Conditions: Leukemia, Myeloid, Acute
Keywords: AML Acute Myeloid Leukemia SGI-110 DNA Hypomethylating Agen
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 815
Healthy volunteers: no

Brief summary:
To compare efficacy and safety between SGI-110 and Treatment Choice in adults with previously untreated AML who are not considered candidates for intensive remission induction chemotherapy.

Detailed description:

Arms:
arm 1: Guadecitabine 60 mg/m\^2 administered subcutaneously (SC) daily for 5 days (Days 1-5) in 28-day cycles. arm 2: One of the following treatment regimens: 20 mg cytarabine administered subcutaneously (SC) twice daily (BID) on Days 1-10 every 28 days; 20 mg/m\^2 decitabine given as a 1-hour intravenous (IV) infusion daily on Days 1-5 every 28 days; or 75 mg/m\^2 azacitidine given IV or SC daily on Days 1-7 every 28 days.

Interventions: intervention 1: SGI-110 (guadecitabine) intervention 2: Treatment Choice
Intervention descriptions: intervention 1: Investigational medicinal product intervention 2: Choice of one: cytarabine, decitabine, or azacitidine

Protocol document:
Prot_000.pdf: 
Astex Pharmaceuticals, Inc. 
IND No. 102743 
Clinical Protocol SGI-110-04  
EUDRACT 2014-001233-89 
CONFIDENTIAL 
This document is a confidential communication of Astex Pharmaceuticals, Inc. Acceptance of the 
document constitutes agreement by the recipient that the contents will not be disclosed to any 
unauthorized personnel without the prior written authorization of Astex Pharmaceuticals, Inc. 
Clinical Study Protocol — SGI-110-04 
A Phase 3, Multicenter, Open-label, Randomized Study of SGI-110 versus Treatment 
Choice (TC) in Adults with Previously Untreated Acute Myeloid Leukemia (AML) Who 
Are Not Considered Candidates for Intensive Remission Induction Chemotherapy 
PROTOCOL TITLE PAGE 
Sponsor: 
Astex Pharmaceuticals, Inc. 
4420 Rosewood Drive, Suite 200 
Pleasanton, CA 94588
Astex Pharmaceuticals 
Medical Monitor: 
Astex Pharmaceuticals 
Global Phone: 
 
Drug Safety: 
North America Toll-Free Fax: 
 
Email:
IND Number:
102743
EudraCT Number:
2014-001233-89
Study Clinical Phase:
Phase 3
Protocol Version:
2.0
Version History/Date: 
Original (01 December 2014) 
Amendment 1 (6 March 2015) 
NCT02348489


Astex Pharmaceuticals, Inc. 
 
IND No. 102743 
Clinical Protocol SGI-110-04  
 
EUDRACT 2014-001233-89 
Confidential Information 
2 
6 March 2015 
 
SPONSOR AND INVESTIGATOR SIGNATURE PAGE 
Astex Pharmaceuticals, Inc. 
4420Rosewood Drive, Suite 200 
Pleasanton, CA 94588 USA 
Study Acknowledgement 
A Phase 3, Multicenter, Open-label, Randomized Study of SGI-110 versus Treatment 
Choice (TC) in Adults with Previously Untreated Acute Myeloid Leukemia (AML) Who 
Are Not Considered Candidates for Intensive Remission Induction Chemotherapy 
Version 2.0, 6 March 2015 
This protocol has been approved by Astex Pharmaceuticals, Inc. The following signature 
documents this approval.  
 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. Further, I agree to conduct this study in accordance with Good Clinical Practice and 
applicable regulatory requirements. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Astex Pharmaceuticals, Inc. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
 
 
 
Principal Investigator Name (printed) 
 
Signature 
 
 
 
Date 
 
Study Center Number 
 
 
 
Institution Name 
 
Center Location: City, State or Province, 
Country 
 
Please forward the original signed Protocol Acceptance Statement to Astex Pharmaceuticals, Inc. 
Retain a copy of this form with the study protocol in your regulatory file. 


Astex Pharmaceuticals, Inc. 
 
IND No. 102743 
Clinical Protocol SGI-110-04  
 
EUDRACT 2014-001233-89 
Confidential Information 
3 
6 March 2015 
 
PROTOCOL APPROVAL PAGE 
A Phase 3, Multicenter, Open-label, Randomized Study of SGI-110 versus Treatment 
Choice (TC) in Adults with Previously Untreated Acute Myeloid Leukemia (AML) Who 
Are Not Considered Candidates for Intensive Remission Induction Chemotherapy 
Version 2.0, 6 March 2015 
 
 


Astex Pharmaceuticals, Inc. 
IND No. 102743 
Clinical Protocol SGI-110-04  
EUDRACT 2014-001233-89 
Confidential Information 
4 
6 March 2015 
PROTOCOL SYNOPSIS 
Study Number and Title: 
SGI-110-04: A Phase 3, Multicenter, Open-label, Randomized Study of SGI-110 versus Treatment Choice (TC) in 
Adults with Previously Untreated Acute Myeloid Leukemia (AML) Who Are Not Considered Candidates for 
Intensive Remission Induction Chemotherapy 
Investigational Drug: SGI-110 for subcutaneous (SC) injection 
Clinical Phase: 3 
Study Centers Planned/Country: Multicenter global study (approximately 100-160 centers) 
Study Objectives: 
Primary Objective 
•
To assess and compare efficacy (complete response [CR] rate and overall survival [OS]) between SGI-110
and TC in adults with previously untreated AML who are not considered candidates for intensive remission
induction chemotherapy.
Secondary Objectives 
•
To assess and compare effects of SGI-110 and TC in adults with previously untreated AML who are not
considered candidates for intensive remission induction chemotherapy with respect to the following variables:
-
Composite CR (CRc = CR + Complete response with incomplete blood count recovery [CRi] + Complete
response with incomplete platelet recovery [CRp]) rate.
-
Number of days alive and out of the hospital.
-
Progression-free survival (PFS).
-
Transfusion needs.
-
Health-related quality of life (QOL).
-
Duration of CR.
-
Safety.
Exploratory Objectives 
•
.
•
Study Design and Investigational Plan:  
Multicenter, randomized, open-label study of SGI-110 versus TC. Blinded central reading of bone marrow and 
disease response will be performed. Subjects will be adults with previously untreated AML who are unfit to 
receive and not considered candidates for intensive remission induction chemotherapy. Approximately 
800 subjects will be randomly assigned (1:1) to 1 of 2 groups:  
•
SGI-110: 60 mg/m2 SGI-110 given SC daily for 5 days (Days 1-5) in 28-day cycles.
•
TC: subjects will be assigned (before randomization) by the investigator to 1 of the following treatment
regimens:
-
20 mg cytarabine given SC twice daily (BID) on Days 1-10 every 28 days.
-
20 mg/m2 decitabine given intravenously (IV) daily on Days 1-5 every 28 days.
-
75 mg/m2 azacitidine given IV or SC daily on Days 1-7 every 28 days.
Data will be reviewed by an independent Data Monitoring Committee (DMC) at regular intervals primarily to 
evaluate safety during study conduct. The co-primary endpoints are CR rate and OS. If either of the co-primary 
efficacy endpoints reaches statistical significance in favor of SGI-110 at either the interim analysis (OS only) or 
final analysis (CR and OS), then the study will be considered positive in efficacy. Randomization and analyses 
will be stratified by age, Eastern Cooperative Oncology Group (ECOG) performance status, study center region, 
and secondary AML or poor-risk cytogenetics. 


Astex Pharmaceuticals, Inc. 
 
IND No. 102743 
Clinical Protocol SGI-110-04  
 
EUDRACT 2014-001233-89 
Confidential Information 
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Study Population: 
Approximately 800 adults with previously untreated AML who are unfit to receive and not considered candidates 
for intensive remission induction chemotherapy at the time of enrollment, with the following criteria. 
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria. 
1.
Able to understand and comply with study procedures, and provides written informed consent before any 
study-specific procedure. 
2.
Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic leukemia) 
according to the 2008 World Health Organization (WHO) classification (bone marrow or peripheral blood 
blast counts 20%). 
3.
Performance status (ECOG) of 0-3. 
4.
Adults with previously untreated AML except for hydroxyurea or corticosteroids. Prior hydroxyurea or 
lenalidomide treatment for myelodysplastic syndrome (MDS) is allowed.  
5.
Unfit to receive or not considered candidates for intensive remission induction chemotherapy at time of 
enrollment based on EITHER: 
a. 75 years of age  
OR 
b. <75 years of age with at least 1 of the following: 
i. Poor performance status (ECOG) score of 2-3.  
ii. Clinically significant heart or lung comorbidities, as reflected by at least 1 of: 
1)
Left ventricular ejection fraction (LVEF) 50%. 
2)
Lung diffusing capacity for carbon monoxide (DLCO) 65% of expected. 
3)
Forced expiratory volume in 1 second (FEV1) 65% of expected. 
4)
Chronic stable angina or congestive heart failure controlled with medication. 
iii. Liver transaminases >3 × upper limit of normal (ULN). 
iv. Other contraindication(s) to anthracycline therapy (must be documented). 
v. Other comorbidity the investigator judges incompatible with intensive remission induction 
chemotherapy, which must be documented and approved by the study medical monitor before 
randomization.  
6.
Creatinine clearance as estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas 
30 mL/min. 
7.
Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy 
test at screening. Women of child-bearing potential and men with female partners of child-bearing potential 
must agree to practice 2 highly effective contraceptive measures during the study and for at least 3 months 
after completing treatment and must agree not to become pregnant or father a child while receiving treatment 
with SGI-110 and for at least 3 months after completing treatment. 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria will be excluded from the study: 
1.
Candidate for intensive remission induction chemotherapy at the time of enrollment.  
2.
Candidate for best supportive care only, ie, not a candidate for any active therapy with the TC comparators.  
3.
Known extramedullary central nervous system (CNS) AML. 
4.
Second malignancy currently requiring active therapy except breast or prostate cancer stable on or responding 
to endocrine therapy.  
5.
Prior treatment with decitabine or azacitidine.  
6.
Hypersensitivity to decitabine, azacitidine, cytarabine, SGI-110, or any of their excipients. 
7.
Treated with any investigational drug within 2 weeks of the first dose of study treatment. 
8.
Total serum bilirubin >2.5 × ULN, except for subjects with Gilbert's Syndrome for whom direct bilirubin is 
<2.5 × ULN, or liver cirrhosis or chronic liver disease Childs-Pugh B or C. 
9.
Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) 
infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed. 
10. Known significant mental illness or other condition such as active alcohol or other substance abuse or 
addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with 
the protocol. 
11. Refractory congestive heart failure unresponsive to medical treatment; active infection resistant to all 
antibiotics; or advanced pulmonary disease requiring >2 liters per minute (LPM) oxygen. 
 


Astex Pharmaceuticals, Inc. 
 
IND No. 102743 
Clinical Protocol SGI-110-04  
 
EUDRACT 2014-001233-89 
Confidential Information 
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Study Treatment: 
•
SGI-110: 60 mg/m2 SGI-110 given SC daily on Days 1-5 in 28-day cycles. Treatment should be given for at 
least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. 
Beyond 6 cycles, treatment should continue as long as the subject continues to benefit based on investigator 
judgment. 
•
TC: before randomization, subjects will be assigned by the investigator to 1 of the following treatment 
regimens (dose, schedule, and administration route; other treatment parameters, such as duration of treatment 
and dose adjustment guidelines, should follow locally approved prescribing information and institutional 
standard practice): 
-
20 mg cytarabine given SC BID on Days 1-10 every 28 days. 
-
20 mg/m2 decitabine given IV daily on Days 1-5 every 28 days. 
-
75 mg/m2 azacitidine given IV or SC daily on Days 1-7 every 28 days. 
Study Endpoints: 
Co-primary Endpoints 
•
CR rate based on modified International Working Group (IWG) 2003 AML Response Criteria. 
•
OS, defined as the number of days from randomization to death. 
Secondary Endpoints 
•
CRc (CR+CRi+CRp) rate. 
•
Number of days alive and out of the hospital. 
•
PFS, defined as the number of days from randomization to disease progression or death, whichever occurs 
first. 
•
Number of red blood cell (RBC) or platelet transfusions (units) over the duration of the study treatment. 
•
Health-related QOL by EQ-5D (consisting of the EQ-5D-5L descriptive system and the EQ Visual Analogue 
Scale [EQ VAS]). 
•
Duration of CR, defined as the time from first CR to time of relapse. 
•
Incidence and severity of adverse events (AEs). 
•
30- and 60-day all-cause early mortality. 
Study Assessments and Procedures: 
A 14-day screening period is allowed (unless otherwise specified). After randomization, visits will occur on every 
treatment day. In addition, visits will occur on Days 8, 15, and 22 of the first 2 cycles of therapy and only on 
Day 15 in Cycles 3-6. In Cycles >6, only the treatment day visits are required, with hematology blood draws only 
on Day 1. Additional visits based on treatment effect and blood counts may be done at the investigator’s 
discretion. Subjects will attend a safety follow-up visit after the last study treatment. For subjects who discontinue 
study treatment before Cycle 6, long-term follow-up visits will occur monthly until 6 months after the start of 
study treatment and then every 3 months thereafter. For subjects who discontinue study treatment after Cycle 6, 
long-term follow-up will be every 3 months. 
Efficacy Assessments: 
Peripheral blood (PB) will be assessed at baseline and on Day 1 of each cycle for response evaluation. Bone 
marrow (BM) aspirate/biopsy will be performed at screening and then at the end of Cycles 2, 4, and 6 unless PB 
shows persistence of leukemic blasts that excludes the possibility of a marrow response. After Cycle 6 BM 
assessment, BM aspirate/biopsy will be repeated every 3 months for the first year on study and then every 
6 months thereafter until PB or BM assessment shows disease progression or relapse. Response evaluation will be 
based on BM blinded assessment and the most concomitant PB counts. After blinded BM response is confirmed, 
assessment of normal count recovery will be done based initially on the most concomitant PB and in later cycles 
on PB counts from Day 1 of each cycle to avoid transient treatment-induced normal count suppression. 
Pharmacokinetic Assessments: 
Sparse PK samples (as specified by the collection schedule) will be collected at selected centers for subjects 
receiving SGI-110 and for subjects in the TC group who receive decitabine IV. Blood samples will be collected 
after drug administration in Cycle 1 (SGI-110 and decitabine IV). 
Biomarker Assessments: 
Blood and BM samples will be collected at screening for AML verification, molecular genetics, and cytogenetics. 
Health-related QOL Assessment: 
EQ-5D 5 level (EQ-5D-5L) will be administered before treatment on Day 1 of each cycle and, for subjects who 
discontinue study treatment before Cycle 6, monthly until 6 months after the start of study treatment. 
 


Astex Pharmaceuticals, Inc. 
 
IND No. 102743 
Clinical Protocol SGI-110-04  
 
EUDRACT 2014-001233-89 
Confidential Information 
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6 March 2015 
Safety Assessments: 
Documented safety assessments will include AEs, concomitant medications, physical examination results, vital 
signs, electrocardiogram (ECG), ECOG performance status, hematology, and chemistry, according to the schedule 
of events. ECGs in triplicate will be conducted predose, 1-2 hours after Cycle 1 Day 1 dosing, and at study 
treatment discontinuation. Clinically significant abnormal ECG at study treatment discontinuation as compared to 
the predose ECG should be followed for recovery or stabilization. 
Sample Size and Statistical Analyses: 
Sample Size Calculation: 
Assuming a CR rate of approximately 0.20 for subjects treated in the TC group and 0.30 or higher for subjects 
treated with SGI-110, 800 subjects (400 per treatment group) will have approximately 89% power to detect the 
overall difference of 0.10 at an alpha level of 0.04 using a 2-sided Cochran Mantel-Haenszel test. 
For survival, an analysis at 670 death events will provide 90% power to detect a hazard ratio of approximately 
0.78 (a difference in median survival of 7 months in the TC group versus 9 months in the SGI-110 group when 
using a 2-sided stratified log-rank test at a 0.05 alpha level. Accrual is expected to be uniform over a 21 month 
enrollment period (with an additional follow-up of 12 months), so the assessment of survival needs approximately 
the same sample size of 800 subjects. Primary response and survival analyses will be performed after 670 death 
events have occurred.  
Efficacy: 
The primary endpoint of CR rate will be compared between the 2 treatment groups using a Cochran Mantel-
Haenszel test at an alpha level of 0.04 stratified by age (<75 or 75 years), ECOG performance status (0-1 or 2-3), 
study center region (North America, Europe, rest of world), and secondary AML or poor-risk cytogenetics (either, 
neither). The co-primary endpoint of OS will be displayed using a stratified Kaplan-Meier estimate and will be 
compared between the 2 treatment groups using a stratified log-rank statistic at an alpha level of 0.05 or 0.01 
(depending on the CR test result), including the same stratification variables used for analysis of CR rate. If 
statistical significance is achieved for both CR rate and OS at targeted levels of significance, hierarchically the 
CRc rate, the number of days alive and out of the hospital (NDAOH), and PFS will be assessed. The CRc rate will 
be compared between the 2 treatment groups using the same method as for CR. The NDAOH will be evaluated 
using a 2-sample t-test. PFS will be evaluated using the same method as for OS. 
Safety: 
Safety will be assessed by subject-reported and investigator-observed AEs, physical examination, laboratory tests 
(hematology and chemistry), vital signs, and ECG. AEs will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) with severity categorization based on Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. Treatment exposure, AEs including relatedness and severity, serious AEs (SAEs), and reasons 
for treatment discontinuation will be tabulated and presented for all subjects who receive any amount of study 
treatment. Concomitant medication will be coded using WHO Drug Dictionary. 
Formal Interim Analysis for Efficacy: 
One interim analysis of OS is planned after approximately half of the required death events have occurred. This 
interim analysis will be conducted by an independent DMC, using the Lan-DeMets implementation of an 
O’Brien-Fleming boundary that will preserve an overall 2-sided 0.01 alpha level. The DMC will also perform 
regular data reviews with the main purpose of ensuring safety of study subjects and quality of trial conduct. 
Study Duration: 
The expected study duration is approximately 36 months including 21 months for completing enrollment and 
approximately 12-15 months follow-up before final analyses. The study is expected to start in Q1 2015.  
Compliance Statement: 
The study will be conducted in accordance with the International Conference on Harmonisation (ICH) Good 
Clinical Practice (GCP) guidelines, US Title 21 CFR Parts 11, 50, 54, 56, and 312; the EU Clinical Trials 
Directive and its successor; principles enunciated in the Declaration of Helsinki; and all human clinical research 
regulations in countries where the study is conducted. 
 


Astex Pharmaceuticals, Inc. 
 
