Abbreviation 
or 
special term
Explanation
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTLA-4
Cytotoxic T–lymphocyte-associated antigen 4
Ctrough,ss
Trough concentration at steady state
CXCL
Chemokine (C-X-C motif) ligand
DoR
Duration of response
EC
Ethics Committee, synonymous to Institutional Review Board and 
Independent Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDoR
Expected duration of response
EGFR
Epidermal growth factor receptor
EU
European Union
FAS
Full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
hCG
Human chorionic gonadotropin
HIV
Human immunodeficiency virus
HR
Hazard ratio
HNSCC
HPV
IB
Head and neck squamous cell carcinoma
Human papillomavirus
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
14
Abbreviation 
or 
special term
Explanation
IFN
Interferon
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IL
Interleukin
ILS
Interstitial lung disease
IM
Intramuscular
IMT
Immunomodulatory therapy
IP
Investigational product 
irAE
Immune-related adverse event
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
mAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cell
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Minister of Health, Labor, and Welfare
miRNA
Micro-ribonucleic acid
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NE
Not evaluable
NSCLC
Non–small-cell lung cancer
OAE
Other significant adverse event
ORR
Objective response rate
OS
Overall survival

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
15
Abbreviation 
or 
special term
Explanation
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PDx
Pharmacodynamic(s)
PFS
Progression-free survival
PFS2
Time to second progression
PGx
Pharmacogenetic research
PK
Pharmacokinetic(s)
PR
Partial response
q2w
Every 2 weeks
q3w
Every 3 weeks
q4w
Every 4 weeks
q6w
Every 6 weeks
q8w
Every 8 weeks
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
Ribonucleic acid
RR
Response rate
RT-QPCR
Reverse transcription quantitative polymerase chain reaction
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Safety analysis set
SCCHN
SD
Squamous cell carcinoma of the head and neck
Stable disease
SNP
Single nucleotide polymorphism
SoC
Standard of Care

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
16
Abbreviation 
or 
special term
Explanation
sPD-L1
Soluble programmed cell death ligand 1
T3
Triiodothyronine
T4
Thyroxine
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
WBDC
Web-Based Data Capture
WHO
World Health Organization

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
17
1.
INTRODUCTION
1.1.1
Head and Neck Squamous Cell Carcinoma Background
Head and neck cancer is a collective term that encompasses the malignant tumors arising out of 
the oral cavity, pharynx, and larynx. Worldwide, over half a million new head and neck cancer 
cases are diagnosed each year, accounting for approximately 5% of all incident cancers. Over 
90% of these head and neck cancers are squamous cell carcinoma subtype (SCCHN). SCCHN 
diagnosed at a localized stage (Stage I/II) can be effectively treated with single-modality 
treatment (either surgery or radiation), and the 5-year survival rate in these cases is over 80%. 
However, about 70% of SCCHN patients are diagnosed with a locally advanced or metastatic 
disease, where the survival rates are poor (Siegel et al 2014). Patients with locally advanced 
disease typically receive a multi-modality treatment with curative intent, usually involving 
varied combinations of surgical resection, radiation therapy, and chemotherapy. Most of these 
patients, however, eventually relapse with either locoregional recurrence, metastatic disease 
(20% to 30% of patients), or both (Vermorken and Specenier 2010).
First-line palliative treatment options for patients with locally recurrent (without salvage 
surgical or radiation option) and/or metastatic SCCHN include supportive care in conjunction 
with systemic therapy. Most regimens involve platinum compounds (cisplatin and carboplatin), 
either as single agents or in combination with other agents. Other most widely used agents 
include taxanes (docetaxel and paclitaxel), methotrexate, 5-fluorouracil, and cetuximab. After 
failure of first-line chemotherapy, objective responses to second-line cytotoxic chemotherapy 
are uncommon. Additionally, these regimens are associated with greater toxicity, and there is 
no evidence that second line treatment prolongs survival. The only approved targeted therapy 
for these second-line patients is Erbitux® (cetuximab), which has shown an objective response 
rate (ORR) of approximately 13% in patients who have failed first-line palliative therapy 
(Vermorken et al 2007).
Patients with recurrent or metastatic disease have a poor prognosis, with ORRs of approximately 
20% to 35% and overall survival (OS) of 7 to 10 months observed with platinum-based 
chemotherapy and cetuximab regimens (Vermorken et al 2008). The management of patients 
with later stage disease is even more challenging, with currently available therapies providing 
ORRs of approximately 4% with methotrexate to 13% with cetuximab and OS of approximately 
6 months (Shin and Khuri 2013, Vermorken et al 2008). In addition to poor response and 
survival outcomes, many palliative treatments may cause substantial toxicity. In summary, 
SCCHN represents a population with a large unmet need for new treatment options in the 
palliative setting (American Cancer Society 2012).

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1.1.2
Immunotherapies
It is increasingly understood that cancers are recognized by the immune system, and, under 
some circumstances, the immune system may control or even eliminate tumors (Dunn 
et al 2004).  Studies in mouse models of transplantable tumors have demonstrated that 
manipulation of co-stimulatory or co-inhibitory signals can amplify T-cell responses against 
tumors (Peggs et al 2009).  This amplification may be accomplished by blocking co-inhibitory 
molecules, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell 
death 1 (PD-1), from binding with their ligands, B7 or B7-H1 (programmed cell death ligand 1 
[PD-L1]).  Biologically, SCCHN has attributes that suggest susceptibility to immune checkpoint 
blockade. Multiple lines of evidence suggest that SCCHN tumors create a highly 
immunosuppressive environment and that the PD-1/PD-L1 axis and inhibition of the activation 
of T cells play an important role in many cancers, including SCCHN, and may be amenable to 
therapeutic intervention with immune-modulating agents (Badoual et al 2010, Badoual et al 
2013, Lyford-Pike et al 2013). Virally driven tumors, including human papillomavirus (HPV)-
associated SCCHN, express viral antigens that may be recognized by the immune system. In 
HPV-associated cancers, the E6 and E7 tumor-specific antigens are known to be immunogenic, 
and studies have shown that HPV-specific T cell responses form upon vaccination with these 
proteins (Kaufmann et al 2002). Administering an immunotherapeutic agent to patients with 
HPV-positive SCCHN may result in an anti-tumor immune response versus HPV tumor-
specific antigens. In patients with HPV-negative SCCHN, the driving etiology is thought to be 
tobacco use. Data suggest that cancers associated with smoking such as non-small-cell lung 
cancer (NSCLC), small-cell lung cancer, and SCCHN may carry a high mutational burden 
(Alexandrov et al 2013, Vogelstein et al 2013). Tumors with high mutational burden produce 
neoantigens, which may generate T-cell immunity. This hypothesis may explain the observation 
that patients with NSCLC with a history of heavy smoking may be more prone to respond to 
anti-PD-1 or anti-PD-L1 therapy as compared to light or never smokers. Specifically, higher 
ORRs following treatment with an anti-PD-L1 monoclonal antibody (mAb) were observed in 
patients with NSCLC with a history of smoking as compared to those without a history of 
smoking (Champiat et al 2014). These data suggest that application of immune-modulating 
therapies in SCCHN may have a positive impact on clinical outcomes.
1.1.3
Durvalumab (MEDI4736)
The non-clinical and clinical experience is fully described in the current version of the 
durvalumab (MEDI4736) Investigator’s Brochure (IB Version 15.0).  
Durvalumab (MEDI4736) is a human monoclonal antibody (mAb) of the immunoglobulin G 
(IgG) 1 kappa subclass that inhibits binding of PD-L1 and is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer.  (MedImmune is a wholly owned 

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subsidiary of AstraZeneca; AstraZeneca/MedImmune will be referred to as AstraZeneca 
throughout this document.)  As durvalumab (MEDI4736) is an engineered mAb, it does not 
induce antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity.  The 
proposed mechanism of action for durvalumab (MEDI4736) is interference of the interaction of 
PD-L1.
PD-L1 is expressed in a broad range of cancers with a high frequency, up to 88% in some types 
of cancers.  In a number of these cancers, including lung, the expression of PD-L1 is associated 
with reduced survival and an unfavorable prognosis.  In lung cancer, only 12% of patients with 
tumors expressing PD-L1 survived for more than 3 years, compared with 20% of patients with 
tumors lacking PD-L1 (Mu et al 2011).  Based on these findings, an anti-PD-L1 antibody could 
be used therapeutically to enhance anti-tumor immune responses in patients with cancer.  
Results of several non-clinical studies using mouse tumor models support this hypothesis, where 
antibodies directed against PD-L1 or its receptor PD-1 showed anti-tumor activity 
(Hirano et al 2005, Iwai et al 2002, Okudaira et al 2009, Zhang et al 2008).
Durvalumab (MEDI4736) has been given to humans as part of ongoing studies as a single drug 
or in combination with other drugs. As of the DCO dates (15Apr2015 to 18Sep2015, 
durvalumab (MEDI4736) IB version 9.0), a total of 1,910 subjects have been enrolled and 
treated in 30 ongoing durvalumab (MEDI4736) clinical studies, including 20 sponsored and 
10 collaborative studies. Of the 1,910 subjects, 1,279 received durvalumab (MEDI4736) 
monotherapy, 454 received durvalumab (MEDI4736) in combination with tremelimumab or 
other anticancer agents, 14 received other agents (1 gefitinib, 13 MEDI6383), and 163 have 
been treated with blinded investigational product. No studies have been completed or terminated 
prematurely due to toxicity. 
As of 09Feb2015, PK data were available for 378 subjects in the dose-escalation and dose-
expansion phases of Study CD-ON-durvalumab (MEDI4736)-1108 following treatment with 
durvalumab (MEDI4736) 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks 
(Q3W). The maximum observed concentration (Cmax) increased in an approximately dose-
proportional manner over the dose range of 0.1 to 15 mg/kg. The area under the concentration-
time curve from 0 to 14 days (AUC0-14) increased in a greater than dose-proportional manner 
over the dose range of 0.1 to 3 mg/kg and increased dose-proportionally at ≥ 3 mg/kg. These 
results suggest durvalumab (MEDI4736) exhibits nonlinear PK likely due to saturable target-
mediated CL at doses < 3 mg/kg and approaches linearity at doses ≥ 3 mg/kg. Near complete 
target saturation (soluble programmed cell death ligand 1 [sPD-L1] and membrane bound) is 
expected with durvalumab (MEDI4736) ≥ 3 mg/kg Q2W. Exposures after multiple doses 
showed accumulation consistent with PK parameters estimated from the first dose. In addition, 

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PK simulations indicate that following durvalumab (MEDI4736) 10 mg/kg Q2W dosing, > 90% 
of subjects are expected to maintain PK exposure ≥ 40 µg/mL throughout the dosing interval.
As of 09Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 
388 subjects (1 subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg 
cohort) were ADA positive with an impact on PK/pharmacodynamics in 1 subject in the 
3 mg/kg cohort.
1.1.4
Tremelimumab
The non-clinical and clinical experience is fully described in the current version of the 
tremelimumab Investigator’s Brochure (IB Version 10.0).  
Tremelimumab is an IgG 2 kappa isotype mAb directed against the cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) also known as CD152 (cluster of differentiation 152). This is an 
immunomodulatory therapy (IMT) that is being developed by AstraZeneca for use in the 
treatment of cancer.  
Binding of CTLA-4 to its target ligands (B7-1 and B7-2) provides a negative regulatory signal, 
which limits T-cell activation.  Anti-CTLA-4 inhibitors antagonize the binding of CTLA-4 to 
B7 ligands and enhance human T-cell activation as demonstrated by increased cytokine 
(interleukin [IL]-2 and interferon [IFN] gamma) production in vitro in whole blood or peripheral 
blood mononuclear cell (PBMC) cultures (Tarhini and Kirkwood 2008).  In addition, blockade 
of CTLA-4 binding to B7 by anti-CTLA-4 antibodies results in markedly enhanced T-cell 
activation and anti-tumor activity in animal models, including killing of established murine 
solid tumors and induction of protective anti-tumor immunity.  (Refer to the tremelimumab IB, 
Edition 6.0, for more information.)  Therefore, it is expected that treatment with an anti-CTLA-4 
antibody, such as tremelimumab, will lead to increased activation of the human immune system, 
increasing anti-tumor activity in patients with solid tumors.  
An extensive program of non-clinical and clinical studies has been conducted for tremelimumab 
both as monotherapy and combination therapy with conventional anticancer agents to support 
various cancer indications using different dose schedules.  As of the data cutoff dates (1 
November 2015 for monotherapy studies and 15 April 2015 to 12 July 2015 for combination 
therapy studies), 34 sponsored clinical studies have been conducted as part of the tremelimumab 
clinical development programme. Of these, 13 studies have completed and 21 are ongoing. 
Eight tremelimumab monotherapy studies have been completed and 3 are ongoing. As of the 
data cutoff date of 1 November 2015, 973 patients received tremelimumab in completed 
monotherapy studies and the ongoing Study D4881C00024 and 569 patients have been treated 
in the ongoing blinded Phase IIb monotherapy Study D4880C00003 [DETERMINE]). In the 

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3rd ongoing monotherapy study (D4884C00001), no patients have been treated as of the data 
cutoff. In addition, approximately 59 patients have been treated with tremelimumab in 
monotherapy arms of combination studies. Five studies of tremelimumab in combination with 
other anticancer agents have been completed and 18 are ongoing. In total, 250 patients with a 
variety of tumour types have received tremelimumab in combination with other anticancer 
agents in these studies. Details on the safety profile of tremelimumab monotherapy are 
summarized in Section 1.4.2.2.  Refer to the current tremelimumab IB for a complete summary 
of non-clinical and clinical information; see Section 6.6 for guidance on management of 
tremelimumab-related toxicities.  
Tremelimumab exhibited a biphasic PK profile with a long terminal phase half-life of 22 days.  
Overall, a low incidence of ADAs (<6%) was observed for treatment with tremelimumab.  
1.1.5
Durvalumab (MEDI4736) in combination with tremelimumab
Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity (Pardoll 
2012) because the mechanisms of action of CTLA-4 and PD-1 are non-redundant; therefore, 
AstraZeneca is also investigating the use of durvalumab (MEDI4736)  + tremelimumab 
combination therapy for the treatment of cancer.
Study D4190C00006 is a Phase Ib dose-escalation study to establish safety, PK/PDx, and 
preliminary anti-tumor activity of durvalumab (MEDI4736) + tremelimumab combination 
therapy in patients with advanced NSCLC.  The dosing schedule utilized is durvalumab 
(MEDI4736) every 2 weeks (q2w) or every 4 weeks (q4w) up to Week 50 and 48 (12 months), 
combined with tremelimumab q4w up to Week 24 for 7 doses then every 12 weeks for 2 
additional doses for up to 12 months.  The study is ongoing and continues to accrue.  
Study D4190C00006: As of 20Feb2015, durvalumab (MEDI4736) PK (n = 55) and 
tremelimumab PK (n = 26) data were available from 10 cohorts (1a, 2a, 3a, 3b, 4, 4a, 5, 5a, 8, 
and 9) following durvalumab (MEDI4736) every 4 weeks (Q4W) or Q2W dosing in 
combination with tremelimumab Q4W regimens. An approximately dose-proportional increase 
in PK exposure (Cmax and area under the concentration-time curve from 0 to 28 days [AUC0-28]) 
of both durvalumab (MEDI4736) and tremelimumab was observed over the dose range of 3 to 
15 mg/kg durvalumab (MEDI4736) Q4W and 1 to 10 mg/kg tremelimumab Q4W. Exposures 
following multiple doses demonstrated accumulation consistent with PK parameters estimated 
from the first dose. It is to be noted that steady state PK parameters are based on limited numbers 
of subjects. The observed PK exposures of durvalumab (MEDI4736)  and tremelimumab 
following combination were consistent with respective monotherapy data, indicating no PK 
interaction between these 2 agents.

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As of 20Feb2015, ADA data were available from 60 subjects for durvalumab (MEDI4736) and 
53 subjects for tremelimumab in Study D4190C00006. Four of 60 subjects were ADA positive 
for anti-durvalumab (MEDI4736) antibodies post treatment. One of 53 subjects was ADA 
positive for anti-tremelimumab antibodies post treatment. There was no clear relationship 
between ADA and the dose of either durvalumab (MEDI4736) or tremelimumab, and no 
obvious association between ADA and safety or efficacy.
Durvalumab (MEDI4736) has also been combined with other anticancer agents, including 
gefitinib, dabrafenib, and trametinib. To date, no PK interaction has been observed between 
durvalumab (MEDI4736) and these agents. 
1.1.6
Azacitidine/Oral Decitabine (ASTX727)
Hypomethylating agents (HMAs), such as decitabine and azacitidine, are effective treatment 
modalities for hematologic cancers and are FDA-approved for higher risk myelodysplastic 
syndromes (MDS). HMAs have also shown promising clinical activity in acute myeloid leukemia 
(AML). Consecutive daily dosing for a minimum of 5 or 7 days in 28-day cycles is the labelled 
schedule and is necessary to achieve the desired effects, particularly in higher risk patients. 
Reduction in the number of days of treatment per cycle have been studied, but have not been pursued 
for marketing approval with health authorities (Jabbour et al 2017; Garcia-Manero et al 2013). 
Continued monthly treatment for patients who respond is now the standard of care to avoid early 
relapse (Cabrero et al 2015). Treatment, ie, 5 to 7 daily visits for a 1-hour intravenous (IV) infusion 
or a large-volume subcutaneous injection continuing for several months or even years, represents a 
significant hardship for patients. A possible consequence is non-compliance or earlier 
discontinuation of a beneficial treatment. More convenient oral administration of HMAs has proven 
difficult due to rapid metabolism by cytidine deaminase (CDA) during passage through the 
gastrointestinal (GI) mucosa and liver. To achieve even modest exposures of drug requires 
administration of large doses, which are associated with Grades 3 and 4 gastrointestinal toxicity 
(nausea, vomiting, and diarrhea) and high variability in systemic exposures (Garcia-Manero et al 
2011). Successful development of an oral HMA will ease the burden of long-duration parenteral 
therapy, particularly for those patients who are benefitting the most and need continuing treatment 
for long periods. 
Astex Pharmaceuticals is developing a drug product composed of the new chemical entity 
(NCE) cedaxuridine (E7727), a CDA inihibitor (Ferraris et al 2014); and decitabine, both to be 
administered orally.  Because cedaxuridine inhibits CDA in the gut and liver, the ASTX727 
fixed-dose combination (FDC) facilitates oral administration of decitbaine, achieving exposure 
and hypomethylation activity similar to IV decitabine at the currently approved dosing schedule 
of 20 mg/m2 daily x 5 days.  Key intrapatient pharmacokinetic (PK) comparison and safety data 
from the Phase 1-2 trial of ASTX727 (ASTX727-01) have enabled justification of a Phase 3 

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Edition Number 13.0
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trial designed to confirm exposure similar to IV decitabine.  Decitabine was approved in 2006 
by the United States Food and Drug Administration (US FDA) as Dacogen® (decitabine, DAC) 
(Dacogen US Package Insert [PI] 2019), administered as a 1-hour IV infusion for the treatment 
of higher risk patients with MDS and chronic myelomonocytic leukemia (CMML) and approved 
by the European Medicines Agency (EMA) in 2012 (Dacogen Summary of Product 
Characetristics 2019) for the treatment of treatment-naïve adult AML patients who are not 
candidates for intensive chemotherapy.
Azacitidine (AZA), an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and DNA synthesis and metabolism, and causes cytotoxicity. 
Since the early 1970s, azacitidine has been investigated in the United States (US) for the 
treatment of acute leukemia. Clinical trials have focused primarily on patients with disease 
refractory to conventional chemotherapy. These investigations indicated azacitidine has activity 
in the treatment of acute myeloid leukemia (AML). Clinical trials from the 1980’s through 
recent years have been conducted to evaluate the effects of azacitidine in a variety of other 
malignant and hematologic disorders, including solid tumors, hemoglobinopathies (thalassemia 
and sickle cell anemia), and myelodysplastic syndromes (MDS) as well as the use of Azacitidine 
in the treatment of AML in elderly patients.
Vidaza® (azacitidine injection) is approved by the US Food and Drug Administration (FDA) for 
5 subtypes of the French-American British (FAB) classification system of myelodysplastic 
syndrome (MDS). Vidaza® is also approved by the European Commission for the treatment of 
adult MDS, acute myeloid leukemia (AML) and chronic myeolomonocytic leukemia (CMMoL) 
patients who are not eligible for hematopoietic stem cell transplantation. Vidaza® can be 
administered by intravenous (IV) or subcutaneous (SC) routes as designated by country 
approval.
After its incorporation into a cell’s DNA during the S-phase of the cell cycle, AZA forms 
covalent adducts with DNA Methyltransferase 1 (DNMT1) and depletes this enzyme required 
for the maintenance of DNA methylation patterns, thereby altering the epigenetic status of the 
cell. Epigenetic changes are covalent modifications of chromatin (DNA and histone proteins) 
that mediate the stable transmission of a gene’s transcriptional status through cell division. One 
of the first recognized epigenetic alterations in cancer was DNA methylation. The addition of a 
methyl group to cytosine in the dinucleotide (CpG) is catalyzed by DNA methyltransferases 
(DNMTs) and is associated with transcriptional repression of genes with high density of CpGs 
(CpG islands) in the vicinity of their promoters (Miranda, 2007). Genomic methylation patterns 
are precisely regulated during normal embryonic development and differentiation and have been 
found to be altered in specific ways in cancer. Specifically, cancer cell genomes are typified by 
reduced methylation globally with focal areas of aberrant hypermethylation in the CpG islands 
of genes encoding known tumor suppressors such as PTEN and BRCA1 as well as genes 
encoding proteins required for apoptosis, including caspase 8, DAPK and Apaf-1. DNA 
methylation-based silencing can thus contribute to the establishment and maintenance of the 
transformed state and limit the effectiveness of anticancer therapies.

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1.1.7
DNA Methyltrasnferase Inhibitor Experience in Solid Tumors 
Both azacitidine and 2'-deoxy-5-azacitidine prevent DNA methylation, and they also have direct 
cytotoxic effects as a result of incorporation into DNA and RNA. Single-agent 2'-deoxy-5-
azacitidine has demonstrated good antitumor activity in nude mice with SCCHN xenografts 
(Braakhuis et al, 1988). A number of phase II studies using single-agent azacitidine or 2'-deoxy-
5-azacitidine have been performed in solid tumors with disappointing results, including breast, 
gastrointestinal, lung, kidney, testicular, melanoma, sarcoma, and lymphomas (Santini et al, 
2001; Weiss et al, 1977). The doses of azacitidine or 2'-deoxy-5-azacitidine used in these trials 
were near the MTD, rather than the optimal biologically effective dose (Aparicio et al, 2002). 
Therefore, single-agent therapeutic responses were disappointing and patients experienced side 
effects that were probably related more to the inherent toxicity of aza-nucleoside inhibitors than 
to their demethylating activity. It has been shown in cancer cells exposed to DNA demethylating 
agent, demethylation of genes can occur at drug concentrations that are substantially lower than 
those required for a cytotoxic effect (Bender et al, 1998). Additionally, genes demethylated can 
be remethylated within a few days (Velicescu et al, 2002). 
Treatment schedules for DNA hypomethylation agents have been modified to include multiple 
courses of treatment to sustain demethylation and reduced drug concentrations to decrease the 
severity of side effects. This has been shown to be maximized for biologic effects and 
minimized for toxicity. In studies conducted in patients with MDS, administration of azacitidine 
has been modified to daily low-dose treatment (75-100 mg/m2), seven out of 28 days, and 
appeared to have been well tolerated, with increased response rates (Silverman et al, 2002).
Chan et al. have conducted a study using daily 3-hour intravenous infusion of azacitidine at a 
dose of 75 mg/m2/d for 7 days (5 days for HIV infected patient) in 10 patients with Epstein-
Barr virus-associated tumors (8 with nasopharyngeal carcinoma, 1 with Hodgkin’s lymphoma, 
and 1 with AIDS-associated lymphoma) (Chan et al, 2004). Tumor biopsy specimens were 
obtained within 72 hours of the conclusion of the last infusion of the first cycle of therapy, and 
compared to pretreatment specimens. They have found substantial degrees of demethylation 
were detected in all latent and lytic Epstein-Barr virus promoters examined, even in patients 
only receiving 5-day treatment. They concluded that pharmacologic reversal of dense CpG 
methylation in tumor tissue can be achieved after 5 to 7 days of intravenous azacitidine 
treatment at the same dose used in MDS.
Given the unimpressive clinical activity of single-agent azacitidine or 2'-deoxy-5-azacitidine 
against various types of solid tumor malignancy, it is likely that combination therapy with other 
anticancer agents will be required to achieve meaningful clinical response. 
A Phase 1/II study of combined epigenetic therapy with azacitidine and entinostat, inhibitors of 
DNA methylation and histone deacetylation, respectively, in extensively pretreated patients 
with recurrent/metastatic non-small cell lung carcinoma was performed (Juergens et al, 2011). 
Ten patients participated in the phase I portion of the study; three patients received 30 mg/m2/d 

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azacitidine and seven received 40 mg/m2/d azacitidine.  Entinonstat was administered to all 
patients at a fixed dose of 7 mg on days 3 and 10 of each cycle. In total, 42 patients, including 
the seven patients from the phase I portion, were treated at the phase II azacitidine dose of 40 
mg/m2.  None of the 3 patients in the 30 mg/m2 azacitidine cohort experienced DLTs. One 
patient in the 40 mg/m2 azacitidine cohort withdrew from the study due to decreasing 
performance status and was replaced. None of the remaining 6 phase I patients had DLTs.  The 
recommended phase II dose was therefore defined as 40 mg/m2 azacitidine given on days 1-6 
and 8-10 plus 7 mg of entinostat given on days 3 and 10 of each 28-day cycle.  All patients 
experienced at least 1 treatment-related adverse event.  The most common treatment-related, 
non-hematologic adverse events included low-grade skin/injection-site reactions (93%), fatigue 
(71%), nausea (73%), vomiting (40%), constipation (36%), anorexia (29%), electrolyte 
disturbances (29%), and hyperglycemia (22%).  These adverse events are anticipated toxicities 
of either azacitidine or entinostat and generally required no intervention except anti-emetics and 
other agents for gastrointestinal side effects, which were easily medically managed.  Anemia 
was the most common hematologic toxicity (40%) and lymphopenia and thrombocytopenia 
were seen in 27% of patients.  Grade 3 or 4 toxicites were seen in 28% of patients during cycle 
1.  The most common grade 3 or 4 toxicity was fatigue.  Grade 3 or 4 hematologic toxicities 
were transient and generally asymptomatic.  Four patients with anemia all improved following 
a one-time red blood cell transfusion.  There were no correlations between the worst grade of 
toxicity and azacitidine or entinostat exposure (p>0.05).  One patient had a complete response 
that lasted 14 months.  A second patient had a partial response that lasted 8 months.  Ten patients 
had stabilization of disease of at least 12 weeks.  One of these patients had stable disease for 18 
months and another for 14 months, both with prolonged symptomatic improvement. The maimal 
dose planned in the phase I dose escalation was 40 mg/m2/d in an effort to remain at an 
epigenetically targeted dose rather than a directly cytotoxic dose.
Phase II studies of 2'-deoxy-5-azacitidine and cisplatin combination using a concurrent 
administration schedule (daily on day 1-3 of a 21 day cycle) have been conducted in patients 
with metastatic non-small cell lung cancer and advanced squamous cell carcinoma of the cervix. 
In cervical cancer patients, this combination produced moderate activity as a first-line treatment, 
achieving 38.1% partial response, 23.8% stable disease, and 19-week median survival. The 
hematological toxicity was rather significant with grades III/IV neutropenia in 68.0% of cases, 
and one out of 25 patients died of complications caused by drug-related neutropenic sepsis (60). 
In non-small cell lung cancer patients, this combination did not show significant activity, only 
achieving 3 minor responses in 14 patients and 15-week median survival, and more than 50% 
of grade III/IV neutropenia toxicity was noted (Schwartsmann et al, 2000). The possible 
explanations for the shortcomings in these studies include the use of MTD not the biologically 
effective dose of 2'-deoxy-5-azacitidine without validation of DNA hypomethylation effect, and 
administration of 2'-deoxy-5-azacitidine concurrently with cisplatin. 
In 2008, Bast et al. reported on a phase IIa study of a sequential regimen administering 
azacitidine 75 mg/m2/day for 5 days plus carboplatin AUC 5 on day 2 once every 28 days in 
patients with platinum resistant or refractory ovarian cancer (Bast et al, 2008). There were 29 
evaluable patients with 1 complete response, 3 partial response (response rate: 14%) and 10 

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stable disease. The median duration of response was 7.5 months. Overall survival at one-year 
was 53%. Patients classified as having platinum-resistant disease had an objective response of 
22% and one-year overall survival of 67%, compared to 0% and 33% in platinum-refractory 
patients, respectively. Side effects were tolerable, including neutropenia (3% grade 4), 
thrombocytopenia (3% grade 4), anemia, fatigue, nausea, and pain/irritation at the injection 
sites.  This study highlights the ability of a hypomethylating agent to reverse platinum resistance 
which is the target population of our proposed study.
In order to utilize the period of demethylation of drug-resistance and/or pro-apoptotic genes as 
a window of epigenetic sensitization for combination therapies, it has been shown in cell culture 
and animal studies that DNA hypomethylation agents need to be given several days before 
chemotherapeutic agents to achieve optimal synergistic effect (Plumb et al, 2000; Soengas et al, 
2001). Importantly, the timing of drug administration appears to be associated with therapeutic 
response. If DNA hypomethylation agents are given at the same time or after the cytotoxic drug 
is administered, sensitization is lost. Therefore, it is recommended in clinical combination trials 
with DNA hypomethylation agents, the administration of the cytotoxic drug should be delayed 
for several days to achieve the highest possible demethylation of tumor DNA (Lyko et al, 2005).  
This study provides the rationale for administering one cycle of the hypomethylating agent prior 
to the immunotherapy.
1.1.8
DNA Methyltransferase Inhibitors in Head and Neck Cancer
Limited data exists with DNA methyltransferase inhibitors in head and neck cancer. A non-
randomized, open label, dose escalation phase I study of azacitidine and cisplatin was conducted 
in advanced head and neck cancer patients. Azacitidine was administered as a subcutaneous 
injection daily from day 1 to day 5 and cisplatin was given at 75 mg/m2 IV on day 8 on a 28-
day cycle.  Four patients received azacitidine 37 mg/m2 daily from day 1 to day 5 and two 
patients were treated with azacitidine 60 mg/m2 daily from day 1 to day 5.  No patient had dose-
limiting toxicities.  Four patients completed at least 2 cycles of treatment and were evaluated 
for clinical response by CT scan and DNA methylation effect.  One partial response was noted 
in a patient eith metastatic tongue squamous cell carcinoma after 2 cycles of treatment with 37 
mg/m2/d.  This patient received a total of 3 cycles of treatment and achieved progression free 
survival for 15 months. Another patient with recurrent salivary gland carcinoma had stable 
disease after 2 cyclces of treatment at a dose of 60 mg/m2/d. There was inhibition of global 
DNA methylation after azacitidine treatment in all four treated patients. This study was not 
completed due to poor patient accrual; however, the preliminary results are intriguing and 
demonstrate global DNA methylation effect at doses as low as 37 mg/m2/day when 
administered from day 1 to day 5 (Liao et al, 2012).
1.2
Research Hypothesis
The hypothesis of this study is that both azacitidine, durvalumab (MEDI4736), and 
tremelimumab combination therapy or oral decitabine (ASTX727) and durvalumab 
(MEDI4736) combination theraoy are safe and will result in a clinically meaningful PFS based 
on RECIST 1.1. It is hypothesized that SCCHN patients who fail immune checkpoint blockade 

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monotherapy (such as anti-PD-1, anti-PD-L1, anti-CTLA-4, and/or others) have a paucity of 
cytotoxic CD8+ T cells within the tumor microenvironment.  Tumor antigens and major 
histocompatibility complex (MHC) Class I/II molecules are epigenetically silenced in solid 
cancers, including SCCHN, and tumor antigen presentation can be enhanced with 
hypomethylating agents, such as azacitidine or decitabine, leading to immune-mediated 
antitumor effects when combined with immune checkpoint blocking antibodies. 
1.3
Rationale for conducting this study
Patients with recurrent and/or metastatic SCCHN who have progressed during or after treatment 
with a platinum-containing regimen for recurrent and/or metastatic disease have a poor 
prognosis with limited standard-of-care therapeutic options, which only have transient and 
limited benefit (ORR: 4% to 13%, progression-free survival [PFS]: 2.5 months, and OS: 5.5 
months) (Shin and Khuri 2013, Vermorken et al 2008). Thus, there is a significant unmet 
medical need for additional treatment options for use in this patient population.
Durvalumab (MEDI4736), an antibody that blocks the interaction between PD-L1 and its 
receptors, may relieve PD-L1-dependent immunosuppressive effects and, therefore, enhance 
the cytotoxic activity of anti-tumor T-cells. This hypothesis is supported by emerging clinical 
data from other mAbs targeting the PD-L1/PD-1 pathway which provide early evidence of 
clinical activity and a manageable safety profile (Brahmer et al 2012, Topalian et al 2012). In 
addition, although clinical experience with durvalumab (MEDI4736) is limited, currently 
available data from Study 1108 indicates encouraging response rates (RRs) and duration of 
response (DoR) with a manageable safety profile in patients with a variety of solid malignancies, 
including patients with SCCHN treated with durvalumab (MEDI4736) as monotherapy. 
Tremelimumab, an anti-CTLA-4 targeting agent that blocks the interaction with CD80 and 
CD86, may help prolong and enhance T-cell activation and expansion. This hypothesis is 
supported by emerging clinical data from both tremelimumab studies (Kirkwood et al 2010, 
Ribas et al 2013) and studies with a related anti-CTLA-4 antibody, ipilimumab. However, data 
for tremelimumab monotherapy in SCCHN are not available. 
The rationale for evaluating the combination of durvalumab (MEDI4736) and tremelimumab is 
supported both by preclinical and clinical data, including safety and tolerability data. Mouse 
models of transplantable solid tumors using surrogate antimouse antibodies show superior 
antitumor activity of combination therapy as compared to monotherapy. Furthermore, the 
CTLA-4 and PD-1/PD-L1 pathways are non-redundant, suggesting that targeting both may have 
additive or synergistic activity. Lastly, the combination of CTLA-4 and PD-1 blockades in 
melanoma has been shown to result in higher ORRs and 1-year survival compared to either 
agent alone (Wolchok et al 2013). Similar results have been observed in an ongoing study of 
durvalumab (MEDI4736) + tremelimumab in NSCLC, with further updated details presented in 
this clinical study protocol.  
Based on the preliminary clinical efficacy and safety data observed in patients with solid tumors, 
including advanced SCCHN, in Study 1108 with durvalumab (MEDI4736) monotherapy, and 

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in patients with NSCLC in Study D4190C00006 with durvalumab (MEDI4736) and 
tremelimumab, there is an ongoing phase II study which will determine the activities of 
durvalumab (MEDI4736) and tremelimumab as a combination therapy in SCCHN patients, as 
well as the efficacy of durvalumab (MEDI4736) and tremelimumab combination therapy versus 
durvalumab (MEDI4736) or tremelimumab monotherapy. The preliminary efficacy, safety, and 
tolerability data of the durvalumab (MEDI4736) and tremelimumab combination in Study 
D4190C00006 support the development of this combination in SCCHN. 
Since patients who progress on immune checkpoint blockade are hypothesized to have a paucity 
of CD8+ T cells, we are not only interested in establishing the role of durvalumab (MEDI4736) 
in combination with tremelimumab but also with other investigational agents and therapies 
which will enhance the CD8+ T cell frequency and improve upon current ORR of 15-27% with 
pembrolizumab monotherapy and a ORR of 11% with durvalumab (MEDI4736) monotherapy 
in locally recurrent and/or metastatic SCCHN patients (Seiwert et al and Segal et al, ASCO 
2015; Cohen EE et al, ESMO 2017).  It is hypothesized that the addition of azacitidine or oral 
decitabine will lead to an increased frequency of CD8+ T cells and, thus, when combined with 
durvalumab (MEDI4736) and tremelimumab will result in an improved PFS and ORR in 
subjects with SCCHN.  A potential way to improve PFS and ORR may be with epigenetic 
therapy through the reactivation of the host immune response through the hypomethylation of 
silenced genes (Kenney, 2014).  This is supported in the scientific literature for SCCHN.
There is frequent wide-spread methylation of cancer-related genes in SCCHN (Colacino JA 
et al, 2013).
A subset of SCCHNs are associated with HPV infection and have documented HPV DNA 
methylation which is associated with silencing of HPV immunodominant antigens (Park et al, 
2011).
Viral lytic reactivation via demethylation may provide a path to targeting viral-associated 
SCCHN.
Azacitidine induces demethylation of the viral genome in SCCHN (Chan, 2004).
DNA methylation inhibitors can reverse chemoresistance and prevent the development of 
acquired drug resistance (Zhang, 2012b).
Promoter hypermethylation is a major mechanism for inactivation of critical tumor 
suppressor genes (p16,RASSF1A) (Lo, 2013).
Based on the current scientific literature, there is strong rationale for evaluating the combination 
of azacitidine or oral decitabine (ASTX727), durvalumab (MEDI4736), and tremelimumab in 
SCCHN patients.
1.3.1
Durvalumab (MEDI4736)  + tremelimumab combination therapy dose rationale
The durvalumab (MEDI4736) + tremelimumab doses and regimen selected for this study are 
based on the goal of selecting an optimal combination dose of durvalumab (MEDI4736) and 
tremelimumab that would yield sustained target suppression (sPD-L1), demonstrate promising 
efficacy, and have an acceptable safety profile.  

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In order to reduce the dosing frequency of durvalumab (MEDI4736) to align with the q4w 
dosing of tremelimumab, while ensuring an acceptable PK/PDx, safety, and efficacy profile, 
cohorts were narrowed to 15 and 20 mg/kg durvalumab (MEDI4736) q4w.  PK simulations 
from the durvalumab (MEDI4736) monotherapy data indicated that a similar area under the 
plasma drug concentration-time curve at steady state (AUCss; 4 weeks) was expected following 
both 10 mg/kg q2w and 20 mg/kg q4w durvalumab (MEDI4736).  The observed durvalumab 
(MEDI4736) PK data from the D4190C00006 study were well in line with the predicted 
monotherapy PK data developed preclinically.  This demonstrates similar exposure of 
durvalumab (MEDI4736) 20 mg/kg q4w and 10 mg/kg q2w, with no alterations in PK when 
durvalumab (MEDI4736) and tremelimumab (doses ranging from 1 to 3 mg/kg) are dosed 
together.  While the median Cmax at steady state (Cmax,ss) is expected to be higher with 20 mg/kg 
q4w (approximately 1.5 fold) and median trough concentration at steady state (Ctrough,ss) is 
expected to be higher with 10 mg/kg q2w (approximately 1.25 fold), this is not expected to 
impact the overall safety and efficacy profile, based on existing preclinical and clinical data.
Monotonic increases in PDx activity were observed with increasing doses of tremelimumab 
relative to the activity observed in patients treated with durvalumab (MEDI4736) monotherapy.  
There was evidence of augmented PDx activity relative to durvalumab (MEDI4736) 
monotherapy with combination doses containing 1 mg/kg tremelimumab, inclusive of both the 
15 and 20 mg/kg durvalumab (MEDI4736) plus 1 mg/kg tremelimumab combinations. 
Patients treated with doses of tremelimumab above 1 mg/kg had a higher rate of adverse events 
(AEs), including discontinuations due to AEs, serious AEs (SAEs), and severe AEs.  Between 
the 10 mg/kg durvalumab (MEDI4736) + 1 mg/kg tremelimumab and 10 mg/kg durvallumab + 
3 mg/kg tremelimumab cohorts treated at the q2w schedule, the number of patients reporting 
any AE, Grade 3 AEs, SAEs, and treatment-related AEs was higher in the 10 mg/kg durvalumab 
(MEDI4736) + 3 mg/kg tremelimumab cohort than the 10 mg/kg durvalumab (MEDI4736) + 
1 mg/kg tremelimumab cohort.  A similar pattern was noted in the q4w regimens, suggesting 
that, as the dose of tremelimumab increased above 1 mg/kg, a higher rate of treatment-related 
events may be anticipated.  Further, the SAEs frequently attributed to immunotherapy, 
pneumonitis and colitis, were more commonly seen in cohorts using either 3 or 10 mg/kg of 
tremelimumab compared to the 1-mg/kg dose cohorts.  Together, these data suggest that a 
combination using a tremelimumab dose of 1 mg/kg appeared to minimize the rate of toxicity 
when combined with durvalumab (MEDI4736).  As a result, all combination doses utilizing 
either the 3 or 10 mg/kg doses of tremelimumab were eliminated in the final dose selection.  
In contrast, cohorts assessing higher doses of durvalumab (MEDI4736) with a constant dose of 
tremelimumab did not show an increase in the rate of AEs.  The data suggested that increasing 

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doses of durvalumab (MEDI4736) may not impact the safety of the combination as much as the 
tremelimumab dose.  Further, safety data between the 10-mg/kg and 20-mg/kg cohorts were 
similar, with no change in safety events with increasing dose of durvalumab (MEDI4736). 
In Study D4190C00006, of all treatment cohorts, the cohort of 11 patients treated in the 
20 mg/kg durvalumab (MEDI4736) + 1 mg/kg tremelimumab group had the fewest AEs, Grade 
≥3 AEs, SAEs, and treatment discontinuations due to AEs, but still showed strong evidence of 
clinical activity.  This cohort had a lower number of treatment-related Grade ≥3 AEs or 
treatment-related SAEs.  No dose-limiting toxicities were reported.  
Preliminary clinical activity of the durvalumab (MEDI4736) and tremelimumab combination 
did not appear to change with increasing doses of tremelimumab.  The 15- and 20-mg/kg 
durvalumab (MEDI4736) q4w cohorts demonstrated objective responses at all doses of 
tremelimumab, and increasing doses of tremelimumab did not provide deeper or more rapid 
responses.
Efficacy data suggested that the 20 mg/kg durvalumab (MEDI4736) + 1 mg/kg tremelimumab 
dose cohort may demonstrate equivalent clinical activity to other dose combinations.  A total of 
5 of 11 patients in the 20 mg/kg durvalumab (MEDI4736) + 1 mg/kg tremelimumab cohort 
were evaluable for efficacy with at least 8 weeks of follow-up.  Of these, there were 2 patients 
(40%) with partial response (PR), 1 patient (20%) with stable disease (SD), and 1 patient (20%) 
with progressive disease (PD).  (The fifth patient had only a single scan, which was conducted 
outside the window for these evaluations.)
Additionally, of all cohorts, the 20 mg/kg durvalumab (MEDI4736) + 1 mg/kg tremelimumab 
dose cohort had the fewest AEs, Grade ≥3 AEs, SAEs, and treatment discontinuations due to 
AEs, but still showed some evidence of clinical activity.  All together, the data suggested that a 
20 mg/kg durvalumab (MEDI4736) + 1 mg/kg tremelimumab dose combination should be 
selected for further development.  
AstraZeneca performed a safety evaluation for subjects randomized to the durvalumab 1500 mg 
Q4W plus tremelimumab 300 mg x 1 dose regimen in study D4190C00022 (Part 2B, Arm D, 
and Part 3, Arm D) as part of the interim analysis. As of May 7, 2018, safety data in the form 
of Tables and Listings are available for 24 subjects: 10 Part 2B, Arm D subjects (6 subjects 
from Japan and 4 from the USA) and 14 subjects from Part 3, Arm D (4 from South Korea, 2 
from Taiwan, 1 from Italy, 5 from USA and 2 from Singapore). These patients all completed at 
least 4-weeks of safety follow up.  
Safety information for these subjects are summarized below (accurate as of 7 May 2018). 

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All 24 subjects treated in Arm D (of Parts 2B and 3) of the study experienced at least one adverse 
event (AE). These events were considered to be treatment-related in 21 (87.5%) subjects.  
Eleven (45.8%) subjects reported at least one event of Grade ≥ 3 severity with the events being 
considered treatment-related in 7 subjects (29.2%).  
One Grade 5 event of acute kidney failure (SOC: Renal and urinary disorders) was reported 
which was assessed as unrelated to study treatment.  This subject received one cycle of treatment 
(durvalumab and tremelimumab combination).  There were no treatment-related deaths 
observed as at the data cut-off of 7 May 2018.
Seven (29.2%) subjects experienced at least one serious adverse event (AE). These events were 
considered to be treatment-related in 2 (8.3%) subjects.  
One subject (4.2%), subject 20015250002, experienced an event of hyperthyroidism (SOC: 
Endocrine disorders), which did not meet serious criteria, but was considered to be treatment 
related.  This subject had received 2 cycles of treatment (one durvalumab and tremelimumab 
combination and one durvalumab monotherapy). The event of hyperthyroidism led to treatment 
discontinuation for this subject.
A total of 22 (91.7%) subjects experienced at least one Adverse Event of Special Interest 
(AESI). Twenty (83.3%) subjects experienced at least one AESI which was considered 
treatment related.  Eleven (45.8%) subjects experienced at least one AESI which was of Grade 
≥ 3 severity. Seven (29.2%) subjects experienced at least one AESI which was considered 
treatment related and of Grade ≥ 3 severity.
Observed treatment-emergent Adverse Events with Severity ≥ Grade 3 are detailed in Table 1.
Table 1
Treatment-emergent Adverse Events with Severity ≥ Grade 3 by 
System Organ Class and Preferred Term
System Organ Class (SOC) & Preferred 
Term
Part 2B 
(n=10)
Part 3 
(n=14)
Total 
(n=24)
Subjects with at least one ≥ grade 3 event
    6 (60.0%)
    5 (35.7%)
11 (45.8%)
Cardiac disorders
    1 (10.0%)
    0
    1 (4.2%)
   Acute myocardial infarction
    1 (10.0%)
    0
    1 (4.2%)
   Atrial fibrillation
    1 (10.0%)
    0
    1 (4.2%)
   Cardiac failure congestive
    1 (10.0%)
    0
    1 (4.2%)

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Table 1
Treatment-emergent Adverse Events with Severity ≥ Grade 3 by 
System Organ Class and Preferred Term
System Organ Class (SOC) & Preferred 
Term
Part 2B 
(n=10)
Part 3 
(n=14)
Total 
(n=24)
Gastrointestinal disorders
    1 (10.0%)
    2 (14.3%)
    3 (12.5%)
   Abdominal pain
    0
    1 (7.1%)
    1 (4.2%)
   Ascites
    1 (10.0%)
    0
    1 (4.2%)
   Pancreatitis
    0
    1 (7.1%)
    1 (4.2%)
Hepatobiliary disorders
    1 (10.0%)
    0
    1 (4.2%)
   Hepatic function abnormal
    1 (10.0%)
    0
    1 (4.2%)
Infections and infestations
    2 (20.0%)
    0
    2 (8.3%)
   Meningitis
    1 (10.0%)
    0
    1 (4.2%)
   Peritonitis bacterial
    1 (10.0%)
    0
    1 (4.2%)
Investigations
    5 (50.0%)
    3 (21.4%)
    8 (33.3%)
   Alanine aminotransferase increased
    1 (10.0%)
    1 (7.1%)
    2 (8.3%)
   Amylase increased
    2 (20.0%)
    0
    2 (8.3%)
   Aspartate aminotransferase increased
    3 (30.0%)
    1 (7.1%)
    4 (16.7%)
   Blood alkaline phosphatase increased
    0
    1 (7.1%)
    1 (4.2%)
   Lipase increased
    3 (30.0%)
2 (14.3%)
    5 (20.8%)
   Neutrophil count decreased
    1 (10.0%)
    0
    1 (4.2%)
Neoplasms benign, malignant and unspecified (incl 
cysts and polyps)
    1 (10.0%)
    0
    1 (4.2%)
   Tumour associated fever
    1 (10.0%)
    0
    1 (4.2%)
Renal and urinary disorders
    0
1 (7.1%)
    1 (4.2%)
   Acute kidney injury
    0
1 (7.1%)
    1 (4.2%)
Skin and subcutaneous tissue disorders
    3 (30.0%)
1 (7.1%)
    4 (16.7%)
   Eczema
    1 (10.0%)
    0
    1 (4.2%)
   Erythema multiforme
    1 (10.0%)
    0
    1 (4.2%)
   Rash
    1 (10.0%)
    0
    1 (4.2%)
   Rash generalised
    1 (10.0%)
    0
    1 (4.2%)
   Rash maculo-papular
    0
    1 (7.1%)
    1 (4.2%)
Vascular disorders
    1 (10.0%)
    0
    1 (4.2%)
   Hypertension
    1 (10.0%)
    0
    1 (4.2%)

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Subjects with at least one serious and related adverse event are outlined in Table 2.
Table 2
Subjects with at Least One Serious Related Event
System Organ Class (SOC) & Preferred Term
Part 2B 
(n=10)
Part 3 
(n=14)
Total 
(n=24)
Subjects with at Least One Serious Related Event
1 (1.0%)
1 (7.1%)
2 (8.3%)
Endocrine disorders
0
0
0
     Adrenal insufficiency
0
0
0
     Hypophysitis
0
0
0
     Hypopituitarism
0
0
0
Gastrointestinal disorders
    1 (10.0%)
    1 (7.1%)
2 (8.3%)
     Autoimmune pancreatitis
0
0
0
     Colitis
0
0
0
     Diarrhoea
    1 (10.0%)
0
1 (4.2%)
     Vomiting
0
    1 (7.1%)
1 (4.2%)
Infections and infestations
0
0
0
     Clostridium difficile colitis
0
0
0
     Encephalitis
0
0
0
Metabolism and nutrition disorders
    1 (10.0%)
    1 (7.1%)
2 (8.3%)
     Decreased appetite
0
0
0
     Dehydration
    1 (10.0%)
    1 (7.1%)
2 (8.3%)
     Diabetic ketoacidosis
0
0
0
     Hyperglycaemia
0
0
0
Other (System organ class with only one PT)
0
0
0
     Fatigue
0
    1 (7.1%)
1 (4.2%)
     Hepatic function abnormal
0
0
0
     Tumour rupture
0
0
0
Hepatic encephalopathy
0
0
0
Adverse Events of Special Interest (AESI), based on Investigator selection, and noted in this 
patient population are detailed in Table 3.