IND No. 102743 
Clinical Protocol SGI-110-04  
 
EUDRACT 2014-001233-89 
Confidential Information 
8 
6 March 2015 
 
TABLE OF CONTENTS 
SPONSOR AND INVESTIGATOR SIGNATURE PAGE ........................................................2 
INVESTIGATOR STATEMENT ................................................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
PROTOCOL SYNOPSIS ..............................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................8 
LIST OF TABLES .......................................................................................................................12 
LIST OF FIGURES .....................................................................................................................13 
LIST OF APPENDICES .............................................................................................................13 
ABBREVIATIONS AND DEFINITIONS .................................................................................14 
1.0 
INTRODUCTION AND BACKGROUND ....................................................................16 
1.1 
Acute Myeloid Leukemia (AML) in Patients Who Are Not Considered 
Candidates for Intensive Remission Induction Therapy and the Elderly ..............16 
1.2 
Treatment Options for Patients with AML Who Are Not Considered 
Candidates for Intensive Remission Induction Therapy ........................................17 
1.3 
Summary of Nonclinical and Clinical Data for SGI-110 .......................................19 
1.3.1 
SGI-110 Nonclinical Data Summary ....................................................19 
1.3.1.1 
Activity ..........................................................................................19 
1.3.1.2 
Pharmacokinetics and Toxicology .................................................19 
1.3.2 
SGI-110 Clinical Data Summary ..........................................................21 
1.3.2.1 
Phase 1 (SGI-110-01 Dose Escalation)..........................................21 
1.3.2.2 
Phase 2 (SGI-110-01 Dose Expansion) .........................................23 
1.3.2.2.1 
Treatment-naïve Elderly AML ................................................23 
1.3.2.2.2 
Relapsed/Refractory AML ......................................................27 
1.4 
Summary of Data for Treatment Choice (TC) .......................................................28 
1.5 
Potential Risks and Benefits to Human Subjects ...................................................28 
2.0 
RATIONALE ...................................................................................................................29 
2.1 
Rationale for the Study ..........................................................................................29 
2.2 
Rationale for SGI-110 Dose and Regimen ............................................................30 
2.2.1 
PK Dose Assessment ............................................................................30 
2.2.2 
PD Dose Assessment: LINE-1 DNA Methylation ................................31 
2.2.3 
Clinical Efficacy and Safety SGI-110 Dose-response ..........................33 
2.2.3.1 
Daily×5 Regimen in AML .............................................................33 
2.2.3.2 
10-day Regimen in AML ...............................................................34 
2.2.4 
Dose Selection Conclusion from Phase 1 and 2 Study .........................34 
3.0 
STUDY OBJECTIVES ....................................................................................................35 


Astex Pharmaceuticals, Inc. 
 
IND No. 102743 
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3.1 
Primary Objective ..................................................................................................35 
3.2 
Secondary Objectives .............................................................................................35 
3.3 
Exploratory Objectives ..........................................................................................35 
4.0 
INVESTIGATIONAL PLAN .........................................................................................35 
4.1 
Overall Study Design .............................................................................................35 
4.2 
Discussion of Study Design ...................................................................................37 
4.3 
Study Endpoints .....................................................................................................38 
4.3.1 
Co-primary Endpoints ...........................................................................38 
4.3.2 
Secondary Endpoints .............................................................................38 
4.4 
Data Monitoring Committee (DMC) .....................................................................38 
4.5 
Study Steering Committee (SSC) ..........................................................................38 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................39 
5.1 
Number of Subjects and Centers ............................................................................39 
5.2 
Inclusion Criteria ...................................................................................................39 
5.3 
Exclusion Criteria ..................................................................................................40 
5.4 
Treatment Discontinuation and Withdrawal of Subjects .......................................41 
5.4.1 
Discontinuation from Study Treatment .................................................41 
5.4.2 
Withdrawal from the Study ...................................................................41 
5.4.3 
Replacement of Subjects .......................................................................41 
6.0 
ENROLLMENT, RANDOMIZATION, AND BLINDING PROCEDURES ............42 
6.1 
Randomization .......................................................................................................42 
6.2 
Blinding..................................................................................................................42 
7.0 
STUDY TREATMENTS .................................................................................................42 
7.1 
Investigational Medicinal Product (IMP): SGI-110 ..............................................42 
7.1.1 
IMP Information ...................................................................................42 
7.1.2 
SGI-110 Regimens and Administration ................................................43 
7.2 
Treatment Choice (TC) Active Comparator ..........................................................44 
7.3 
Guidelines for Adjusting or Withholding Study Treatment ..................................44 
7.3.1 
Guidelines for SGI-110 .........................................................................44 
7.3.2 
Guidelines for TC ..................................................................................45 
7.4 
Emergency Treatment for Subjects with Highly Proliferative Progressive 
AML .......................................................................................................................45 
7.5 
Concomitant Treatment .........................................................................................46 
7.5.1 
Supportive, Prophylactic, or Other Treatments ....................................46 
7.5.1.1 
Antibiotics or Anti-fungals ............................................................46 
7.5.1.2 
Hematopoietic Growth Factors ......................................................46 


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7.5.1.3 
Hydroxyurea and/or Leukapheresis ...............................................46 
7.5.2 
Prohibited Concomitant Treatment .......................................................46 
7.6 
Overdose Instructions ............................................................................................47 
8.0 
RISKS/PRECAUTIONS .................................................................................................47 
9.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................48 
9.1 
Eligibility ...............................................................................................................48 
9.2 
Efficacy ..................................................................................................................48 
9.3 
Pharmacokinetics ...................................................................................................48 
9.4 
Safety .....................................................................................................................49 
9.5 
Study Procedures ...................................................................................................49 
9.5.1 
Schedule of Events ................................................................................49 
9.5.2 
Screening and Baseline Procedures ......................................................54 
9.5.3 
Treatment and Follow-up Procedures (Cycles 1 and 2) ........................55 
9.5.3.1 
Day 1 (Before Dosing) ...................................................................55 
9.5.3.2 
Day 1 (During and After Dosing) ..................................................56 
9.5.3.3 
Dosing Days (Days 2-5, Days 2-7, or Days 2-10, Depending on 
Study Treatment) ...........................................................................56 
9.5.3.4 
Days 8, 15, and 22..........................................................................56 
9.5.4 
Treatment and Follow-up Procedures for Cycles 3 ............................56 
9.5.4.1 
Day 1 (Before Dosing), Cycles 3 .................................................57 
9.5.4.2 
Dosing Days (Days 2-5, Days 2-7, or Days 2-10, Depending on 
Study Treatment), Cycles 3 .........................................................57 
9.5.4.3 
Day 15 (Cycles 3) ........................................................................57 
9.5.5 
Treatment Discontinuation and Safety Follow-up Visit .......................58 
9.5.6 
Long-term Follow-Up ...........................................................................58 
9.6 
Unscheduled Visits ................................................................................................59 
9.7 
Missed Evaluations ................................................................................................59 
10.0 
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS ......60 
10.1 
Definitions..............................................................................................................60 
10.1.1 
Adverse Event (AE) ..............................................................................60 
10.1.2 
Serious Adverse Events (SAEs) ............................................................60 
10.2 
Adverse Event Reporting and Descriptions ...........................................................61 
10.2.1 
Severity .................................................................................................61 
10.2.2 
Relationship to Study Treatment (Suspected Adverse Reactions) ........62 
10.2.3 
Pregnancy and Abortion ........................................................................63 
10.3 
Reporting and Evaluation of Serious Adverse Events ...........................................63 
10.3.1 
Reporting Requirements for Serious Adverse Events (SAEs) ..............63 


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10.4 
Follow-up for Adverse Events ...............................................................................64 
11.0 
STATISTICS ....................................................................................................................64 
11.1 
Sample Size ............................................................................................................64 
11.2 
Data Sets to be Analyzed .......................................................................................65 
11.2.1 
Efficacy .................................................................................................65 
11.2.2 
Safety ....................................................................................................65 
11.2.3 
Pharmacokinetics ..................................................................................65 
11.2.4 
Pharmacodynamics Analyses ................................................................66 
11.3 
Schedule of Analyses .............................................................................................66 
11.4 
Disposition .............................................................................................................66 
11.5 
Analysis of Demographic and Baseline Data ........................................................66 
11.6 
Efficacy Analyses ..................................................................................................66 
11.6.1 
Criteria for Response Assessment .........................................................67 
11.6.2 
Complete Response (CR) ......................................................................68 
11.6.3 
Overall Survival (OS) ...........................................................................68 
11.6.4 
Composite CR (CRc) ............................................................................69 
11.6.5 
Number of Days Alive and Out of the Hospital (NDAOH) ..................69 
11.6.6 
Progression-free Survival (PFS) ...........................................................69 
11.6.7 
Test Sequence and Procedures of Statistical Tests for Efficacy 
Endpoints ..............................................................................................70 
11.6.8 
Number of Red Blood Cell (RBC) or Platelet Transfusions .................72 
11.6.9 
EQ-5D-5L .............................................................................................72 
11.6.10 
Duration of CR ......................................................................................72 
11.6.11 
Subgroup Analyses ...............................................................................72 
11.7 
Safety Analyses ......................................................................................................73 
11.8 
Pharmacokinetic Analyses .....................................................................................74 
11.9 
Interim Analysis .....................................................................................................74 
11.10 Procedures for Handling Missing, Unused, and Spurious Data.............................74 
12.0 
STUDY DURATION .......................................................................................................74 
13.0 
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS ...............................75 
13.1 
Compliance Statement ...........................................................................................75 
13.2 
Informed Consent...................................................................................................75 
13.3 
Institutional Review Board or Independent Ethics Committee (IRB/IEC) ...........75 
14.0 
ADMINISTRATIVE PROCEDURES ...........................................................................75 
14.1 
Sponsor Responsibilities ........................................................................................75 
14.1.1 
Study Supplies .......................................................................................76 


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14.1.2 
Investigator Training .............................................................................76 
14.1.3 
Ongoing Communication of Safety Information during the Study .......76 
14.1.4 
Study Monitoring ..................................................................................76 
14.1.5 
Study Auditing and Inspecting ..............................................................77 
14.2 
Investigator Responsibilities ..................................................................................77 
14.2.1 
Subject Screening Log ..........................................................................77 
14.2.2 
Study Treatment Accountability ...........................................................77 
14.2.3 
Reporting and Recording of Study Data ...............................................78 
14.2.4 
Source Documentation ..........................................................................78 
14.2.5 
Tissue and Blood Sample Collection/Storage .......................................79 
14.2.6 
Records Retention .................................................................................79 
14.3 
Clinical Trial Insurance ..........................................................................................79 
14.4 
Study Administrative Letters and Protocol Amendments .....................................80 
15.0 
POLICY FOR PUBLICATION AND PRESENTATION OF DATA ........................80 
16.0 
REFERENCES .................................................................................................................81 
17.0 
APPENDICES ..................................................................................................................86 
  
LIST OF TABLES 
Table 1: 
Heavily-pretreated AML Responses and Characteristics (Phase 1) ..........23 
Table 2: 
Characteristics of Previously Untreated Elderly (65 Years) Subjects 
with AML in the SGI-110 Phase 2 Study (Daily×5 Regimen) ..................25 
Table 3: 
60 vs 90 mg/m2 (Daily×5 Regimen): Complete Response for 
Previously Untreated Elderly (65 Years) Subjects with AML 
(Phase 2).....................................................................................................25 
Table 4: 
60 vs 90 mg/m2 (Daily×5 Regimen): Previously Untreated Elderly 
Subjects with AML (Phase 2): Grade 3 AEs with Incidence 15%, 
Regardless of Relationship to SGI-110......................................................26 
Table 5: 
60 vs 90 mg/m2 (Daily×5 Regimen): All-Cause Mortality in 
Previously Untreated Elderly Subjects with AML Treated with SGI-
110 (Phase 2)..............................................................................................26 
Table 6: 
Complete Response for Relapsed/Refractory Subjects with AML 
(Phase 2).....................................................................................................27 
Table 7: 
Grade 3 AEs with Incidence 15%, Regardless of Relationship to 
SGI-110, in Relapsed/Refractory Subjects with AML (Phase 2) ..............27 
Table 8: 
All-Cause Mortality in Relapsed/Refractory Subjects with AML 
(Phase 2).....................................................................................................28 
Table 9: 
SGI-110 Response Compared with Other Therapies for Previously 
Untreated Elderly Subjects with AML ......................................................30 


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Table 10: 
SGI-110 Safety Compared with Other Therapies for Previously 
Untreated Elderly Subjects with AML ......................................................30 
Table 11: 
Dose Selection PK Data: Decitabine Exposure (Mean ± SD) after 
SGI-110 Treatment (36–125 mg/m2/day on Days 1-5) ..............................31 
Table 12: 
Dose Selection (60 vs 90 mg/m2/day, 5-day regimen): Complete 
Response Summary in Subjects with AML (Phase 2) ...............................33 
Table 13: 
Dose Selection (60 vs. 90 mg/m2/day, 5-day regimen): Grade 3 AEs 
with Incidence 15%, Regardless of Relationship to SGI-110 in 
Subjects with AML (Phase 2) ....................................................................33 
Table 14: 
Dose Selection (60 vs 90 mg/m2/day, 5-day regimen): All-Cause Early 
Mortality in Subjects with AML (Phase 2) ................................................34 
Table 15: 
SGI-110 Dosing Adjustment Guideline Based on End of Cycle 2 
(C2, Day 29 or Later) Peripheral Blood Blasts and Counts ....................45 
Table 16: 
Schedule of Events .....................................................................................50 
Table 17: 
Clinical Laboratory Tests ...........................................................................55 
Table 18: 
Modified 2003 IWG AML Response Criteria ...........................................67 
  
LIST OF FIGURES 
Figure 1: 
LINE-1 Demethylation Results from the Dose Escalation Part of 
SGI-110-01 Using 2 Regimens ..................................................................22 
Figure 2: 
Dose Selection PD (60 vs 90 mg/m2/day, 5-Day Regimen SGI-110): 
Mean LINE-1 Demethylation in Treatment-naïve Subjects (top) and 
Relapsed/Refractory Subjects with AML (bottom) ...................................32 
Figure 3: 
Study Schema.............................................................................................36 
Figure 4: 
The Hierarchical Test Order and Related Alpha Values ...........................71 
  
LIST OF APPENDICES 
Appendix 1: 
ECOG Performance Status ........................................................................87 
Appendix 2: 
Poor-risk Cytogenetics Specification .........................................................88 
Appendix 3: 
National Cancer Institute Common Terminology Criteria for Adverse 
Events .........................................................................................................89 
Appendix 4: 
EQ-5D-5L Sample .....................................................................................90 
Appendix 5: 
Summary of Changes, Amendment 1 ........................................................94 
  


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ABBREVIATIONS AND DEFINITIONS 
ADL 
activities of daily living 
AE 
adverse event 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AUC 
area under the curve 
BED 
biologically effective dose 
BID 
twice daily 
BM 
bone marrow 
BMT 
bone marrow transplant 
BSA 
body surface area 
CBC 
complete blood count 
CBF 
core binding factor 
CDA 
cytidine deaminase 
C-G 
Cockroft-Gault 
CI 
confidence interval 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response 
CRc 
composite complete response (CR+CRi+CRp) 
CRF/eCRF 
case report form/electronic case report form 
CRi 
complete response with incomplete blood count recovery 
CRp 
complete response with incomplete platelet recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMEA 
European Agency for the Evaluation of Medicinal Products 
EQ-5D™ 
a standardized instrument for use as a measure of health outcome 
EQ-5D-5L 
EQ-5D 5 level health questionnaire 
EQ VAS 
EQ visual analog scale 
FAB 
French-American-British 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in the first second 
FIH 
first-in-human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCT 
hematopoietic cell transplant 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
HMA 
hypomethylating agent 
HNSTD 
highest non-severely toxic dose 
HR 
hazard ratio 
IB 
Investigator Brochure 


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ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee  
IMP 
investigational medicinal product (the specific Astex drug product under study) 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IWG 
International Working Group 
LDAC 
low-dose Ara-C 
LINE-1 
long interspersed nucleotide element-1 
LPM 
liters per minute 
LVEF 
left ventricular ejection fraction 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSDS 
material safety data sheet 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NDAOH 
number of days alive and out of the hospital 
NOAEL 
no observed adverse event level 
NR 
no response 
OS 
overall survival 
OSHA 
Occupational Safety and Health Administration 
PB 
peripheral blood 
PBMC 
peripheral blood mononuclear cells 
PD 
pharmacodynamic(s) 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PS 
performance status 
PT 
preferred term 
QOL 
quality of life 
QT 
QT interval 
QTc 
heart rate corrected interval 
RBC 
red blood cells 
ROW 
rest of world 
R/R 
relapsed/refractory 
RR 
relative risk 
SAE 
serious adverse event 
SC 
subcutaneous 
SEER 
Surveillance, Epidemiology and End Results 
SOC 
system organ class 
SSC 
Study Steering Committee 
STD10 
dose severely toxic to 10% of animals/rodents 
SUSAR 
serious unexpected suspected adverse reaction 
TC 
treatment choice 
TEAE 
treatment-emergent AE 
TN 
treatment-naïve 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 


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The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) Good Clinical Practice (GCP) guidelines, US Title 21 CFR Parts 11, 50, 54, 56, and 312; 
the EU Clinical Trials Directive and its successor; principles enunciated in the Declaration of 
Helsinki; and all human clinical research regulations in countries where the study is conducted 
(see Section 13.0). 
1.0
INTRODUCTION AND BACKGROUND 
1.1
Acute Myeloid Leukemia (AML) in Patients Who Are Not Considered Candidates 
for Intensive Remission Induction Therapy and the Elderly 
Acute myeloid leukemia (AML) is a genetically heterogeneous group of cancers that have in 
common clonal proliferation and arrested differentiation of myeloid precursors. Incidence 
increases with age and is about 12 cases per 100,000 for those at and above the median age at 
diagnosis of 65 years (Schiffer and Anastasi 2014). Overall 5-year survival is 15% and varies 
substantially with age (Shah et al 2013). Patients age 70-79 years and over age 79 years have 
5-year survival rates of 3% and 0%, respectively.  
In a recent analysis of US Surveillance, Epidemiology and End Results (SEER) data, trends in 
relative survival by age were compared over 3 successive decades from 1977 through 2006 for 
19,000 patients at least 65 years of age with AML (Thein et al 2013). Overall, survival improved 
for each successive decade in patients from 65-74 years old. In this age range, 12-month survival 
increased from 20% to 25% to 30% in the 3 successive cohorts. However, survival rates did not 
significantly improve in patients at least 75 years of age. The oldest old, at least 85 years of age, 
had the lowest survival, with no improvement. Thus, despite ongoing incremental improvements 
in both AML chemotherapy and supportive care since the mid-1970s, mortality following an 
AML diagnosis remains persistently high and without improvement in patients 75 years of age. 
In addition to age, other adverse prognostic indicators in AML include poor performance status, 
adverse cytogenetic or molecular genetic findings, past exposure to cytotoxic or radiation 
therapy, and history of myelodysplasia or another hematologic disorder (Schiffer et al 2014). 
There is a correlation between age at diagnosis of AML and complex cytogenetic disease 
characteristics. Complex karyotype also correlates with disease resistance to therapy (Grimwade 
et al 2001). In summary, AML in patients who are not considered candidates for intensive 
remission induction chemotherapy, particularly elderly patients, remains a persistent unmet 
medical need. 
For young patients, an AML diagnosis necessitates immediate intensive remission induction 
therapy. The goal is complete and prolonged disease remission. Yet for elderly patients with 
AML, intensive chemotherapy is often inappropriate due to adverse disease factors that cause 
chemo-resistance and comorbidities that exacerbate therapy-induced toxicity. Multivariate 
analyses in 2 retrospective series confirm that an unfavorable karyotype is an independent 
negative prognostic indicator in adults receiving induction chemotherapy (Kantarjian et al 2006; 
Kantarjian et al 2010). 