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Table 3
Adverse Events of Special Interest (Investigator Selection)
Event
Part 2B (n=10)
Part 3 (n=14)
Total (n=24)
Subjects with at least one event of 
special interest
    8 (80.0%)
   14 (100.0%)
22 (9.2%)
Dermatitis
    8 (80.0%)
    9 (64.3%)
17 (70.8%)
Select hepatic events
    5 (50.0%)
    4 (28.6%)
9 (37.5%)
Diarrhoea
    3 (30.0%)
    2 (14.3%)
5 (20.8%)
Pancreatitis
    4 (40.0%)
    5 (35.7%)
9 (37.5%)
Hyperthyroidism
    1 (10.0%)
    2 (14.3%)
3 (12.5%)
Hypothyroidism
    1 (10.0%)
0
1 (4.2%)
Nephritis/Acute Renal Failure
0
    1 (7.1%)
1 (4.2%)
Hypophysitis
0
0
0
Colitis
0
0
0
Adrenal insufficiency
0
0
0
Infusion related/ Hypersensitivity/ Anaphy
0
0
0
Overall, the safety data remain consistent with the observed toxicity profile for the standard 
dosing regimen of 1500 mg Q4W durvalumab and 75 mg Q4W x 4 doses tremelimumab. The 
observed safety data is also consistent with PK modelling predictions which were performed to 
compare 300 mg tremelimumab single dose with tremelimumab 75 mg Q4W for 4 doses 
(standard dose).  This PK modelling predicted that the same cumulative AUC tremelimumab 
exposure would be expected for both dose regimens and thus a similar safety profile could be 
anticipated.  
1.3.2
Rationale for 4 cycles of combination therapy followed by durvalumab 
(MEDI4736) monotherapy
Long-term follow up on melanoma patients treated with ipilimumab, an anti-CTLA-4 targeting 
antibody (dosed every 3 weeks [q3w] for 4 doses and then discontinued), shows that patients 
responding to ipilimumab derive long-term benefit, with a 3-year OS rate of approximately 
22%.  Furthermore, the survival curve in this population reached a plateau at 3 years and was 
maintained through 10 years of follow up (Schadendorf et al 2013). 
Similar data have been presented for other anti-PD-1/PD-L1 targeting antibodies: 
Nivolumab (anti-PD-1) was dosed q2w for up to 96 weeks in a large Phase I dose-escalation 
and expansion study, and showed responses were maintained for a median of 22.94 months for 

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melanoma (doses 0.1 mg/kg to 10 mg/kg), 17 months for NSCLC (doses 1, 3, and 10 mg/kg), 
and 12.9 months for renal cell carcinoma patients (doses 1 and 10 mg/kg) at the time of data 
analysis (Hodi et al 2014, Brahmer et al 2014, Drake et al 2013).  Furthermore, responses were 
maintained beyond treatment discontinuation in the majority of patients who stopped nivolumab 
treatment (either due to protocol specified end of treatment, complete response [CR], or 
toxicity) for up to 56 weeks at the time of data analysis (Topalian et al 2014). 
MPDL3280a (anti-PD-L1) and the combination of nivolumab with ipilimumab, in which 
patients were dosed for a finite time period and responses maintained beyond treatment 
discontinuation have been reported (Herbst et al 2013, Wolchok et al 2013).
Similar long-term results may be expected with use of other immune-mediated cancer 
therapeutics including anti-CTLA-4 antibodies such as tremelimumab, anti PD-L1 antibodies 
such as durvalumab (MEDI4736), or the combination of the two.  
1.3.3
Rationale for study design
The safety and efficacy of  oral decitabine (ASTX727) and durvalumab (MEDI4736) 
combination therapy are being evaluated in patients with recurrent or metastatic SCCHN who 
have progressed during or after treatment with a platinum-containing regimen for recurrent or 
metastatic disease.
1.4
Benefit/risk and ethical assessment
The following sections include summaries of the potential benefits and risks associated with 
oral decitabine (ASTX727) and durvalumab (MEDI4736) combination therapy, respectively, 
prior to the overall benefit:risk assessment.
1.4.1
Potential benefits
1.4.1.1
Durvalumab (MEDI4736)
The majority of the safety and efficacy data currently available for durvalumab (MEDI4736)  
are based on the first time in-human, single-agent study (Study 1108) in patients with advanced 
solid tumors.  Data from Study 1108 were presented at the European Society for Medical 
Oncology 2014 Congress.  Overall, 456 of 694 subjects treated with durvalumab (MEDI4736) 
10 mg/kg Q2W were evaluable for response (defined as having ≥ 24 weeks follow-up, 
measurable disease at baseline, and ≥ 1 follow-up scan, or discontinued due to disease 
progression or death without any follow-up scan). In PD-L1 unselected patients, the objective 
response rate (ORR), based on investigator assessment per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% in bladder 

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cancer (n = 15), and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% in triple-
negative breast cancer (TNBC; n = 24) to 39.1% in advanced cutaneous melanoma (n = 23). 
PD-L1 status was known for 383 of the 456 response evaluable subjects. Across the PD-L1-
positive tumors, ORR was highest for bladder cancer, advanced cutaneous melanoma, 
hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), NSCLC (n = 86, 26.7%), and 
squamous cell carcinoma of the head and neck (SCCHN; n = 22, 18.2%). In the PD-L1-positive 
subset, DCR-24w was highest in advanced cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 
86, 36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%). 
(Antonia et al 2014b).  
1.4.1.2
Tremelimumab
In a single-arm, Phase II study (Study A3671008) of tremelimumab administered at 15 mg/kg 
every 90 days to patients with refractory melanoma, an RR of 7% and a median OS of 10 months 
in the second-line setting (as compared to approximately 6 months with best supportive care 
reported from a retrospective analysis; Korn et al 2008) were observed (Kenney 2014
Kenney SC, Mertz JE. Regulation of the latent-lytic switch in Epstein-Barr virus. Semin Cancer 
Biol 2014;26:60-68. Available at: http://dx.doi.org/10.1016/j.semcancer.2014.01.002. 
Kirkwood et al 2010).  In a randomized, open-label, first-line Phase III study of tremelimumab 
(administered at 15 mg/kg every 90 days) versus chemotherapy (dacarbazine or temozolomide) 
in advanced melanoma (Study A3671009), results of the final analysis showed an RR of 11% 
and a median OS of 12.58 months in this first-line setting as compared to 10.71 months with 
standard chemotherapy; however, these results were not statistically significant (Ribas et al 
2013.  Additionally, a Phase II maintenance study (Study A3671015) in patients with Stage IIIB 
or IV NSCLC who had responded or remained stable failed to achieve statistical significance.  
The primary endpoint of PFS at 3 months was 22.7% in the tremelimumab arm (15 mg/kg) 
compared with 11.9% in the best supportive care arm (Study A3671015).  
1.4.1.3
Durvalumab (MEDI4736) + tremelimumab
The preclinical and clinical justification for this combination as noted in Section 1.1.4 also 
supports the synergy of this combination.  Available data, such as those presented by 
Wolchok et al, suggest that the combination of agents targeting PD-1/PD-L1 and CTLA-4 may 
have profound and durable benefits in patients with melanoma (Wolchok et al 2013).  Of the 
102 subjects with advanced NSCLC treated with durvalumab (MEDI4736) in combination with 
tremelimumab in Study D4190C00006, 63 subjects with at least 16 weeks of follow-up were 
evaluable for response (defined as measurable disease at baseline and at least 1 follow-up scan; 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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this included discontinuations due to disease progression or death without follow-up scan). Of 
the 63 evaluable subjects, 17 (27%) had a best overall response of PR, 14 (22%) had SD, 22 
(35%) had PD, and 10 (16%) were not evaluable. The ORR (confirmed and unconfirmed CR or 
PR) was 27% and the DCR (CR, PR, or SD) was 49% as assessed by RECIST v1.1.
Current experience with single-agent IMT studies suggests that clinical responses may be 
restricted to a subset of any given patient population and that it might be beneficial to enrich the 
patient population by selecting patients likely to respond to therapy.  To date, no assay has been 
established or validated, and no single approach has proven accurate, for patient enrichment for 
IMTs.  However, independent data from multiple sources using different assays and scoring 
methods suggests that PD-L1 expression on tumor cells and/or tumor infiltrating cells may be 
associated with greater clinical benefit.
Data from ongoing studies with durvalumab (MEDI4736) and other agents targeting the PD-
1/PD-L1 pathway suggest, as shown in a number of tumor types (eg, NSCLC, renal cell 
carcinoma, and melanoma), that monotherapy may be more efficacious (in terms of ORR) in 
patients who are PD-L1-positive. 
Given these findings, a number of ongoing studies are assessing the activity of agents in patients 
with PD-L1–positive tumors.  There is also an unmet medical need in patients with PD-L1–
negative tumors that needs to be addressed.  Data, as of 27 January 2015 from Study 006 show 
that with the addition of tremelimumab to durvalumab (MEDI4736), the ORR can be increased 
to 25% in patients with PD-L1 negative NSCLC.  As patients with PD-L1 positive disease can 
also have an increase in ORR, from 25% with durvalumab (MEDI4736) monotherapy, to 36% 
with the combination of durvalumab (MEDI4736) and tremelimumab, the study will enroll all 
patients with NSCLC, with an emphasis on those determined to be PD-L1 negative.  
1.4.1.4
Azaciditine/Oral Decitabine (ASTX727)
Azacitidine can be administered by intravenous (IV) or SC routes. When azacitidine is given 
SC, it is rapidly absorbed, reaching a peak plasma concentration within 30 minutes. The 
bioavailability is 89% when administered via an IV route, and azacitidine is metabolized by the 
liver into six metabolites. It has a mean half-life of approximate 40 minutes for the parent 
compound and a mean elimination half-life of four hours for the parent drug and metabolites. 
Azacitidine and/or its metabolites are rapidly cleared by the kidneys. The effects of renal or 
hepatic impairment, gender, age, and race on the pharmacokinetics of azacitidine have not been 
studied (Marcucci et al, 2005).

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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The MTD of azacitidine following SC administration has not been determined, although SC 
doses as high as 100 mg/m2 daily for 7 days every 28 days were administered in the MDS studies 
without reaching dose-limiting toxicities (Marcucci et al, 2005). In contrast, the MTD for IV 
administration of azacitidine was reported to be in the range of 150 to 200 mg/m2/day when 
given daily for 5 days every 14 to 28 days, with the major toxicities being leukopenia, 
thrombocytopenia, nausea and vomiting in patients with leukemia, lymphoma, or colorectal 
cancer (von Hoff et al, 1976). The MTD IV dose was reported to be as high as 500 mg/m2 when 
given once weekly or 150 mg/m2 when given twice weekly to patients with solid tumors 
(Marcucci et al, 2005; Karon et al 1973).  Our proposed dose of azaciditine is 40 mg/m2/d and 
75 mg/m2/d administered via SC injection which is much lower than the dose administered in 
other clinical trials.
Clinical efficacy of ASTX727 is consistent with efficacy described for IV decitabine in MDS 
patients. At the therapeutic dose of 100 mg cedazuridine and 35 mg decitabine (administered 
concomitantly as separate capsules or as the FDC tablet), the overall Phase 2 results from Study 
ASTX727-01 showed complete response (CR) rate of 21. 3%, with hematologic improvement 
in an additional 16.3% of subjects. In subjects who were transfusion-dependent at baseline, 
ASTX727 was associated with 50% transfusion-independence.
Study ASTX727-02 is a multicenter, randomized, crossover study of the ASTX727 FDC tablet 
(100 mg cedazuridine + 35 mg decitabine) in subjects with MDS/CMML or AML subjects with 
a primary endpoint of AUC equivalence with IV decitabine. Enrollment of MDS/CMML 
subjects for the primary PK analysis was completed in late 2018, with 124 subjects treated with 
ASTX727 as of 25 January 2019. Enrollment (including enrollment of AML subjects) is 
continuing with a target enrollment of approximately 200 subjects.
1.4.2
Potential risks
1.4.2.1
Durvalumab (MEDI4736)
Potential risks, based on the mechanism of action of durvalumab (MEDI4736) and related 
molecules, 
include 
immune-mediated 
reactions, 
such 
as 
enterocolitis, 
dermatitis, 
hepatitis/hepatotoxicity, endocrinopathy, pneumonitis, and neuropathy or neurologic events.  
Additional important potential risks include infusion-related reactions, hypersensitivity, 
anaphylaxis or serious allergic reactions, serious infections, and immune complex disease.  
Study CD-ON-durvalumab (MEDI4736)-1108: The safety profile of durvalumab 
(MEDI4736) monotherapy in the 694 subjects with advanced solid tumors treated at 10 mg/kg 
Q2W in Study CD-ON-durvalumab (MEDI4736)-1108 has been broadly consistent with that of 
the overall 1,279 subjects who have received durvalumab (MEDI4736) monotherapy (not 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
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including subjects treated with blinded investigational product) across the clinical development 
program. The majority of treatment-related AEs were manageable with dose delays, 
symptomatic treatment, and in the case of events suspected to have an immune basis, the use of 
established treatment guidelines for immune-mediated toxicity. As of 07May2015, among the 
694 subjects treated with durvalumab (MEDI4736) 10 mg/kg Q2W in Study CD-ON-
durvalumab (MEDI4736)-1108, a total of 378 subjects (54.5%) experienced a treatment-related 
AE, with the most frequent (occurring in ≥ 5% of subjects) being fatigue (17.7%), nausea 
(8.6%), diarrhea (7.3%), decreased appetite (6.8%), pruritus (6.3%), rash (6.1%), and vomiting 
(5.0%). A majority of the treatment-related AEs were Grade 1 or Grade 2 in severity with 
≥ Grade 3 events occurring in 65 subjects (9.4%). Treatment-related ≥ Grade 3 events reported 
in 3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 1.7%); increased aspartate 
aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase (GGT; 
6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 0.7%); and colitis, 
vomiting, decreased appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects had 
treatment-related Grade 4 AEs (upper gastrointestinal hemorrhage, increased AST, dyspnea, 
neutropenia, colitis, diarrhea, and pneumonitis) and 1 subject had a treatment-related Grade 5 
event (pneumonia). Treatment-related serious adverse events (SAEs) that occurred in ≥ 2 
subjects were colitis and pneumonitis (3 subjects each). A majority of the treatment-related 
SAEs were ≥ Grade 3 in severity and resolved with or without sequelae. AEs that resulted in 
permanent discontinuation of durvalumab (MEDI4736) were considered as treatment related in 
18 subjects (2.6%), with colitis being the most frequent treatment-related AE resulting in 
discontinuation (3 subjects). A majority of the treatment-related AEs resulting in 
discontinuation of durvalumab (MEDI4736) were ≥ Grade 3 in severity and resolved with or 
without sequelae. 
Study D4191C00003/ATLANTIC: The safety profile of durvalumab (MEDI4736) 
monotherapy in Study CD-ON-durvalumab (MEDI4736)-1108 is generally consistent with that 
of Study D4191C00003/ATLANTIC in subjects with locally advanced or metastatic non-small-
cell lung cancer (NSCLC) treated with durvalumab (MEDI4736) 10 mg/kg Q2W. As of 
05May2015, 
264 of 
303 subjects 
(87.1%) 
reported 
any 
AE 
in 
Study 
D4191C00003/ATLANTIC. Overall, events reported in ≥ 10% of subjects were dyspnea 
(18.8%), fatigue (17.8%), decreased appetite (17.5%), cough (14.2%), pyrexia (12.2%), 
asthenia (11.9%), and nausea (11.2%). Nearly two-thirds of the subjects experienced AEs that 
were Grade 1 or 2 in severity and manageable by general treatment guidelines as described in 
the current durvalumab (MEDI4736) study protocols. Grade 3 or higher AEs were reported in 
107 of 303 subjects (35.3%). A total of 128 subjects (42.2%) reported AEs that were considered 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
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by the investigator as related to investigational product. Treatment-related AEs (all grades) 
reported in ≥ 2% of subjects were decreased appetite (6.6%); fatigue (5.9%); asthenia (5.0%); 
nausea (4.6%); pruritus (4.3%); diarrhea, hyperthyroidism, hypothyroidism, and pyrexia (3.3% 
each); rash (2.6%); weight decreased (2.3%); and vomiting (2.0%). Treatment-related Grade 3 
AEs reported in ≥ 2 subjects were pneumonitis (3 subjects) and increased GGT (2 subjects). 
There was no treatment-related Grade 4 or 5 AEs. Ninety-four of 303 subjects (31.0%) reported 
any SAE. SAEs that occurred in ≥ 1.0% of subjects were dyspnea (6.6%); pleural effusion, 
general physical health deterioration (2.3% each); pneumonia (2.0%); hemoptysis, pulmonary 
embolism (1.3% each); and pneumonitis, respiratory failure, disease progression (1.0% each). 
Nine subjects had an SAE considered by the investigator as related to durvalumab (MEDI4736). 
Each treatment-related SAE occurred in 1 subject each with the exception of pneumonitis, 
which occurred in 3 subjects. Fifteen of 303 subjects (5.0%) have died due to an AE (pneumonia 
[3 subjects]; general physical health deterioration, disease progression, hemoptysis, dyspnea [2 
subjects each]; pulmonary sepsis, respiratory distress, cardiopulmonary arrest [verbatim term 
(VT)], hepatic failure, and sepsis [1 subject each]). None of these events was considered related 
to durvalumab (MEDI4736). Twenty-three of 303 subjects (7.6%) permanently discontinued 
durvalumab (MEDI4736) treatment due to AEs. Events that led to discontinuation of 
durvalumab (MEDI4736) in ≥ 2 subjects were dyspnea, general physical health deterioration, 
and pneumonia. Treatment-related AEs that led to discontinuation were increased ALT and 
increased hepatic enzyme, which occurred in 1 subject each.
1.4.2.2
Tremelimumab
Potential risks, based on the mechanism of action of tremelimumab and related molecules 
(ipilimumab) include potentially immune-mediated gastrointestinal (GI) events including 
enterocolitis, intestinal perforation, abdominal pain, dehydration, nausea and vomiting, and 
decreased appetite (anorexia); dermatitis including urticaria, skin exfoliation, and dry skin; 
endocrinopathies including hypophysitis, adrenal insufficiency, and hyperthyroidism and 
hypothyroidism; hepatitis including autoimmune hepatitis and increased serum ALT and AST; 
pancreatitis including autoimmune pancreatitis and lipase and amylase elevation; respiratory 
tract events including pneumonitis and interstitial lung disease (ILD); nervous system events 
including encephalitis, peripheral motor and sensory neuropathies, and Guillain-Barré 
syndrome; cytopenias including thrombocytopenia, anemia, and neutropenia; infusion-related 
reactions; anaphylaxis; and serious allergic reactions.  The profile of AEs and the spectrum of 
event severity have remained stable across the tremelimumab clinical program and are 
consistent with the pharmacology of the target.  To date, no tumor type or stage appears to be 
associated with unique AEs (except for vitiligo that appears to be confined to patients with 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
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melanoma).  Overall, 944 of the 973 patients (97.0%) treated with tremelimumab monotherapy 
as of the data cutoff date of 12 November 2014 (for all studies except D4190C00006 that has a 
cutoff date of 04 December 2014 and not including 497 patients who have been treated in the 
ongoing blinded Phase IIb Study D4880C00003) experienced at least 1 AE.  The events resulted 
in discontinuation of tremelimumab in 10.0% of patients, were serious in 36.5%, were Grade 
≥3 in severity in 49.8%, were fatal in 67.7%, and were considered to be treatment related in 
79.1% of patients.  The frequency of any AEs and Grade ≥3 AEs was generally similar across 
the tremelimumab dose groups.  However, a higher percentage of patients in the 10 mg/kg every 
28 days and 15 mg/kg every 90 days groups compared with the All Doses <10 mg/kg group 
experienced treatment-related AEs, SAEs, AEs resulting in discontinuation of investigational 
product (IP), and deaths.  
1.4.2.3
Durvalumab (MEDI4736)  + tremelimumab
No safety studies in animals have been performed combining tremelimumab with durvalumab 
(MEDI4736).  As both CTLA-4 and PD-L1 have mechanisms of actions that enhance activation 
of immune cells, their potential to induce cytokine release was tested in a whole-blood assay 
system.  Durvalumab (MEDI4736) and tremelimumab, either alone or in combination, did not 
induce cytokine release in blood from any donor.
Study D4190C00006: The safety profile of durvalumab (MEDI4736) and tremelimumab 
combination therapy in the 102 subjects with advanced NSCLC in Study D4190C00006 is 
generally consistent with that observed across 177 subjects treated with durvalumab 
(MEDI4736) and tremelimumab combination therapy (not including subjects treated with 
blinded investigational product). As of 15Apr2015, 95 of 102 subjects (93.1%) reported at least 
1 AE. All subjects in the tremelimumab 3 and 10 mg/kg dose cohorts experienced AEs; subjects 
in the durvalumab (MEDI4736) 20 mg/kg and tremelimumab 1 mg/kg Q4W cohort experienced 
the lowest AE rate (77.8%). Treatment-related AEs were reported in 74 of 102 subjects (72.6%), 
with events occurring in > 10% of subjects being diarrhea (27.5%), fatigue (22.5%), increased 
amylase and pruritus (14.7% each), rash (12.7%), colitis (11.8%), and increased lipase (10.8%). 
Treatment-related ≥ Grade 3 AEs reported in ≥ 5% of subjects were colitis (8.8%), diarrhea 
(7.8%), and increased lipase (5.9%). Five subjects reported treatment-related Grade 4 events 
(sepsis, increased ALT, and increased AST in 1 subject; increased amylase in 2 subjects; 
myasthenia gravis in 1 subject; and pericardial effusion in 1 subject) and 2 subjects had 
treatment-related Grade 5 events (polymyositis and an uncoded event of neuromuscular disorder 
[VT]); the Grade 4 event of myasthenia gravis and Grade 5 polymyositis occurred in 1 subject. 
There were 2 subjects (both in the MEDI4736 20 mg/kg + tremelimumab 3 mg/kg Q4W cohort) 
with dose-limiting toxicities (DLTs): 1 subject with Grade 3 increased AST, and 1 subject with 
Grade 3 increased amylase and Grade 4 increased lipase. Fifty-six subjects (54.9%) reported 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
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SAEs, with events occurring in > 5% of subjects being colitis (9.8%) and diarrhea (7.8%). 
Thirty-six subjects (35.3%) experienced treatment-related SAEs. Twenty-seven subjects 
(26.5%) permanently discontinued treatment due to AEs. Treatment-related AEs resulting in 
discontinuation in ≥ 2 subjects were colitis (7 subjects), pneumonitis (5 subjects), diarrhea (3 
subjects), and increased AST (2 subjects). Additional safety results from this study are 
presented in Section 1.3.1 and the durvalumab (MEDI4736) IB. 
In the literature (Wolchok et al 2013), using the combination of the same class of drugs 
(eg, anti-PD-1 and anti-CTLA4 antibodies), specifically nivolumab + ipilimumab in a study 
involving patients with malignant melanoma, the safety profile of this combination had shown 
occurrences of AEs assessed by the Investigator as treatment-related in 93% of treated patients, 
with the most frequent events being rash (55% of patients), pruritus (47% of patients), fatigue 
(38% of patients), and diarrhea (34% of patients).  Grade 3 or 4 AEs, regardless of causality, 
were noted in 72% of patients, with Grade 3 or 4 events assessed by the Investigator as 
treatment-related in 53%.  The most frequent of these Grade 3 or 4 events assessed by the 
Investigator as treatment-related include increased lipase (in 13% of patients), AST (in 13%), 
and ALT levels (in 11%).  Frequent Grade 3 or 4 selected AEs assessed by the Investigator as 
treatment-related in the combination therapy included hepatic events (in 15% of patients), GI 
events (in 9%), and renal events (in 6%).  Isolated cases of pneumonitis and uveitis were also 
observed.  
1.4.2.4
Fixed Dosing for durvalumab (MEDI4736) and tremelimumab 
A population PK model was developed for durvalumab (MEDI4736) using monotherapy data 
from a Phase 1 study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; 
solid tumors). Population PK analysis indicated only minor impact of body weight (WT) on PK 
of durvalumab (MEDI4736) (coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg 
Q2W) and fixed dosing (750 mg Q2W) of durvalumab (MEDI4736) 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 patients were simulated using body WT 
distribution of 40–120 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.  
Similarly, a population PK model was developed for tremelimumab using data from Phase 1 
through Phase 3 (N=654; doses= 0.01 to 15 mg/kg Q4W or Q90D; metastatic melanoma) 
[Wang et al. 2014]. Population PK model indicated minor impact of body WT on PK of 
tremelimumab (coefficient of ≤ 0.5). The WT-based (1 mg/kg Q4W) and fixed dosing (75 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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mg/kg Q4W; based on median body WT of ~75 kg) regimens were compared using predicted 
PK concentrations (5th, median and 95th percentiles) using population PK model in a simulated 
population of 1000 patients with body weight distribution of 40 to 120 kg. Similar to 
durvalumab (MEDI4736), simulations indicated that both body WT-based and fixed dosing 
regimens of tremelimumab yield similar median steady state PK concentrations with slightly 
less between-subject variability with fixed dosing regimen. 
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 
2012,Narwal et al 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 . In addition, they investigated 18 therapeutic proteins and peptides and 
showed that fixed dosing performed better for 12 of 18 in terms of reducing the between-subject 
variability in pharmacokinetic/pharmacodynamics parameters [Zhang et al 2012]. 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and variability, 
we considered it feasible to switch to fixed dosing regimens. Based on average body WT of 75 
kg, a fixed dose of 750 mg Q2W MEDI4736 (equivalent to 10 mg/kg Q2W), 1500 mg Q4W 
durvalumab (MEDI4736) (equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab 
(equivalent to 1 mg/kg Q4W) is included in the current study. 
Fixed dosing of durvalumab (MEDI4736) and tremelimumab are recommended only for 
subjects with > 30kg body weight due to endotoxin exposure. 
1.4.2.5
Azacitidine/Oral Decitabine (ASTX727)
Results from safety pharmacology studies with cedazuridine do not highlight an off-target 
concern for cardiovascular, respiratory, or other organ systems (see Section 4.1.3 for more 
details). The cumulative data from in vitro and in vivo safety pharmacology studies indicate that 
cedazuridine does not show CV effects. Cedazuridine had negligible inhibition of hERG current 
up to 300 μM (100422.FJT) and did not have an effect on heart rate, blood pressure, ECG, or 
respiratory parameters in conscious telemetered male monkeys administered cedazuridine up to 
200 mg/kg (20123940). In addition, cardiovascular assessments included as part of a 4-cycle 
GLP toxicity study in cynomolgus monkeys showed no abnormalities in ECG parameters 
following dosing with cedazuridine up to 200 mg/kg/day for 7 consecutive days (28-day cycles) 
(20124863). 
The toxicology program for ASTX727 has focused on cedazuridine as a single agent, as the 
toxicities of decitabine administered as a 5-day dosing regimen are well understood due to 

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extensive clinical experience (although toxicology studies are being conducted to assess toxicity 
of decitabine with more extended dosing regimens). Administration of cedazuridine for 7 days 
resulted in a NOAEL of 1000 mg/kg/day in CD-1 mice and 200 mg/kg/day in rhesus monkeys 
(the highest doses tested in each species) (Table 17). In longer term studies (approximately 3 
months) in which cedazuridine was administered daily for 7 days in 28-day cycles, the NOAEL 
was 300 mg/kg in male mice, 100 mg/kg in female mice, and 60 mg/kg in cynomolgus monkeys. 
Target organs for toxicity in mice were microscopic changes in lymph nodes, bone marrow, and 
testes and ovaries, and changes in hematology parameters. In monkeys, cedazuridine affected 
hematology parameters and mucosal epithelial cells of the GI tract; these findings were not 
deemed severely toxic, thus the highest non-severely toxic dose (HNSTD) in monkeys was 200 
mg/kg. 
The clinical dose of 100 mg cedazuridine in humans offers an approximately 40-fold margin 
based on dose comparison and using the HNSTD from monkeys converted to the human 
equivalent dose (HED). Continuous dosing of cedazuridine for 28 days in mice showed similar 
toxicology effects to the 7-day cyclic dosing with a NOAEL of 300 mg/kg and effects on 
lymphoid tissues and testes. In a combination one-cycle study with limited toxicity evaluation 
of cedazuridine and decitabine in monkeys, findings were limited to reversible reductions in 
hematology parameters, dose-related increased in bone marrow M:E ratio in males but not in 
females, and possible test article-related hepato-celluar centriolobular vacuolation in 1 female. 
At the clinically relevant dose of oral decitabine (2 mg/kg, HED of approximately 24 mg/m2) 
co-administration with cedazuridine at up to 6 mg/kg produced decitabine systemic exposures 
approximately 4.7- to 4.9-fold higher than reported in the clinic for IV decitabine (20 mg/m2 1-
hour infusion). 
Cedazuridine was found to be mutagenic but only at the highest concentration tested (Ames 
test) and genotoxic (chromosomal aberrations test) at concentrations that were also cytotoxic, 
but was negative in the in vivo mouse micronucleus test at doses up to 2000 mg/kg. 
Carcinogenicity studies have not been conducted.
Toxicokinetic exposures in mice and monkeys showed no meaningful accumulation of 
cedazuridine on Day 7 vs Day 1, or on Day 63 vs Day 1. Based on cedazuridine systemic 
exposures seen after a 100 mg dose in humans, toxicokinetic exposure margins achieved in 
monkeys (combined male plus female) after the HNSTD of 200 mg/kg (3-month GLP) were 
approximately 28-fold. Exposure margins in mice at the NOAEL dose (3-month GLP study) 
were approximately 22-fold in females (after NOAEL of 100 mg/kg) and 54-fold in males 
(NOAEL 300 mg/kg). 
Additional toxicology information is provided in Section 4.3 in the IBv6. 

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Refer to to the Dacogen US PI (2019) and for additional nonclinical information regarding 
decitabine.
At this stage of development, no new clinically significant safety issues have been identified for 
ASTX727 that are inconsistent with the safety profile of IV decitabine. (Refer to Dacogen US 
PI 2019.)
Results from clinical trials and other studies demonstrate that the most common toxicities 
associated with azacitidine are gastrointestinal (nausea, vomiting, diarrhea, constipation, 
anorexia), constitutional (fatigue, fever, rigors), musculoskeletal and connective tissue 
(arthralgia, pain in limb, weakness), pulmonary (cough, dyspnea), skin or soft tissue (injection 
site bruising from SC injection, rash, erythema), and hematologic (neutropenia, anemia, 
leukopenia). Nausea, vomiting and diarrhea are among the most common adverse effects of 
azacitidine and appear to be self-limiting with repeated cycles of therapy. Myelosuppression 
also occurs in a majority of patients, and accounts for the most common reason of dose reduction 
and treatment termination during clinical trials. Infrequent adverse effects include 
neuromuscular aches, generalized weakness, renal tubular acidosis, and liver enzyme 
abnormalities. Erythema and burning at the injection site can occur following SC 
administration, which usually resolves within 24-72 hours.
1.4.3
Overall benefit-risk and ethical assessment
There remains a significant unmet medical need for additional treatment options for patients 
with recurrent and/or metastatic SCCHN who have progressed during or after treatment with a 
platinum-containing regimen for recurrent or metastatic disease. Treatment with agents 
targeting PD-1/PD-L1 or CTLA-4 has shown activity in several tumor types, in a subset of 
patients deriving meaningful and durable benefit. Duravalumab has shown clinical activity in 
patients with recurrent or metastatic SCCHN as a single agent. In addition, preliminary data 
generated with durvalumab (MEDI4736) + tremelimumab combination therapy in patients with 
NSCLC have shown promising activity with objective, durable responses. Thus, these agents 
may potentially offer benefit to this patient population. The study design aims to minimize 
potential risks, and intensive monitoring, including early safety assessment, is in place for those 
risks deemed to be most likely based on prior experience with the investigational products (IPs). 
The toxicity profile of the combination durvalumab (MEDI4736) + tremelimumab includes 
fatigue, colitis, diarrhea, AST or ALT increases, amylase and lipase increases, rash and pruritus 
and other immune-mediated reactions, which were mostly reversible and manageable by the 
available protocol treatment guidelines.
In the literature (Wolchok et al 2013), using the combination of the same class of drugs (eg, 
anti-PD-1 and anti-CTLA4 antibodies), specifically nivolumab + ipilimumab in a study 
involving patients with malignant melanoma, the safety profile of this combination had shown 
occurrences of treatment-related AEs in 93% of treated patients, with the most frequent events 
being rash (55% of patients), pruritus (47% of patients), fatigue (38% of patients), and diarrhea 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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(34% of patients). Grade 3 or 4 AEs, regardless of causality, were noted in 72% of patients, 
with grade 3 or 4 treatment-related events in 53%. The most frequent of these grade 3 or 4 
treatment related events include increased lipase (in 13% of patients), AST (in 13%), and ALT 
levels (in 11%). SAEs related to the treatment were noted in 49% of patients. Frequent grade 3 
or 4 selected AEs related to the combination therapy included hepatic events (in 15% of 
patients), gastrointestinal (GI) events (in 9%), and renal events (in 6%). Isolated cases of 
pneumonitis and uveitis were also observed.
No safety studies in animals have been performed combining tremelimumab with durvalumab 
(MEDI4736) or with azacitidine in combination with tremelimumab and durvalumab 
(MEDI4736). As both CTLA 4 and PD-L1 have mechanisms of actions that enhance activation 
of immune cells, their potential to induce cytokine release was tested in a whole-blood assay 
system. Durvalumab (MEDI4736) and tremelimumab, either alone or in combination did not 
induce cytokine release in blood from any donor.
Based upon the available non-clinical and clinical safety data, the limited survival benefit 
provided by the currently available treatment options to patients, the limited life expectancy due 
to malignant disease, and the strength of the scientific hypotheses under evaluation, the 
durvalumab (MEDI4736) + tremelimumab treatment proposed for evaluation in this study may 
have the potential to provide meaningful clinical benefit with a manageable safety and 
tolerability profile by generating durable clinical responses, thereby improving QoL and 
potentially extending survival. Patients with recurrent/metastatic SCCHN who have failed a 
prior line of therapy have a dismal prognosis with median survival of less than 6 months. Agents 
targeting the PD-1/PD-L1 pathway have shown promising activity in patients with 
recurrent/metastatic SCCHN. Although the patients who may be more likely to benefit from 
therapies with PD-1/PD-L1 targeting agents are those whose cancers express PD-L1 in the 
tumor microenvironment (see Section 1.2.4), an unmet need remains for patients with PD-L1 
negative tumors despite the potential impact of immunotherapy. Preclinical and clinical 
evidence indicate that combination of PD-1/PD-L1 and CTLA4 targeting agents may provide 
synergistic antitumor activity, regardless of PD-L1 expression levels (Wolchok et al 2013). 
Therefore, the investigation of the potential therapeutic efficacy of durvalumab (MEDI4736) + 
tremelimumab combination in patients with recurrent/metastatic disease with PD-L1–negative 
tumors is acceptable, and the overall benefit/risk assessment is reasonable per the proposed 
study design.
2.
STUDY OBJECTIVE
2.1.1
Primary objective(s)
To determine the Biologically Effective Dose (BED) of oral decitabine (ASTX727) in 
combination with durvalumab (MEDI4736) therapy. 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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2.1.2
Secondary Objective:
To assess the safety of oral decitabine (ASTX727) in combination with durvalumab (MEDI4736) 
therapy.
3.
STUDY DESIGN
3.1
Overview of study design
This is a non-randomized, open-label, Phase Ib study to assess the safety and efficacy of oral 
decitabine (ASTX727) and durvalumab  (MEDI4736) combination therapy in the treatment of 
patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck 
(SCCHN) who have progressed during or after treatment with anti-PD-1, anti-PD-L1, and/or 
anti-CTLA-4 for recurrent and/or metastatic disease. The primary endpoint is to determine the 
BED of oral decitabine (ASTX727) in combination with durvalumab (MEDI4736) therapy.  The 
secondary endpoint is to assess the safety of oral decitabine (ASTX727) in combination with 
durvalumab (MEDI4736) therapy.  
The trial opened with the use of subcutaneous (SC) injection of azacitidine.  All patients 
received azacitidine SC injection on either Days 1-5 alone or Days 1-5 and 8-12 in a 4-week 
cycle, durvalumab (MEDI4736) 1500 mg via intravenous (IV) infusion every 4 weeks (q4w), 
and tremelimumab 75 mg via IV infusion q4w.  Azacitidine was administered alone in Cycle 1 
and the combination of azacitidine, durvalumab, and tremelimumab therapy was started in 
Cycle 2. Dose Limiting Toxicity (DLT) was assessed through 28 days post Cycle 2. After cycle 
2, patients continued with azacitidine, durvalumab and tremelimumab combination therapy for 
Cycles 3-5 and azacitidine and durvalumab for Cycles 6-12 or until confirmed PD, initiation of 
alternative cancer therapy, unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met, whichever occured first.  However, treatment consisting of 5 to 
10 daily visits for a large-volume SC injection continuing for several months or even years, 
represented a significant hardship for patients with possible consequences of non-compliance 
or earlier discontinuation of a beneficial treatment.  Therefore, an oral DNA methyltransferase 
inhibitor is being evaluated to ease the burden of daily visits for those patients who are 
benefitting the most and need continuing treatment for long periods. Furthermore, since the oral 
DNA methyltransferase inhibitor is investigational, we plan to combine it with the FDA 
approved durvalumab.
Therefore, all patients enrolled with or after protocol version 11.0 will receive an oral tablet of 
ASTX727 (35 mg decitabine/100 mg cedazuridine) daily on either Days 1-3, Days 1-4, or Days 
1-5 and durvalumab (MEDI4736) 1500 mg via IV infusion x 1 in a 4-week cycle. Oral

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Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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decatibine (ASTX727) will be administered alone in Cycle 1 and the combination of oral 
decatibine (ASTX727) and durvalumab therapy will be administered in Cycles 2-12 or until 
confirmed PD, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion is met, whichever occurs first. The BED will be 
assessed on pre-treatment and post-treatment biopsies obtained at week 8.  BED is defined as 
the dose of oral decatibine (ASTX727) that results in at least a 10% decrease in LINE-1 
methylation from the baseline biopsy sample to the 8-week on-treatment tumor biopsy sample 
in at least 50% of patients treated within the same dose level. Accrual will be suspended until 
review of the LINE-1 methylation level in tissue from baseline and 8 weeks post baseline has 
been completed from patients entered into the first 2 dose levels (oral decitabine on Days 1-3 
alone and Days 1-4 in a 4-week cycle).  If the BED has not been determined in the first 2 dose 
levels and it is safe to do so, then the study will re-open to accrual and a subsequent group of 3 
patients will receive the 3rd dose level. If both the first 2 dose levels result in > 10% decrease in 
LINE-1 methylation, then the dose which induces the greatest fold change in HLA Class I/II 
APM expression and/or CD8+ T cell infiltration and with the lowest AE profile will be the dose 
utilized for the dose expansion group.  Once the BED is determined, dose escalation will stop 
and the BED will be used in the expansion cohort. Dose Limiting Toxicity (DLT) will be 
assessed through 28 days post Cycle 2.
Although assessment of the BED is primary, the dose also needs to be safe. Each dose will be 
assessed for safety according to a stopping rule and a DLT toxicity definition as outlined in the 
protocol and statistical section.  Subjects will be sequentially assigned to the cohorts.  The first 
6 enrolled subjects will receive one tablet daily on Days 1-3 of a 28-day cycle.  If two or more 
of the first six subjects experience a DLT, then the dose will be reduced and an additional six 
patients will be treated at the reduced dose. If two or more of the six at the reduced dose 
experience a DLT, then the study will be terminated. If at any time during accrual to a cohort, 
2 or more patients in a cohort experience DLT, enrollment to that cohort will be terminated. If 
less than two of the six patients treated at dose level 1 experience a DLT, a subsequent group of 
six patients will receive dose level 2. 
Subjects cannot change groups or dose assignments upon the initiation of the study protocol. 
Tumor assessments will be performed using CT or MRI. Efficacy and survival for all patients 
will be assessed by objective tumor assessments every 8 weeks (q8w) +/- 7 days for the first 48 
weeks (relative to the date of the first infusion) then q12w in patients who have disease control 
after 12 months until confirmed objective disease progression as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Categorization of objective tumor 
response assessment will be based on RECIST 1.1: complete response (CR), partial response 
(PR), stable disease (SD), and progressive disease (PD).  Objective tumor response (CR or PR) 
will be confirmed at the next scheduled visit and not less than 4 weeks after the visit when the 
response was first observed. All scans showing PD should be confirmed at the next scheduled 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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visit and no earlier than 4 weeks after the initial assessment of PD in the absence of clinically 
significant deterioration. Treatment with IP should continue between the initial assessment of 
progression and its confirmation. If progression is not confirmed, then the patient should 
continue receiving study treatment and participate in study assessments.
Patients who achieve and maintain disease control (ie, CR, PR, or SD) through the end of the 
12-month treatment period will enter follow-up. When these patients experience evidence of
PD, with or without confirmation, during follow-up and meet the criteria for treatment in the
setting of PD, they will be given the option to restart their assigned IP treatment for up to an
additional 12 months with the same treatment guidelines followed during the initial 12-month
treatment period. Patients should have a baseline tumor assessment within 28 days of restarting
treatment with their assigned IP; all further scans should occur q8w (relative to the date of
restarting treatment) until study treatment is stopped (maximum of 12 months of further
treatment). Only patients whom the Investigators determine do not have any significant,
unacceptable, or irreversible toxicities and would continue to receive benefit from therapy can
restart a second 12 months of retreatment upon PD. Patients with confirmed progression with
azacitidine or oral decitabine (ASTX727), durvalumab (MEDI4736), and/or tremelimumab
combination therapy cannot continue therapy or obtain retreatment if the progression occurred
during dosing and after confirmed response in the target lesions (ie, the response and
progression events both occurred while receiving active IP during the same treatment period in
the target lesions).
Following completion or discontinuation of treatment, patients will enter a follow-up period.
3.2
Study schema
Figure 1. Study Flow Chart
Cohort (# of pts)
Azacitidine
(28-day cycle)
Grade 3
or higher
2-fold DNMT1 inhibition
in >50% of patients
D-1 (6)
20 mg/m2 on 
Days 1-5
MTD2
BED3
1 (6)
40 mg/m2 on 
Days 1-5
MTD2
BED3
Patients with recurrent or 
metastatic SCCHN who have 
progressed after treatment 
with an immunotherapy for 
recurrent or metastatic disease
Progression Free Survival
Objective Response Rate
Overall Survival
Biomarkers
Durvalumab +/- tremelimumab + 
dose escalation of DNA 
methyltrasnferas inhibitor
(refer to charts below)

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Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
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2 (6)
40 mg/m2 on 
Days 1-5 and 8-12
MTD2
BED3
3 (6)
75 mg/m2 on
Days 1-5
MTD2
BED3
1Azacitidine will be given starting Cycle 1 and durvalumab and tremelimumab will be given   
starting Cycle 2
2MTD (maximally tolerated dose)
3BED (biologically effective dose)
Cohort (# of pts)
Oral Decitabine (ASTX727)
(28-day cycle)
Grade 3
or higher
10% decrease in LINE-1 
methylation
in >50% of patients
BD-1 (6)
ASTX727 one tablet on 
Days 1-2
MTD2
BED3
B1 (6)
ASTX727 one tablet on 
Days 1-3
MTD2
BED3
B2 (6)
ASTX727 one tablet on
Days 1-4
MTD2
BED3
B3 (6)
ASTX727 one tablet on
Days 1-5
MTD2
BED3
1Oral decitabine (ASTX727) will be given starting Cycle 1 and durvalumab will be given 
starting Cycle 2
2MTD (maximally tolerated dose)
3BED (biologically effective dose)
4.
PATIENT SELECTION, ENROLLMENT, RANDOMIZATION,
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL
Each patient must meet all of the inclusion criteria (Section 4.1) and none of the exclusion 
criteria (Section 4.2) for this study. 
4.1
Inclusion criteria
For inclusion in the study, patients should fulfill the following criteria:
1.
Written informed consent and any locally-required authorization (e.g., HIPAA in the
USA, EU Data Privacy Directive in the EU) obtained from the subject prior to
performing any protocol-related procedures, including screening evaluations
2.
Age > 18 years at time of study entry or adult male or female (according to age of
majority as defined as ≥18 years)

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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3.
Histologically confirmed recurrent or metastatic SCCHN (oral cavity, oropharynx,
hypopharynx, larynx, or unknown primary) not amenable to therapy with curative
intent (surgery or radiation therapy with or without chemotherapy). Patients who
refuse radical resection are eligible.
4.
Tumor progression or recurrence during or after treatment with anti-PD1, anti-PDL1,
anti-PDL2, anti-CTLA4, and/or other combination of immunotherapy.
5.
Must give valid written consent to provide archival FFPE and/or newly acquired
tumor tissue for the purpose of establishing baseline PD-L1 status as well as consent
to provide on- and/or post-treatment tumor biopsy sample.
6.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at
enrollment
7.
Life expectancy of > 6 months
8.
At least 1 lesion that can be accurately measured at baseline as > 10 mm in the longest
diameter (except lymph nodes which must have a short axis >15 mm) with CT or
MRI and that is suitable for accurate repeated measurements as per RECIST 1.1
guidelines.
9.
Adequate normal organ and marrow function as defined below (within 28 days prior
to study registration):

Hemoglobin ≥ 8.0 g/dL

Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (> 1500 per mm3)

Platelet count ≥ 100 x 109/L (>100,000 per mm3)

Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).  This will not 
apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent 
hyperbilirubinemia that is predominantly unconjugated in the absence of 
hemolysis or hepatic pathology), who will be allowed only in consultation with 
their physician.

AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present, in which case it must be ≤ 5x ULN

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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
Serum creatinine level <1.5 x ULN and CL>40 mL/min by the Cockcroft-Gault 
formula (Cockcroft and Gault 1976) or by 24-hour urine collection for 
determination of creatinine clearance:
Males:
Creatinine 
CL 
(mL/min)
=
Weight 
(kg) 
x 
(140 
– 
Age) 
.
72 x serum creatinine (mg/dL)
Females:
Creatinine 
CL 
(mL/min)
=
Weight (kg) x (140 – Age)     
x 
0.85
72 x serum creatinine (mg/dL)
10.
Female subjects must either be of non-reproductive potential (ie, post-menopausal by
history: ≥60 years old and no menses for 1 year without an alternative medical
cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history
of bilateral oophorectomy) or must have a negative serum pregnancy test upon study
entry.
11.
Male subjects with a female partner of childbearing potential must commit to true
abstinence from heterosexual contact or commit to the use of male condom plus
spermicide throughout the course of the study, and avoid fathering a child during the
course of the study (including dose interruptions) and for 6 months following the last
dose of azacitidine.
12.
All men and women of childbearing potential must use acceptable methods of birth
control throughout the study as described below:
Females of childbearing potential: Recommendation is for at least one highly effective 
contraceptive methods during the study and must agree to continue using such 
precautions for 180 days after the last dose of investigational product.  
Non-sterilized males : Non-sterilized male patients who are sexually active with a 
female partner of childbearing potential must use male condom plus spermicide from 
screening through 180 days after the last dose of investigational product. 
13.
Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including
follow up.

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
Date 09202024
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Inclusion criteria for genetics research study (optional)
For inclusion in the optional (DNA) genetics research study, patients must fulfill the following
criteria:
1.
Provide informed consent for genetic sampling and analyses.
2.
If a patient declines to participate in genetics research, there will be no penalty or loss
of benefit to the patient. A patient who declines genetics research participation will not
be excluded from any other aspect of the main study.
4.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff
and/or staff at the study site)
2. Histologically confirmed squamous cell carcinoma of any other primary anatomic location
in the head and neck (eg. paranasal cavity) and non-squamous histologies (eg.
nasopharynx or salivary gland)
3. History of another primary malignancy except for:
•
Malignancy treated with curative intent and with no known active disease ≥5
years before the first dose of study drug and of low potential risk for recurrence
•
Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease
•
Adequately treated carcinoma in situ without evidence of disease eg, cervical
cancer in situ
4.
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies,
other investigational agent) ≤ 21days prior to the first dose of study drug
5. Current or prior use of immunosuppressive medication within 28 days before the first dose
of durvalumab (MEDI4736) or tremelimumab, with the exceptions of intranasal and
inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not
to exceed 10 mg/day of prednisone, or an equivalent corticosteroid

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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6. Any unresolved toxicity NCI CTCAE grade 2 from previous anti-cancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
-
Patients with Grade > 2 neuropathy will be evaluated on a case-by-case basis
and may be included after consultation with the Study Physician.
-
Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with their assigned IP (eg, hearing loss) may be included after
consultation with the Study Physician.
7. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE >Grade 1
8. Abnormal coagulation parameters (PT >15 secondss, PTT>40 seconds, and/or INR >1.5)
9. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects
with vitiligo, Grave’s disease, psoriasis, diabetes, hypothyroidism, and/or other
autoimmune disease that is readily managed with treatment and not at risk for serious
exacerbation on study treatment  are not excluded.
10. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative
colitis)
11. History of primary immunodeficiency
12. History of allogeneic organ transplant
13. History of hypersensitivity to durvalumab (MEDI4736), tremelimumab, or any excipient
14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection,
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina
pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months, active peptic
ulcer disease or gastritis, active bleeding diatheses including any subject known to have
evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus
(HIV), or psychiatric illness/social situations that would limit compliance with study
requirements or compromise the ability of the subject to give written informed consent
15. Known history of previous clinical diagnosis of tuberculosis

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Edition Number 13.0
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16. Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing 
signs/symptoms related to the infection without improvement despite appropriate 
antibiotics, antiviral therapy and/or other treatment)
17. History of leptomeningeal carcinomatosis
18. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 
days of receiving durvalumab (MEDI4736) or tremelimumab
19. Female subjects who are pregnant, breast-feeding or male or female patients of 
reproductive potential who are not employing an effective method of birth control
20. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results
21. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive 
of but not limited to surgery, radiation and/or corticosteroids. 
22. Subjects with uncontrolled seizures.
23. Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ effective birth control from screening 
to 180 days after the last dose of azacitidine, durvalumab (MEDI4736) and/or 
tremelimumab therapy. Lactating females must agree not to breast feed throughout this 
period.
Procedures for withdrawal of incorrectly enrolled patients are presented in Section 4.3
If a patient withdraws from participation in the study, then his or her enrollment/randomization 
code cannot be reused.  Withdrawn patients will not be replaced.
4.3
Withdrawal of Subjects from Study Treatment and/or Study
Permanent discontinuation of study treatment 
An individual subject will not receive any further investigational product if any of the following 
occur in the subject in question:
1.
Withdrawal of consent or lost to follow-up
2.
Adverse event that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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3.
Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk
4.
Pregnancy or intent to become pregnant
5.
Any AE that meets criteria for discontinuation as defined in Section 10.3.
6.
Dose-limiting toxicity (See Section 5.5 for definition of DLT) 
7.
Grade ≥ 3 infusion reaction
8.
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; eg, refusal to adhere to scheduled visits
9.
Initiation of alternative anticancer therapy including another investigational agent
10.
Confirmation of PD and investigator determination that the subject is no longer 
benefiting from treatment with azacitidine, durvalumab (MEDI4736), and 
tremelimumab
Subjects who are permanently discontinued from further receipt of investigational product, 
regardless of the reason (withdrawal of consent, due to an AE, other), will be identified as 
having permanently discontinued treatment. 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety per Section 10.0 and Appendix 1 or 2, including the collection of any 
protocol-specified blood specimens, unless consent is withdrawn or the subject is lost to 
follow-up or enrolled in another clinical study.  All patients including those who discontinue 
protocol therapy early, will be followed for response until first disease progression and 
survival until 24 months from study registration. All subjects will be followed for survival.  
Subjects who decline to return to the site for evaluations will be offered follow-up by phone 
every 3 months as an alternative.
Withdrawal of consent
If consent is withdrawn, the subject will not receive any further investigational product or 
further study observation. 

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5.
INVESTIGATIONAL PRODUCT(S)
5.1
Durvalumab (MEDI4736) and tremelimumab
The Investigational Products Supply section of AstraZeneca/MedImmune will supply 
durvalumab (MEDI4736) and tremelimumab to the investigator as a solution for infusion after 
dilution.  
5.1.1
Formulation/packaging/storage
Durvalumab (MEDI4736)
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for 
infusion after dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) 
polysorbate 80; it has a pH of 6.0. The nominal fill volume is 10 mL.  Investigational product 
vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Durvalumab 
(MEDI4736)  must be used within the individually assigned expiry date on the label.
Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 400-mg or 25-mg vial solution for 
infusion after dilution. The solution contains 20 mg/mL of tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, 
and 0.27 mM disodium edetate dihydrate (EDTA); it has a pH of 5.5. The nominal fill volume 
is 20 mL. Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not 
be frozen. Drug product should be kept in original container until use to prevent prolonged 
light exposure. Tremelimumab must be used within the individually assigned expiry date on 
the label.
5.1.2
Treatment regimens
Durvalumab (MEDI4736) + tremelimumab combination therapy
For patients receiving azacitidine, patients will receive 1500 mg durvalumab (MEDI4736) via 
IV infusion q4w for up to 4 doses/cycles and 75 mg tremelimumab via IV infusion q4w for up 
to 4 doses/cycle or 300 mg tremelimumab via IV infusion x1, and then continue 1500 mg 
durvalumab (MEDI4736) q4w starting on Week 16 or Week 8 for up to 8 months.  For patients 
receiving decitabine, patients will receive 1500 mg durvalumab (MEDI4736) via IV infusion 
q4w starting on Week 4 for up to 12 months.  Dosing outside the window should be discussed 
with the Study Physician.  Tremelimumab will be administered first.  Durvalumab (MEDI4736) 
infusion will start approximately 1 hour after the end of tremelimumab infusion.  The duration 

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will be approximately 1 hour for each infusion.  A 1-hour observation period is required after 
the first infusion of durvalumab (MEDI4736) and tremelimumab.  If no clinically significant 
infusion reactions are observed during or after the first cycle, subsequent infusion observation 
periods can be at the Investigator’s discretion (suggested 30 minutes after each durvalumab 
(MEDI4736) and tremelimumab infusion).  
5.1.3
Duration of treatment and criteria for retreatment
Retreatment is allowed (once only) for patients meeting the retreatment criteria below.  The 
same treatment guidelines followed during the initial 12-month treatment period will be 
followed during the retreatment period, including the same dose and frequency of treatments 
and the same schedule of assessments.  
Patients receiving the combination of durvalumab (MEDI4736) and tremelimumab may 
undergo retreatment in 2 clinical scenarios, described below:  
1. Patients who achieve and maintain disease control (ie, CR, PR, or SD) through to the 
end of the 12-month treatment period may restart treatment with the combination upon 
evidence of PD, with or without confirmation according to RECIST 1.1, during follow-
up. 
2. Patients who complete the 4 dosing cycles of the combination of durvalumab 
(MEDI4736) and tremelimumab portion of the regimen (with clinical benefit per 
Investigator judgment), but subsequently have evidence of PD during the durvalumab 
(MEDI4736) monotherapy portion of the combination regimen, with or without 
confirmation according to RECIST 1.1, may restart treatment with the combination.  
3. Before restarting their assigned treatment, the Investigator should ensure that the patient:  
4. Does not have any significant, unacceptable, or irreversible toxicities that indicate 
continuing treatment will not further benefit the patient
5. Still fulfils the eligibility criteria for this study, including re-consenting to restart 
durvalumab (MEDI4736) and tremelimumab
6. Has not have received an intervening systemic anticancer therapy after their assigned 
treatment discontinuation.  
7. Has had a baseline tumor assessment within 28 days of restarting their assigned 
treatment; all further scans should occur with the same frequency as during the initial 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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12 months of treatment (relative to the date of randomization) until study treatment is 
stopped (maximum of 12 months of further treatment).  
During the retreatment period, patients receiving azacitidine, durvalumab (MEDI4736) + 
tremelimumab may resume durvalumab (MEDI4736) dosing at 1500 mg q4w with 75 mg of 
tremelimumab q4w for 4 doses each and continue durvalumab (MEDI4736) monotherapy at 
1500 mg q4w, beginning at Week 16, 4 weeks after the last dose of combination therapy (a total 
of 9 additional doses).  For those patients receiving decitabine and durvalumab (MEDI4736), 
the patient may resume durvalumab (MEDI4736) dosing at 1500 mg q4w beginning at Week 4 
(a total of 12 additional doses). 
Treatment through progression is at the Investigator’s discretion, and the Investigator should 
ensure that patients do not have any significant, unacceptable, or irreversible toxicities that 
indicate that continuing treatment will not further benefit the patient.  A patient with a confirmed 
progression receiving durvalumab (MEDI4736) + tremelimumab cannot continue therapy or 
obtain retreatment if dosing is ongoing in the combination portion of therapy (q4w dosing) and 
progression occurs in a target lesion that has previously shown a confirmed response.
Patients who the Investigator determines may not continue treatment will enter follow-up.  
5.1.4
Study drug preparation of durvalumab (MEDI4736) and tremelimumab
Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (MEDI4736) 
(equivalent to 20 mg/kg Q4W) and 75 mg Q4W tremelimumab (equivalent to 1 mg/kg Q4W) 
or 300 mg x 1 tremelimumab (equivalent to 1 mg/kg total) is included in the current study.
Preparation of durvalumab (MEDI4736) doses for administration with an IV bag
The dose of durvalumab (MEDI4736) for administration must be prepared by the Investigator’s 
or site’s designated IP manager using aseptic technique.  Total time from needle puncture of the 
durvalumab (MEDI4736) vial to the start of administration should not exceed: 
•
24 hours at 2°C to 8°C (36°F to 46°F)
•
4 hours at room temperature
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. 
Infusion solutions must be allowed to equilibrate to room temperature prior to commencement 
of administration. 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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No incompatibilities between durvalumab (MEDI4736) and polyvinylchloride or polyolefin IV 
bags have been observed. Dose of 1500mg durvalumab (MEDI4736) for patients >30 kg will 
be administered using an IV bag containing 0.9% (w/v) saline or 5% dextrose, with a final 
durvalumab (MEDI4736) concentration ranging from 1 to 20 mg/mL, and delivered through an 
IV administration set with a 0.2- or 0.22-μm in-line filter.  Remove 30.0 mL of IV solution from 
the IV bag prior to addition of durvalumab (MEDI4736).  Next, 30.0 mL of durvalumab 
(MEDI4736) (ie, 1500 mg of durvalumab (MEDI4736)) is added to the IV bag such that final 
concentration is within 1 to 20 mg/mL (IV bag volumes 100 to 1000 mL).  Mix the bag by 
gently inverting to ensure homogeneity of the dose in the bag.
Patient weight at baseline should be used for dosing calculations unless there is a ≥10% change 
in weight.  Dosing day weight can be used for dosing calculations instead of baseline weight 
per institutional standard.  
Durvalumab (MEDI4736) will be administered at room temperature (approximately 25°C) by 
controlled infusion via an infusion pump into a peripheral or central vein. Following preparation 
of durvalumab (MEDI4736), the entire contents of the IV bag should be administered as an IV 
infusion over approximately 60 minutes (+10/-5 minutes), using a 0.2, or 0.22-μm in-line filter. 
Less than 55 minutes is considered a deviation.
The IV line will be flushed with a volume of IV solution (0.9% [w/v] saline equal to the 
priming volume of the infusion set used after the contents of the IV bag are fully administered, 
or complete the infusion according to institutional policy to ensure the full dose is 
administered and document if the line was not flushed.
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  The table below summarizes 
time allowances and temperatures.
Durvalumab (MEDI4736) hold and infusion times
Maximum time from needle puncture to start 
of administration
4 hours at room temperature, 24 hours at 2°C to 
8°C
Maximum time for IV bag infusion, including 
interruptions
8 hours at room temperature