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Among 998 subjects age 65 years or older with AML or high-risk myelodysplastic syndrome 
(MDS) who received intensive chemotherapy between 1980 and 2004, independent negative 
prognostic indicators for complete response (CR), induction (8-week) mortality, and survival 
included age 75 years, unfavorable karyotype, Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) 3 or 4, longer duration of antecedent hematologic disorder, treatment 
outside a laminar airflow room, and abnormal organ function (Kantarjian et al 2006). 
A subsequent analysis focused on 446 subjects 70 years of age with AML (>20% blasts) treated 
with cytarabine-based intensive chemotherapy between 1990 and 2008 to identify risk groups for 
high induction (8-week) mortality. By multivariate analysis, risk factors for 8-week mortality 
(36%) after intensive chemotherapy included age 80 years, 3 cytogenetic abnormalities, 
ECOG PS 2, and serum creatinine >1.3 mg/dL (Kantarjian et al 2010). Additional series 
support these conclusions (Grimwade et al 2001, Appelbaum et al 2006, Knipp et al 2007). Thus, 
factors predicting failure of intensive induction chemotherapy in AML include elderly age, 
complex karyotype, and patient characteristics including performance status and organ function. 
Recently, the Italian hematology groups published a consensus-based definition of unfitness for 
intensive chemotherapy that includes age >75 years, cardiac or pulmonary comorbidity, low 
performance status, and any other comorbidity judged by the physician to be incompatible with 
intensive chemotherapy (Ferrara et al 2013). 
1.2
Treatment Options for Patients with AML Who Are Not Considered Candidates for 
Intensive Remission Induction Therapy 
No standard therapy exists for patients with previously untreated AML who are not candidates 
for intensive remission induction chemotherapy. The National Comprehensive Cancer Network 
(NCCN), European Leukemia Net, and European Society for Medical Oncology all recommend 
possible treatments with low-dose Ara-C (LDAC), azacitidine, or decitabine in addition to 
enrolling patients in experimental treatment clinical trials.  
Median overall survival in trials of these therapies varies from 5 to 25 months after initial 
diagnosis, depending on baseline subject features and therapy received (Fenaux et al 2010; 
Dombret et al 2014; Kantarjian, Thomas et al. 2012; Estey 2007). The most common Grade 3 
AEs in all these trials are hematologic, including febrile neutropenia, neutropenia, 
thrombocytopenia, and anemia, with incidence from 20% to 94%. Thirty-day all-cause mortality 
ranged from 8% to 26%, and 60-day all-cause mortality ranged from 18% to 23%. Studies from 
which these results were derived are described individually below.  
In a Phase 3 trial comparing LDAC to hydroxyurea in subjects with AML or high-risk MDS not 
considered fit for intensive treatment, LDAC led to an AML CR rate of 18% (compared with 1% 
for hydroxyurea) and improved survival (odds ratio 0.60; 95% confidence interval [CI] 0.44–
0.81; p=.0009) (Burnett et al 2007). Similarly, a Phase 3 trial comparing azacitidine to 
conventional care in MDS subjects using French-American-British (FAB) criteria led to a CR 
rate of 18% in the subset of MDS subjects re-categorized as AML by World Health Organization 


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(WHO) criteria (blasts 20% to 30%; Swerdlow et al 2008) with azacitidine (compared with a CR 
rate of 16% with conventional care) and improved survival (median 24.5 months compared with 
16.0 months, respectively) (Fenaux et al 2010). A more recent phase 3 study of azacitidine 
versus conventional care regimens (best supportive care, LDAC, or intensive chemotherapy 7+3 
treatment) in 488 subjects showed no difference in CR rate and no statistically significant 
difference in overall survival (OS), although a trend toward OS improvement was evident for 
azacitidine (median survival of 10.4 months for azacitidine versus 6.5 months for conventional 
care regimens with a hazard ratio of 0.85, p=0.10) (Dombret et al 2014). Similarly, in a Phase 3 
trial comparing decitabine to LDAC or best supportive care in 485 subjects 65 years of age with 
AML, decitabine in a 5-day regimen led to a CR rate of 16% (compared with 8% for LDAC) and 
improved survival at the final analysis (median 7.7 months compared with 5.0 months, 
respectively; nominal p=.037) (Kantarjian, Thomas et al 2012).  
After the randomized study of the 5-day decitabine regimen in subjects with AML who were 
65 years of age, multivariate analysis was performed to investigate effects of baseline 
characteristics on survival (Mayer et al 2014). Results were in general similar to those of 
retrospective series assessing factors predicting survival in elderly subjects undergoing intensive 
induction therapy for AML. Independent negative prognostic indicators included age 75 years, 
ECOG PS >1, poor cytogenetics, baseline blasts >50%, low baseline platelets, and high baseline 
white blood cell (WBC) counts. However, in contrast to results observed in patients receiving 
intensive chemotherapy, decitabine responses occurred across all risk groups. The authors 
conclude that response to decitabine was better than response to cytarabine or best supportive 
care and most clearly demonstrated in patients 75 years of age. 
Health-related quality of life (QOL) evaluation is sparse in patients with AML. A 2008 review of 
QOL assessed in randomized, controlled trials in leukemia identified only 4 trials in AML that 
measured QOL and called for more QOL research (Efficace et al 2008). A recently published 
single-center trial evaluating QOL concluded that, in 92 AML survivors, QOL was worse than 
the QOL in the general population (Leunis 2014). Another trial evaluating QOL in 20 adults 
60 years of age with AML suggested that complete remission was associated with improved 
global health, physical function, and role function (Alibhai 2009).  
In AML, supportive care is also often used to maximize quality of life, while not necessarily 
prolonging life. Supportive care for AML is imprecisely defined and “generally refers to 
treatment with antibiotics, transfusions of blood and blood products, hydroxyurea, and 
hematapoietic growth factors” (Ritchie and Roboz 2010). 
A recent retrospective report described the outcomes of 43 elderly patients with AML who were 
referred to palliative care (Cheng et al 2015). Of these 43 patients, about half received only 
supportive care after their AML diagnosis. Approximately half died in acute hospital settings, 
while about 30% died in palliative care settings. Over half spent their entire final month of life in 
a hospital, and infections accounted for more than half of the deaths overall. Median time from 
diagnosis to death was 9 months. Thus, life expectancy, harm, and quality of life appear to be 
similar to or worse with supportive care only, as compared with therapy. A separate review 


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article also suggests that any therapy is better than supportive care alone (Nazha and Ravandi 
2014). 
1.3
Summary of Nonclinical and Clinical Data for SGI-110 
Please refer to the most recent Investigator Brochure (IB) for the complete and most up-to-date 
information. 
1.3.1
SGI-110 Nonclinical Data Summary 
1.3.1.1
Activity 
SGI-110 is a dinucleotide of decitabine and deoxyguanosine, designed to protect the active 
decitabine moiety from inactivation by cytidine deaminase (Griffiths, Choy 2013). In vitro 
evidence suggests that SGI-110 has a longer half-life than decitabine in the presence of cytidine 
deaminase (Yoo et al 2007). SGI-110 has been investigated in a number of nonclinical studies 
for its pharmacodynamic effects on global DNA methylation and on the re-expression of specific 
genes that are silenced in cancer cells due to an altered methylation status of their DNA 
sequence. SGI-110 induced a dose-dependent decrease of proliferation and clonogenic survival 
in many different human cancer cell lines, including AML cell lines (Jueliger et al 2014, 
Srivastava et al 2014). These effects were associated with a decrease of global DNA and gene 
specific methylation. Re-expression of tumor suppressor genes like p16, p15, MLH1 and 
RASSF1A was also observed in xenografts at tolerated and efficacious regimens (Fang et al 
2014). 
1.3.1.2
Pharmacokinetics and Toxicology 
Pharmacokinetic (PK) studies in nonclinical species showed that upon subcutaneous (SC) 
administration, SGI-110 converts to decitabine with species differences in conversion rates 
(slower in primates and faster in rodents). Conversion appears to occur in blood and plasma but 
may also occur intracellularly in tissues. SGI-110 is stable in hepatic microsomes and in 
incubations with hepatocytes. In the presence of cytosolic fractions, SGI-110 converted to 
decitabine. SGI-110 did not inhibit CYP 450 enzymes and is unlikely to cause drug-drug 
interactions mediated by CYPs. SGI-110 did not inhibit hERG channel activity in vitro at up to 
300 ȝM. 
Nonclinical toxicology of SGI-110 was evaluated initially over one 28-day cycle (plus recovery) 
in rats and rabbits. To support the intended Phase 3 regimen in the clinic, 3-cycle studies used 
the Daily×5 dosing schedule in rats and monkeys. 
SGI-110 toxicity findings in rat and rabbit studies are similar to the nonclinical study findings of 
decitabine. Myelosuppression, thymus weight reduction, and testicular atrophy were the main 
study findings, similar to results in repeat-dose toxicity studies with decitabine in mice, rats, 
rabbits, and dogs. Myelosuppression and thymus toxicities were reversible during recovery 
periods, 
whereas 
testicular 
atrophy 
persisted 
for 
both 
SGI-110 
and 
decitabine. 


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Myelosuppression, particularly neutropenia, has been reported as a dose-limiting toxicity (DLT) 
for decitabine in human clinical studies. 
Additional non-GLP studies in cynomolgus monkeys showed that PKs of SGI-110 and 
decitabine were most representative of human PK data. Hematologic parameters from the 
2-cycle non-GLP study in monkeys confirmed a profile consistent with the pharmacological 
action of SGI-110 in humans.  
In the 3-cycle GLP toxicology study in rats, mortalities occurred at the higher dose levels of 
40 mg/kg starting later in the second cycle and for 20 mg/kg later in the third cycle. The cause of 
these mortalities appeared to be opportunistic infections secondary to severe neutropenia. 
Decitabine exposures at SGI-110 dose levels of 20 and 40 mg/kg in rats were greater than 340- 
and 600-fold higher, respectively, than human clinical exposures after the 60 mg/m2 dose. STD10 
in rats was 20 mg/kg over 2 cycles and between 10 and 20 mg/kg over 3 cycles. Hematologic 
changes at all SGI-110 dose levels were reversible and consistent with the expected 
pharmacodynamic effect of SGI-110. Organ weight changes and/or other reversible microscopic 
changes were noted in the low-dose animals, including effects on testes, epididymides, thymus, 
spleen, and adrenal glands at dose levels of 5 mg/kg. Histologic changes were completely or 
partially reversible for all organs within a 28-day recovery period. Toxicokinetic exposures of 
decitabine observed in rats offer considerable margins relative to exposures at the proposed 
clinical Phase 3 dose of 60 mg/m2. Relative to clinical exposures, the area under the curve 
(AUC) exposures in rats were ~90-fold higher at 5 mg/kg and more than 300-fold higher at the 
2-cycle STD10 dose of 20 mg/kg. 
In monkeys, the highest tested dose over 3 cycles was 4.5 mg/kg/dose (human equivalent dose 
[HED] 54 mg/m2), which was found to be the no observed adverse event level (NOAEL). Highest 
non-severely toxic dose (HNSTD) was not identified in this study. Dose-dependent bone marrow 
(BM) hypocellularity was the main finding, which correlated with hematological changes. There 
were no clinical signs or macroscopic findings; no effects on body weight or food consumption; 
and no effects on ophthalmologic, electrocardiographic, serum chemistry, and urinalysis 
parameters. Hematologic and histologic changes in BM at all SGI-110 dose levels were 
reversible and consistent with the expected pharmacologic effect of SGI-110. Possible SGI-110-
related injection site changes of hyperkeratosis at Day 85 and residual inflammation following a 
28-day dose-free recovery were noted for individual animals at the highest dose tested 
(4.5 mg/kg). Toxicokinetic exposures (AUC) in monkeys at the NOAEL dose of 4.5 mg/kg/dose 
were in the range of AUCs observed in the clinic after 60 mg/m2, the recommended Phase 3 
dose. 
In summary, the main effect observed in nonclinical toxicology evaluation of SGI-110 was BM 
suppression, consistent with its intended pharmacological action. 


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1.3.2
SGI-110 Clinical Data Summary 
Study SGI-110-01 was a first-in-human (FIH) study in subjects with MDS or AML. It was 
conducted in 2 phases and enrolled approximately 400 subjects:  
•
Phase 1 Dose Escalation in 93 subjects established the maximal tolerated dose (MTD) and 
biologically effective dose (BED) based on long interspersed nucleotide element-1 (LINE-1) 
demethylation. LINE-1 demethylation relative to baseline in peripheral blood mononuclear 
cells (PBMC) provides a reliable surrogate of global hypomethylation by hypomethylating 
agents (HMAs). Phase 1 tested 28-day regimens of SGI-110 of (1) once daily for the first 
5 days (Daily×5) or (2) once weekly for 3 weeks. LINE-1 demethylation was greater for the 
Daily×5 regimen. Subsequently, a third 28-day regimen was studied: twice weekly SGI-110 
for 3 weeks.  
•
Phase 2 Dose Expansion in over 300 subjects established response rate and safety in different 
subject populations of MDS and AML using 3 different doses/regimens. Five-day regimens 
of 60 and 90 mg/m2/day were tested in both AML and MDS subjects. After safety and 
activity were established with the 5-day regimen, a single-arm 10-day regimen with 
60 mg/m2/day was studied in AML subjects. 
1.3.2.1
Phase 1 (SGI-110-01 Dose Escalation) 
Dose escalation was in subjects with refractory or relapsed MDS or AML who had ECOG 
PS 0-2 and acceptable liver and kidney function (Kantarjian, Roboz et al 2012). Co-primary 
endpoints were MTD and BED; results are described below.  
•
MTD 
•
Daily×5 MTD was reached for MDS subjects at 90 mg/m2/day but was not reached for 
AML subjects up to 125 mg/m2. Of 12 subjects enrolled at the 125 mg/m2 dose level, 
3 had MDS, and 9 had AML. Although none of the subjects with AML experienced DLT, 
2 of 3 subjects with MDS treated at 125 mg/m2 Daily×5 experienced DLTs (febrile 
neutropenia + bacteremia in 1 subject, and febrile neutropenia + thrombocytopenia + fatal 
sepsis in another subject). 
•
The MTD was not reached for the once weekly (up to 125 mg/m2/dose) or the twice 
weekly (up to 90 mg/m2/dose) regimens. 
•
BED (defined as the minimum dose that achieves maximal demethylation of LINE-1 from 
3 successive cohorts) 
•
The Daily×5 regimen had the greatest effect on LINE-1 demethylation, and the BED was 
60 mg/m2/day (Figure 1). Similar LINE-1 demethylation occurred at 60, 90, and 
125 mg/m2.  
•
Less demethylation was observed with the Once Weekly regimen; the Twice Weekly 
regimen did not lead to better LINE-1 demethylation than the Daily×5 regimen. 


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Figure 1: 
LINE-1 Demethylation Results from the Dose Escalation Part of 
SGI-110-01 Using 2 Regimens 
 
 
Source: Kantarjian, Roboz  et al 2012 
A total of 74 subjects with relapsed/refractory AML were treated with SGI-110 in the Phase 1 
dose escalation segment. Responses were observed starting at the 36 mg/m2 dose level (Table 1). 
Of 49 subjects treated at 36 mg/m2 or higher in the daily and weekly regimens, 5 CRc (CR + 
complete response with incomplete blood count recovery [CRi] + complete response with 
incomplete platelet recovery [CRp]), including 2 CRs, were observed. Three of 5 responses 
occurred with the 60 mg/m2/day dose. 