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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In the event that either preparation time or infusion time exceeds the time limits outlined in 
the table, a new dose must be prepared from new vials.  Durvalumab (MEDI4736) does not 
contain preservatives, and any unused portion must be discarded.
Preparation of tremelimumab doses for administration with an IV bag
The dose of tremelimumab for administration must be prepared by the Investigator’s or site’s 
designated IP manager using aseptic technique.  Total time from needle puncture of the 
tremelimumab vial to the start of administration should not exceed: 
•
24 hours at 2°C to 8°C (36°F to 46°F)
•
4 hours at room temperature
It is recommended that the prepared final IV bag be stored in the dark at 2ºC-8°C (36°F-46°F) 
until needed. If storage time exceeds these limits, a new dose must be prepared from new vials. 
The refrigerated infusion solutions in the prepared final IV bag should be equilibrated at room 
temperature for about 2 hours prior to administration. Tremelimumab does not contain 
preservatives and any unused portion must be discarded.
No incompatibilities between tremelimumab and polyvinylchloride or polyolefin IV bags have 
been observed. Doses of either 75 mg tremelimumab or 300 mg tremelimumab for patients >30 
kg will be administered using an IV bag containing 0.9% (w/v) saline, with a final 
tremelimumab concentration ranging from 0.1 mg/mL to 10 mg/mL, and delivered through an 
IV administration set with a 0.2 μm or 0.22 μm in-line filter. To prepare a 75 mg dose,  remove 
3.75  mL of IV solution from the IV bag prior to addition of tremelimumab.  Next, 3.75 mL of 
tremelimumab (ie, 75 mg of tremelimumab) is added to the IV bag such that final concentration 
is within 0.1 mg/mL to 10 mg/mL (IV bag volumes 50 to 500 mL).  Mix the bag by gently 
inverting to ensure homogeneity of the dose in the bag. To prepare the 300 mg dose, remove 15 
ml of IV solution from the IV bag prior to addition of tremelimumab.  Next,  mL of 
tremelimumab (ie, 300 mg of tremelimumab) is added to the IV bag such that final concentration 
is within 0.1 mg/mL to 10 mg/mL (IV bag volumes 50 to 500 mL).  Mix the bag by gently 
inverting to ensure homogeneity of the dose in the bag.
Patient weight at baseline should be used for dosing calculations unless there is a ≥10% change 
in weight.  Dosing day weight can be used for dosing calculations instead of baseline weight 
per institutional standard.  
Tremelimumab will be administered at room temperature (approximately 25°C) by controlled 
infusion via an infusion pump into a peripheral or central vein. Following preparation of 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
Date 09202024
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tremelimumab, the entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 minutes (+10/-5 minutes), using a 0.2, or 0.22-μm in-line filter. Less than 55 
minutes is considered a deviation.
The IV line will be flushed with a volume of 0.9% (w/v) saline equal to the priming volume of 
the infusion set used after the contents of the IV bag are fully administered, or complete the 
infusion according to institutional policy to ensure the full dose is administered and document 
if the line was not flushed.
Standard infusion time is 1 hour.  However, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature.  The table below summarizes 
time allowances and temperatures.
Tremelimuab hold and infusion times
Maximum time from needle puncture to start 
of administration
4 hours at room temperature, 24 hours at 2°C to 
8°C
Maximum time for IV bag infusion, including 
interruptions
8 hours at room temperature
In the event that either preparation time or infusion time exceeds the time limits outlined in 
the table, a new dose must be prepared from new vials.  Tremelimumab does not contain 
preservatives, and any unused portion must be discarded.
5.1.5
Monitoring of dose administration
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Study Protocol.
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion.  For patients with a ≤Grade 2 infusion-related 
reaction, subsequent infusions may be administered at 50% of the initial rate.  Acetaminophen 
and/or an antihistamine (eg, diphenhydramine) or equivalent medications per institutional 
standard may be administered at the discretion of the investigator.  If the infusion-related 
reaction is ≥Grade 3 or higher in severity, study drug 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 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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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 patients to an intensive care unit if necessary
5.1.6
Accountability and dispensation
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  Receipt and dispensing of trial medication must be recorded by an 
authorized person at the trial site.
5.1.7
Disposition of unused investigational study drug
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Astrazeneca/MedImmune and ASTX Pharmaceuticals, the amount dispensed to and 
returned by the subjects and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines 
and procedures, and provided that appropriate records of disposal are kept.  Certificates of 
delivery and destruction must be signed.
5.2
Azacitidine/Oral Decitabine (ASTX727)
Azacitidine, Vidaza®, has the following chemical structure:
Figure 2a. Chemical Structure of Azacitidine
Azacitidine is (4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one). The empirical formula is 
C8H12N4O5. The molecular weight is 244 amu.

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ASTX727 is under development as an FDC tablet for oral administration of cedazuridine (E7727) 
(100 mg), a novel cytidine deaminase inhibitor (CDAi), and decitabine (35 mg), an FDA-
approved HMA for IV infusion (Figure 2b and Figure 2c). The CDAi cedazuridine enables the 
oral bioavailability of decitabine. 
Figure 2b. Molecular Structure of Cedazuridine
Figure 2c. Molecular Structure of Decitabine
Nomenclature and properties of the components of ASTX727 (cedazuridine and decitabine) are provided in 
Table 4.
Table 4: Nomenclature and Properties: Cedazuridine and Decitabine
Cedazuridine 
Decitabine 
Compendial Name 
cedazuridine 
decitabine 
Chemical Name (IUPAC) 
(4R)-1-[(2R,4R,5R)-3,3-difluoro-4-
hydroxy-5-
(hydroxymethyl)oxolan-2-yl]-4-
hydroxy-1,3-diazinan-2-one 
4-amino-1-[(2R,4S,5R)-4-hydroxy-
5-(hydroxymethyl)oxolan-2-yl]-
1,3,5-triazin-2(1H)-one
(CAS) Registry Number 
1141397-80-9 
2353-33-5 
Chemical Formula 
C9H14F2N2O5 
C8H12N4O4 
Molecular Weight 
268.21 Daltons 
228.21 Daltons 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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Pharmacologic Class 
Cytidine deaminase inhibitor 
Anatomical therapeutic chemical 
(ATC) code L01BC08, 
Antineoplastic and 
immunomodulating agents, 
pyrimidine analogues. 
Decitabine is a cytosine 
deoxynucleoside analogue that 
inhibits DNA methyltransferase.a 
Solubility 
Soluble in dimethylsulfoxide and 
0.1 M HCl, sparingly soluble in 
water and pH 7.2 buffer, slightly 
soluble in methanol and ethanol, 
and insoluble in n-heptane, ethyl 
acetate, acetonitrile, 1-octanol, and 
methyl tert-butyl ether. Not 
hygroscopic. 
Slightly soluble in ethanol/water 
(50/50), methanol/water (50/50) 
and methanol, sparingly soluble in 
water and soluble in 
dimethylsulfoxide (DMSO). 
a Source: Decitabine European Public Assessment Report (EPAR) accessed 09 April 2019. 
https://www.ema.europa.eu/en/documents/product-information/dacogen-epar-product-information_en.pdf 
5.2.1
Formulation/packaging/preparation/storage
Azacitidine (Vidaza®) is supplied as a lyophilized powder in 100 mg single-use vial, and should 
be reconstituted aseptically with 4 mL sterile water for injection. The diluent should be injected 
slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. 
The suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL.
Preparation for Immediate Administration:  
Azacitidine doses should be drawn up into 1 to 4 syringes of equal volume per institutional 
guidelines. The product must be administered within 1 hour after reconstitution when stored at 
room temperature. 
Preparation for Delayed Administration:  
The reconstituted product may be kept in the vial or drawn into a syringe.  The product must be 
refrigerated immediately, and may be held under refrigerated conditions (2ºC - 8ºC, 36ºF- 46ºF) 
for up to 8 hours. After removal from refrigerated conditions, the suspension may be allowed 
to equilibrate to room temperature for up to 30 minutes prior to administration. 
Reconstituted azacitidine may be stored for up to 1 hour at 25°C (77°F) or for up to 8 hours 
between 2 and 8°C (36 and 46°F).  The azacitidine vial is single-use and does not contain any 
preservatives. Unused portions of each vial should be discarded properly.  Do not save any 
unused portions for later administration.
Azacitidine is a cytotoxic drug and, as with other potentially toxic compounds, caution should 
be exercised when handling. Several guidelines on this subject have been published (ASHP, 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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2006; NIH, 1999; NIOSH, 2004; OSHA, 1999; Polovich, 2005). If reconstituted azacitidine 
comes into contact with the skin, immediately and thoroughly wash with soap and water. If it 
comes into contact with mucous membranes, flush thoroughly with water.  Procedures for 
proper handling and disposal of azacitidine should be applied according to standards established 
at each facility for cytotoxic drugs. 
Prior to development of ASTX727 tablet (see below), cedazuridine and decitabine were 
administered separately in capsules. 
The new ASTX727 tablet is a fixed-dose combination of 100 mg cedazuridine and 35 mg 
decitabine for oral administration. The drug product is a red, oval shaped film-coated, 
immediate-release tablet (Figure 3). The formulation excipients include lactose, hypromellose, 
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and Opadry II 85F15458 
Red. The Opadry is a tablet coating formula that contains titanium dioxide, polyvinyl alcohol, 
polyethylene glycol, talc, and iron oxide red. The clinical drug products are either plain faced 
on both sides, or have a debossed marking of “H35” on one side and plain faced on the other.  
This tablet was used in the Phase 3 trial.
Figure 3. ASTX727 Tablet
All drug products are packed in 5-count opaque high-density polyethylene (HDPE) bottle with a 
child resistant closure. Each bottle contains either 1 or 2 desiccant canisters for moisture absorption. 
The desiccant canisters should remain in the bottle at all times and must not be ingested. Tablets are 
to be stored on site as indicated in the study-specific Pharmacy Manual (provided by Astex). Tablets 
should be dispensed by the study pharmacist according to institutional policy and per study protocol, 
and at-home storage instructions should be given to the study subject. 

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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5.2.2
Doses and treatment regimens
All subjects will be administered either a fixed dose and schedule of durvalumab (MEDI4736) 
and tremelimumab with azacitidine or a fixed dose and schedule of durvalumab (MEDI4736) 
with ASTZ727  The dose and schedule of azacitidine or decitabine will determined by the dose 
escalation schema (Sections 3.2 and 6.2, Table 2).  For those patients receiving azacitidine, in 
Cycle 2, azacitidine will be administerd 60 minutes following the infusion of durvalumab.  For 
subsequent cycles, azacitidine will be administered after the completion of the durvalumab 
infusion.
5.2.3
Dose administration
Subjects who enter screening will be assigned the next available subject number. All eligible 
subjects will receive oral decitabine (ASTX727) at the assigned dose. Subjects will complete a 
self administration drug diary (Appendix 8). The dose will be taken at the same time (+/-1 hour) 
for the first 5 days of each cycle.  If the subject misses the dose and remembers before 6:00 PM 
that day, the subject may make-up the dose.  If it is after 6:00PM, the subject should wait until 
the next scheduled dosing time (the next day) and take the next scheduled dose.  If the dose is 
vomited, the patient should not re-dose.  The tablets cannot be crushed, chewed, or dissolved in 
water.  The drug should be taken with 8 fluid ounces of water. The drug should be taken in the 
fasted state (no food for at least 2 hours before and 2 hours after taking the dose). The bottles 
containing the tablets should be stored at room temperature.
5.2.4
Accountability and dispensation 
Accurate recording of all IP administered will be made in the appropriate section of the subject’s 
case report form (CRF) and source documents, including patient drug diaries (Appendix 8). 
The subject should bring the drug diary and any empty or partially empty bottles into the clinic 
for their scheduled visits. The Investigator or designee is accountable for the compliance of all 
study-specific IP either administered or in their custody during the course of the study. 
5.2.5
Disposition of unused investigational study drug
Any unused investigational study drug will be returned to the Pharmacy for proper disposal in 
accordance with hospital policy of any unused chemotherapeutic agents.

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6.
TREATMENT PLAN
6.1
Subject enrollment
6.1.1
Assignment of screening number
All consented subjects will be given a unique screening number that will be used to identify the 
subject for all procedures that occur prior to randomization or treatment allocation. Each subject 
will be assigned only one screening number. Screening numbers must not be re-used for 
different subjects. Any subject who is screened multiple times will retain the original screening 
number assigned at the initial screening visit.
6.1.2
Procedures for randomization
This is not a randomized study. All eligible subjects will be allocated, by non-random 
assignment, to trial treatment and will receive a unique number. This unique number is termed 
a randomization number throughout the protocol for operational purposes. The randomization 
number identifies the subject for all procedures occurring after treatment allocation. Once a 
randomization number is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than one unique number. Treatment assignment will 
be done based on the schema described in Sections 3.2 and 6.2, Table 2. All patients will 
receive the same fixed dose of durvalumab (MEDI4736) and tremelimumab (based on a weight 
greater than 30 kg) and oral decitabine (ASTX727) will be dose escalated if safe to do so.  
Enrolled patients will be sequentially assigned to the cohorts.  After the enrollment of 6 
evaluable patients into the 1st group (eligible patients who at least begin protocol treatment and 
have an evaluable pre- and on-treatment (8-week) biopsy sample available), the next 6 patients 
will be enrolled into the 2nd cohort if safe to do so.  After the enrollment of 6 evaluable patients 
into the 2nd cohort, the next 6 patients will be enrolled into the 3rd cohort only if the BED has 
not been determined, and the group in which the BED has been determined will be expanded to 
enroll 10 patients.  Additional subjects may be enrolled into the cohort(s) to ensure that the 
required number of evaluable pre- and on-treatment biopsy samples are available to adequately 
determine the BED. Patients cannot change groups or dose assignments upon the initiation of 
the study protocol. 
6.1.3
Procedures for handling subjects incorrectly enrolled
Subjects who fail to meet the eligibility criteria should not receive study medication. Subjects 
who are incorrectly enrolled but found to not meet all the eligibility criteria must not be initiated 
on treatment and must be withdrawn from the study as a screen failure.  If a subject, who in 
error is assigned a randomization number or incorrectly started on treatment, in spite of not 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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meeting all of the inclusion/exclusion criteria, will be withdrawn from the study and the 
assigned randomization number will not be re-assigned to another subject and the subject will 
not be counted toward any treatment cohort.
6.2
Dosage and Administration
This is a phase Ib, open label dose escalation and safety evaluation of durvalumab (MEDI4736) 
and oral decitabine (ASTX727) combination therapy.  This trial opened with the administration 
of subcutaneous (SC) injection of azacitidine. Treatment i.e. 5 to 10 daily visits for a large-
volume SC injection continuing for several months or even years, represents a significant 
hardship for patients.  A possible consequence is non-compliance or earlier discontinuation of 
a beneficial treatment.  Successful development of an oral DNA methyltransferase inhibitor 
eases the burden of long duration SC therapy, particularly for those patients who are benefiting 
the most and need continuing treatment for long periods.  In our trial with SC injection of 
azacitidine, we were achieving global tumor hypomethylation with clinical benefit.  
Furthermore, a tolerable AE profile was being observed.  These preliminary results rationalize 
the continuation of this study but with an oral DNA methyltransferase inihibitor for reasons 
stated above. Since the oral DNA methyltransferase inhibitor is an investigational drug, we will 
administer the oral drug with the FDA approved durvalumab.  We will continue treatment of 
azacitidine SC for those patients already enrolled into the study.  However, all newly enrolled 
patients will receive an oral tablet of ASTX727 (35 mg decitabine/100 mg cedazuridine) daily 
on either Days 1-3, Days 1-4, or Days 1-5, and durvalumab (MEDI4736) 1500 mg via IV 
infusion x 1 in a 4 week cycle. Oral decatibine (ASTX727) will be administered alone in Cycle 
1 and the combination of oral decatibine (ASTX727) and durvalumab therapy will be given in 
Cycles 2-12 or until confirmed PD, initiation of alternative cancer therapy, unacceptable 
toxicity, withdrawal of consent, or another discontinuation criterion is met, whichever occurs 
first. The BED will be assessed on pre-treatment and post-treatment biopsies obtained at week 
8. BED is defined as the dose of oral decatibine (ASTX727) that results in at least a 10%
decrease in LINE-1 methylation from the baseline biopsy sample to the 8-week on-treatment
tumor biopsy sample in at least 50% of patients treated within the same dose level. Accrual will
be suspended until assessment of the LINE-1 methylation levels in the first 2 dose cohorts.  If
the BED has not been determined in the first 2 dose levels and it is safe to do so, then the study
will re-open to accrual and a subsequent group of 3 patients will receive the 3rd dose level. If
both the first 2 dose levels result in > 10% decrease in LINE-1 methylation, then the dose which
induces the greatest fold change in HLA Class I/II APM expression and/or CD8+ T cell
infiltration and with the lowest AE profile will be the dose utilized for the dose expansion group.
Dose Limiting Toxicity (DLT) will be assessed through 28 days post Cycle 2.

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Although assessment of the BED is primary, the dose also needs to be safe. Each dose will be 
assessed for safety according to a stopping rule and a DLT toxicity definition as outlined in the 
protocol and statistical section. Decisions will then be made about dose escalations of oral 
decatibine (ASTX727). Subjects will be sequentially assigned to the cohorts.  The first 6 
enrolled subjects will ingest one tablet daily on Days 1-3 of a 28-day cycle.  If two or more of 
the first six subjects experience a DLT, then the dose will be reduced and an additional six 
patients will be treated at the reduced dose. If two or more of the six at the reduced dose 
experience a DLT, then the study will be terminated. If at any time during accrual to a cohort, 
2 or more patients in a cohort experience DLT, enrollment to that cohort will be terminated. If 
less than two of the six patients treated at dose level 1 experience a DLT, a subsequent group of 
six patients will receive dose level 2. 
Patients cannot change groups or dose assignments upon the initiation of the study protocol.  
Please refer to Sections 5.1.2, 5.1.3, and 5.2.4. for the administration and monitoring of 
administration of durvalumab (MEDI4736) and tremelimumab.  Please refer to Section 5.3 for 
the administration and monitoring of administration of oral decitabine (ASTX727).
Table 5a:   Cohort size and dose escalation for oral decitabine (ASTX727)
Cohort (# of pts)
Oral decitabine (ASTX727)
(28 day cycle)
Grade 3
or higher
2-fold DNMT1 inhibition
in >50% of patients
BD-1 (6)
ASTX 727 one tablet daily on
Days 1-2
MTD1
BED2
B1 (6)
ASTX 727 one tablet daily on
Days 1-3
MTD1
BED2
B2 (6)
ASTX 727 one tablet daily on
Days 1-4
MTD1
BED2
B3 (6)
ASTX 727 one tablet daily on
Days 1-5
MTD1
BED2
1MTD (maximally tolerated dose) will be defined as that dose of azacitidine that results in <2 
of 6 patients experiencing a DLT
2BED (biologically effective dose) will be defined as that dose of oral decitabine (ASTX727) 
that results in at least a 10% decrease in LINE-1 methylation in pre- and on-treatment biopsy 
samples in >50% of treated subjects
Table 5b:   Cohort size and dose escalation for azacitidine

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Cohort (# of pts)
Azacitidine
(28-day cycle)
Grade 3
or higher
2-fold DNMT1 inhibition
in >50% of patients
D-1 (6)
20 mg/m2 on 
Days 1-5
MTD2
BED3
1 (6)
40 mg/m2 on 
Days 1-5
MTD2
BED3
2 (6)
40 mg/m2 on 
Days 1-5 and 8-12
MTD2
BED3
3 (6)
75 mg/m2 on
Days 1-5
MTD2
BED3
The overall safety of the combination therapy will be evaluated by following patients up to 28 days for 
DLTs after the first dose of oral decitabine (ASTX727) and durvalumab (MEDI4736) combination 
therapy (end of cycle 2 (which is the first cycle of the combination)).
6.3
Dose Escalation Decision Rules
Dose escalation monitoring
In order to ensure that patients are receiving the assigned dose of drug, oral decitabine 
(ASTX727), several measures will be employed.
Printed orders will be available.  
The principal investigator, research nurse, and data manager will review the available toxicity 
data prior to continuing to escalate the dose and enrolling patients into the new cohort. 
Prior to the start of each new dose level (i.e. accrual of a new cohort), a dated letter will be sent 
to the pharmacy which describes the change in dose.
Stopping rules
Dose escalations will continue until one of the following stopping rules has been satisfied:
1.The BED has been determined.
2.If at any time during accrual to a cohort, 2 or more patients in a dose cohort experience
DLT, enrollment to that dose cohort will be terminated and dose escalation will stop.  
3. Two of six patients treated at a reduced dose of oral decitabine (ASTX727) on Days 1-2
of a 28 day cycle experience a DLT

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6.3.1
Definition of BED
Biologically effective dose (BED) is defined as the dose of oral decitabine (ASTX727) that 
results in at least a 10% decrease in LINE-1 methylation level from the baseline sample to the 
8 week post baseline tumor sample in at least 50% of patients treated within a dose level.   As 
LINE-1 (long interspersed element-1) is a repetitive DNA retrotransposon that duplicates via a 
copy-and-paste genetic mechanism.  As LINE-1 constitutes approximately 17% of the human 
genome, the extent of LINE-1 methylation is regarded as a surrogate marker of global DNA 
methylation.  ASTX Pharmaceuticals has assessed changes in LINE-1 methylation with 
ASTX727 as a marker of efficacy in their prior clinical trials.  The change in LINE-1 
methylation is a working rule and a panel of markers will be assessed and the dose with the 
most viable panel and lowest adverse event profile will be used in the expansion cohort of the 
study.
6.4
Definition of DLT
Dose-limiting toxicities (DLTs) will be evaluated during the dose escalation phase of the trial.  
The period for evaluating DLTs will be from the time of first administration of oral decitabine 
(ASTX727) until after 28 days after the first dose of oral decitabine (ASTX727), durvalumab 
(MEDI4736), and tremelimumab combination therapy (end of Cycle 2 (which is the first cycle 
of the triple combination)).
Subjects who do not remain on the study up to this time for reasons other than DLT will be 
replaced with another subject at the same dose level. Grading of DLTs will follow the guidelines 
provided in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
A DLT will be defined as any Grade 3 or higher toxicity that occurs during the DLT evaluation 
period. Toxicity that is clearly and directly related to the primary disease or to another etiology 
is excluded from this definition. The following will be DLTs:

Any Grade 4 irAE

Any ≥ Grade 3 colitis

Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration

Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation of 
maximal supportive care

Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 within 
3 days after onset of the event despite optimal medical management including systemic 
corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days

Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN

Any ≥ Grade 3 non-irAE, except for the exclusions listed below

Grade 4 neutropenia lasting > 10 days or accompanied by fever (defined as > 38.5°C requiring 

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hospitalization)

Grade 3 thrombocytopenia with clinically significant bleeding
The definition excludes the following conditions: 

Grade 3 fatigue lasting ≤ 7 days

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed 
with or without systemic corticosteroid therapy and/or hormone replacement therapy and the 
subject is asymptomatic

Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
reaction at sites of metastatic disease, lymph nodes, etc)

Concurrent vitiligo or alopecia of any AE grade

Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) 
that resolves within 6 hours with appropriate clinical management

Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that improves by 
at least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia will be a DLT regardless 
of duration or reversibility

Grade 3 or 4 lymphopenia

Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that requires 
medical intervention, and improves by at least 1 grade within 3 days

Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or symptoms 
and are reversed with appropriate maximal medical intervention within 3 days

Grade 3 emesis that responds to optimal antiemetic therapy within 72 hours 

Grade 3 diarrhea that responds to optimal medical management within 72 hours 
Immune-related AEs are defined as AEs of an immune nature (ie, inflammatory) in the absence 
of a clear alternative etiology. In the absence of a clinically significant abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to 
designation as a DLT. 
If a DLT occurs, the patient will be removed from further treatment in the protocol. The patient 
will be followed for their DLT until there is complete resolution of the observed toxicity. These 
toxicities will effect dose escalation decisions.  Any occurrence of grade 4 or greater toxicity 
will prompt the sponsor and the principal investigator to conduct a thorough evaluation of the 
available safety information to justify a decision to enroll new subjects into the study.

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6.5
Dose Modification and Toxicity Management
6.5.1
Durvalumab (MEDI4736) and tremelimumab
For adverse events (AEs) that are considered at least partly due to administration of 
durvalumab (MEDI4736) the following dose adjustment guidance may be applied:

Treat each of the toxicities with maximum supportive care (including holding the
agent suspected of causing the toxicity where required).

If the symptoms promptly resolve with supportive care, consideration should be given
to continuing the same dose of durvalumab (MEDI4736) or tremelimumab along with
appropriate continuing supportive care.  If medically appropriate, dose modifications
are permitted for durvalumab (MEDI4736) and tremelimumab (see Appendix 1).