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Table 1: 
Heavily-pretreated AML Responses and Characteristics (Phase 1) 
Subject 
Dose  
(mg/m2) 
# Prior Regimens /  
Prior BMT 
Prior HMA Exposure  
(prior response) 
Response to  
SGI-110 
 
36 
1 / No 
No 
CRi 
 
60 
4 / Yes 
Decitabine (UNK) 
CR 
 
60 
5 / Yes 
No 
CR 
60 
4 / No 
Decitabine (NR)  
Azacitidine (NR) 
CRi 
 
125 
6 / No 
No 
CRp 
BMT: BM transplant; HMA: hypomethylating agent; NR: no response; CR: complete response; CRi: CR with 
incomplete blood count recovery; CRp: CR with incomplete platelet recovery; UNK: unknown. 
Source: Roboz et al 2013; data on file 
In summary, Phase 1 showed that the Daily×5 regimen induced maximal DNA demethylation, 
and the dose of 60 mg/m2/day Daily×5 was the BED. The 90 mg/m2/day Daily×5 regimen was 
the highest well-tolerated dose for both MDS and AML subjects. Once weekly and twice weekly 
regimens were well tolerated at all doses but did not improve biological or clinical activity 
relative to the Daily×5 regimen. 
1.3.2.2
Phase 2 (SGI-110-01 Dose Expansion) 
Phase 2 dose expansion was opened as a multicenter, open-label, randomized dose-response 
comparison of 60 vs 90 mg/m2 SGI-110 SC Daily×5. Subjects were stratified by disease type 
(treatment-naïve elderly AML, relapsed/refractory AML, treatment-naïve MDS, and 
relapsed/refractory MDS). Approximately 50 subjects were enrolled for each disease cohort. The 
60 mg/m2 Daily×5 dose was chosen because it represented the BED from Phase 1, while 
90 mg/m2 was chosen to explore benefit from a higher dose that was still well tolerated in both 
MDS and AML subjects. After safety and preliminary efficacy were established with the 
Daily×5 regimen, a 10-day regimen with 60 mg/m2/day was studied in AML, first in 
relapsed/refractory subjects and then in treatment-naïve elderly subjects. 
1.3.2.2.1
Treatment-naïve Elderly AML 
Eligibility for treatment-naïve elderly subjects with AML in Study SGI-110-01 Phase 2 is 
defined below. Each eligibility criterion is recognized as high risk for more intensive therapy 
(Estey 2007). In addition to being 65 years of age, study subjects must have met at least one of 
these criteria: 


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•
Secondary AML. 
•
Poor-risk cytogenetics (monosomies or partial deletions of chromosome 5 or 7, abnormalities 
of 3q or 11q, translocation (6p23;9q34) or (9q34;22q11.2), or at least 3 unrelated cytogenetic 
abnormalities of any kind). 
•
Pre-existing clinically significant dysfunction of the heart (left ventricular ejection fraction 
[LVEF] <50%) or lung (diffusing capacity of the lung for carbon monoxide [DLCO] or 
forced expiratory volume in the first second [FEV1] <50% of expected), unrelated to 
leukemia. 
•
Poor ECOG PS of 2. 
Subjects were first randomly assigned to either 60 or 90 mg/m2/day SGI-110 Daily×5. The 
primary endpoint for AML subject cohorts was CRc (CR+CRi+CRp) rate at any time based on 
International Working Group (IWG) criteria (Cheson et al 2003). Adverse events (AEs) and 
LINE-1 DNA methylation pharmacodynamics were secondary endpoints for safety and 
biological activity. 
Table 2 presents subject and disease characteristics of previously untreated elderly (65 years) 
subjects with AML enrolled in the study. Of 51 subjects enrolled in this cohort, 24 and 27 were 
randomized to dose levels of 60 mg/m2/day and 90 mg/m2/day, respectively. The deleterious 
effect of advanced age generally remains after accounting for other covariates (Appelbaum et al 
2006). Subjects with advanced age 75 years represented 73% of subjects in the study. In 
addition 47%, 45%, and 35% had poor-risk cytogenetics, secondary AML, and ECOG PS 2, 
respectively. Subject characteristics were generally balanced between the 2 dose groups with few 
exceptions. Median age was 78 and 77 years; ECOG PS 2 was 46% and 26%; 58% and 59% 
were male; and 50% and 44% had poor-risk cytogenetics in the 60 and 90 mg/m2/day dose 
groups, respectively. The proportion of subjects with poor PS and/or poor-risk cytogenetics was 
higher in the 60 mg/m2 dose group. Overall, 31% of subjects had multiple criteria beyond 
advanced age that excluded them from candidacy for intensive induction chemotherapy. These 
criteria are established risk factors for more intensive induction chemotherapy for AML (Estey 
2007). 


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Table 2: 
Characteristics of Previously Untreated Elderly (65 Years) Subjects 
with AML in the SGI-110 Phase 2 Study (Daily×5 Regimen) 
Subject Characteristics 
60 mg/m2  
(N=24) 
90 mg/m2  
(N=27) 
Total  
(N=51) 
Median Age, years (range) 
78 (62-92) a  
77 (66-92) 
77 (62-92) a 
Age 75 years (n, %) 
16 (67) 
21 (78) 
37  
(73) 
Gender (n, %) 
 
 
 
 
  Men 
14 (58) 
16 (59) 
30  
(59) 
  Women 
10 (42) 
11 (41) 
21  
(41) 
ECOG Performance Status (n, %) 
 
 
 
 
  0 
3 (13) 
8 (30) 
11  
(22) 
  1 
10 (42) 
12 (44) 
22  
(43) 
  2 
11 (46) 
7 (26) 
18  
(35) 
Median % BM Blast at Baseline (range) 
40 (21-90) b 
46 (13-94) b 
40 (13-94) b 
Secondary AML (n, %) 
10 (42) 
13 (48) 
23  
(45) 
Poor-risk Cytogenetics c (n, %)  
12 (50) 
12 (44) 
24  
(47) 
Major Organ Dysfunction (n, %) 
1 
(4) 
2 
(7) 
3  
(6) 
Subjects with >1 criteria other than age (n, %) 
8 (33) 
8 (30) 
16  
(31) 
a 
One 62-year-old subject had 2 comorbidities (secondary AML and poor-risk cytogenetics) and was allowed 
into the study on that basis.  
b 
Four subjects had baseline BM differential blast counts of <20%: 2 of them had baseline peripheral blood (PB) 
blasts of 27% and 39%; the other 2 had BM pathology reports indicating either 40% blasts of total cellularity 
(Subject 
) or 55% normoblasts (Subject 
) and were thus diagnosed as AML (Listing BTA_Baseline 1 
[15 April 2014] and BM pathology reports).  
c 
Based on sponsor assessment. 
Source: Table EOP2_DEMO 1 (14 May 2014) and EOP2_BASELINE 1 (7 May 2014) 
The 60 and 90 mg/m2 doses for the Daily×5 regimen showed similar activity (Table 3). CRc was 
observed in 13 subjects (8 CR+5 CRi; 54%) and 15 subjects (9 CR+6 CRi; 56%) for 60 and 
90 mg/m2 dose groups, respectively. CRc for both doses combined was achieved in 28 of 
51 subjects (17 CR, 11 CRi, no CRp; 55%). CR rates were identical for the 2 doses at 33%. 
Table 3: 
60 vs 90 mg/m2 (Daily×5 Regimen): Complete Response for Previously 
Untreated Elderly (65 Years) Subjects with AML (Phase 2) 
Response Categorya 
Response Rate (n, %) 
60 mg/m2  
(N=24) 
90 mg/m2  
(N=27) 
Total  
(N=51) 
Complete response (CR) 
8 (33) 
[95% CI: 16,55] 
9 (33) 
[95% CI: 17,54] 
17 (33) 
[95% CI: 21,48] 
CR with incomplete blood count 
recovery (CRi) 
5 (21) 
6 (22) 
11 (22) 
CR with incomplete platelet 
recovery (CRp) 
0 
0 
0 
CRc rate (CR+CRi+CRp) 
13 (54) 
[95% CI: 33,74] 
15 (56) 
[95% CI: 35,75] 
28 (55) 
[95% CI: 40,69] 
a 
IWG 2003 AML Response Criteria (Cheson et al 2003). 
Source: Table EOP2_RESP 3 (1 May 2014) 


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Table 4 shows that safety was generally comparable between 60 and 90 mg/m2 SGI-110 doses in 
the Phase 2 study. Higher Grade 3 neutropenia was observed at the 90 mg/m2 dose.  
Table 4: 
60 vs 90 mg/m2 (Daily×5 Regimen): Previously Untreated Elderly 
Subjects with AML (Phase 2): Grade 3 AEs with Incidence 15%, 
Regardless of Relationship to SGI-110 
 
Number (%) of Subjects 
Adverse Event (AE) 
(MedDRA Preferred Term) 
60 mg/m2  
(N=24) 
90 mg/m2  
(N=27) 
Total  
(N=51) 
Any Grade 3 AE 
22 (92) 
25 (93) 
47 (92) 
Febrile neutropenia 
13 (54) 
13 (48) 
26 (51) 
Thrombocytopenia 
12 (50) 
10 (37) 
22 (43) 
Neutropenia 
  5 (21) 
12 (44) 
17 (33) 
Anemia 
  7 (29) 
  6 (22) 
13 (25) 
Leukopenia 
  5 (21) 
  7 (26) 
12 (24) 
Pneumonia 
  5 (21) 
  5 (19) 
10 (20) 
Source: Table EOP2 AE_G3 6.3 (2 May 2014) 
Treatment-related mortality in elderly patients on intensive induction remission therapy is 
usually high (on the order of 25% and up to 50%). Table 5 presents all-cause mortality in elderly 
subjects with AML from the Phase 2 study after SGI-110 treatment. The 30- and 60-day 
all-cause mortality rates were low (5.9% and 15.7%, respectively) when compared with intensive 
induction even though most intensive induction studies in the elderly reported only 
treatment-induced mortality rather than all-cause mortality (Estey 2007).  
Table 5: 
60 vs 90 mg/m2 (Daily×5 Regimen): All-Cause Mortality in Previously 
Untreated Elderly Subjects with AML Treated with SGI-110 
(Phase 2) 
Dose 
N 
Number (%) of Subjects 
30-day Mortality 
60-day Mortality 
All Previously Untreated AML  
51 
3 (5.9) 
8 (15.7) 
 
60 mg/m2 
24 
2 (8.3) 
4 (16.7) 
 
90 mg/m2 
27 
1 (3.7) 
4 (14.8) 
Source: EOP2_DEATH (26 Apr 2014 database cut-off date) 
LINE-1 DNA methylation data before and after treatment were available in 49 subjects (96%). 
Average maximum LINE-1 demethylation was similar for the 60 mg/m2 and 90 mg/m2 dose 
groups (-19% for 60 mg/m2 and -21% for 90 mg/m2).  
Based on a trend of improvement in response rate in relapsed/refractory AML with a 10-day 
regimen of SGI-110 (Section 1.3.2.2.2), a new cohort of 52 treatment-naïve elderly subjects with 
AML was treated with the 10-day regimen. Emerging preliminary data (study is still ongoing) 
suggest that this 10-day regimen in treatment-naïve elderly subjects is unlikely to be associated 


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with a significantly higher response rate than the Daily×5 regimen in this population and may be 
associated with higher toxicity. 
1.3.2.2.2
Relapsed/Refractory AML 
Subjects with relapsed/refractory AML were first randomly assigned to either 60 or 
90 mg/m2/day SGI-110 Daily×5. After completion of the SGI-110 Daily×5 cohort, an additional 
cohort of subjects with relapsed/refractory AML was treated with a 10-day regimen at the 
60 mg/m2 dose level (Days 1-5 and 8-12 every 28 days). After 2Ǧ4 cycles of the 10-day regimen, 
investigators were allowed to consolidate with the Daily×5 at 60 mg/m2/day until progression. 
Table 6, Table 7, and Table 8 show clinical responses, common Grade 3 AEs, and all-cause 
mortality for subjects with relapsed/refractory AML. Data from the Daily×5 regimen are 
presented for both 60 and 90 mg/m2 doses combined (there were no major differences between 
these doses; see Section 2.2.3.1) versus the 10-day regimen. 
Table 6: 
Complete Response for Relapsed/Refractory Subjects with AML 
(Phase 2) 
Response Categorya 
Response Rate (n, %) 
Daily×5 Regimen  
(60 or 90 mg/m2) 
(N=50) 
10-day Regimen  
(60 mg/m2) 
(N=53) 
Complete response (CR) (%) 
3b (6) 
[95% CI: 1,17] 
10 (19) 
[95% CI: 9,32] 
CR with incomplete blood count recovery  
(CRi) 
4 (8) 
2 (4) 
CR with incomplete platelet recovery  
(CRp) 
1 (2) 
4 (8) 
CRc rate (CR+CRi+CRp) 
8c (16) 
[95% CI: 7,29] 
16 (30) 
[95% CI: 18,44] 
a IWG 2003 AML Response Criteria (Cheson et al 2003). 
b 2 CR on 60 mg/m2 and 1 CR on 90 mg/m2. 
c 3 CRc on 60 mg/m2 and 5 on 90 mg/m2. 
Source: Tables EOP2_RESP 2 (1 May 2014) and EOP2_RESP 1 (8 May 2014) 
Table 7: 
Grade 3 AEs with Incidence 15%, Regardless of Relationship to 
SGI-110, in Relapsed/Refractory Subjects with AML (Phase 2) 
AE 
(MedDRA Preferred Term) 
Daily×5 Regimen  
(60 or 90 mg/m2) 
(N=50) 
10-day Regimen  
(60 mg/m2) 
(N=53) 
Any Grade 3 AE (n, %) 
45 (90) 
48 (91) 
Febrile neutropenia (n, %) 
30 (60) 
31 (59) 
Thrombocytopenia (n, %) 
10 (20) 
20 (38) 
Neutropenia (n, %) 
  4  (8) 
  8 (15) 
Anaemia (n, %) 
  9 (18) 
19 (36) 
Pneumonia (n, %) 
12 (24) 
15 (28) 
Source: Table EOP2 AE_G3 6.3 (2 May 2014) 
 


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Table 8: 
All-Cause Mortality in Relapsed/Refractory Subjects with AML 
(Phase 2) 
Dose 
N 
Mortality 
30-day (%) 
60-day (%) 
Daily×5 Regimen (60 or 90 mg/m2) 
50 
3 (6.0) 
6 (12.0) 
10-day Regimen (60 mg/m2) 
53 
1 (1.9) 
6 (11.3) 
Source: EOP2_DEATH (26 Apr 2014 database cut-off date) 
SGI-110 showed clinical activity, but complete responses with SGI-110 in relapsed/refractory 
AML (CRc rate of 16% and 30% for the Daily×5 and 10-day regimens, respectively; Table 6) 
were lower than what was observed in treatment-naïve elderly subjects with AML (CRc rate of 
55% for the Daily×5 regimen; Table 3). In relapsed/refractory AML, the 10-day regimen showed 
a trend of higher response rate and higher Grade 3 myelosuppression, with no difference in 
early all-cause mortality.  
1.4
Summary of Data for Treatment Choice (TC) 
Treatment choice (TC) will be compared with SGI-110 therapy in this study because no standard 
therapy exists for patients with previously untreated AML who are not considered candidates for 
intensive remission induction therapy. Available local TCs will depend on which TCs are 
approved locally. TC includes any of the following: 
•
20 mg cytarabine given SC twice daily (BID) on Days 1-10 every 28 days. 
•
20 mg/m2 decitabine given intravenously (IV) daily on Days 1-5 every 28 days. 
•
75 mg/m2 azacitidine given IV or SC daily on Days 1-7 every 28 days. 
As detailed in Section 1.2, each of these choices is supported by data from randomized clinical 
multicenter trials (Burnett et al 2007; Fenaux et al 2010; Kantarjian, Thomas et al 2012; Dombret 
et al. 2014). They are used as standard of care and/or recommended by the NCCN, European 
Leukemia Net, and European Society for Medical Oncology. There have been no direct 
comparisons among them, and regional treatment standards vary. 
1.5
Potential Risks and Benefits to Human Subjects 
Commonly observed AEs in Study SGI-110-01 in subjects with AML or MDS include injection 
site AEs, febrile neutropenia, thrombocytopenia, anemia, diarrhea, fatigue, and nausea. All these 
AEs are expected risks of SGI-110 in this Phase 3 trial in AML. These and additional risks in 
humans are described further in Section 8.0, Risks/Precautions. For more detailed information, 
please refer to the IB for SGI-110.  
Potential benefits of SGI-110 include symptom improvement, achieving leukemia disease 
remission, delayed disease progression, delayed need for subsequent anticancer therapy, and 
prolongation of survival.  


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For risks and benefits of TC therapies, refer to the latest locally-approved Prescribing 
Information for each therapy (USA examples: Cytarabine 2008, Dacogen 2010, Vidaza 2014). 
Risk-benefit considerations favor performance of this trial. This study population has limited 
therapeutic options, and available therapies are of limited utility. SGI-110 has demonstrated 
clinical activity and the potential to generate improved benefit over TC in AML. 
2.0
RATIONALE 
2.1
Rationale for the Study 
Rationale for this study comes from SGI-110's molecular structure, PK, pharmacodynamic (PD), 
and clinical data.  
SGI-110's dinucleotide structure protects the active decitabine moiety from inactivation by 
cytidine deaminase (CDA). Human PK data confirms that gradual in vivo dinucleotide cleavage 
increases decitabine exposure time and effective half-life relative to decitabine IV infusion. 
Prolonged exposure time is predicted to increase efficacy because decitabine activity is 
dependent on its incorporation into DNA during DNA synthesis, ie, S-phase of the cell cycle (
Griffiths, Choy et al 2013; Karahoca and Momparler 2013). Prolonged exposure results in more 
cancer cells susceptible to decitabine activity as they enter into S-phase. Also, a lower decitabine 
Cmax after SGI-110 relative to decitabine IV infusion might improve safety for toxicities 
associated with peak decitabine concentrations.  
During the FIH Phase 1 SGI-110-01 Dose Escalation, potent DNA demethylation, CR and other 
clinical responses were observed in heavily pretreated subjects with AML and MDS, including 
those previously treated with other existing HMAs (decitabine and azacitidine). 
In the Phase 2 SGI-110-01 Dose Expansion, 51 elderly subjects with AML who had other poor 
prognostic features and were not eligible for intensive chemotherapy received SGI-110. The 
observed CR rate of 33% and CRc rate of 55% exceeded those observed for currently available 
therapies in randomized, multicenter studies (see Table 9). Due to heterogeneity of subjects in 
single-center, nonrandomized studies with the consequent risk of selection bias, we selected 
recently published, randomized, multicenter studies of agents commonly used as standard of care 
for elderly patients with AML. Data in Table 9 indicate that SGI-110 may improve efficacy over 
other therapies for this AML patient population. 
 


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Table 9: 
SGI-110 Response Compared with Other Therapies for Previously 
Untreated Elderly Subjects with AML 
Response 
Number (%) Subjects 
Phase 2 
 Kantarjian, Thomas et al. 2012
Dombret et al 2014  Burnett et al 2007
SGI-110  
(N=51) 
Decitabine IV 
(N=242) 
LDAC 
(N=215) 
Azacitidine 
(N=241) 
LDAC  
(N=102) 
CR 
17 (33)  
[21~48]a 
38 (16) 
17 (8) 
48 (20) 
18 (18) 
CRc 
28 (55) 
[40~69]a 
67 (28) 
24 (11) 
67 (28) 
Unknown 
a 
95% CI based on a binomial distribution. 
Source: SGI-110 Phase 2: Table EOP2_RESP 3 (1 May 2014) 
Safety as assessed by early 30- and 60-day all-cause mortality rates, as well as Grade 3 
toxicities, are comparable to those of TC therapies except for a higher incidence of febrile 
neutropenia on SGI-110 (Table 10).   
Table 10: 
SGI-110 Safety Compared with Other Therapies for Previously 
Untreated Elderly Subjects with AML 
Common  
Grade 3 AEs  
and All-Cause 
Mortality 
% Subjects 
Phase 2 
 Kantarjian, Thomas et al. 2012
Dombret et al 2014  Burnett et al 2007
SGI-110 
(N=51) 
Decitabine IV 
(N=238)a 
LDAC 
(N=208)a 
Azacitidine  
(N=241) 
LDAC  
(N=102)a 
Febrile Neutropenia 
51% 
32% 
25% 
28% 
Unknown 
Thrombocytopenia 
43% 
40% 
35% 
24% 
Unknown 
Neutropenia 
33% 
32% 
20% 
26% 
Unknown 
Anemia 
25% 
34% 
27% 
16% 
Unknown 
30-day mortality 
5.9% 
9% 
8% 
6.6% 
26% 
60-day mortality 
15.7% 
19.7% 
23% 
16.2% 
Unknown 
a 
Number of subjects smaller than in  
Table 9, reflecting subjects who actually received treatment. 
 
2.2
Rationale for SGI-110 Dose and Regimen 
The dose and regimen of SGI-110 proposed for this Phase 3 study is based on dose-response data 
evaluated from all PK, PD, efficacy, and safety information available from Phase 1 and 2 
investigations. 
2.2.1
PK Dose Assessment 
PK profiles from 85 subjects who received doses ranging from 3 to 125 mg/m2 showed that the 
dose levels of 60 and 90 mg/m2 bracket the AUC expected from active metabolite decitabine at 
the FDA-approved dose of 20 mg/m2 of decitabine IV. Decitabine AUCs resulting from 


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treatment with SGI-110 at dose levels of 60 and 90 mg/m2 are 78% and 130%, respectively, of 
the AUC of decitabine IV (20 mg/m2) (Table 11). 
Table 11: 
Dose Selection PK Data: Decitabine Exposure (Mean ± SD) after 
SGI-110 Treatment (36–125 mg/m2/day on Days 1-5) 
 
Dose (N) 
Cmax  
(ng/mL) 
Cmax  
fraction of IVa  
AUClast 
(ng*hr/mL) 
AUC  
fraction of IVa 
  36 mg/m2 (12) 
 
16.5 ±  8.1 
0.11 
56.7 ± 18.7 
0.49 
  60 mg/m2 (20) 
 
27.4 ± 21.5 
0.19 
89.2 ± 52.9 
0.78 
  90 mg/m2 (14) 
 
41.4 ± 20.4 
0.28 
149 ± 54.7 
1.30 
125 mg/m2 (18) 
 
64.2 ± 24.4 
0.44 
239 ± 68.0 
2.08 
a 
Relative to values from decitabine IV (1-hr, 20 mg/m2) Cmax 147 ng/mL; AUC0-t 115 ng*hr/mL. 
Source: SGI-110 IB 
 
2.2.2
PD Dose Assessment: LINE-1 DNA Methylation 
In the SGI-110-01 Dose Escalation study, we assessed weekly LINE-1 DNA methylation in 
Cycle 1 as a surrogate of global DNA methylation and biological activity in 65 subjects on 
either the Daily×5 schedule (35 subjects) or the Once Weekly schedule (30 subjects) over a 
range of 8 dose levels: 3, 9, 18, 36, 60, 90, or 125 mg/m2/day). Data showed superior dose-
dependent-biological activity of the Daily×5 schedule over the Once Weekly schedule 
(Figure 1). Of 35 subjects on the Daily×5 schedule, dose-dependent increase in demethylation 
occurred up to 60 mg/m2/day with no further demethylation at higher doses. These data support 
an increase in DNA demethylation up to 60 mg/m2/day on Days 1-5 (Figure 1). 
Maximum demethylation at 60 mg/m2/day for 5 days met the prospectively defined BED 
endpoint in the Phase 1 study. This observation was later confirmed in the Phase 2 
randomization between 60 and 90 mg/m2/day on Days 1-5, where in 93 AML patients (49 with 
treatment-naïve elderly AML and 44 with relapsed/refractory AML), there was no significant 
difference in LINE-1 demethylation between 60 and 90 mg/m2 Daily×5 (Figure 2).  


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Figure 2: 
Dose Selection PD (60 vs 90 mg/m2/day, 5-Day Regimen SGI-110): 
Mean LINE-1 Demethylation in Treatment-naïve Subjects (top) and 
Relapsed/Refractory Subjects with AML (bottom) 
 
-35
-30
-25
-20
-15
-10
-5
0
0
5
10
15
20
25
30
%LINE-1 Demethylation
days
TN 5D (60 mg/m²) (N=24)
TN 5D (90 mg/m²) (N=25)
Maximum LINE1 change
Mean (Median) 60mg -18.6 (-17.9)
90mg -20.5 (-18.4)
P-value  0.5078*
 
  
-35
-30
-25
-20
-15
-10
-5
0
0
5
10
15
20
25
30
%LINE-1 Demethylation
days
R/R 5D (60 mg/m²) (N=22)
R/R 5D (90 mg/m²) (N=22)
Maximum LINE1 change
Mean (Median) 60mg -20.0 (-21.3)
90mg -21.3 (-20.9)
P-value  0.6162 *
 
* Overall group effect from a repeated measures mixed model analysis. 
TN=treatment-naïve; R/R=relapsed/refractory; 5D=5-day regimen (Daily×5) 
Source: Yee et al 2014 (top), Kantarjian et al 2013 (bottom) 


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2.2.3
Clinical Efficacy and Safety SGI-110 Dose-response 
2.2.3.1
Daily×5 Regimen in AML 
We conducted a randomized, dose-response, Phase 2 study in 101 subjects with AML 
(51 treatment-naïve elderly and 50 relapsed/refractory) that compared therapy with 60 versus 
90 mg/m2/day SGI-110 on Days 1-5 (see also Section 1.3.2.2). While the CR rate differed 
between the 2 different AML subject populations, efficacy of the 2 doses was remarkably similar 
(Table 12). Compared with the 60 mg/m2/day dose, the 90 mg/m2/day dose showed increased 
Grade 3 febrile neutropenia and pneumonia in relapsed/refractory AML subjects, and increased 
Grade 3 neutropenia in treatment-naïve AML subjects (Table 13). Overall, the incidence of 
AEs Grade 3 was similar between the doses. Mortality rates were low overall at both dose 
levels (Table 14). In conclusion, with the Daily×5 regimen, the dose of 60 mg/m2/day is selected 
based on similar efficacy to the higher dose of 90 mg/m2/day and potential for lower toxicity. 
Table 12: 
Dose Selection (60 vs 90 mg/m2/day, 5-day regimen): Complete 
Response Summary in Subjects with AML (Phase 2) 
 
Response Rate (Number [%] of Subjects) 
Response Categorya 
Relapsed/Refractory 
 
Treatment-naïve Elderly 
 
All 
60 mg/m2 
(N=24) 
90 mg/m2
(N=26) 
 
60 mg/m2 
(N=24) 
90 mg/m2 
(N=27) 
 
60 mg/m2 
(N=48) 
90 mg/m2 
(N=53) 
CR 
2 (8) 
1 (4) 
8 (33) 
9 (33) 
10 (21) 
10 (19) 
CRp 
0
 
1 (4) 
0
 
0
 
0 
 
1 (2) 
CRi 
1 (4) 
3 (12) 
5 (21) 
6 (22) 
6 (13) 
9 (17) 
CRc (CR+CRp+CRi) 
3 (13) 
5 (19) 
13 (54) 
15 (56) 
16  (33) 
20 (38) 
a 
IWG 2003 AML Response Criteria (Cheson et al. 2003). 
Source: Table EOP2_RESP1 (8 May 2014), Table EOP2_RESP3 (1 May 2014) (Database 26 April 2014) 
Table 13: 
Dose Selection (60 vs. 90 mg/m2/day, 5-day regimen): Grade 3 AEs 
with Incidence 15%, Regardless of Relationship to SGI-110 in 
Subjects with AML (Phase 2) 
 
Number (%) of Subjects 
Event 
Relapsed/Refractory 
 
Treatment-naïve Elderly 
 
All 
60 mg/m2 
(N=24) 
90 mg/m2
(N=26) 
 
60 mg/m2 
(N=24) 
90 mg/m2 
(N=27) 
 
60 mg/m2 
(N=48) 
90 mg/m2 
(N=53) 
Any Grade 3 AE 
20 (83) 
25 (96) 
 
22 (92) 
25 (93) 
42 (88) 
50 (94) 
Febrile neutropenia 
12 (50) 
18 (69) 
 
13 (54) 
13 (48) 
25 (52) 
31 (58) 
Thrombocytopenia 
6 (25) 
4 (15) 
 
12 (50) 
10 (37) 
18 (38) 
14 (26) 
Neutropenia 
2   (8) 
2   (8) 
 
5 (21) 
12 (44) 
7 (15) 
14 (26) 
Leukopenia 
3 (13) 
2 (12) 
 
5 (21) 
7 (26) 
8 (17) 
9 (17) 
Anemia 
5 (21) 
4 (15) 
 
7 (29) 
6 (22) 
12 (25) 
10 (19) 
Pneumonia 
4 (17) 
8 (31) 
 
5 (21) 
5 (19) 
9 (19) 
13 (25) 
Hypokalemia 
5 (21) 
3 (12) 
 
2   (8) 
5 (19) 
7 (15) 
8 (15) 
Source: EOP2_AE_G3 6.1 (2 May 2014; from database 26 April 2014) 
 


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Table 14: 
Dose Selection (60 vs 90 mg/m2/day, 5-day regimen): All-Cause Early 
Mortality in Subjects with AML (Phase 2) 
 
Number (%) of Subjects 
Mortality 
Relapsed/Refractory 
 
Treatment-naïve Elderly 
 
All 
60 mg/m2 
(N=24) 
90 mg/m2
(N=26) 
 
60 mg/m2 
(N=24) 
90 mg/m2 
(N=27) 
 
60 mg/m2 
(N=48) 
90 mg/m2 
(N=53) 
30-day 
2   (8.3) 
1 (3.8) 
2   (8.3) 
1   (3.7) 
4   (8.3) 
2 (3.8) 
60-day 
4 (16.7) 
2 (7.7) 
4 (16.7) 
4 (14.8) 
8 (16.7) 
6 (11.3) 
Source: EOP2_DEATH (database date 26 April 2014) 
 
2.2.3.2
10-day Regimen in AML 
The results of the 10-day regimen using 60 mg/m2/day in relapsed/refractory AML are 
presented in Section 1.3.2.2.2 (Table 6, Table 7, and Table 8). While the 10-day regimen 
showed a trend toward improved response rate in relapsed/refractory AML, it also resulted in 
more myelosuppression. Study of treatment-naïve elderly AML subjects with the 10-day 
regimen of SGI-110 is ongoing, but emerging preliminary data suggest that response rates are 
unlikely to be significantly higher than those observed with the Daily×5 regimen (CRc of 55%) 
and that the toxicity of the 10-day regimen in these older subjects could be more pronounced. 
The results of the 10-day regimen in these subjects after at least 3 months follow-up showed a 
CRc and CR of only 44% and 25%, respectively (compared with 55% and 33%, respectively, for 
the 5-day regimen) with higher 60-day all-cause mortality of 19.2% (compared with 15.7% for 
the 5-day regimen). In addition, the safety database at the time of analysis shows drug-related 
serious adverse events (SAEs) of 42% (compared to 16% for the 5-day regimen). Based on 
absence of higher response rate and the trend of higher early mortality and drug-related SAEs 
with the 10-day regimen in elderly subjects who are not candidates for intensive chemotherapy, 
the 5-day regimen is selected as the one associated with the best benefit-risk in this population. 
Higher response rates and favorable safety for the SGI-110 Daily×5 regimen compared with 
other treatments have already been observed in the proposed study population (Section 2.1, 
Table 9), so it is reasonable to propose this regimen in the phase 3 study. 
2.2.4
Dose Selection Conclusion from Phase 1 and 2 Study 
The SGI-110 Daily×5 regimen at 60 mg/m2/day provides the best benefit-risk ratio for the 
treatment of treatment-naïve elderly AML subjects based on available data. This regimen is 
supported by PK, PD, efficacy, and safety data from Study SGI-110-01. Results were similar 
but not demonstrably better at the 90 mg/m2 dose level, and based on potential dose-limiting 
myelosuppression, the 60 mg/m2 dose level is likely to be better tolerated over time.  


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3.0
STUDY OBJECTIVES 
3.1
Primary Objective 
To assess and compare efficacy (CR rate and OS) between SGI-110 and TC in adults with 
previously untreated AML who are not considered candidates for intensive remission induction 
chemotherapy. 
3.2
Secondary Objectives 
To assess and compare effects of SGI-110 and TC in adults with previously untreated AML who 
are not considered candidates for intensive remission induction chemotherapy with respect to the 
following variables:  
•
CRc (CR+CRi+CRp) rate. 
•
Number of days alive and out of the hospital (NDAOH). 
•
Progression-free survival (PFS). 
•
Transfusion needs. 
•
Health-related quality of life (QOL). 
•
Duration of CR. 
•
Safety. 
3.3
Exploratory Objectives 
•
 
  
•
 
4.0
INVESTIGATIONAL PLAN 
4.1
Overall Study Design 
This is a phase 3, multicenter, randomized, open-label study of SGI-110 versus TC. Blinded 
central reading of marrow and disease response will be performed. Subjects will be adults with 
previously untreated AML who are unfit to receive and not candidates for intensive remission 
induction chemotherapy.  
Approximately 800 subjects from approximately 100-160 study centers will be randomly 
assigned (1:1) to 1 of 2 groups: 
•
SGI-110: 60 mg/m2 SGI-110 given SC daily for 5 days (Days 1-5, Daily×5) in 28-day cycles. 
•
TC: subjects will be assigned (before randomization) by the investigator to 1 of the following 
treatment regimens: 


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•
20 mg cytarabine given SC BID on Days 1-10 every 28 days. 
•
20 mg/m2 decitabine given IV daily on Days 1-5 every 28 days. 
•
75 mg/m2 azacitidine given IV or SC daily on Days 1-7 every 28 days. 
Data will be reviewed by an independent Data Monitoring Committee (DMC) at regular intervals 
primarily to evaluate safety during study conduct. Refer to Section 4.4. 
The co-primary endpoints will be CR rate and OS. If either of the co-primary efficacy endpoints 
reaches statistical significance in favor of SGI-110 at either the interim analysis (OS only) or 
final analysis (CR and OS), then the study will be considered positive in efficacy. Randomization 
and analyses will be stratified by age, ECOG performance status (see Appendix 1), study center 
region, and secondary AML or poor-risk cytogenetics (see Appendix 2). 
Figure 3: 
Study Schema 
 
Approximately 800 adults 
with previously untreated AML who are not candidates for 
intensive remission induction chemotherapy
Study treatment randomized 1:1
28-day cycles
SGI-110 a
60 mg/m2 SC Days 1-5
Treatment Choice (TC)b: 
Cytarabine (Ara-C) 20 mg SC BID Days 1-10
or
Decitabine IV 20 mg/m2 Days 1-5 
or
Azacitidine 75 mg/m2 IV/SC Days 1-7
Primary analyses  (CR and OS) after at least 670 death events have occurred
 
a Treatment with SGI-110 should continue for at least 6 cycles in the absence of unacceptable toxicity or 
AML progression requiring alternative therapy. Beyond 6 cycles, treatment should continue as long as 
the subject continues to benefit based on investigator judgment. 
b TC will be determined before randomization and treatment with the regimens described (Section 7.2) 
should be used. Other treatment parameters should be applied according to institutional standard practice 
and approved local prescribing information. 


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4.2
Discussion of Study Design 
This trial compares SGI-110 and TC for treatment of subjects with AML who are not considered 
candidates for intensive remission induction chemotherapy at the time of enrollment. While the 
7+3 intensive chemotherapy for remission induction with potential for hematopoietic cell 
transplant (HCT) has been an established standard of care for decades in patients who are fit to 
receive this intensive treatment, there is no standard of care or universally approved therapies for 
treatment of AML patients who are not candidates for standard intensive remission induction 
chemotherapy. For these patients, goals of therapy are to prolong and improve quality of life by 
inducing complete remission for as long as possible, as well as to avoid treatment-induced early 
mortality.  
Eligibility for this trial is based on precedented criteria of unsuitability for intensive remission 
induction chemotherapy (Ferrara et al 2013; Kantarjian et al 2006; Kantarjian et al 2010) and 
other randomized trials in a similar patient population (Burnett et al 2007; Kantarjian, Thomas et 
al 2012; Dombret et al 2014). The co-primary endpoints for this trial are CR rate and OS.  
FDA has accepted durable CR in hematological malignancies as an established surrogate for 
clinical benefit because patients who achieve durable CR have been shown to survive longer than 
those who do not (Appelbaum et al 2007). Numerous studies have demonstrated that subjects 
achieving CR survive longer than subjects not achieving CR (Sievers et al 2001; Larson et al 
2005; de Greef et al 2005; Kantarjian et al 2003). FDA has also granted regular approval for 
treatment of hematologic malignancies on the basis of durable CR. In these settings, durable CRs 
were considered an established surrogate for a better life and possibly a longer life (Johnson et al 
2003).  
The trial includes a co-primary endpoint of OS to confirm no decrement in survival from severe 
toxicity. Secondary endpoints include CRc (CR+CRi+CRp) rate, NDAOH, PFS, number of 
transfusions, health-related QOL, duration of CR, and safety.  
TC, the control therapy for this study, includes treatments listed in Section 4.1. These therapies 
have not been compared directly, and regional treatment standards vary. Hence, all of these are 
allowed. All TC comparators are approved regimens for these agents mainly for other indications 
but have shown evidence of efficacy and safety from randomized trials in AML patient 
populations similar to the study population (Burnett et al 2007; Kantarjian, Thomas et al 2012; 
Dombret et al 2014). Each country will use the TC option(s) that are locally approved. 
This study is open-label. It is difficult to conduct such a trial in a blinded fashion because of the 
significant differences in the treatment schedules and the multiple treatment choices. The risk of 
observer bias can be controlled effectively by a central pathologist and a central response 
reviewer, who will be blinded to treatment assignment and independent (Section 6.2). OS 
endpoint is not prone to observer bias.  


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4.3
Study Endpoints 
4.3.1
Co-primary Endpoints 
•
CR rate based on modified IWG 2003 AML Response Criteria. 
•
OS, defined as the number of days from randomization to death. 
4.3.2
Secondary Endpoints 
•
CRc (CR+CRi+CRp) rate. 
•
NDAOH. 
•
PFS, defined as the number of days from randomization to disease progression or death, 
whichever occurs first. 
•
Number of red blood cell (RBC) or platelet transfusions (units) over the duration of the study 
treatment. 
•
Health-related QOL by EQ-5D (consisting of the EQ-5D-5L descriptive system and the EQ 
Visual Analogue Scale [EQ VAS]). 
•
Duration of CR, defined as defined as the time from first CR to time of relapse. 
•
Incidence and severity of AEs. 
•
30- and 60-day all-cause mortality. 
4.4
Data Monitoring Committee (DMC) 
An independent DMC will be established for this study. The DMC is an independent 
multidisciplinary group consisting of hematologic oncology experts and 1 biostatistician who, 
collectively, have experience in the treatment of subjects with AML and in the conduct and 
monitoring of clinical studies. The DMC will independently analyze accumulating data and 
make recommendations to the sponsor and the Study Steering Committee (SSC), as needed, to 
modify or discontinue the trial. DMC reviews will occur approximately each 6 months and as 
needed following study initiation until the final analyses. The DMC will also conduct 
independent interim analysis of OS as detailed in Section 11.0 and in a separate DMC Charter. 
The DMC will not stop the trial early based on the observed difference in CR. 
Details of DMC membership, responsibilities, meeting frequency and format, review materials, 
and communication plan will also be described in the DMC Charter. 
4.5
Study Steering Committee (SSC) 
An SSC composed of the lead investigators in the different study center regions, and sponsor 
representatives, will be formed to review study conduct at regular intervals, address any issues or 
recommend changes during the study conduct, and advise the sponsor on implementation of any 
DMC recommendations. SSC operational details will be described in a separate document.  