All dose modifications should be documented with clear reasoning and documentation
of the approach taken.
In addition, there are certain circumstances in which durvalumab (MEDI4736) or 
tremelimumab should be permanently discontinued.
Following the first dose of durvalumab (MEDI4736) or tremelimumab, subsequent 
administration of durvalumab (MEDI4736) or tremelimumab can be modified based on 
toxicities observed (see Appendix 1). Reductions in the dose administered are not permitted. 
Based on the mechanism of action of durvalumab (MEDI4736) or tremelimumab leading to T-
cell activation and proliferation, there is the possibility of observing immune related Adverse 
Events (irAEs) during the conduct of this study.  Potential irAEs include immune-mediated 
enterocolitis, dermatitis, hepatitis, and endocrinopathies. Subjects should be monitored for 
signs and symptoms of irAEs.  In the absence of an alternate etiology (e.g., infection or PD) 
signs or symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy should be 
considered to be immune-related.  
Dose modification recommendations and toxicity management guidelines for immune-
mediated reactions, for infusion-related reactions, and for non-immune-mediated reactions are 
detailed in Appendix 1.  
In addition, management guidelines for adverse events of special interest (AESIs) are detailed 
in Section 10.1.3. All toxicities will be graded according to NCI CTCAE v4.03. 
6.5.2
Azacitidine/Oral decitabine (ASTX727)
6.5.2.1
Dose Adjustment Guidelines

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A maximum of 1 dose reduction will be allowed from the original dose.  Please refer to Table 
2 for the dose cohorts.
Azacitidine or oral decitabine may be withheld for up to 7 days between the end of 1 cycle and 
the start of the next cycle to allow hematologic criteria to recover sufficiently for the next cycle 
to begin. 
The maximum number of days that a azacitidine or decitabine dose may be withheld without 
requiring a dose reduction is 7 days. 
The maximum number of days that azacitidine or oral decitabine may be withheld due to 
unacceptable toxicity before a subject is permanently discontinued from the study is 14 days. 
For the purposes of dose adjustments, unacceptable toxicity will be defined as any AE that is 
deemed by the Investigator to be related to azacitidine or oral decitabine (ASTX727) that poses 
a medical risk or substantial discomfort to the subject including, but not limited to, Grade 3 or 
4 hematologic or non- hematologic toxicity. Subjects should be discontinued after the 
3
rdepisode. 
Please refer to Table 6 for the Dose Adjustment Guidelines due to unacceptable toxicity. 
Table 6: Dose Adjustments and Dose Delays for Toxicity 
Toxicity 
Recommendation 
Grade 2 hematologic toxicity causing 
delay to the planned start of a Cycle
Absolute Neutrophil Count (ANC) < 1.0 x 
109/L 
Platelets < 75 x 109/L 
Hold azacitidine or decitabine until ANC & Platelets > 
1.0x109/L 
Delay ≤ 7 days, resume azacitidine or decitabine at 
same dose 
Delay 8 – 14 days, reduce azacitidine ordecitabine by 
a dose cohort  level
Delay > 14 days, permanently discontinue azacitidine 
or decitabine 
Grade 3 neutropenia or thrombocytopenia 
causing delay to the planned start of a 
Cycle 
ANC 0.5-0.99 x 109/L
Platelets 25-49 x 109/L 
Hold azacitidine or decitabine until ANC & 
Platelets recover to ANC ≥ 1.0 x 109/L, 
Platelets ≥ 75 x 109/L)
Recovery in ≤ 7 days, resume azacitidine or 
decitabine at same dose 
Recovery in 8–14 days, reduce azacitidine or 

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decitabine by a dose cohort level 
No recovery by 14 days, 
permanently discontinue azacitidine 
or decitabine
Grade 4 neutropenia or thrombocytopenia 
causing delay to the planned start of a 
Cycle 
ANC < 0.5 x 109/L
Platelets < 25 x 109/L
For ANC < 0.5 x 109/L
The initiation of G-CSF is left at the 
Investigator’s discretion. If initiated 
administer G-CSF per institutional 
practice or package insert and continue 
until ANC recovers to ≥ 2.0 x 109/L
Hold azacitidine or decitabine until ANC & 
Platelets recover to < Grade 1 (ANC ≥ 1.5 x 
109/L, Platelets ≥ 75 x 109/L)
Recovery in ≤ 7 days, reduce azacitidine or 
decitabine by a dose cohort level
No recovery by 7 days, permanently 
discontinue azacitidine or decitabine
Grade 3 or 4 Nausea or Vomiting 
Grade 3 or 4 Diarrhea
Grade 3 or 4 Fatigue/Asthenia 
Hold until resolution to ≤ Grade 1 
and provide optimal medical 
management. If response ≤ 72 
hours (3 days), and recovery ≤ 7 
days, reduce azacitidine or 
decitabine by a dose cohort level 
If event recurs after re-challenge at 
reduced dose, discontinue 
azacitidine or decitabine.
If no recovery by 7 days, 
discontinue azacitidine or 
decitabine. 
Grade 3 or 4 any other non-hematologic 
toxicity 
Hold until resolution to ≤ Grade 1 
and provide optimal medical 
management. 
If recovery ≤ 7 days, reduce 
azacitidine or decitabine by a dose 
cohort level. 
If event recurs after re-challenge at 
reduced dose, discontinue 
azacitidine or decitabine
If no recovery by 7 days, 

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discontinue azacitidine or 
decitabine
ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; ESMO = 
European Society for Medical Oncology; G-CSF = granulocyte colony stimulating factor. 
Note: The initiation of G-CSF is left at the Investigator’s discretion.
Note: Granulocyte colony stimulating factor (G-CSF) should only be utilized in accordance to 
ASCO or ESMO recommendations.
Note: If Grade 3 or 4 neutropenia associated with fever or Grade ≥ 3 thrombocytopenia with 
clinically significant bleeding occurs at any time, the dose adjustment guidelines for Grade 4 
hematological toxicity should be enacted.
Note: If neutropenia is associated with fever and severe diarrhea, subject should be managed 
appropriately according to the local practice. In case of recurrence of the diarrhea with 
neutropenia and fever, the continuation of the subject in the study should be 
discussed on a case-by-case basis with the sponsor’s study monitor. 
Note: Any Grade 3 or 4 toxicity that is not clinically significant, as judged by the treating 
physician and/or PI, does not require any dose reductions of azacitidine or decitabine.
6.5.2.2
Dose Adjustment Based on Hematology Toxicity
Hematological toxicity is defined as the lowest count reached in a given cycle (nadir) if 
platelets fall below 50.0 x 109/L and/or ANC below 1.0 x 109/L.  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 x (baseline count – nadir count)].  Please refer to the Table in Section 2.3 of 
the PI.
For Patients Without Reduced Baseline Counts: WBCs ≥ 3.0 x 109/L, ANC ≥ 1.5 x 109/L, 
and Platelets ≥ 75.0 x 109/L:
If hematological toxicity is observed following azacitidine or decitabine treatment, the next 
cycle of azacitidine or decitabine 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, the dose should be 
reduced.
Following dose modifications, the cycle duration should return to 28 days.
For Patients with Reduced Baseline Blood Counts: WBC < 3.0 x 109/L,
ANC < 1.5 x 109/L, and Platelets < 75.0 x 109/L:

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Following azacitidine or decitabine treatment, if the decrease in WBC or ANC or platelets 
from baseline 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 WBC or ANC or platelets is greater than 50% from that prior to treatment, 
with no improvement in cell line differentiation, the next cycle of azacitidine or decitabine 
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).  Following dose modifications, the 
cycle duration should return to 28 days.
6.5.2.3
Missing Doses
All efforts should be made to administer IP on all of the scheduled days of each 28-day treatment 
cycle.  Patients who have a dose interruption due to toxicity at any point in the first 12 months 
of treatment may resume treatment with their assigned IP and complete the 12-month treatment 
period. Any missed doses during that period should not be added after the last scheduled day of 
administration to compensate for missed doses. 
7.
RESTRICTIONS DURING THE STUDY AND CONCOMITANT 
TREATMENT(S)
7.1
Restrictions during the study
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after:
Females of childbearing potential who are sexually active with a non-sterilized male partner 
must use at least one highly effective method of contraception (Table 4) from the time of 
screening and must agree to continue using such precautions for 180 days after the last dose 
of study drug; cessation of birth control after this point should be discussed with a responsible 
physician.  Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of birth control. Male partners of a female subject must use male condom 
plus spermicide throughout this period.

Females of childbearing potential are defined as those who are not surgically 
sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete 

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hysterectomy) or post-menopausal (defined 12 months with no menses without 
an alternative medical cause).
Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use male condom plus spermicide from screening through 180 days after receipt 
of the final dose of study drug. Female partners of a male subject must use a highly 
effective method of contraception throughout this period.
Highly effective methods of contraception are described in Table 4. A highly effective method 
of contraception is defined as one that results in a low failure rate (i.e. less than 1% 
per year) when used consistently and correctly. Note that some contraception 
methods are not considered highly effective (e.g. male or female condom with or 
without spermicide; female cap, diaphragm, or sponge with or without spermicide; 
non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action 
[excluding Cerazette/desogestrel which is considered highly effective]; and triphasic 
combined oral contraceptive pills). 
Restrictions relating to concomitant medications are described in Section 7.2.
Table 7            Highly Effectivea Methods of Contraception
Barrier/Intrauterine Methods
Hormonal Methods
•
Copper T intrauterine device
•
Levonorgesterel-releasing intrauterine 
system (eg, Mirena®)b
•
Etonogestrel implants: e.g. Implanon or 
Norplan
•
Intravaginal device: e.g. ethinylestradiol 
and etonogestrel
•
Medroxyprogesterone injection: e.g. 
Depo-Provera 
•
Normal and low dose combined oral 
contraceptive pill
•
Norelgestromin/ethinylestradiol  
transdermal system
•
Cerazette (desogestrel)

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Table 7            Highly Effectivea Methods of Contraception
Barrier/Intrauterine Methods
Hormonal Methods
a
Highly effective (i.e. failure rate of <1% per year) 
b
This is also considered a hormonal method
   
Blood donation
Subjects should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of durvalumab (MEDI4736) or tremelimumab or 28 days following 
the last dose of azacitidine or decitabine, whichever is the longest time period.
7.2
Concomitant treatment(s)
The Principal Investigator must be informed as soon as possible about any medication taken 
from the time of screening until the end of the clinical phase of the study (final study visit).  Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the CRF.  
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables.  Refer to Section 6.6 for guidance on management of IP-related toxicities.
7.2.1
Permitted concomitant medications
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed in Section 7.2.2.
Antiemetics are not required during the study; however, at the Investigator’s discretion, subjects 
may receive prophylactic antiemetics approximately 30 minutes prior to each dose of azacitidine 
or decitabine. 
Treatment with antidiarrheal medications should be prescribed at the first sign of diarrhea. Pre-
medication with antidiarrheal medication for subsequent doses of azacitidine or decitabine may 
be appropriate at the Investigator’s discretion. 

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7.2.2
Excluded Concomitant Medications
The following medications are considered exclusionary during the study. 
1. Any investigational anticancer therapy other than the protocol specified therapies
2. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment, other than any 
stated combination regimens. Concurrent use of hormones for non cancer-related 
conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.  
NOTE: Local treatment of isolated non-target lesions for palliative intent is acceptable 
(e.g., by local surgery or radiotherapy)
3. Any decitabine, or other demethylating or histone deacetylating agents.
4. Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses not exceeding 10 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the 
management of investigational product-related AEs or in subjects with contrast allergies 
is acceptable. In addition, use of inhaled and intranasal corticosteroids is permitted. A 
temporary period of steroids will be allowed for different indications, at the discretion 
of the principal investigator (e.g., chronic obstructive pulmonary disease, radiation, 
nausea, etc).   
5. Live attenuated vaccines within 30 days of durvalumab (MEDI4736) and tremelimumab 
dosing (ie, 30 days prior to the first dose, during treatment with durvalumab 
(MEDI4736) and tremelimumab for 30 days post discontinuation of durvalumab 
(MEDI4736) and tremelimumab.  Inactivated vaccines, such as the injectable influenza 
vaccine, are permitted.
6. Drugs known to be metabolized by CDA (eg, cytarabine, gemcitabine, azacitidine, 
vidarabine, zalcitabine, zidovudine, telbivudine, didanosine, stavudine, lamivudine, 
abacavir, emtricitabine, entecavir, apricitabine, idoxuridine, trifluridine, tenofovir, and 
adefovir) should not be administered on the same days with cedazuridine or ASTX727.

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Table 8. Prohibited and Rescue Medications
Prohibited medication/class of drug:
Usage:
Additional investigational anticancer therapy 
concurrent with those under investigation in this 
study
Should not be given whilst the patient is on IP 
treatment  
mAbs against CTLA-4, PD-1, or PD-L1
Should not be given whilst the patient is on IP 
treatment  through 90 days after the last dose of IP.
Any concurrent chemotherapy, local therapy 
(except palliative radiotherapy for non-target 
lesions, 
eg, 
radiotherapy, 
surgery, 
radiofrequency ablation), biologic therapy, or 
hormonal therapy for cancer treatment
Should not be given whilst the patient is on IP 
treatment (including SoC).  (Concurrent use of 
hormones 
for 
non-cancer-related 
conditions 
[eg, insulin for diabetes and hormone replacement 
therapy] is acceptable.)
Immunosuppressive medications, including, 
but not limited to, systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or its 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor α blockers  
Should not be given whilst the patient is on IP 
treatment 
(including 
SoC). 
 
(Use 
of 
immunosuppressive medications for the management 
of IP-related AEs or in patients with contrast allergies 
is acceptable.  In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted.
Live attenuated vaccines
Should not be given through 30 days after the last dose 
of IP (including SoC) during the study
Rescue/supportive medication/class of drug:
Usage:
Concomitant 
medications 
or 
treatments 
(eg, acetaminophen 
or 
diphenhydramine) 
deemed necessary by the Investigator to provide 
adequate prophylactic or supportive care, 
except for those medications identified as 
“prohibited” as listed above
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc])
Should be used when necessary for all patients

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Rescue/supportive medication/class of drug:
Usage:
Best supportive care (including antibiotics, 
nutritional support, growth factor support, 
correction of metabolic disorders, optimal 
symptom control, and pain management 
[including palliative radiotherapy, etc])
Should be used when necessary for all patients
8.
STUDY PROCEDURES
8.1
Schedule of study procedures
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated.  The 
Schedules of Assessments during the screening and treatment period is provided following the 
Protocol Synopsis. 
8.1.1
Screening Phase
Screening procedures will be performed up to 28 days prior to study registration, unless 
otherwise specified.  All subjects must first read, understand, and sign the IRB/REB/IEC-
approved ICF before any study-specific screening procedures are performed.  After signing the 
ICF, completing all screening procedures, and being deemed eligible for entry, subjects will be 
enrolled in the study.  Procedures that are performed prior to the signing of the ICF and are 
considered standard of care may be used as screening assessments if they fall within the 28-day 
screening window. An archived pre-treatment tumor biopsy obtained outside of the 28-day 
screening window may be used for PD-L1 staining if the subject has not received any interval 
treatment since undergoing the biopsy. 
The following procedures will be performed during the Screening Visit:

Informed Consent

Review of eligibility criteria

Medical history and demographics

Adverse event/serious adverse event assessment with prior immunotherapy

Complete physical exam 

ECOG Performance Status

Vitals signs, weight and height 

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
12-lead ECG (in triplicate [2-5 minutes apart])

Tumor biopsy

Peripheral blood draw for research analysis

Review of prior/concomitant medications 

Imaging by CT/MRI 

Bone scan

Clinical laboratory tests for:
o
Hematology (see Table 7)
o
Clinical chemistry (see Table 8)
o
TSH
o
Coagulation (PT, PTT, INR)
o
Creatinine Clearance
o
Serum pregnancy test (for women of childbearing potential only)
o
Hepatitis B and C serologies
o
HIV testing
o
Urinalysis (see Table 9)
8.1.2
Treatment Phase 
Procedures to be conducted during the treatment phase of the study are presented in the Schedule 
of Assessments.  Screening procedures performed within 72 hours of Cycle 1 Day 1 (C1D1) of 
protocol treatment do not need to be repeated on C1D1.  The treatment to be used in this trial is 
outlined below in Table 6. 

Complete physical exam 

Vitals signs and weight 

12-lead ECG (in triplicate [2-5 minutes apart]), as clinically indicated

ECOG Performance Status

Adverse event/serious adverse event assessment 

Review of prior/concomitant medications 

Clinical laboratory tests for:
o
Hematology (see Table 7)
o
Clinical chemistry (see Table 8)
o
TSH
o
Coagulation (PT, PTT, INR), as clinically indicated
o
Creatinine Clearance
o
Serum pregnancy test (for women of childbearing potential only)
o
Urinalysis (see Table 9)

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
Pharmacokinetic assessment

Imaging by CT/MRI

Bone scan, if baseline bone scan demonstrates metastatic disease

Tumor biopsy sample for research analysis

Peripheral blood draw for research analysis
Table 9  Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Durvalumab
(MEDI4736)
1500 mg 
Q4W
IV infusion
Day 1 of each 4 week 
cycle for 12 cycles a
Experimental
Tremelimumab
75 mg 
Q4W
IV infusion
Day 1 of each 4 week 
cycle for 4 cycles a
Experimental
Tremelimumab
300 mg
Once
IV infusion
Day 1 of Cycle 2
Experimental
Azacitidine
40 mg/m2 
or 75 
mg/m2
QD
SC
Days 1-5 or Days 1-5 
and 8-12 of each 4 week 
cycle for 12 cycles a
Experimental
Decitabine 
(ASTX727)
35 mg 
decitabine
QD
PO
Days 1-3, 1-4, or 1-5 of 
each 4-week cycle for 12 
cyclesa
Experimental
aAzacitidine or decitabine will be administered alone in Cycle 1. For those patients receiving azacitidine, the 
combination of azacitidine, durvalumab, and tremelimumab therapy will start in Cycle 2. Patients will continue 
with azacitidine, durvalumab and tremelimumab combination therapy for Cycles 3-5 and azacitidine and 
durvalumab for Cycles 6-12. For those patients receiving decatibine, the combination of decatibine and durvalumab 
therapy will be given in Cycles 2-12. 
8.1.3
End of Treatment
End of treatment is defined as the last planned dosing visit within the 12-month dosing period. 
For subjects who discontinue azacitidine or oral decitabine (ASTX727), durvalumab 
(MEDI4736), or tremelimumab prior to completing the 12 months of treatment with 
combination therapy, end of treatment is considered the last visit where the decision is made to 
discontinue treatment. All required procedures must be completed within  ± 28 days of the end 
of treatment visit. Repeat disease assessment is not required if performed within 28 days prior 
to the end of treatment visit.
Assessments for subjects who have completed azaciditine, or oral decitabine, durvalumab 
(MEDI4736), and tremelimumab treatment and achieved disease control, or have discontinued 

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azaciditine, or decitabine, durvalumab (MEDI4736) or tremelimumab due to toxicity in the 
absence of confirmed progressive disease are provided in APPENDIX 2   
Assessments for subjects who have discontinued azaciditine, or decitabine, durvalumab 
(MEDI4736), or tremelimumab treatment due to confirmed PD are presented in Appendix 3.
All subjects will be followed for survival until the end of the study regardless of further 
treatments, or until the sponsor ends the study.
8.2
Description of study procedures
8.2.1
Medical history and physical examination, electrocardiogram, weight and vital 
signs
Findings from medical history (obtained at screening) and physical examination shall be given 
a baseline grade according to the procedure for AEs. Increases in severity of pre-existing 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the pre-study grade or below.
Physical examinations will be performed on study days noted in the Schedule of Assessments.
8.2.2
Physical examination
Physical examinations will be performed according to the assessment schedule.  Full physical 
examinations will include assessments of the head, eyes, ears, nose, and throat and the 
respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems.  Height will be measured at Screening only.  
Targeted physical examinations are to be utilized by the Investigator on the basis of clinical 
observations and symptomatology.  Situations in which physical examination results should be 
reported as AEs are described in Section 10  
8.2.3
Electrocardiograms
Resting 12-lead ECGs will be recorded at screening and as clinically indicated throughout the 
study.  ECGs should be obtained after the patient has been in a supine position for 5 minutes 
and recorded while the patient remains in that position.
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 
2 additional 12-lead ECGs should be obtained over a brief period (eg, 30 minutes) to confirm 
the finding.  
Situations in which ECG results should be reported as AEs are described in Section 10.0.  

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8.2.4
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the assessment schedules.  
On infusion days, patients receiving durvalumab (MEDI4736) + tremelimumab treatment will 
be monitored during and after infusion of IP as presented in the bulleted list below.  
Supine BP will be measured using a semi-automatic BP recording device with an appropriate 
cuff size, after the patient has rested for at least 5 minutes.  BP and pulse will be collected from 
patients receiving durvalumab (MEDI4736) + tremelimumab treatment before, during, and after 
each infusion at the following times (based on a 60-minute infusion):  
Prior to the beginning of the infusion (measured once from approximately 30 minutes before up 
to 0 minutes [ie, the beginning of the infusion]).  
Approximately 30 minutes +/- 5 minutes during the infusion (halfway through infusion).  
At the end of the infusion (approximately 60 minutes +/-5 minutes).  
In the 1-hour observation period post-infusion: 30 and 60 minutes after the infusion (ie, 90 and 
120 minutes from the start of infusion) (+/- 5 minutes) is required after the first 
infusion of durvalumab (MEDI4736) and tremelimumab and then for subsequent 
infusions as clinically indicated. 
If no clinically significant infusion reactions are observed during or after the first cycle, 
subsequent infusion observation periods can be at the Investigator’s discretion (suggested 30 
minutes +/- 5 minutes after each durvalumab (MEDI4736) and tremelimumab infusion).  
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the 
principles as described above or be taken more frequently if clinically indicated.  The date and 
time of collection and measurement will be recorded on the appropriate eCRF.  Additional 
monitoring with assessment of vital signs is at the discretion of the Investigator per standard 
clinical practice or as clinically indicated.  
Body weight is also recorded along with vital signs on the days of infusion of durvalumab +/-   
tremelimumab.  
Situations in which vital signs results should be reported as AEs are described in Section 10.3.  
A complete physical examination will be performed and will include an assessment of the 
following (as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, 

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skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-
skeletal (including spine and extremities), genital/rectal, and neurological systems and at 
screening only, height.  
8.2.5
Clinical laboratory tests
The following clinical laboratory tests will be performed (see the Schedule of Assessments)

Coagulation parameters: Activated partial thromboplastin time and International normalised 
ratio to be assessed at baseline and as clinically indicated 

Pregnancy test (female subjects of childbearing potential only)
o
Urine human chorionic gonadotropin
o
Serum beta-human chorionic gonadotropin (at screening only)

Thyroid Stimulating Hormone
o
free T3 and free T4 only if TSH is abnormal
Table 10. Hematology Laboratory Tests
Basophils
Mean corpuscular volume
Eosinophils
Monocytes
Hematocrit
Neutrophils
Hemoglobin
Platelet count
Lymphocytes
Red blood cell count
Mean corpuscular hemoglobin
Total white cell count
Mean corpuscular hemoglobin concentration

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Table 11. Clinical chemistry (Serum or Plasma) Laboratory Tests
Albumin
Glucose
Alkaline phosphatase
Lactate dehydrogenase
Alanine aminotransferase
Lipase
Amylase
Magnesium
Aspartate aminotransferase
Potassium
Bicarbonate
Sodium
Calcium 
Total bilirubina
Chloride
Total protein
Creatinine
Urea or blood urea nitrogen, depending on local practice
Gamma glutamyltransferaseb
Uric acid
a   If Total bilirubin is ≥2xULN (and no evidence of Gilbert’s syndrome) then fractionate into direct and indirect  
bilirubin
b At screening, Cycle 1 Day1, and as clinically indicated
Table 12. Urinalysis Testsa
Bilirubin
pH
Blood
Protein
Glucose
Specific gravity
Ketones
Colour and appearance
a  Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red 
blood cells
8.3
Biological sampling procedures 
8.3.1
Biomarker sampling and evaluation methods
A tumor biopsy will be obtained pre- and either on- or post-treatment while on the study. A 
biopsy will be obtained on week 8 during the phase 1b dose-escalation portion of the study. The 
tumor samples will be evaluated for changes in LINE-1 methylation and/or expression of CD8+ 
T cells and MHC Class I/II by immunofluorscent staining and quantitative analysis.  Other 
immune biomarkers which will be evaluated include, but are not limited to: PD-1, PD-L1, PD-
L2, CD80, CD4, CD8, FoxP3, CTLA-4, Lag-3, Tim-3, IFN-g, and HPV-specific CD8+ T cells 
for HPV-associated tumors.

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In addition, blood and stool samples for correlative biomarker studies will be collected at pre- 
and either on- or post-treatment. The blood will be evaluated for changes in circulating HPV-
specific CD8+ T cells, for tumor DNA circulating markers, and cytokines. The stool will be 
used to characterize the microbiome in the gut and the microbiome correlated with response to 
immunotherapy.
PD-L1 Testing
To ensure comparability of data across all studies of durvalumab (MEDI4736) and/or 
tremelimumab and to gain real world experience on the performance of this assay, it is strongly 
encouraged that all studies that include PD-L1 testing utilize the Ventana SP263 assay.  Testing 
should be restricted to the Ventana SP263 assay and should be performed in accordance with 
the package insert on the Ventana Benchmark platform (Ultra or XT).  
The Ventana SP263 assay is fully analytically validated test characterized through to the 
completion of reader precision studies in the non-small cell lung cancer (NSCLC) and squamous 
cell carcinoma of the head & neck (SCCHN).  For these tumors, the Ventana SP263 assay has 
a fully reproducibility data package supporting cut-off and scoring algorithm.  
Sample collection for PD-L1 testing

The preferred tumor sample for the determination of a patient’s PD-L1 status is the one 
taken following the completion of the most recent prior line of therapy.  Samples taken 
at this time reflect the current PD-L1 status of the tumor and considered clinically most 
relevant.  

The preferred sample for PD-L1 testing is less than or equal to 3 months old.  In cases 
where a sample a less than 3 months old is not available, patients can be asked to undergo 
a new biopsy if considered clinically appropriate by their treating physician.  

Samples should be collected via a core needle of 18 gauge or larger or be collected by 
an incisional or excisional tumor biopsy.  Where institutional practice uses a smaller 
gauge needle, samples should be evaluated for tumor cell quantity (i.e. >100 tumor cells) 
to allow for adequate PD-L1 immunohistochemistry analyses.  

When the collection of a new sample is not clinically appropriate, archival samples may 
be utilized provided the specimen it is not older than 3 years of age.  When archival 
samples are used to assess PD-L1 status, the age of the sample / date of collection should 
be captured.  