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5.0
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1
Number of Subjects and Centers 
Approximately 800 subjects will be enrolled in this study at approximately 100-160 study 
centers. 
5.2
Inclusion Criteria 
To be eligible for the study, subjects must fulfill all of the following inclusion criteria: 
1. Able to understand and comply with the study procedures, understand the risks involved in 
the study, and provide written informed consent before any study-specific procedure. 
2. Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic 
leukemia) according to the 2008 WHO classification (with BM or PB blast counts 20%). 
3. Performance status (ECOG) of 0-3. 
4. Adults with previously untreated AML except for hydroxyurea or corticosteroids. Prior 
hydroxyurea or lenalidomide treatment for MDS is allowed.  
5. Unfit to receive or not considered candidates for intensive remission induction chemotherapy 
at time of enrollment based on EITHER: 
a.
75 years of age  
OR 
b. <75 years of age with at least 1 of the following: 
i. Poor performance status (ECOG) score of 2-3.  
ii. Clinically significant heart or lung comorbidities, as reflected by at least 1 of: 
1) LVEF 50%. 
2) DLCO 65% of expected. 
3) FEV1 65% of expected. 
4) Chronic stable angina or congestive heart failure controlled with medication. 
iii. Liver transaminases >3 × upper limit of normal (ULN). 
iv. Other contraindication(s) to anthracycline therapy (must be documented). 
v. Other comorbidity the investigator judges incompatible with intensive remission 
induction chemotherapy which must be documented and approved by the study 
medical monitor before randomization. 
6. Creatinine clearance as estimated by the Cockroft-Gault (C-G) or other medically acceptable 
formulas 30 mL/min. 


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7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a 
negative pregnancy test at screening. Women of child-bearing potential and men with female 
partners of child-bearing potential must agree to practice 2 highly effective contraceptive 
measures during the study and for at least 3 months after completing treatment and must 
agree not to become pregnant or father a child while receiving treatment with SGI-110 and 
for at least 3 months after completing treatment. Contraceptive measures which may be 
considered highly effective comprise combined hormonal contraception (oral, vaginal, or 
transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion, sexual abstinence, and surgically successful vasectomy. 
Abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of birth control. 
5.3
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Candidate for intensive remission induction chemotherapy at the time of enrollment. 
2. Candidate for best supportive care only, ie, not a candidate for any active therapy with the 
TC comparators.  
3. Known extramedullary central nervous system (CNS) AML. 
4. Second malignancy currently requiring active therapy except breast or prostate cancer stable 
on or responding to endocrine therapy. 
5. Prior treatment with decitabine or azacitidine.  
6. Hypersensitivity to decitabine, azacitidine, cytarabine, SGI-110, or any of their excipients. 
7. Treated with any investigational drug within 2 weeks of first dose of study treatment. 
8. Total serum bilirubin >2.5 × ULN, except for subjects with Gilbert's Syndrome for whom 
direct bilirubin is <2.5 × ULN, or liver cirrhosis or chronic liver disease Childs-Pugh B or C. 
9. Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C 
virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals 
is allowed. 
10. Known significant mental illness or other condition such as active alcohol or other substance 
abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk 
of noncompliance with the protocol. 
11. Refractory congestive heart failure unresponsive to medical treatment; active infection 
resistant to all antibiotics; or advanced pulmonary disease requiring >2 liters per minute 
(LPM) oxygen. 


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5.4
Treatment Discontinuation and Withdrawal of Subjects 
Subjects who discontinue study treatment will be followed up for important study data, as 
described below, unless they withdraw consent from further follow-up. 
5.4.1
Discontinuation from Study Treatment 
Subjects who discontinue study treatment will still continue study follow-up procedures. 
Investigators are encouraged to assess all subjects according to the study protocol after 
discontinuation from study treatment.  
•
Investigators can discontinue subjects from study treatment in case of unacceptable toxicity, 
noncompliance, disease progression requiring alternative therapy, if the investigator 
determines it is in the subject's best interest, or if the subject becomes pregnant.  
•
Astex Pharmaceuticals may require that a subject is discontinued from treatment for safety 
reasons or for noncompliance.  
In all cases, the reason(s) for discontinuation from study treatment must be recorded in the 
source document and on the relevant page of the subject's electronic case report form (eCRF).  
It is important to obtain protocol-specified follow-up information on any subject discontinued 
from study treatment. Section 10.0 describes follow-up for AEs. At minimum, subjects should be 
followed up for safety until 30 days after the last dose of study treatment (ie, discontinuation of 
treatment in the study) (see Section 10.2). 
5.4.2
Withdrawal from the Study 
Subjects may withdraw consent for the study at any time, or subjects may be lost to follow-up. It 
is important to obtain follow-up information, according to standard medical practice, on any 
subject withdrawn prematurely from the study. Every effort must be made to undertake at least 
standard assessments that are critical for efficacy or safety evaluation, such as disease 
progression (if the subject did not withdraw because of disease progression), subsequent anti-
leukemia treatment, survival information, and safety data. 
The investigator must also ensure the subject understands that his or her medical records will 
continue to be available for the follow-up period as described in the approved informed consent 
form (ICF) for the entire study period. 
5.4.3
Replacement of Subjects 
Subjects will not be replaced in this study. 


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6.0
ENROLLMENT, RANDOMIZATION, AND BLINDING PROCEDURES 
Subjects will be screened at each study center for assessment of eligibility for the study. Each 
subject will be assigned a unique number (subject number) which will comprise the center 
number and the assigned subject number within the center. This number will be used to identify 
the subject throughout the study. 
6.1
Randomization 
Eligible subjects will be randomly assigned to study treatment. Treatment assignments for the 
individual subjects will be determined through a computer generated randomization scheme and 
accessed through an interactive response system. Instructions for access and use of the 
interactive response system for randomization will be provided to participating study centers 
separately. Randomization will be 1:1 between SGI-110 and TC groups, and will be stratified by 
age (<75 or 75 years), ECOG performance status (0-1 or 2-3; see Appendix 1 for the ECOG 
criteria), study center region (North America, Europe, rest of world [ROW]), and secondary 
AML (secondary to MDS or other antecedent hematologic disorder) or poor-risk cytogenetics 
(either, neither; see Appendix 2). Selection of 1 of the TCs must be made prior to the 
randomization of each subject. Subjects should receive study treatment as soon as possible after 
randomization (maximum of 1 week between randomization and treatment). 
6.2
Blinding 
The sponsor, investigators and study subjects are not blinded in this study. However, to minimize 
the potential bias associated with assessment of treatment outcome, response will be determined 
by a blinded independent central response reviewer, based on assessment by a blinded 
independent central pathologist. Refer to Section 11.6. The specific process used for handling 
test samples and reports will be described separately.  
7.0
STUDY TREATMENTS 
SGI-110 is the Investigational Medicinal Product (IMP) (Section 7.1), and Treatment Choice 
(TC) is the active comparator (Section 7.2). 
7.1
Investigational Medicinal Product (IMP): SGI-110 
SGI-110 
chemical 
name: 
Sodium 
(2R,3S,5R)-5-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl)-2 
(hydroxymethyl) 
tetrahydrofuran-3-yl 
((2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9(6H)-yl)-3-
hydroxytetrahydrofuran-2-yl)methyl phosphate 
7.1.1
IMP Information 
SGI-110 product is supplied in a two-vial configuration. 


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SGI-110 for Injection, 100 mg is a glass vial containing lyophilized SGI-110 drug powder for 
reconstitution and SC injection using the custom diluent supplied in a separate vial. Each vial is 
stoppered and sealed with a flip-off cap.  
SGI-110 Diluent for Reconstitution, 3 mL is a glass vial with 3 mL of custom diluent. Each vial 
is stoppered and sealed with a flip-off cap. The diluent comprises 3 commonly used excipients, 
propylene glycol, glycerin, and ethanol, that are generally recognized as safe. 
Store the SGI-110 for Injection, 100 mg vial, in the original packaging, refrigerated (2°C to 8°C) 
in a secure, locked facility accessible only to authorized study personnel until use. Store SGI-110 
Diluent for Reconstitution, 3 mL at 2°C to 30°C in the upright position until use. Both vials are 
preservative free and for single use only. The sponsor will retest the SGI-110 at regular intervals, 
according to ICH guidelines, and if warranted, the expiration date will be extended and 
documented accordingly. 
The sponsor recommends following Occupational Safety and Health Administration (OSHA) 
Guidelines for handling cytotoxic drugs outlined in Yodaiken and Bennett 1986 or similar 
institutional or country-specific guidelines. Preparation should occur according to institutional 
practice. For skin contact or spillage, refer to the material safety data sheet (MSDS) for treatment 
options. 
Reconstituted drug product is intended for SC administration at a recommended concentration of 
100 mg/mL.  
7.1.2
SGI-110 Regimens and Administration 
The SGI-110 regimen for this study is 60 mg/m2 given Daily×5 (Days 1-5 in a 28-day cycle) for 
at least 6 cycles in the absence of unacceptable toxicity or AML progression for which the 
investigator intends to offer an alternative therapy. Beyond 6 cycles, treatment should continue 
as long as the subject continues to benefit based on investigator judgment. In the ongoing 
phase 2 dose expansion study (Section 1.3.2.2), some subjects responded late to treatment: of 
51 treatment-naïve elderly AML subjects, 2 subjects responded, and another 2 subjects improved 
their response status from CRi or CRp to CR, after more than 6 treatment cycles with SGI-110. 
Administer SGI-110 by SC injection, preferably in the abdominal area, upper thigh, or arm. The 
total amount (in mg) of SGI-110 to be administered is determined by body surface area (BSA). 
In calculating BSA, use actual heights and weights. Do not adjust to "ideal" body weight. The 
institutional standard for calculating BSA is acceptable.  
Take care to avoid intradermal injection, as this may result in injection site pain  
(see Section 8.0).  
Additional guidelines regarding SC injection will be detailed in the study procedures manual.  


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Investigators are prohibited from supplying SGI-110 to any subject not enrolled in this study or 
to any physicians or scientists except those designated as sub-investigators. The investigator 
must ensure that subjects receive SGI-110 only from personnel who fully understand the 
procedures for administering the study treatment. 
7.2
Treatment Choice (TC) Active Comparator  
TC will be one of the following treatment regimens (dose, schedule, and administration route) 
based on regimens approved by regulatory agencies, on published randomized studies, and on 
recommendations by the NCCN, European Leukemia Net, and European Society for Medical 
Oncology: 
•
20 mg cytarabine given SC twice daily (BID) on Days 1-10 every 28 days. 
•
20 mg/m2 decitabine given IV daily on Days 1-5 every 28 days. 
•
75 mg/m2 azacitidine given IV or SC daily on Days 1-7 every 28 days. 
Other use and treatment parameters of TC drugs (such as duration of treatment and dose 
adjustment guidelines) should follow locally approved prescribing information and institutional 
standard practice. 
Examples of locally approved prescribing information are the following: Cytarabine 2008, 
Dacogen 2010, Vidaza 2014 (USA); and Cytarabine 20mg/ml 2014, Dacogen 50 mg powder for 
concentrate for solution for infusion 2014, Vidaza 25 mg/ml powder for suspension for injection 
2014 (UK). 
If a subject must discontinue TC study treatment, alternative therapy should be determined by 
the physician or institutional standard practice. Subjects randomly assigned to TC study 
treatment will not be allowed to receive SGI-110 as alternative therapy. 
7.3
Guidelines for Adjusting or Withholding Study Treatment 
7.3.1
Guidelines for SGI-110 
SGI-110 study therapy is intended to be administered for a minimum of 6 total cycles.  
It is recommended that the initial dose of SGI-110 is given on schedule (every 28 days) for the 
first 2 cycles without dose modification regardless of blood counts recovery to ensure initial dose 
intensity. Timing of cycle initiation and dose level of SGI-110 starting Cycle 3 will be guided by 
peripheral blood (PB) blast and neutrophil/platelet counts after the prior cycle, as indicated in 
Table 15, which describes dose modification based on Day 29 or later PB counts.  


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Table 15: 
SGI-110 Dosing Adjustment Guideline Based on End of Cycle 2 
(C2, Day 29 or Later) Peripheral Blood Blasts and Counts 
Neutrophils 
Platelets 
Threshold 
Peripheral Blood (PB) Blasts 
Presence of leukemic blasts
No leukemic blasts and 
recovery within <2 weeks 
No leukemic blasts and 
recovery after >2 weeks 
Neutrophils <1000/ȝL 
or 
Platelets <50,000/ȝL 
Administer full dose on 
schedule. 
Delay SGI-110 until counts 
>threshold, then administer 
full dose. 
Delay study drug until counts 
>threshold, then reduce 
1 dose level. 
Neutrophils 1000/ȝL 
and 
Platelets 50,000/ȝL 
Administer full dose on 
schedule. 
Administer full dose on 
schedule. 
Delay study drug until counts 
>threshold, then reduce 
1 dose level. 
For subjects with CRi or CRp for at least 2 cycles, SGI-110 treatment should be reduced 1 dose 
level at a time in each subsequent cycle until normal counts recover to levels of full CR 
(neutrophils 1000/ȝL and platelets 100,000/ȝL). The highest dose level that achieves normal 
counts recovery should be kept for subsequent cycles. Recommended reduced SGI-110 dose 
levels should be from 60 mg/m2/day to 45 mg/m2/day, then to 30 mg/m2/day, and then to 
15 mg/m2/day with the Daily×5 regimen. 
Beyond 6 cycles, treatment should continue at the dose level reached as long as the subject 
continues to benefit based on investigator judgment and subject response and tolerability.  
7.3.2
Guidelines for TC 
For dose adjustment of TC therapies, refer to the latest locally-approved Prescribing Information 
for each therapy (USA examples: Cytarabine 2008, Dacogen 2010, Vidaza 2014) in the relevant 
region. Dose adjustments should be made according to institutional standards and relevant 
locally approved Prescribing Information. 
7.4
Emergency Treatment for Subjects with Highly Proliferative Progressive AML 
This study allows enrollment of subjects with proliferative AML (total WBC count 20,000). 
For those subjects, pretreatment with hydroxyurea or leukapheresis before randomization may be 
warranted to decrease total WBC count. However, hydroxyurea, leukapheresis, or other anti-
leukemia therapy is not allowed after subjects are randomly assigned to study treatment. After 
the first cycle of study treatment, subjects who continue to have rapidly increasing total WBC 
counts with increasing PB blasts % are allowed to start the next study treatment cycle earlier than 
Day 29. Early administration of study treatment allows such subjects to remain on study and 
potentially benefit from treatment. Benefit may require multiple cycles given the lower intensity 
treatments in this study (as compared with intensive remission induction therapy).  
Any deviation from the study schedule should be clearly explained and documented in the eCRF. 
After the proliferative phase subsides and the subject responds to treatment, the standard 
treatment cycle duration of 28 days should be resumed and maintained. 


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7.5
Concomitant Treatment 
On the concomitant medication CRF/eCRF, document all medications a subject takes, starting 
from 14 days before randomization and ending 30 days after the last dose of study treatment. 
Include supportive or palliative treatment (see below), whether prescription or nonprescription, 
and medications taken for procedures (eg, biopsy). Include start and stop dates and indication.  
7.5.1
Supportive, Prophylactic, or Other Treatments 
The investigator is permitted to prescribe supportive treatment(s) at his or her discretion. 
Appropriate hydration and supportive care, including blood and platelet transfusions, may be 
administered according to study-center standards. Aggressive surveillance, prophylaxis, and/or 
treatment of bacterial, fungal, viral, and opportunistic infections are essential to prevent 
morbidity and mortality. Any supportive treatment or infusion should be documented in the 
provided CRFs/eCRFs. 
7.5.1.1
Antibiotics or Anti-fungals 
Antibiotics and/or anti-fungals may be used to manage febrile neutropenia based on institutional 
standard practice.  
7.5.1.2
Hematopoietic Growth Factors 
Use is permitted if deemed to be medically necessary by the treating physician and should be 
guided by accepted practice or institutional guidelines. 
7.5.1.3
Hydroxyurea and/or Leukapheresis 
Hydroxyurea and/or leukapheresis will be allowed for all subjects before randomization to 
reduce WBC counts in subjects with highly proliferative disease. Hydroxyurea and leukapheresis 
are prohibited after randomization. If, after initiation of study treatment, a subject's disease 
remains highly proliferative, where WBC counts and blast % are high and start to rise again 
before Day 28, the investigator may administer the subsequent treatment cycle earlier than 
Day 28 as described in Section 7.4. This should be documented in the eCRF. 
7.5.2
Prohibited Concomitant Treatment 
Other anticancer therapies, unless specified in the protocol, are not to be used. Cytotoxic 
chemotherapy and investigational treatments are prohibited for as long as subjects remain on 
study treatment. 
Vaccination with live vaccines is prohibited while subjects remain on study treatment. 


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7.6
Overdose Instructions 
Record the actual dose of study drug administered in the source document and on the Dosing 
CRF/eCRF. Record any adverse clinical signs and symptoms associated with a potential 
overdose on the AE CRF/eCRFs. Report signs and symptoms of a potential overdose that meet 
serious adverse event (SAE) criteria (defined in Section 10.1.2) to Astex on the SAE form within 
24 hours (see Section 10.3). Treat any AE (including SAE) based on standard care for the 
specific signs and symptoms.  
8.0
RISKS/PRECAUTIONS 
Refer to the SGI-110 IB for the most current risks and precautions, as well as a complete list of 
AEs considered expected with SGI-110 therapy. 
Common AEs observed in the AML/MDS population treated with SGI-110 include injection site 
AEs, febrile neutropenia, thrombocytopenia, anemia, diarrhea, fatigue, and nausea. The most 
common SAEs were febrile neutropenia and pneumonia. MDS and AML subjects commonly 
have severely compromised BM and blood counts. Severe or prolonged myelosuppression have 
been reported as related to SGI-110, particularly on high doses (ie, 125 mg/m2). Two 
AML/MDS subjects (1 MDS and 1 AML of 357 subjects total) treated with SGI-110 had drug-
related SAEs of sepsis with an outcome of death at doses of 125 mg/m2/day for 5 days (MDS) 
and 18 mg/m2/day for 5 days (AML). 
Refer to Section 7.3 for guidelines to adjust study treatment dose. 
Injection site reactions, such as pain, irritation, inflammation, erythema, and burning have been 
reported in the AML/MDS population and in subjects with solid tumors. Injection site reactions 
are related to SGI-110 SC administration. Care must be taken to avoid intradermal injection. 
Administer SGI-110 by slow SC injection. If injection site pain is reported upon injection, apply 
ice packs to the injection site both before and after injection. If injection site AEs are reported at 
subsequent injections despite slow injection and use of ice packs, pretreatment with topical or 
systemic analgesics can be considered. 
Use of decitabine, the active metabolite of SGI-110, alters fertility and is mutagenic. Because of 
the possibility of infertility, men should seek advice on conservation of sperm, and women of 
child-bearing potential should seek consultation regarding oocyte cryopreservation before study 
treatment is started. 
For risks and benefits of TC therapies, refer to the latest locally-approved Prescribing 
Information for each therapy (USA examples: Cytarabine 2008, Dacogen 2010, Vidaza 2014).  


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9.0
STUDY ASSESSMENTS AND PROCEDURES 
9.1
Eligibility 
Eligibility will be assessed by the investigator for the purpose of randomization and study entry; 
however, AML diagnosis will be confirmed by the central pathologist. Investigators are 
encouraged to request central pathologist confirmation of eligibility before randomization if they 
believe the AML diagnosis would be in doubt. Such confirmation will minimize the number of 
subjects the central pathologist may deem as having unconfirmed AML. 
9.2
Efficacy 
PB will be assessed at screening and on Day 1 of each cycle for response evaluation. BM 
aspirate or biopsy will be performed at screening then at the end of Cycles 2, 4, and 6 (Day 1 of 
Cycles 3, 5, and 7) unless PB shows persistence of leukemic blasts that excludes the possibility 
of a marrow response. After Cycle 6 BM assessment (Day 1 of Cycle 7), BM aspirate/biopsy will 
be repeated every 3 months for the first year on study and then every 6 months thereafter until 
PB or BM assessment shows disease progression or relapse. 
CR will be assessed by modified IWG 2003 AML Response Criteria (see Section 11.6), 
based on blood sampling and BM aspirate/biopsy. Response assessment will be based on BM 
blinded review and the most concomitant PB counts. After blinded BM response is confirmed, 
assessment of normal count recovery will be done based initially on the most concomitant PB 
counts and in later cycles on PB counts from Day 1 of each cycle to avoid transient treatment-
induced normal count suppression. The central pathologist who evaluates BM and PB counts 
for response assessment, as well as the central response reviewer, will be blinded to 
treatment assignment (Section 6.2).  
9.3
Pharmacokinetics 
PK parameters will be assessed using population PK analysis. At selected study centers, sparse 
PK samples will be collected within windows at the time points specified below (with time of 
sampling recorded). 
For subjects who receive SGI-110, blood sample collection will be assigned to the following 
time points:  
•
Cycle 1, Day 1, at 1.5 hours (±30 minutes) and 3 hours (±1 hour) postdose.  
(1.5-hours sample is intended to be time-matched with the on-treatment ECG evaluation.) 
AND 
•
Cycle 1, Day 5, at 1 hour (±30 minutes) and 5 hours (±2 hours) postdose. 
For subjects in the TC group receiving decitabine IV, blood sample collection will be assigned to 
one of the following time points: 


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•
Cycle 1, Day 1, at 30 minutes (±10 minutes) into the IV infusion, and then immediately 
before the end of infusion (at 1 hour). 
OR 
•
Cycle 1, Day 5, immediately before the end of infusion (at 1 hour); and at 5 minutes 
(±2 minutes) and 3 hours (±1 hour) after the end of infusion. 
9.4
Safety 
Safety assessments will be based on AEs, concomitant medications, physical examination, vital 
signs, ECOG status, electrocardiogram (ECG) measurements, and clinical laboratory parameters 
(hematology and chemistry). 
9.5
Study Procedures 
9.5.1
Schedule of Events 
Table 16 presents the complete schedule of events for the study, with details following in text. 
Additional information on the study procedures is provided in the study procedures manual.  
Clinical and diagnostic laboratory evaluations are detailed before study entry, throughout the 
study, and at the follow-up evaluation. The purpose of obtaining these detailed measurements is 
to ensure adequate assessments of efficacy, safety, and tolerability. Repeat clinical evaluations 
and laboratory studies more frequently if clinically indicated. 
Note any deviation from protocol procedures. Investigators are responsible for implementing 
appropriate measures to prevent the recurrence of violations and deviations and to report to their 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) according to policy. 
 


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Table 16: 
Schedule of Events 
Cycles (28 Days) 
1 and 2 
3 
Tx Dsc 
Safety FUc Long Term 
Follow-Upd 
Cycle Day 1 
2 
3 
4 
5 
6 
7 
8b 
(±2) 9 
10
15 
(±3)
22 
(±3)
1  
(+7) 2 
3 
4 
5 
6 
7 
8b
9 
10
15 
(±3)
Study Treatmentb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SGI-110 SC Days 1-5 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
TC: Cytarabine SC BID Days 1-10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
TC: Decitabine IV Days 1-5 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
TC: Azacitidine IV/SC Days 1-7 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Procedures 
Screeninga 
(D -14 to -1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, including 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
X 
Xe
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signsf 
X 
X 
X 
X 
X 
X Xf
Xf
Xf
Xf
Xf
 
 
X 
X 
X 
X 
X Xf
Xf
Xf
Xf
Xf
 
X 
 
ECOG performance status 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
12-lead ECG (triplicate)g 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Health-related QOL (EQ-5D-5L)h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xd 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and BSA calculation (use 
height from screening)i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/concomitant medicationsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization (before dosing) 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 16: 
Schedule of Events (Contd) 
Cycles (28 Days) 
1 and 2 
3 
Tx Dsc 
Safety FUc Long Term 
Follow-Upd 
Cycle Day 1 
2 
3 
4 
5 
6 
7 
8b 
(±2) 9 
10
15 
(±3)
22 
(±3)
1  
(+7) 2 
3 
4 
5 
6 
7 
8b
9 
10
15 
(±3)
Laboratory Assessments 
Screeninga 
(D -14 to -1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyk 
X 
Xk
 
 
 
 
 
 
X 
 
 
X 
X Xk 
 
 
 
 
 
 
 
 
 
Xk
X 
Xd 
Serum chemistryl 
X 
Xl
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine pregnancy testm 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Pharmacokinetics (PK)n 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Molecular genetics and cytogeneticso 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM aspirate or biopsyp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xd 
Hospitalizations/Transfusionsq 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Xd 
Subsequent anti-leukemia therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Disease progression statusr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xd 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
a. 
Screening (and Randomization): Screening must occur within 14 days of randomization, except that BM aspirate/biopsy and molecular genetics/cytogenetics will be 
collected within 28 days before Cycle 1 Day 1. Randomization should occur as close as possible to Cycle 1 Day 1 and may occur on Cycle 1 Day 1. A maximum of 1 week 
between randomization and treatment is allowed. 
b. Study Treatment: Dosing days are consecutive according to approved prescribing information.  
c. 
Treatment discontinuation and safety follow-up (Tx Dsc Safety FU) visit: Must occur 30 (+7) calendar days after the last dose of study treatment. If the subject cannot 
attend the clinic, the visit may be conducted by telephone to collect, at minimum, AE information. 
d. Long-term follow-up visits: Start after treatment discontinuation. Monthly (±7 days) visits are required for subjects who discontinue study treatment before Cycle 6, until 
6 months after the start of study treatment. After monthly visits for at least 6 months, long-term follow-up visits will be every 3 months (±2 weeks) until death. Health-related 
QOL, hospitalizations, and transfusions are done only at monthly visits. Hematology, BM aspirate or biopsy, and disease progression assessment are done only for subjects 
who have not progressed at treatment discontinuation. Visits may be conducted by telephone. 
e. 
Physical examination: Complete physical examination includes weight and examination of body systems according to institutional standards. A complete physical 
examination is required. Day 1 physical examination does not need to be repeated if it was done within 4 days. 


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f. 
Vital signs: Assess before dosing on every dosing day in the clinic (ie, Days 6 and 7 only for TC therapies cytarabine and azacitidine, and Days 8-10 only for cytarabine), 
after subject has rested in the sitting position for at least 3 minutes. Vital signs include blood pressure (systolic/diastolic), respiration rate, heart rate, and body temperature. If 
dosing is done at home (according to local standards), vital sign assessment is not required. 
g. 12-Lead ECG (triplicate): ECGs in triplicate will be conducted predose and 1-2 hours postdose only on Day 1 of Cycle 1, and at study treatment discontinuation. Acquired 
and reviewed according to institutional procedure (rhythm, atrial rate, ventricular rate, PR interval, QRS duration, and QT/QTc, morphology and overall interpretation). The 
QT correction method should be the same for all ECGs for a given subject. Clinically significant abnormal ECG at study treatment discontinuation as compared to the predose 
ECG should be followed for recovery or stabilization. 
h. Health-related QOL: Administer EQ-5D-5L (see Appendix 4) before treatment on Day 1 of each cycle. For subjects who discontinue treatment before Cycle 6, administer 
EQ-5D-5L at monthly visits until 6 months after the start of study treatment. Not required for visits every 3 months in long-term follow-up. 
i. 
Weight and BSA (body surface area) calculation: Weigh subjects on Day 1 of each cycle. BSA recalculation is only required if weight changes ±10% or more from 
screening. 
j. 
Concomitant medications: Document all concomitant medications within 14 days before randomization to 30 days after the last dose of study treatment. 
k. Hematology: Include complete blood count with manual differential. Day 1 hematology for all cycles does not need to be repeated if done within 4 days of Day 1. For 
Cycles >6, hematology will be required only on Day 1. Additional hematology assessment may be done for safety or for subject management at the investigator’s discretion. 
Collection, analysis, and reporting information are described in the Study Lab Manual. 
l. 
Serum chemistry: Refer to Table 17. Day 1 chemistry for all cycles does not need to be repeated if done within 4 days of Day 1. Additional chemistry assessment may be 
done for safety or for subject management at the investigator’s discretion. Collection, analysis, and reporting information are described in the Study Lab Manual. 
m. Pregnancy test: Women of child-bearing potential only. The screening test must be done within 7 days of Cycle 1 Day 1 (ie, Day -7 to -1); test not required on Cycle 1 Day 1 
if done at screening. 
n. PK: At selected study centers: Subjects receiving SGI-110 and subjects in the TC group who receive decitabine IV in Cycle 1 only. Refer to Section 9.3 for details. 
o. Molecular genetics and cytogenetics: BM and blood samples will be collected within 28 days before starting study treatment to evaluate cytogenetics (chromosome 
abnormalities) and gene mutations (such as FLT3-ITD, NPM1, CEBPA).  
p. BM aspirate or biopsy: BM aspirate and/or biopsy differential count will be performed according to local standard practice. The screening aspirate must be collected within 
28 days before starting study treatment. If BM aspirate/biopsy was completed before consent for this study, center must be able to obtain slides for central reader and samples 
for screening cytogenetic assessments. A biopsy should be done if no spicules are observed in the aspirate. Marrow aspirate or biopsy differential may include the following: 
• Total cells counted 
• Blasts 
• Promyelocytes 
• Myelocytes 
• Metamyelocytes 
• Segmented neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Plasma cells 
• Monocytes 
• Pronormoblasts 
• Normoblasts 
• M:E ratio 
• Auer rods 
 
• Megakaryocytes: increased, normal, decreased, absent 
• Presence of dysplasia: dysE, dysG, dysM 
• Cellularity: % cellularity: hypocellular, hypercellular, normocellular  
• Other 
 
Slides should be Wright Giemsa or May Grunwald Giemsa stained. Send 1 or 2 PB and BM slides for each subject at each time point. Detailed instructions on collection, 
labeling and shipping are described in the Study Lab Manual. A BM sample adequate for analysis must be obtained. Repeat the BM sample if not interpretable. 
 
Response assessment is done on Day 1 of Cycles 2 based on BM aspirate/biopsy and the most concomitant PB. Assess PB at screening and on Day 1 of each cycle. Perform 
BM aspirate/biopsy at screening and then at the end of Cycles 2, 4, and 6 (ie, Day 1 of Cycles 3, 5, and 7 [±7-day window]) unless PB shows persistence of leukemic blasts 
that excludes the possibility of a marrow response. After blinded BM response is confirmed, assessment of normal count recovery is done based initially on the most 
concomitant PB counts and in later cycles on PB counts from Day 1 of each cycle to avoid transient treatment-induced normal count suppression. Subjects who discontinue 
treatment before Cycle 6 Day 1 before documented disease progression must undergo response assessment until disease progression or relapse is confirmed. After Cycle 6, 


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repeat BM aspirate/biopsy every 3 months for the first year on study and then every 6 months thereafter until PB or BM assessment shows disease progression or relapse. 
Refer to Section 9.2. 
q. Hospitalizations/Transfusions: Document all blood and platelet transfusions (blood product transfused and units) within 28 days before starting study treatment. Document 
all hospital admission and discharge dates and main reason for hospitalization, as well as all blood and platelet transfusions (blood product transfused and units), from Cycle 1 
Day 1 and then monthly to 6 months after the first dose or to the Tx Dsc Safety FU visit, whichever is later. Not required for visits every 3 months in long-term follow-up. 
r. 
Disease progression status: For subjects who discontinue study treatment before disease progression is documented, PB and BM aspirate/biopsy assessments as described in 
footnote “p” should continue until disease progression or relapse is confirmed.  
 


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9.5.2
Screening and Baseline Procedures 
After the investigator or sub-investigator confirms that a subject is eligible and willing to 
participate in the study, study center personnel will randomly assign the subject to study 
treatment according to the study procedures manual.  
Within 14 days before randomization (unless otherwise specified), perform the following study 
procedures and tests: 
•
Written informed consent. The ICF must be signed and dated by the subjects before any 
study-specific samples are collected or study-specific procedures are initiated. 
•
Complete medical history, including demographics. Record disease history, including the 
date of initial diagnosis and list prior treatments and responses to these treatments. Document 
concurrent medical signs and symptoms to establish baseline conditions. Prior treatments for 
MDS or other hematologic disorder, CMML, and AML should be recorded. 
•
Investigator's confirmation of eligibility. Perform all necessary procedures and evaluations to 
document that the subject meets each eligibility criterion. 
•
Complete physical examination including weight and examination of body systems according 
to institutional standards.  
•
Vital signs include resting systolic/diastolic blood pressure, resting respiration rate, resting 
heart rate, and body temperature.  
•
ECOG performance status.  
•
Height measurement (for BSA calculation). 
•
All study-procedure-related AEs from the time of informed consent. 
•
Record concomitant medications within 14 days before randomization. 
•
Blood and urine sample collection for laboratory assessments. (See Table 17) 
•
Serum or urine pregnancy test: for women of child-bearing potential only, collected within 
7 days before starting study treatment. Results must be negative for the subject to be eligible 
for enrollment into the study. 
•
Blood sample collection for cytogenetics and molecular genetics, collected within 28 days 
before starting study treatment. 
•
BM aspirate or biopsy for baseline disease assessment, cytogenetics, and molecular genetics, 
collected within 28 days before starting study treatment. 
•
All blood and platelet transfusions (blood product transfused and units) within 28 days before 
starting study treatment.  
•
Study treatment randomization, after eligibility is confirmed. Randomize as close as possible 
to the first dose of study treatment (on Cycle 1 Day 1), within a maximum of 1 week from 
Cycle 1 Day 1. 


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Table 17: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Serology 
• Complete blood count 
(CBC) 
 - Hemoglobin 
 - Hematocrit 
 - RBC counts 
 - WBC counts 
 - Platelets 
• WBC differential 
 - Blasts 
 - Promyelocytes 
 - Myelocytes 
 - Metamyelocytes 
 - Monoblasts 
 - Promonocytes 
 - Neutrophils 
 - Band neutrophils 
 - Segmented neutrophils 
 - Eosinophils 
 - Basophils 
 - Lymphocytes 
 - Monocytes 
• Albumin 
• Alkaline phosphatase 
• Alanine transaminase  
• BUN 
• Calcium 
• Chloride 
• Creatinine 
• Glucose 
• Magnesium  
• Potassium 
• Sodium 
• Total bilirubin 
• Direct bilirubin (only if 
medically indicated) 
• Total protein 
• Dipstick (analysis based 
on institutional standards)
• Pregnancy test (if 
applicable) 
• Pregnancy test (if 
applicable) 
 
 
9.5.3
Treatment and Follow-up Procedures (Cycles 1 and 2) 
The following text represents Cycles 1 and 2 assessments and procedures unless otherwise 
specified (PK and ECG assessments are done only in Cycle 1). Refer to Table 16.  
9.5.3.1
Day 1 (Before Dosing) 
•
Complete physical examination (not required if done 4 days before Day 1). 
•
Vital signs. 
•
ECOG performance status. 
•
Triplicate 12-lead ECG (rhythm, atrial rate, ventricular rate, PR interval, QRS duration, and 
QT/QTc, morphology and overall interpretation). 
•
Health-related QOL by EQ-5D 5 level (EQ-5D-5L) (Appendix 4). 
•
Weight and BSA calculation (use height from screening; BSA recalculation if weight 
changes ±10% or more from screening). 
•
All study-procedure-related AEs and concomitant medications. 
•
Sample collection for laboratory assessments, including: 
•
Hematology (see Table 17) (not required if done 4 days before Day 1). 
•
Serum chemistry (see Table 17) (not required if done 4 days before Day 1). 
•
Serum or urine pregnancy test (Cycle 2 only): for women of child-bearing potential only. 