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
Samples submitted for PD-L1 testing should be formalin fixed and embedded in 
paraffin.  Samples from fine needle aspirates (FNA) or decalcified bone are not 
appropriate for PD-L1 analysis.  
8.3.2
Estimate of volume of blood to be collected
The total volume of blood that will be drawn from each subject in this study is as follows:
Table 13. Volume of blood to be drawn from each subject
Assessment
Sample volume 
(mL)
No. of samples
Total 
volume 
(mL)
Safety
Clinical chemistry
5
12
60
Hematology
5
12
60
Biomarker
50
2
100
Total
220
8.3.3
Archival tumor samples and fresh tumor biopsies
8.3.3.1
Archival tumor samples
A pre-treatment tumor biopsy sample will be retrieved when available, either as a formalin-
fixed paraffin-embedded (FFPE) tissue block or up to 20 unstained slides. The archival tumor 
biopsy sample will be shipped to and stored in the laboratory of Dr. Pai for analysis. Analyses 
which will be conducted include, but are not limited to, LINE-1 methylation status, PD-L1 
expression, tumor mutation analysis, RNA analysis, and MHC Class I/II and CD8+ T cell 
immunohistochemistry. After the clinical study report has been finalized, the archival FFPE will 
be returned to the original hospital, if requested, and any unstained slides will be retained for 
future research.
8.3.3.2
Fresh tumor biopsies
A fresh tumor biopsy will be obtained in all subjects pre-treatment and either on- or post-
treatment, if safely accessible for biopsy as determined by the treating physician. A biopsy will 
be obtained on week 8 during the phase 1b dose-escalation portion of the study.  The fresh tumor 
biopsy sample will be shipped to and stored in the laboratory of Dr. Pai for analysis. Analyses 
which will be conducted include, but are not limited to, LINE-1 methylation, PD-L1 expression, 
tumor mutation analysis, RNA analysis, and MHC Class I, II and CD8+ T cell 
immunofluorescence. The pre-, on- or post-treatment biopsy can only be waived if the location 

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of the lesion is not safely accessible for biopsy, as determined by the treating physician.  The 
on-treatment biopsy will be performed at the time of confirmed PR on imaging, as outlined 
above.  For the non-superficial lesions, the on-treatment core needle biopsy will be performed 
under image guidance, either CT, MRI, or ultrasound. For dermal lesions, a core needle, 
excisional, or punch biopsy can be performed without image guidance. Biopsies will be 
obtained of lesion(s) which have decreased in size. A biopsy of a progressing lesion can also be 
obtained at the same time based on the discretion of the physician performing the procedure and 
the Investigator.  Any biopsied lesion(s) can no longer be included in the objective tumor 
response assessment except for those patients whom only have one target lesion which is greater 
than 2 cm in diameter in any one direction. A post-treatment biopsy will be obtained in those 
patients who stop study treatment prior to completing 12 months of therapy or any patients who 
completes 12 months of therapy but did not undergo an on-treatment biopsy.  Patients who had 
an on-treatment biopsy may undergo a post-treatment biopsy at the time of completing 12 
months of therapy; however, this is not a mandatory biopsy. Any patient who restarts treatment 
will require another biopsy prior to restarting treatment. The fresh tumor biopsy sample will be 
shipped to and stored in the laboratory of Dr. Pai for analysis.  At a minimum, 3 core biopsies 
will be obtained and 1 core will be formalin fixed and the other 1-2 cores will be flash frozen. 
Analyses which will be conducted include, but are not limited to, LINE-1 methylation, PD-L1 
expression, tumor mutation analysis, RNA analysis, and MHC Class I/II and CD8+ T cell 
immunohistochemistry. After the clinical study report has been finalized, any retaining tissue 
will be retained for future research.
8.3.4
Stool Collection
The subject(s) will be given kits for the collection of stool pre-treatment and at Week 8 (+/- 7 
days). The stool samples will be shipped to the Broad Institute for sequencing of the 
microbiota flora in the stool.
8.3.5
Withdrawal of informed consent for donated biological samples
If a subject withdraws consent to the use of donated samples, the samples will be disposed 
of/destroyed, and the action documented.  
The Principal Investigator:

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/destroyed, the action documented 
and the signed document returned to the study site

Ensures that the subject is informed about the sample disposal.

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9.
DISEASE EVALUATION AND METHODS
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following (Wolchok et al 2009, Nishino et al 2013):

Response to immunotherapy may be delayed

Response to immunotherapy may occur after PD by conventional criteria

The appearance of new lesions may not represent PD with immunotherapy

SD while on immunotherapy may be durable and represent clinical benefit.
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of anti-
cancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating anti-
cancer compounds, the study may wish to implement the following in addition to standard 
RECIST 1.1 criteria:

RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the absence 
of clinically significant deterioration.  Treatment with durvalumab (MEDI4736), 
tremelimumab, and azacitidine or oral decitabine (ASTX727) would continue between 
the initial assessment of progression and confirmation for progression. 

In addition, subjects may continue to receive durvalumab (MEDI4736), tremelimumab, 
and azacitidine or oral decitabine (ASTX727) beyond confirmed PD in the absence of 
clinically significant deterioration and if investigators consider that subjects continue to 
receive benefit from treatment. 
Modification of RECIST as described may discourage the early discontinuation of durvalumab 
(MEDI4736), tremelimumab, and azacitidine or oral decitabine (ASTX727) and provide a more 
complete evaluation of its anti-tumor activity than would be seen with conventional response 
criteria.  Nonetheless, the efficacy analysis will be conducted by programmatically deriving 
each efficacy endpoint based on RECIST 1.1 criteria.
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anti-cancer therapy other than durvalumab (MEDI4736) + 
tremelimumab or with symptomatic progression that requires urgent medical intervention (e.g., 
central nervous system metastasis, respiratory failure due to tumor compression, spinal cord 
compression).

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9.1.1
Response Assessments
Response assessments (tumor evaluations) should be performed at screening within 28 days 
before the start of IP, and every 8 weeks (± 7 days) from Cycle 1 Day 1 until disease progression, 
start of a new anticancer therapy, or withdrawal of consent from the entire study. Subjects with 
historical tumor scans evaluable per RECIST v1.1 performed ≤ 28 days before the first dose 
need not repeat scans for the purposes of screening. Evaluation of response should be performed 
using the modified RECIST guidelines, as described above and by Investigator assessment. 
Response will be assessed using RECIST v1.1, according to Investigator assessment. Response 
assessments include computed tomography (CT) scan or magnetic resonance imaging (MRI) of 
the neck with supraclavicular node imaging, the chest and abdomen/pelvis, neurological 
examination with facial nerve evaluation, and bone scans at baseline for all subjects. Bone scans 
will be repeated only if the subject is symptomatic or with known bone metastasis, per standard 
of care. 
The same mode of imaging for lesion evaluation at screening must be used consistently 
throughout the study. Adherence to the planned imaging schedule is critical regardless of dose 
delays or unscheduled or missed assessments. 
The CT imaging should include contrast unless medically contraindicated. Conventional CT 
should be performed with contiguous cuts of 5 mm or less in slice thickness. Spiral CT should 
be performed by use of a 5 mm contiguous reconstruction algorithm. 
All subjects with evidence of objective tumor response (CR or PR) should have the response 
confirmed with repeat assessments at the next scheduled scan, but after no less than 4 weeks. 
Response assessments must have occurred ≥ 6 weeks from Cycle 1 Day 1 to be considered as 
SD for a best response. 
Subjects who have disease control following completion of 12 months of treatment or subjects 
who are withdrawn from durvalumab (MEDI4736), tremelimumab, and azacitidine or oral 
decitabine (ASTX727) treatment for reasons other than confirmed PD will continue to have 
objective tumor assessments (see Appendix 3).  
10.
ASSESSMENT OF SAFETY
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section.

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10.1.1
Safety Parameters
10.1.1.1
Definition of adverse events
The International Conference on Harmonization (ICH) Guideline for Good Clinical Practice 
(GCP) E6 (R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
an action or intervention by the investigator, or a finding judged by the investigator to represent 
a change beyond the range of normal physiologic fluctuation, should be reported as an AE.
Adverse events may be treatment emergent (ie, occurring after initial receipt of investigational 
product) or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, 
disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition, that did not 
worsen from baseline, is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
The term AE is used to include both serious and non-serious AEs.
10.1.2
Definition of serious adverse events
A serious adverse event is an AE occurring during any study phase (i.e., screening, run-in, 
treatment, wash-out, follow-up), at any dose of the study drugs that fulfils one or more of the 
following criteria:
Results in death
Is immediately life-threatening
Requires in-patient hospitalization or prolongation of existing hospitalization 

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Results in persistent or significant disability or incapacity 
Is a congenital abnormality or birth defect in offspring of the subject
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above: 

Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse.
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca.
10.1.3
Durvalumab (MEDI4736) + tremelimumab 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 non-serious. 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.
AESIs for durvalumab (MEDI4736) and tremelimumab 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 (MEDI4736) monotherapy and combination therapy. An immune-related adverse 
event (irAE) 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 irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin, or other etiologic causes of the irAE. 
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician.
AESIs observed with durvalumab (MEDI4736) and tremelimumab include:
Diarrhea / Colitis and intestinal perforation

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Pneumonitis / ILD
Hepatitis / transaminase increases
Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypothyroidism and type I diabetes mellitus)
Rash / Dermatitis
Nephritis / Blood creatinine increases
Pancreatitis  / serum lipase and amylase increases  
Myocarditis
Myositis / Polymyositis
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis)
Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis 
and other events involving the eye,skin, haematological and rheumatological events, 
vasculitis, non-infectious meningitis and non-infectious encephalitis.
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab (MEDI4736) and tremelimumab Investigator Brochures. More 
specific guidelines for their evaluation and treatment are described in detail in Table 1.   
10.1.4
Immune-related adverse events
Based on the mechanism of action of durvalumab (MEDI4736) and tremelimumab leading to 
T-cell activation and proliferation, there is a possibility of observing irAEs during the conduct 
of this study.  Potential irAEs may be similar to those seen with the use of ipilimumab, BMS-
936558 (anti-PD-1 mAb), and BMS-936559 (anti-PD-L1 mAb) and may include immune-
mediated enterocolitis, dermatitis, hepatitis (hepatotoxicity), pneumonitis, and endocrinopathies 
(Hodi et al 2010, Braakhuis et al, 1998
Braakhuis, B. J., van Dongen, G. A., van Walsum, M., Leyva, A., and Snow, G. B. Preclinical 
antitumor activity of 5-aza-2'-deoxycytidine against human and neck cancer xenografts 
[corrected]. Invest New Drugs, 6: 299-304, 1988.

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Brahmer et al 2012, Topalian et al 2012).  These AEs are inflammatory in nature and can affect 
any organ.  With anti-PD-L1 and anti-CTLA-4 combination therapy, the occurrence of 
overlapping or increasing cumulative toxicities that include irAEs could potentially occur at 
higher frequencies than with either durvalumab (MEDI4736) or tremelimumab monotherapy.  
Patients should be monitored for signs and symptoms of irAEs.  In the absence of an alternate 
etiology (eg, infection or PD), an immune-related etiology should be considered for signs or 
symptoms of enterocolitis, dermatitis, pneumonitis, hepatitis, and endocrinopathy.  In addition 
to the dose modification guidelines provided in Table 3, it is recommended that irAEs are 
managed according to the general treatment guidelines outlined for ipilimumab (Weber et al 
2012).  These guidelines recommend the following:

Patients should be evaluated to identify any alternative etiology.

In the absence of a clear alternative etiology, all events of an inflammatory nature should 
be considered immune related.

Symptomatic and topical therapy should be considered for low-grade events.

Systemic corticosteroids should be considered for a persistent low-grade event or for a 
severe event.

More potent immunosuppressives should be considered for events not responding to 
systemic steroids (eg, infliximab or mycophenolate).

If the Investigator has any questions in regards to an AE being an irAE, the Investigator 
should immediately contact the Study Physician. 

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10.2
Assessment of safety parameters
10.2.1
Assessment of severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of
AEs and SAEs. Severity will be graded according to the NCI CTCAE v4.03.
The determination of severity for all other events not listed in the CTCAE should be made by
the investigator based upon medical judgment and the severity categories of Grade 1 to 5 as
defined below.
Grade 1 (mild) 
An event that is usually transient and may require only minimal
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Grade 2 (moderate) 
An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the subject.
Grade 3 (severe) 
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical 
status of the subject.
Grade 4 (life threatening) An event, and/or its immediate sequelae, that is associated with
an imminent risk of death or with physical or mental disabilities that affect 
or limit the ability of the subject to perform activities of daily living (eating, 
ambulation, toileting, etc).
Grade 5 (fatal) 
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 9.2.1. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE. Seriousness, not severity, serves as a guide for defining regulatory 
obligations.

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10.2.2
Assessment of relationship
The Investigator must determine the relationship between the administration of investigational 
product and the occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected: Means a causal relationship of the adverse event to investigational product 
administration is unlikely or remote, or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event.
Suspected: Means there is a reasonable possibility that the administration of investigational 
product caused the adverse event. ‘Reasonable possibility’ means there is evidence to suggest a 
causal relationship between the investigational product 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 an investigational product, the name of the 
manufacturer (Astrazeneca/MedImmune or ASTX Pharmaceuticals) will be included when 
reporting the event.
10.3
Recording of adverse events and serious adverse events
Adverse events will be recorded in electronic CRFs using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for severity, 
relationship to the investigational product, possible etiologies, and whether the event meets criteria 
of an SAE and therefore requires immediate notification to AstraZeneca/MedImmune and ASTX 
Pharmaceuticals Patient Safety. 
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

Changes in NCI CTCAE grade and the maximum CTC grade attained

Whether the AE is serious or not

Investigator causality rating against durvalumab (MEDI4736) or tremelimumab (yes or no) 
or oral decitabine (ASTX727) (yes or no)

Action taken with regard to durvalumab (MEDI4736) + tremelimumab combination or 
azacitidine or oral decitabine (ASTX727) agent

Outcome

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In addition, the following variables will be collected for SAEs as applicable:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to <<criteria>>

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Description of AE

Causality assessment in relation to Study procedure(s)

Causality assessment in relation to durvalumab (MEDI4736), tremelimumab, or azacitidine 
or oral decitabine (ASTX727)
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study.
10.3.1
Study recording period and follow-up for adverse events and serious adverse 
events
Adverse events and serious adverse events will be recorded from time of signature of informed 
consent, throughout the treatment period and including the follow-up period (90 days after the last 
dose of durvalumab (MEDI4736) + tremelimumab and 28 days after the last dose of azacitidine or 
oral decitabine (ASTX727)).
During the course of the study all AEs and SAEs should be proactively followed up for each 
subject. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion.
If a subject discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until the 
patient is considered to have confirmed PD and will have no further tumor assessments.
The investigator is responsible for following all SAEs until resolution, until the subject returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain chronic, 
even if this extends beyond study participation.

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Follow-up of unresolved adverse events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF.  After 
90 days, only subjects with ongoing investigational product-related SAEs will continue to be 
followed for safety.
AstraZeneca/MedImmune retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Post study events
After the subject has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AE or SAEs occurring in former study subjects 
after the 90-day safety follow-up period for patients treated with azacitidine or oral decitabine 
(ASTX727), durvalumab (MEDI4736) + tremelimumab.  However, if an investigator learns of any 
SAEs, including death, at any time after the subject has been permanently withdrawn from study, 
and he/she considers there is a reasonable possibility that the event is related to study treatment, 
the investigator should notify the study sponsor, and AstraZeneca/MedImmune Drug Safety.
10.3.2
Reporting of serious adverse events
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period immediately 
following the time that study drug is administered through 90 days after the last dose of 
durvalumab (MEDI4736) + tremelimumab, 28 days after the last dose of azacitidine or oral 
decitabine (ASTX727), or until the initiation of alternative anticancer therapy.  The investigator 
and/or Sponsor are responsible for informing the Ethics Committee and/or the Regulatory 
Authority of the SAE as per local requirements.
The investigator and/or sponsor must inform the FDA, via a MedWatch/AdEERs form, of any 
serious or unexpected adverse events that occur in accordance with the reporting obligations of 21 
CFR 312.32, and will concurrently forward all such reports to AstraZeneca and ASTX 
Pharmaceuticals.  A copy of the MedWatch/AdEERs report must be faxed to AstraZeneca and 
ASTX  Pharmaceuticals at the time the event is reported to the FDA.  It is the responsibility of the 
sponsor to compile all necessary information and ensure that the FDA receives a report according 
to the FDA reporting requirement timelines and to ensure that these reports are also submitted to 
AstraZeneca and ASTX Pharmaceuticals at the same time.
* A cover page should accompany the MedWatch/AdEERs form indicating the following:

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
“Notification from an Investigator Sponsored Study”

The investigator IND number assigned by the FDA

The investigator’s name and address

The trial name/title and AstraZeneca ISS reference number (ESR-15-11430)
* Sponsor must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined 
by the principal investigator.
* Send SAE report and accompanying cover page by way of email to AstraZeneca’s designated 
mailbox:   AEMailboxClinicalTrialTCS@astrazeneca.com
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA.
Serious adverse events that do not require expedited reporting to the FDA still need to be reported 
to AstraZeneca preferably using the MedDRA coding language for serious adverse events.  This 
information should be reported on a monthly basis and under no circumstance less frequently than 
quarterly. 
10.3.2.1
Reporting of deaths
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
durvalumab (MEDI4736) + tremelimumab safety follow-up period must be reported as follows:

Death that is clearly the result of disease progression should be documented but should not 
be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the AE 
causing the death must be reported to as a SAE within 24 hours (see Section 10.3.2 for 
further details).  The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and contributory causes of 
death.  

Deaths with an unknown cause should always be reported as a SAE.  
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab 
(MEDI4736) and tremelimumab or 28 days post-last-dose of azacitidine or oral decitabine 

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(ASTX727) safety follow-up period will be documented as events for survival analysis, but will 
not be reported as an SAE.
10.3.3
Other events requiring reporting
10.3.3.1
Overdose
An overdose is defined as a subject receiving a dose of durvalumab (MEDI4736), tremelimumab, 
or azacitidine or oral decitabine (ASTX727) in excess of that specified in the Investigator’s 
Brochure, unless otherwise specified in this protocol.
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of durvalumab (MEDI4736), tremelimumab, or azacitidine or oral decitabine (ASTX727) 
assigned to a given patient, regardless of any associated adverse events or sequelae.
PO
any amount over the protocol-specified dose
IV
10% over the protocol-specified dose 
SC
10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.  
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified rate.  
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.   
Any overdose of a study subject with durvalumab (MEDI4736), tremelimumab, or azacitidine or 
oral decitabine (ASTX727), with or without associated AEs/SAEs, is required to be reported 
within 24 hours of knowledge of the event to the sponsor, AstraZeneca/MedImmune Patient 
Safety, or designee using the designated Safety e-mailbox (see Section 10.3.2 for contact 
information). If the overdose results in an AE, the AE must also be recorded as an AE (see Section 
10.3). Overdose does not automatically make an AE serious, but if the consequences of the 
overdose are serious, for example death or hospitalization, the event is serious and must be 
recorded and reported as an SAE (see Section 10.3 and Section 10.3.2). There is currently no 
specific treatment in the event of an overdose of durvalumab (MEDI4736), tremelimumab, or 
azacitidine or oral decitabine (ASTX727). 
The investigator will use clinical judgment to treat any overdose.

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10.3.3.2
Hepatic function abnormality
Hepatic function abnormality (as defined in Section 10.1.3.) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” within 
24 hours of knowledge of the event to the sponsor and AstraZeneca/MedImmune Patient Safety 
using the designated Safety e-mailbox (see Section 10.3.2 for contact information), unless a 
definitive underlying diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) 
that is unrelated to investigational product has been confirmed.

If the definitive underlying diagnosis for the abnormality has been established and is unrelated to 
investigational product, the decision to continue dosing of the study subject will be based on the 
clinical judgment of the investigator.

If no definitive underlying diagnosis for the abnormality is established, dosing of the study subject 
must be interrupted immediately. Follow-up investigations and inquiries must be initiated by the 
investigational site without delay.
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune. 
10.3.3.3
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject or partner of a 
male subject are immediately reportable events. 
10.3.3.3.1 Maternal exposure
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of reproductive potential, regardless of disease state) occurring while the subject is 
on IP, or within 90 days of the subject’s last dose of IP, are considered immediately reportable 
events. The IPs should be discontinued immediately.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately, but no 
later than 24 hours of when he or she becomes aware of it using the Pregnancy Initial Report 
Form, or approved equivalent form.  The female subject should be referred to an obstetrician-
gynecologist, or another appropriate healthcare professional for further evaluation.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication.  The Investigator will follow 
the female subject until completion of the pregnancy outcome and up to 1 year to monitor the baby, 

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and must notify AstraZeneca Patient Safety within 1 to 5 calendar days for SAEs and within 30 
days for all other pregnancies about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form and Infant Follow-Up Form, or approved 
equivalent form.  
Congenital abnormalities or birth defects, stillbirth, neonatal death, spontaneous or therapeutic 
abortion or miscarriage should be reported and handled as SAEs using the SAE Report Form, or 
approved equivalent form.  In addition, any infant death after 28 days that the Investigator suspects 
is related to the in utero exposure to the IP should also be reported to Astrazeneca Patient Safety 
immediately 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. Elective 
abortions without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) should be followed up and documented even if the patient was discontinued from the 
study.  
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs and within 30 days for all other pregnancies.  
10.3.3.3.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of study drug.  
Pregnancy of the patient’s partner is not considered to be an AE.  However, if a female partner of 
a male subject taking investigational product becomes pregnant, the male subject taking IP should 
notify the Investigator immediately, and the pregnant female partner should be advised to call their 
healthcare provider immediately. In addition, the outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) 
occurring from the date of the first dose until 90 days after the last dose should, if possible, be 
followed up and documented.  
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner.  Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the relevant 
Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.

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Drug Substance Azacitidine/Decitabine (ASTX727) 
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Edition Number 13.0
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11
STATISTICAL 
METHODS 
AND 
SAMPLE 
SIZE 
DETERMINATION
Rational for Changes from SC Injection to Oral Drug
This trial opened with use of subcutaneous (SC) injection of azacitidine. Treatment, ie, 5 to 10 daily 
visits for a large-volume subcutaneous injection continuing for several months or even years, 
represents a significant hardship for patients. A possible consequence is non-compliance or earlier 
discontinuation of a beneficial treatment. Successful development of an oral DNA methyltransferase 
inhibitor will ease the burden of long-duration SC therapy, particularly for those patients who are 
benefitting the most and need continuing treatment for long periods. 
The primary objective and design and number of doses to be tested with oral decitabine remain the 
same as in the original protocol which used SC injection of azacitidine. The overall sample size has 
been revised to account for accrual of patients who receive oral decitabine in addition to the patients 
accrued when the original protocol opened using SC injection of azacitidine.
The primary objective of the phase I trial is to determine the BED. The BED is to be determined 
among evaluable patients (eligible patients who at least begin protocol treatment and have an 
evaluable pre- and on-treatment (8-week) biopsy sample available). Three doses of oral decitabine 
(ASTX727) are scheduled to be tested. BED is defined as the dose of oral decitabine (ASTX727) 
that results in at least a 10% decrease in LINE-1 methylation from the baseline biopsy to the 8-
week on-treatment tumor biopsy in at least 50% of patients treated within the same dose level. If 
the BED has not been determined in the first 2 dose levels and it is safe to do so, then the study 
will re-open to accrual and a subsequent group of 3 patients will receive the 3rd dose level. IF both 
the first 2 dose levels result in > 10% decrease in LINE-1 methylation, then the dose which induces 
the greatest fold change in HLA Class I/II APM expression and/or CD8+ T cell infiltration and 
with the lower adverse event profile will be the dose utilized for the dose expansion cohort.  The 
change  is a working rule and a panel of markers will be assessed and the dose with the most viable 
panel and lowest adverse event profile will be used in the expansion cohort.
Although assessment of the BED is primary, the dose also needs to be safe. Each dose will also be 
assessed for safety. Six patients will be entered into dose level 1. Adverse events (i.e. dose limiting 
toxicity (DLT) assessment as defined in section 6.4) will be assessed through 28 days post cycle 
2.  If two or more of the first six subjects experience a DLT, then the dose will be reduced and an 
additional six patients will be treated at the reduced dose. If two or more of the six at the reduced 
dose experience a DLT, then the study will be terminated. If at any time during accrual to a dose 
cohort, 2 or more patients in a dose cohort experience DLT, enrollment to that dose cohort will be 
terminated. If less than two of the six patients treated at dose level 1 experience a DLT, a 
subsequent group of six patients will receive dose level 2. 

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Accrual will be suspended until review of the BED rate in tissue from baseline and 8 weeks post 
baseline has been completed from patients entered into the first 2 dose levels. If the BED has not 
been determined in the first 2 dose levels and it is safe to do so, then the study will re-open to 
accrual and a subsequent group of 6 patients will receive the 3rd dose level. Once the BED is 
determined, dose escalation will stop and the BED will be used in the expansion cohort. 
Approximately 28  evaluable patients (eligible patients who at least begin protocol treatment and 
have an evaluable pre- and on-treatment (8-week) biopsy sample available) are estimated to be 
accrued during the BED assessment phase with the oral decitabine. This is based on studying 6 
evaluable patients per dose level with a total of 3 dose levelsand an additional 10 evaluable patients  
entered at the BED (‘expansion cohort’ accrued to ensure that the BED rate is acceptable). The 
further assessment of the BED will be based on studying these 10 additional patients. Additional 
subjects may be enrolled into the cohort(s) to ensure that the required number of evaluable pre- 
and on-treatment biopsy samples are available to adequately determine the BED. See end of this 
statistical section for overall sample size.
BED is defined as outlined above. Six evaluable patients are estimated to be accrued per dose level 
with the additional 10 evaluable patients in the expansion cohort. The below table gives the 
probabilities of observing at least 33% of patients within a dose level with the BED for the first 6 
patients for varying true rates of the BED.
True BED rate
Probability of ≥2 out of 
6 patients in a dose 
level meet BED 
definition.
Probability of ≥7 out of 16 meet BED definition 
(given that ≥2 out of 6 patients in the dose 
level from original testing meet the BED 
definition plus the expansion cohort)
50%
.89
.73
55%
.93
.84
60%
.96
.92
For example, if the true rate of BED is 50%, the probability of observing ≥2 out of 6 patients in a 
dose level with the BED is 89%. The above table also shows the probabilities of successfully 
declaring the BED after cohort expansion (the additional 10 patients to a dose level) (last column). 
With 6 patients entered in a dose level and 10 in the expansion cohort (with cutpoints as in the 
above table), if the true BED rate were instead as low as 27%, the probability of a dose level being 
used as the BED in the phase II portion of this trial is only 10%.
With an estimated monthly accrual of 2 patients, accrual with use of the oral agent is estimated to 
complete in approximately 9 months. As of October 1, 2019, n=11 patients have been registered 

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to receive SC injection of azacitidine. Accrual for patients to receive SC injection of azacitidine 
continues during review and approval of this amendment to change to administration of oral 
decitabine. With approximately 2-3 more patients enrolled to receive SC injection of azacitidine 
during amendment review, a total of up to N=41 (13 SC injection of azacitidine + up to 28 oral 
decitabine) patients could be entered.
12
ETHICAL AND REGULATORY REQUIREMENTS
12.1 Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements Subject data protection.
12.2 Ethics and regulatory review
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed and approved by a properly constituted IRB governing 
each study location.
All decisions of the IRB concerning the conduct of the study must be made in writing.
12.3
Informed consent
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. The 
participant must be given a copy of the signed and dated consent document. The original 
signed copy of the consent document must be retained in the medical record or research file. 
12.4
Changes to the protocol and informed consent form
Any changes made to the protocol and informed consent form must be submitted as amendments 
and must be approved by the IRB prior to implementation. Any changes in study conduct must 
be reported to the IRB. The Principal Investigator (or Protocol Chair) will disseminate protocol 
amendment information to all participating investigators.

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12.5
Audits and inspections
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the Principal 
Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed, and accurately reported in accordance with the 
protocol, institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements. 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue during 
protocol performance and completion. 
13
STUDY MANAGEMENT
a.
Data Reporting 
i.
Method 
The QACT will collect, manage, and monitor data for this study. 
13.1.2 Data Submission 
The schedule for completion and submission of case report forms (electronic) to the ODQ (Office 
of Data Quality) is as follows:
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration with ODQ
On Study Form
Within 14 days of registration

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Baseline Assessment Form
Within 14 days of registration
Treatment Form
Within 10 days of the last day of the cycle
Adverse Event Report Form
Within 10 days of the last day of the cycle
Response Assessment Form
Within 10 days of the completion of the 
cycle required for response evaluation
Off Treatment/Off Study 
Form
Within 14 days of completing treatment or 
being taken off study for any reason
Follow up/Survival Form
Within 14 days of the protocol defined 
follow up visit date or call
b.
Safety Meetings
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this trial. The committee is composed of clinical specialists with experience in 
oncology and who have no direct relationship with the study. Information that raises any questions 
about participant safety will be addressed with the Principal Investigator and study team.
The DSMC will meet approximately quarterly and/or more often if required to review toxicity and 
accrual data. Information to be provided to the committee may include:  up-to-date participant 
accrual; current dose level information; all grade 2 or higher unexpected adverse events that have 
been reported; summary of all deaths occurring within 30 days for Phase I or II protocols; summary 
of all deaths while being treated and during active follow-up; any response information; audit results, 
and a summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 

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c.
Monitoring of the study
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the Principal 
Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed, and accurately reported in accordance with the 
protocol, institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements. 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue 
during protocol performance and completion. 
14. DATA MANAGEMENT
The investigator must prepare and maintain adequate and accurate case histories designed to record 
all observations and other data pertinent to the study for each research participant. This information 
enables the study to be fully documented and the study data to be subsequently verified.
Original source documents supporting entries in the electronic-based case report forms include but 
are not limited to hospital records, clinical charts, laboratory and pharmacy records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x rays.
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. 
For the purposes of data analysis associated with the publication of the final manuscript and 
requirements from the journal review of the manuscript, the Investigator/Study PI will be able 
to extract data from the EPIC medical records of participants to supplement the information 
available in Inform. The extracted information will include details about HPV status, therapies 
received after the completion of treatment or following progression; details regarding prior 
chemotherapy and radiation treatments for R/M disease; primary therapies and duration of 
therapies for the patient’s disease prior to development of R/M. In addition, the 
Investigator/Study PI will access Hematology labs within EPIC to determine what peripheral 
blood analysis was performed.

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a.
Study governance and oversight
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives, respectively, in consultation with Patient Safety.  Issues identified 
will be addressed; for instance, this could involve amendments to the study protocol and letters to 
Investigators.
15.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
a.
Identity of investigational product(s)
Table 44. List of investigational products for this study
Investigational product
Dosage form and strength
Manufacturer
Durvalumab (MEDI4736)
1500 mg, solution, IV
MedImmune
Tremelimumab
75 mg, solution, IV
MedImmune
Tremelimumab
300 mg, solution, IV
MedImmune
Azacitidine
40 mg/m2 or 
75-mg/m2, suspension, SC 
Celgene
Decitabine
35 
mg 
decitabine/100 
mg 
cedrizine, PO
ASTX Pharmaceuticals
16.
LIST OF REFERENCES
ASHSP 2006
American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous 
Drugs 2006.
Andorsky et al 2011
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Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
125 (167)
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Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
126 (167)
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Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
127 (167)
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Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
128 (167)
Appendix 1: Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-
Related, and Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With 
Tremelimumab or Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v4.03)
General Considerations regarding Immune-Mediated Reactions
Dose Modifications
Toxicity Management
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03 (unless indicated otherwise).
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/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 of the start of the immune-mediated 
adverse event (imAE)

Grade 3 recurrence of a previously experienced treatment-related imAE 
following resumption of dosing
Grade 1
No dose modification
Grade 2
Hold study drug/study regimen dose until Grade 2 resolution to 
Grade ≤1.
If toxicity worsens, then treat as Grade 3 or Grade 4.
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper.
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions:
1.
The event stabilizes and is controlled.
2.
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement.
3.
Doses of prednisone are at ≤10 mg/day or equivalent.
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, patients 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., 
myocarditis, 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 for specific type of 
immunosuppressive) should be considered for events not responding to 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
129 (167)
Appendix 1: Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-
Related, and Non-Immune–Mediated Reactions (MEDI4736 Monotherapy or Combination Therapy With 
Tremelimumab or Tremelimumab Monotherapy) 17 October 2019 Version (CTCAE v4.03)
General Considerations regarding Immune-Mediated Reactions
Dose Modifications
Toxicity Management
Grade 3
Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines below.
Grade 4
Permanently discontinue study drug/study regimen.
Note: For asymptomatic amylase or lipase levels of >2.0×ULN, hold study 
drug/study regimen, and if complete work up shows no evidence of pancreatitis, 
study drug/study regimen may be continued or resumed.
Note: Study drug/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 study drug/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 study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus). 
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 study drug/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 study drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient.
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.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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Pediatric Considerations regarding Immune-Mediated Reactions
Dose Modifications
Toxicity Management
The criteria for permanent discontinuation of study drug/study regimen based on 
CTC grade/severity is the same for pediatric patients as it is for adult patients, as 
well as to permanently discontinue study drug/study regimen if unable to reduce 
corticosteroid ≤ a dose equivalent to that required for corticosteroid replacement 
therapy within 12 weeks of the start of the immune-mediated event
−
All recommendations for specialist consultation should occur with a 
pediatric specialist in the specialty recommended.
−
The recommendations for dosing of steroids (i.e., mg/kg/day) and for IV IG 
and plasmapheresis that are provided for adult patients should also be used 
for pediatric patients.
−
The infliximab 5 mg/kg IV dose recommended for adults is the same as 
recommended for pediatric patients ≥ 6 years old.  For dosing in children 
younger than 6 years old, consult with a pediatric specialist.
−
For pediatric dosing of mycophenolate mofetil, consult with a pediatric 
specialist.
−
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
131 (167)
Specific Immune-Mediated Reactions
Adverse Events
Severity Grade of the 
Event (NCI CTCAE 
version 4.03)
Dose Modifications
Toxicity Management
Any Grade
General Guidance
For Any Grade:
−
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients 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 study drug/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 consults.
Pneumonitis/Interstitial 
Lung Disease (ILD)
Grade 2
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL)
Hold study drug/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 study 
drug/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 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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TMGs, Version 17 October 2019, CTCAE v4.03
132 (167)
general guidance before using infliximab.
−
Once the patient 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)a
−
Consider Pulmonary and Infectious Disease consults.
−
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 study drug/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 consults; consider, as 
necessary, discussing with study physician.
−
Hospitalize the patient.
−
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 the patient 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).a
Diarrhea/Colitis
Large intestine 
perforation/Intestine 
perforation
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).
−
When symptoms or evaluation indicate a perforation is 
suspected, consult a surgeon experienced in abdominal surgery 
immediately without any delay.
−
Patients should be thoroughly evaluated to rule out any 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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TMGs, Version 17 October 2019, CTCAE v4.03
133 (167)
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, including 
perforation.
−
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)
(Perforation: 
symptomatic; medical 
intervention indicated*)
Hold study drug/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 study drug/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 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.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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TMGs, Version 17 October 2019, CTCAE v4.03
134 (167)
* “medical 
intervention” is not 
invasive
−
Consider, as necessary, discussing with study physician if no 
resolution to Grade ≤1 in 3 to 4 days.
−
Once the patient 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).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 Perforation: 
severe symptoms, 
elective* operative 
intervention indicated; 
Grade 4 Perforation: 
life-threatening 
consequences, urgent 
intervention indicated)
Grade 3
Permanently discontinue study drug/study 
regimen for Grade 3 if toxicity does not 
improve to Grade ≤1 within 14 days; 
study drug/study regimen can be resumed 
after completion of steroid taper.
Grade 4
Permanently discontinue 
study drug/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. If perforation is suspected, 
consult a surgeon experienced in abdominal surgery 
immediately without any delay.
−
Once the patient 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).a

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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TMGs, Version 17 October 2019, CTCAE v4.03
135 (167)
*This guidance 
anticipates that Grade 3 
operative interventions  
of perforations are 
usually not elective
Any Elevations in 
AST, ALT or TB  as 
Described Below
General Guidance
For Any Elevations Described:
−
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB.
−
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications).
 AST or ALT >ULN 
and ≤3.0×ULN if 
baseline normal, 1.5-
3.0×baseline if 
baseline abnormal; 
and/or TB > ULN and  
≤1.5×ULN  if baseline 
normal, >1.0-
1.5×baseline if 
baseline abnormal

No dose modifications.

If it worsens, then treat as described 
for elevations in  the row below.
−
Continue LFT monitoring per protocol.
Hepatitis 
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-related hepatitis.
AST or 
ALT >3.0×ULN and 
≤5.0×ULN if baseline 
normal, >3-5×baseline 
if baseline abnormal; 
and/or 
TB >1.5×ULN and  
≤3.0×ULN if baseline 

Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal.

If toxicity worsens, then treat as  
described for elevation in the row 
below.

If toxicity improves to AST or ALT 
−
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 AST or ALT ≤3.0×ULN and/or TB 
≤1.5×ULN if baseline normal, or to AST or ALT ≤3.0×baseline 
and/or TB ≤1.5×baseline if baseline abnormal, 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 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
136 (167)
normal, >1.5- 
3.0×baseline if 
baseline abnormal
≤3.0×ULN and/or TB ≤1.5×ULN if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal, 
resume study drug/study regimen 
after completion of steroid taper.
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 patient 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).a
AST or 
ALT >5.0×ULN if 
baseline normal, 
>5×baseline if baseline 
abnormal; and/or 
TB >3.0×ULN if 
baseline normal; 
>3.0×baseline if 
baseline abnormal
For elevations in transaminases ≤8×ULN 
and/or in TB ≤5×ULN if baseline normal, 
or for elevations in transaminases 
≤8×baseline and/or TB ≤5×baseline if 
baseline abnormal:

Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN  if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal

Resume study drug/study regimen if 
elevations downgrade to AST or ALT 
≤3.0×ULN and/or TB ≤1.5×ULN  if 
baseline normal, or to AST or ALT 
≤3.0×baseline and/or TB 
≤1.5×baseline if baseline abnormal, 
within 14 days and after completion 
of steroid taper.

Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade as described in 
bullet above within 14 days
For elevations in transaminases >8×ULN 
or elevations in TB >5×ULN if baseline 
normal, or for elevations in transaminases 
−
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.
−
Request Hepatology consult, and perform abdominal workup 
and imaging as appropriate.
−
Once the patient 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).a

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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TMGs, Version 17 October 2019, CTCAE v4.03
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>8×baseline and/or TB >5×baseline if 
baseline abnormal, permanently 
discontinue study drug/study regimen.
Permanently discontinue study drug/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
Any Elevations in 
AST, ALT or TB as 
Described Below
General Guidance
For Any Elevations Described:
−
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+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg
−
For HCV+ patients: evaluate quantitative HCV viral load
−
Consider consulting hepatologist/Infectious Disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient 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
Hepatitis 
(elevated LFTs)
Infliximab should not be 
used for management of 
immune-related 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 
Isolated AST or ALT 
>ULN and ≤5.0×ULN, 

No dose modifications.

If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as  
described for elevations in the row 
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
138 (167)
DILI/liver 
decompensation
whether normal or 
elevated at baseline 
below.
For all transaminase elevations, 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
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 study drug/study regimen dose 
untilresolution to AST or ALT 
≤5.0×ULN.

If toxicity worsens, then treat as  
described for elevations in the rows 
below.
If toxicity improves to AST or ALT 
≤5.0×ULN, resume study drug/study 
regimen after completion of steroid taper.
−
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.
Isolated AST or ALT 
>8.0×ULN and 

Hold study drug/study regimen dose 
until resolution to  AST or ALT 
≤5.0×ULN
−
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 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
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≤20.0×ULN, if normal 
at baseline
Isolated AST or ALT 
>12.5×ULN and 
≤20.0×ULN, if  
elevated >ULN at 
baseline

Resume study drug/study regimen if 
elevations downgrade to AST or ALT 
≤5.0×ULN within 14 days and after 
completion of steroid taper.

Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to AST or ALT 
≤5.0×ULN within 14 days
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria, in the absence of any alternative 
cause.b
liver perfusion; and consider 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 patient 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).a
Isolated AST or ALT 
>20×ULN,  whether 
normal or elevated at 
baseline
Permanently discontinue study drug/study 
regimen.
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  each level of transaminase rise as instructed for the next highest level of transaminase riseFor example, manage dosing for second level of 
transaminase rise (i.e.,  AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT >2.0×baseline and ≤12.5×ULN, if elevated >ULN at 
baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and ≤20.0×ULN, if normal at baseline, or AST or ALT 
>12.5×ULN and ≤20.0×ULN, if  elevated >ULN at baseline)
-
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
140 (167)
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).
−
Patients 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.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
141 (167)
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 study drug/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 study 
drug/study regimen after completion 
of steroid taper.
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 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 patient 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).a
−
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol.
Grade 3 or 4
(Grade 3: serum 
creatinine 
>3.0×baseline; >3.0 to 
Permanently discontinue study drug/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 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
142 (167)
6.0×ULN)
(Grade 4: serum 
creatinine >6.0×ULN)
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 patient 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).a
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 STUDY 
DRUG DISCONTINUED IF SUSPECT STEVENS-
JOHNSON SYNDROME OR TOXIC EPIDERMAL 
NECROLYSIS.
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).
Rash or Dermatitis
(including Pemphigoid)
Grade 2
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/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.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
143 (167)
−
Consider skin biopsy if the event is persistent for >1 to 2 weeks 
or recurs.
Grade 3 or 4
For Grade 3:
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study drug/study 
regimen.
For Grade 4:
Permanently discontinue study drug/study 
regimen.
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].
−
Consider skin biopsy (preferably more than 1) as clinically 
feasible.
−
Once the patient 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).a
−
Consider, as necessary, discussing with study physician.
Endocrinopathy
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
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 patients 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.
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections).

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
144 (167)
−
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 asymptomatic elevations in serum amylase and lipase 
>ULN and <3×ULN, corticosteroid treatment is not indicated 
as long as there are no other signs or symptoms of pancreatic 
inflammation.
−
If a patient 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 autoimmune antibody testing.
Grade 1
No dose modifications.
For Grade 1 (including those with asymptomatic TSH elevation):
−
Monitor patient 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.
amylase/lipase increased 
also included in this 
section)
Grade 2
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until patient is clinically stable.

If toxicity worsens, then treat as 
Grade 3 or Grade 4.
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper.
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 patients 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 study drug/study regimen interruption, and 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
145 (167)
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement.
3.
Doses of prednisone are ≤10 mg/day 
or equivalent.
without corticosteroids.
−
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids.
−
Once patients 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).a
−
For patients 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 study drug/study regimen 
dose until endocrinopathy symptom(s) are 
controlled. 
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper.
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions:
1.
The event stabilizes and is 
controlled.
2.
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement.
3.
Doses of prednisone are ≤10 mg/day 
or equivalent.
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 patients 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 study drug/study regimen interruption, and 
without corticosteroids.
−
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids.
−
Once patients 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 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
146 (167)
NCCN guidelines for treatment of cancer-related infections).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:
−
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes, or 
medications).
−
Monitor patient 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 Neurology consult as 
appropriate.
−

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
147 (167)
Grade 1
No dose modifications.
For Grade 1:
−
See “Any Grade” recommendations above.
Grade 2
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade ≤1.
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade ≤1.
If toxicity worsens, then treat as 
Grade 3 or 4.
Study drug/study regimen can be resumed 
once event improves to Grade ≤1 and 
after completion of steroid taper.
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 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 study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days.
For Grade 4:
Permanently discontinue study drug/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 
Any Grade
General Guidance
For Any Grade:
−
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations that can result 
in substantial morbidity or in the worst case, death. Special care 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
148 (167)
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.
−
Patients 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 patients with underlying cancer, due to the 
multiple potential confounding effects of cancer (and its 
treatments) throughout the neuraxis. Given the importance of 
prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a Neurology 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. Patients 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 patients for sentinel symptoms 
of a potential decompensation as described above.
−
Obtain a Neurology consult.
and myasthenia gravis)
Grade 2
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study drug/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 patients 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).

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat 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
Patients 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 patient.
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
Patients 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 study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study drug/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 instability.
For Grade 3 or 4 (severe or life-threatening events):
−
Consider, as necessary, discussing with study physician.
−
Recommend hospitalization.
−
Monitor symptoms and obtain Neurology consult.
MYASTHENIA GRAVIS:
o
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist.
o
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
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For Grade 4:
Permanently discontinue study drug/study 
regimen.
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
Patients 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 patients with baseline 
cardiopulmonary disease and reduced cardiac function. 
−
Consider, as necessary, discussing with the study physician.
−
Monitor patients 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.
−
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.
−
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections)
Grade 1
No dose modifications required unless 
For Grade 1 (no definitive findings):

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
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(asymptomatic with 
laboratory [e.g., BNP] 
or cardiac imaging 
abnormalities)
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0.
-
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.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
152 (167)
Grade 2, 3 or 4
(Grade 2: Symptoms 
with mild to moderate 
activity or exertion)
 (Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; 
intervention indicated)
(Grade 4: Life-
threatening 
consequences; urgent
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic support))
- If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate 
study drug/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 study drug/study regimen.
If Grade 3-4, permanently discontinue 
study drug/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 patient 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).a
Myositis/Polymyositis 
(“Poly/myositis”)
Any Grade
General Guidance
For Any Grade:
−
Monitor patients 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; 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
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refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD. 
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation.
−
Consider, as necessary, discussing with the study physician.
−
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, 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.
Patients 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 study drug/study regimen dose until 
resolution to Grade ≤1.
- Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency.
For Grade 2:
−
Monitor symptoms daily and consider hospitalization.
−
Obtain Neurology consult, and initiate evaluation.
−
Consider, as necessary, discussing with the study physician.
−
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 
IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
along with receiving input from Neurology consultant 
−
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
154 (167)
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD.
bFDA 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  
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 patient 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).a
Grade 3 or 4
(pain associated with 
severe weakness; 
limiting self-care 
ADLs)
For Grade 3:
Hold study drug/study regimen dose until 
resolution to Grade ≤1.
Permanently discontinue study drug/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 study 
drug/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 using infliximab.
−
Consider whether patient may require IV IG, plasmapheresis.
−
Once the patient 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).a

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
155 (167)
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.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
156 (167)
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 patients 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 study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event.
For Grade 2:
The infusion rate of study drug/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 study drug/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.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
157 (167)
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 study drug/study regimen until resolution to ≤Grade 1 or 
baseline.
Treat accordingly, as per institutional standard.
Grade 3
Hold study drug/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 study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen.
Treat accordingly, as per institutional standard.
Grade 4
Discontinue study drug/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.
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.”
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
158 (167)
Appendix 2
Schedule of study procedures: follow-up for subjects who have completed 
azacitidine or oral decitabine (ASTX727), durvalumab (MEDI4736) and tremelimumab 
combination treatment and achieved disease control (until confirmed progression of 
disease) and subjects who have discontinued azacitidine or oral decitabine 
(ASTX727), durvalumab (MEDI4736), or tremelimumab due to toxicity in the absence of 
confirmed progression of disease
Time Since Last Dose of Study Treatment
Day (±3)
Months (±1 week)
Evaluation
30
2
3
4
6
8
10
12 Months and Every 6 Months 
(±2 weeks)
Physical examinationa
X
Vital signs (temperature, respiratory rate, blood 
pressure, pulse)
X
Weight
X
Urine hCG or serum βhCG
X
AE/SAE assessment
X
X
X
Concomitant medications
X
X
X
Palliative radiotherapy
As clinically indicated 
ECOG performance status
X
X
X
X (and month 9)
X
Subsequent anti-cancer therapy
X
X
X
X
X
X
X
X
Survival status: phone contact with subjects who 
refuse to return for evaluations and agree to be 
contacted
X
X
X
X
X
X
X (every 2 months)
Hematology
X
X
X
X
Serum chemistry 
X
X
X

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
159 (167)
Appendix 2
Schedule of study procedures: follow-up for subjects who have completed 
azacitidine or oral decitabine (ASTX727), durvalumab (MEDI4736) and tremelimumab 
combination treatment and achieved disease control (until confirmed progression of 
disease) and subjects who have discontinued azacitidine or oral decitabine 
(ASTX727), durvalumab (MEDI4736), or tremelimumab due to toxicity in the absence of 
confirmed progression of disease
Time Since Last Dose of Study Treatment
Day (±3)
Months (±1 week)
Evaluation
30
2
3
4
6
8
10
12 Months and Every 6 Months 
(±2 weeks)
Thyroid function tests (TSH, and fT3 and fT4)b 
X
Tumor biopsy
X
Peripheral blood
X
Tumour assessment (CT or MRI)
For subjects who achieve disease control following 12 months of treatment, tumour assessments should be performed 
every 12 weeks relative to the date of first infusion thereafter until confirmed PD by RECIST 1.1 by investigational site 
review.  
For subjects who discontinue MEDI4736 due to toxicity (or symptomatic deterioration), tumour assessments should be 
performed relative to the relative to the date of first infusion as follows: every 8 weeks for the first 48 weeks (per Schedule 
of Assessments), then every 12 weeks until confirmed PD by RECIST 1.1 by investigational site review.  Please refer to 
Schedule of Assessments for timings of confirmatory scans.  
Upon confirmed PD, scans should be conducted according to local standard clinical practice and submitted for central 
review until a new treatment is started (these scans are optional).
a 
Full physical exam
b
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the endocrine 
system.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
160 (167)
Appendix 3
Schedule of study procedures: follow-up for subjects who have discontinue 
azacitidine or oral decitabine (ASTX727), durvalumab (MEDI4736), and tremelimumab 
combination treatment due to confirmed progression of disease at the investigator 
discretion
Time Since Last Dose of Study Treatment
Day (±3)
Months (± 30 days)
Evaluation
30
2
3
4
6
8
10
12 Months and Every 6 Months 
(± 30 days)
Physical examinationa
X
Vital signs (temperature, respiratory rate, blood pressure, pulse)
X
Weight
X
AE/SAE assessment
X
X
Concomitant medications
X
X
Palliative radiotherapy
As clinically indicated
ECOG performance statusb
X
X
Subsequent anti-cancer therapy
X
X
X
X
Survival status: phone contact with subjects who refuse to return for 
evaluations and agree to be contacted
X
X
X (every 3 months)
Urine hCG or serum βhCG
X
Hematology
X
X
Serum chemistry 
X
X
Thyroid function tests (TSH, and fT3 and fT4)c
X
Tumor Biopsy
X

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
161 (167)
Appendix 3
Schedule of study procedures: follow-up for subjects who have discontinue 
azacitidine or oral decitabine (ASTX727), durvalumab (MEDI4736), and tremelimumab 
combination treatment due to confirmed progression of disease at the investigator 
discretion
Time Since Last Dose of Study Treatment
Day (±3)
Months (± 30 days)
Evaluation
30
2
3
4
6
8
10
12 Months and Every 6 Months 
(± 30 days)
PBMCs
X
  Tumour assessment (CT or MRI)
For subjects who continue on MEDI4736 post-confirmed progression at the investigator’s 
discretion (following consultation with the sponsor), tumour assessments should be performed 
relative to the date of first infusionuntil MEDI4736 is stopped.
For subjects who discontinue MEDI4736 following confirmed progression, scans should be 
conducted according to local clinical practice and submitted for central review until a new 
treatment is started (these scans are optional).
a  
Full physical exam
b
PS to be collected if available at the 2 monthly calls to obtain subsequent anti-cancer therapy and survival status
c
Free T3 and free T4 will only be measured if TSH is abnormal. They should also be measured if there is clinical suspicion of an adverse event related to the endocrine 
system.

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
162 (167)
Appendix 4. Durvalumab (MEDI4736)  DOSE CALCULATIONS 
For durvalumab (MEDI4736) dosing done depending on subject weight:
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X (mg/kg) × Y (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = XY mg / 50 (mg/mL) 
where 50 mg/mL is durvalumab (MEDI4736)  nominal concentration.
The corresponding volume of durvalumab (MEDI4736) should be rounded to the nearest tenth mL (0.1 mL). Dose adjustments for 
each cycle are only needed for greater than 10% change in weight.
5. The theoretical number of vials required for dose preparation is the next greatest whole number of vials from the following formula:
Number of vials = Dose (mL) / 10.0 (mL/vial)
Example: 
1. Cohort dose: 10 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg)

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
163 (167)
4. Dose to be added into infusion bag: 
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL
5. The theoretical number of vials required for dose preparation: 
Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials
Appendix 5. Durvalumab (MEDI4736)  DOSE VOLUME CALCULATIONS
For durvalumab (MEDI4736)  flat dosing:
1. Cohort dose: X g
2. Dose to be added into infusion bag: 
Dose (mL) = X g × 1000 / 50 (mg/mL) 
where 50 mg/mL is durvalumab (MEDI4736) nominal concentration.
The corresponding volume of durvalumab (MEDI4736) should be rounded to the nearest tenth mL (0.1 mL). 
3. The theoretical number of vials required for dose preparation is the next greatest whole number of vials from the following formula:
Number of vials = Dose (mL) / 10.0 (mL/vial)
Example: 
1. Cohort dose: 1.5 g

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
164 (167)
2. Dose to be added into infusion bag: 
Dose (mL) = 1.5 g ×1000 / 50 (mg/mL) = 30.0 mL
3. The theoretical number of vials required for dose preparation: 
Number of vials = 30.0 (mL) / 10.0 (mL/vial) = 3 vials
Appendix 6. Tremelimumab DOSE CALCULATIONS 
For tremelimumab dosing done depending on subject weight:
1. Cohort dose: X mg/kg
2. Subject weight: Y kg
3. Dose for subject: XY mg = X (mg/kg) × Y (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = XY mg / 20 (mg/mL) 
where 20 mg/mL is tremelimumab nominal concentration.
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 mL). Dose adjustments for each cycle are 
only needed for greater than 10% change in weight.
5. The theoretical number of vials required for dose preparation is the next greatest whole number of vials from the following formula:
Number of vials = Dose (mL) / 20.0 (mL/vial)

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
165 (167)
Example: 
1. Cohort dose: 1 mg/kg
2. Subject weight: 30 kg
3. Dose for subject: 30 mg = 1 (mg/kg) × 30 (kg)
4. Dose to be added into infusion bag: 
Dose (mL) = 30 mg / 20 (mg/mL) = 1.5 mL
5. The theoretical number of vials required for dose preparation: 
Number of vials = 1.5 (mL) / 20.0 (mL/vial) = 1 vials
Appendix 7. Tremelimumab DOSE VOLUME CALCULATIONS 
For tremelimumab flat dosing:
1. Cohort dose: X mg
2. Dose to be added into infusion bag: 
Dose (mL) = X mg / 20 (mg/mL) 
where 20 mg/mL is tremelimumab nominal concentration 
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL (0.1 mL). 

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
166 (167)
3. The theoretical number of vials required for dose preparation is the next greatest whole number of vials from the following formula:
Number of vials = Dose (mL) / 20 (mL/vial)
Example: 
1. Cohort dose: 75 mg
2. Dose to be added into infusion bag: 
Dose (mL) = 75 mg / 20 (mg/mL) = 3.8 mL
3. The theoretical number of vials required for dose preparation: 
Number of vials = 3.8 (mL) / 20 (mL/vial) = 1 vial

Clinical Study Protocol
Drug Substance Azacitidine/Decitabine (ASTX727) 
Study Code 15-11430
Edition Number 13.0
Date 09202024
CONFIDENTIAL AND PROPRIETARY
TMGs, Version 17 October 2019, CTCAE v4.03
167 (167)