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•
Hospital admission and discharge dates (and the main reason for hospitalization), as well as 
all blood and platelet transfusions (blood product transfused and units), since the last visit. 
9.5.3.2
Day 1 (During and After Dosing) 
•
12-lead ECG (triplicate) in Cycle 1 only: at 1-2 hours postdose. 
•
At selected centers: sample collection for PK in Cycle 1 only: Refer to Section 9.3 for details 
about sampling. 
•
For assigned subjects receiving SGI-110: postdose at 1.5 hours (±30 minutes) and 3 hours 
(±1 hour), with time of sampling recorded. 
•
For assigned subjects receiving decitabine IV: at 30 minutes (±10 minutes) into the 
infusion, and then immediately before the end of infusion (at 1 hour) 
•
All treatment-emergent AEs and concomitant medications. 
9.5.3.3
Dosing Days (Days 2-5, Days 2-7, or Days 2-10, Depending on Study Treatment) 
•
Vital signs (before dosing). 
•
All AEs and concomitant medications.  
•
Cycle 1 only: At selected centers: Day 5 sample collection for PK: Refer to Section 9.3 for 
details about sampling. 
•
For assigned subjects receiving SGI-110: postdose at 1 hour (±30 minutes) and 5 hours 
(±2 hour), with time of sampling recorded. 
•
For assigned subjects receiving decitabine IV: immediately before the end of infusion (at 
1 hour); and at 5 minutes (±2 minutes) and 3 hours (±1 hour) after the end of infusion, 
with time of sampling recorded. 
9.5.3.4
Days 8, 15, and 22 
•
All AEs and concomitant medications. 
•
Hematology (see Table 17). 
•
Hospital admission and discharge dates (and the main reason for hospitalization), as well as 
all blood and platelet transfusions (blood product transfused and units), since the last visit. 
9.5.4
Treatment and Follow-up Procedures for Cycles 3 
Table 16 shows assessments and procedures for Cycles 3. 


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9.5.4.1
Day 1 (Before Dosing), Cycles 3 
Day 1 for Cycles 3 has a visit window of +7 days, unless otherwise specified below. 
•
Complete physical examination (not required if done 4 days before Day 1). 
•
Vital signs. 
•
ECOG performance status. 
•
Health-related QOL EQ-5D-5L (Appendix 4). 
•
Weight and BSA calculation (use height from screening; BSA recalculation if weight 
changes ±10% from screening). 
•
All AEs and concomitant medications. 
•
Sample collection for laboratory assessments, within 4 days of Day 1, including: 
•
Hematology (see Table 17). 
•
Serum chemistry (see Table 17). 
•
Serum or urine pregnancy test: for women of child-bearing potential only. 
•
BM aspirate/biopsy required at the end of Cycles 2, 4, and 6 (Day 1 of Cycles 3, 5, and 7, 
±7 days) unless PB shows persistence of leukemic blasts that excludes the possibility of a 
marrow response. After BM assessment at the end of Cycle 6 (Day 1 of Cycle 7), repeat BM 
aspirate/biopsy every 3 months for the first year on study and then every 6 months thereafter 
until PB or BM assessment shows disease progression or relapse. (See Section 9.2.) 
•
Hospital admission and discharge dates (and the main reason for hospitalization), as well as 
all blood and platelet transfusions (blood product transfused and units), since the last visit. 
9.5.4.2
Dosing Days (Days 2-5, Days 2-7, or Days 2-10, Depending on Study Treatment), 
Cycles 3 
•
Vital signs (before dosing). 
•
All AEs and concomitant medications.  
9.5.4.3
Day 15 (Cycles 3) 
•
All AEs and concomitant medications. 
•
Hematology (see Table 17). 
•
Hospital admission and discharge dates (and the main reason for hospitalization), as well as 
all blood and platelet transfusions (blood product transfused and units), since the last visit. 


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9.5.5
Treatment Discontinuation and Safety Follow-up Visit 
Each subject should be followed up, to document the occurrence of any new AEs, for at least 
30 (+7) days after his or her last dose of study treatment, or until any AE or SAE assessed as 
related to study treatment or procedures has resolved to a clinically acceptable or stable 
resolution (see Section 10.4). Subjects who withdraw consent should still be encouraged to 
complete this visit. The following evaluations are to be performed: 
•
Complete physical examination.  
•
Vital signs. 
•
ECOG performance status. 
•
12-lead ECG (triplicate). 
•
Health-related QOL EQ-5D-5L (Appendix 4). 
•
All AEs and concomitant medications. 
•
Sample collection for clinical laboratory tests, including: 
•
Hematology (see Table 17). 
•
Serum chemistry (see Table 17). 
•
Serum or urine pregnancy test: for women of child-bearing potential only. 
•
Hospital admission and discharge dates (and the main reason for hospitalization), as well as 
all blood and platelet transfusions (blood product transfused and units), since the last visit. 
•
Subsequent anti-leukemia therapy (regimen and start date). 
•
Disease progression status (subjects who discontinue treatment before documented disease 
progression must undergo PB and BM aspirate/biopsy assessments until disease progression 
or relapse is confirmed).  
The treatment discontinuation and safety follow-up visit may be conducted by telephone if 
needed to collect, at minimum, AE information. 
9.5.6
Long-term Follow-Up 
Long-term follow-up starts after subjects discontinue study treatment. Long-term follow-up 
visits will be either monthly or every 3 months, depending on when the subject discontinues 
study treatment: 
•
For subjects who discontinue treatment before Cycle 6, initial follow-up visits will be 
conducted monthly (±7 days) until 6 months after the start of study treatment, and then visits 
will be conducted every 3 months (±2 weeks), until death. 
•
For subjects who discontinue treatment after Cycle 6, long-term follow-up visits are required 
every 3 months (±2 weeks), until death. 


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Monthly long-term follow-up procedures (for subjects who discontinue treatment before 
Cycle 6): 
•
Health-related QOL EQ-5D-5L (Appendix 4). 
•
Hospital admission and discharge dates (and the main reason for hospitalization), as well as 
all blood and platelet transfusions (blood product transfused and units), since the last visit. 
•
Subsequent anti-leukemia therapy (regimen and start date). 
•
For subjects with no documented disease progression on treatment: 
•
Hematology and/or BM aspirate/biopsy (1 year after the start of study treatment, BM 
aspirate/biopsy every 6 months) until disease progression or relapse is documented. 
•
Disease progression status. 
•
Survival follow-up. 
Long-term follow-up procedures for visits every 3 months (±2 weeks) (for subjects who 
discontinue treatment after Cycle 6 and for subjects have completed the monthly long-term 
follow-up visits described above):  
•
Subsequent anti-leukemia therapy (regimen and start date). 
•
For subjects with no documented disease progression: 
•
Hematology and/or BM aspirate/biopsy (1 year after the start of study treatment, BM 
aspirate/biopsy every 6 months). 
•
Disease progression status. 
•
Survival follow-up. 
Long-term follow-up visits may be conducted by telephone if needed. 
9.6
Unscheduled Visits 
Additional visits (not specified in Table 16) may be conducted for PB assessment, BM 
aspirate/biopsy, chemistry assessment, or AE evaluation, at the investigator’s discretion. 
9.7
Missed Evaluations 
Evaluations should occur within the visit window specified by the protocol. If an evaluation is 
missed, reschedule and perform it as close as possible to the original date. If rescheduling 
becomes, in the investigator's opinion, medically unnecessary because the evaluation would 
occur too close to the next scheduled evaluation, it may be omitted. 


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10.0
EVALUATION, RECORDING, AND REPORTING OF ADVERSE EVENTS 
10.1
Definitions 
10.1.1
Adverse Event (AE) 
Adverse Event (AE): Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including a clinically significant abnormal finding in laboratory tests or other 
diagnostic procedures), symptom, or disease temporally associated with the use of a drug, 
without any judgment about causality. An AE can arise from any use of the drug and from any 
route of administration, formulation, or dose, including an overdose.  
Disease progression is not considered to be an AE or SAE. If there are specific AEs that are 
always part of disease progression, these do not need to be reported as AEs or SAEs. Pre-existing 
medical conditions (other than natural progression of the disease being studied) judged by the 
investigator or subject to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period will be reported as AEs or SAEs as appropriate. 
An AE or SAE can also be a complication that occurs as a result of protocol mandated 
procedures (eg, invasive procedures such as biopsies). 
10.1.2
Serious Adverse Events (SAEs) 
An AE is considered serious, if in the view of either the investigator or sponsor, it results in any 
of the following outcomes: 
•
Death. 
•
A life-threatening AE. 
An AE is considered "life-threatening" if in the view of either the investigator, or sponsor, its 
occurrence places the subject at immediate risk of death. It does not include an AE that, had 
it occurred in a more severe form, might have caused death.  
•
Inpatient hospitalization or prolongation of an existing hospitalization.  
•
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
•
A congenital anomaly or birth defect. 
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered serious when, based on the appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAE. Examples of such medical events are intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or development of drug dependency or drug abuse. For clarification, 
Grade 3 or 4 cytopenias that are not associated with a life-threatening or otherwise medically 


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significant clinical AE as defined above, and do not result in hospitalization, are not considered 
SAEs. 
10.2
Adverse Event Reporting and Descriptions 
Record new AEs from the start of study treatment until 30 days after the last dose of study 
treatment (ie, discontinuation of treatment in the study) or until the subject starts new anti-
leukemic treatment, including new investigational treatment. Also record screening 
procedure-related AEs that occur before the start of study treatment. 
Record all treatment-emergent AEs (AEs occurring after the start of study treatment) either 
observed by the investigator or one of his or her medical collaborators, or reported by the subject 
spontaneously, or in response to the direct question below, in the AEs section of the subject's 
CRF/eCRF, in the source document, and if applicable, record on the SAE form. Whenever 
possible, the investigator should group signs and symptoms (including laboratory tests or other 
results of diagnostic procedures) into a single diagnosis under a single term. For example, cough, 
rhinitis, and sneezing might be reported as "upper respiratory infection" or a pulmonary infiltrate, 
positive sputum culture and fever might be reported as "pneumonia." 
To optimize consistency of AE reporting across centers, ask the subject a standard, general, non-
leading question to elicit any AEs (such as "Have you had any new symptoms, injuries, illnesses 
since your last visit?").  
Death is an outcome of an SAE and usually not itself an SAE, unless it is death with no 
identifiable cause or event. In all other cases, record the cause of death as the SAE. Investigators 
will assess the status of previously reported, and occurrence of new, AEs and SAEs at all subject 
evaluation time points during the study. 
10.2.1
Severity 
Use the definitions found in the Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03 for grading the severity (intensity) of AEs (Appendix 3). The CTCAE v4.03 displays 
Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE. Should 
a subject experience any AE not listed in the CTCAE v4.03, use the following grading system to 
assess severity: 
•
Grade 1 – Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
•
Grade 2 – Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL), such as preparing meals, shopping 
for groceries or clothes, using the telephone, managing money, etc. 


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•
Grade 3 – Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL, such as bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
•
Grade 4 – Life-threatening consequences; urgent intervention indicated. 
•
Grade 5 – Death related to AE. 
10.2.2
Relationship to Study Treatment (Suspected Adverse Reactions) 
Assess all AEs/SAEs for relationship to study treatment or if applicable, to study procedure. 
If an AE/SAE occurs before the first dose of study treatment, report it only if it is considered 
related to a study-specific procedure (eg, bleeding or local infection after skin punch biopsy). 
Those events will be recorded in the study database but will not be part of the treatment- 
emergent AE analysis.  
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
general guideline shown below. Multi-drug regimens should have a causality assessment of each 
component to aid in analysis. 
Related  
(Suspected 
Adverse Reaction) 
A suspected adverse reaction means any AE for which there is a reasonable 
possibility that the drug caused the AE. Reasonable possibility means there 
is evidence to suggest a causal relationship between the drug and the AE 
such as a plausible temporal relationship between the onset of the AE and 
administration of the drug; and/or the AE follows a known pattern of 
response to the drug; and/or the AE abates or resolves upon discontinuation 
of the drug or dose reduction and, if applicable, reappears upon 
rechallenge. Further examples of type of evidence that would suggest a 
causal relationship between the drug and the AE: 
•
A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (eg, angioedema, hepatic injury, 
Stevens-Johnson Syndrome), 
•
One or more occurrences of an event that is not commonly associated 
with drug exposure, but is otherwise uncommon in the population 
exposed to the drug (eg, acute myocardial infarction in a young 
woman), 
•
An aggregate analysis of specific events observed in a clinical study 
(such as known consequences of the underlying disease or condition 
under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events 
occur more frequently in the drug treatment group that in a concurrent 
or historical control group. 


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Not Related  
(Not Suspected) 
Adverse events that do not meet the definition above. 
10.2.3
Pregnancy and Abortion 
Report any pregnancy that occurs in a subject or male subject's female partner during the time 
between the first study-specific procedure and 60 days after the last dose of study treatment. 
Record any occurrence of pregnancy on the Pregnancy Report Form Part I and send to Astex 
Pharmaceuticals Drug Safety within 24 hours of learning of the event. After the birth of the baby, 
collect additional information on the baby until the baby is 1 year old by completing the 
Pregnancy Report Form Part II.  
A subject must immediately inform the investigator if the subject or subject's partner becomes 
pregnant during the time between the first study-specific procedure and 60 days after the last 
dose of study treatment. Any female subjects receiving study treatment who become pregnant 
must immediately discontinue study treatment. The investigator should counsel the subject, 
discussing any risks of continuing the pregnancy and any possible effects on the fetus. 
Report any abortion and the reason for it, whether therapeutic, elective, or spontaneous, to Astex 
Pharmaceuticals Drug Safety within 24 hours, through the SAE reporting process (Section 10.3). 
10.3
Reporting and Evaluation of Serious Adverse Events 
10.3.1
Reporting Requirements for Serious Adverse Events (SAEs) 
All SAEs regardless of causality will be reported by the investigator to Astex Pharmaceuticals 
through the 30-day period after the last dose of study treatment. Deaths and SAEs occurring after 
the 30-day safety follow-up period AND considered related to study treatment or study 
procedures must also be reported. 
Report all SAEs (initial and follow-up information) on an SAE form and send the form to Astex 
Pharmaceuticals Drug Safety, or designee, within 24 hours of the discovery of the event or 
information (see below). Astex Pharmaceuticals may request follow-up and other additional 
information from the investigator (eg, hospital admission or discharge notes, laboratory results). 
Astex Pharmaceuticals Drug Safety Contact Information 
PRIMARY CONTACT: Email 
 
Global Phone 
 
North America Toll-Free Fax 
 
 
Report all deaths with the primary cause of death as the SAE term, as death is the outcome of the 
event, not the event itself. If an autopsy was performed, report the primary cause of death on the 
autopsy report as the SAE term. Forward autopsy and postmortem reports to Astex 
Pharmaceuticals Drug Safety, or designee, as outlined above. 


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If study treatment is discontinued, temporarily suspended, or dose reduced because of an SAE, 
include this information in the SAE report. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that qualify for 
mandatory expedited reporting to regulatory authorities where the SAE is suspected to be caused 
by the study treatment and is considered unexpected (ie, not defined as expected in the current 
IB, clinical study protocol, or approved labeling for marketed drugs). In this case, Astex 
Pharmaceuticals Drug Safety or designee will report to the relevant regulatory authorities and 
forward a formal notification describing the SUSAR to investigators, according to regulatory 
requirements. Each investigator must then notify his or her IRB/IEC of the SUSAR as required 
by local regulatory authorities and in accordance with IRB/IEC policy. 
10.4
Follow-up for Adverse Events 
Follow-up all AEs and SAEs assessed as related to study treatment or study procedures that are 
encountered during the protocol-specified AE reporting period (1) to resolution, (2) until the 
investigator assesses the subject as stable and the event is following a clinically expected 
outcome, or (3) until the subject is lost to follow-up or withdraws consent. 
11.0
STATISTICS 
Statistical analyses will be performed by Astex Pharmaceuticals or its designee. 
Data summaries and listings will be generated using SAS version 9.3 or a more recent version 
(SAS Institute Inc., Cary, NC, USA). 
The statistical analysis plan and/or the clinical study report will provide additional details of the 
analysis, which may include details of missing and, if applicable, unused data, as well as 
additional sensitivity analyses of the primary and secondary variables. The clinical study report 
will describe deviations from the statistical analysis plan, if any. 
11.1
Sample Size 
By trial design, the overall (2-sided) alpha level of 0.05 is split between the co-primary endpoints 
of CR (0.04) and OS (0.01). A formal interim analysis will be performed only for OS using a 
group sequential boundary preserving an overall (2-sided) 0.01 alpha level. The sample size 
calculation for the primary analysis of CR is based on testing at the 0.04 nominal alpha level. If 
statistical significance is achieved for CR, hierarchically, the final analysis of OS will be 
conducted to preserve an overall 2-sided 0.05 alpha level, accounting for alpha spent at the 
interim analysis of OS, as described in Section 11.6.7 and Section 11.9. The sample size 
calculation for OS will be shown for the setting of a 2-sided 0.05 alpha level. 
Assuming a CR rate of approximately 0.20 (Kantarjian, Thomas et al 2012; Fenaux et al 2010; 
Burnett et al 2007) for subjects treated in the TC group (all TC therapies combined) and 
assuming an increase in CR rate to 0.30 or higher can be achieved by treating subjects with 


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SGI-110, 800 subjects (400 per treatment group) will provide approximately 89% power to 
detect the overall difference of 0.10 when using a 2-sided Cochran Mantel-Haenszel test having 
2-sided alpha level of 0.04. For the purpose of this sample size calculation, the constant CR rates 
of 0.20 and 0.30 for the TC and SGI-110 groups, respectively, are assumed for each stratum. 
For survival, an analysis at 670 death events will provide 90% power to detect a hazard ratio of 
approximately 0.78 (a difference in median survival of 7 months in the TC group versus 
9 months in the SGI-110 group), when using a 2-sided stratified log-rank test at an 0.05 alpha 
level. Accrual is expected to be uniform over a 21 month enrollment period, with an additional 
follow-up of 12 months. Hence, the assessment of survival needs approximately the same sample 
size of 800 subjects. Primary response and survival analyses will be performed after 670 death 
events have occurred. For the purpose of this sample size calculation, a constant hazard ratio of 
approximately 0.78 was assumed for all strata defined by the stratification factors. 
11.2
Data Sets to be Analyzed 
11.2.1
Efficacy 
Efficacy analyses will be based on intent-to-treat (ITT) principle. The efficacy data set will 
include data from all subjects randomly assigned to study treatment. All data will be included 
and no subjects excluded because of protocol violations. For the analysis of efficacy data, 
subjects will be included in the treatment group according to their randomly assigned treatment. 
A secondary efficacy dataset will be analyzed for the co-primary endpoints of CR and OS based 
on treatment actually received. 
For NDAOH, transfusions, and health-related QOL by EQ-5D-5L datasets, the primary analysis 
will include only the data collected during the first 6 months of the study because, during this 
study period, subjects are assessed whether or not they are still on study treatment. Secondary 
analysis datasets may also be analyzed (eg, over the period of study treatment). 
11.2.2
Safety 
The safety data set will include data from all subjects randomly assigned to study treatment who 
receive any amount of study treatment or any component of a multi-dose study treatment 
regimen. All data will be included and no subjects excluded because of protocol violations. 
For safety data analysis, subjects will be included in the treatment group according to the 
treatment they actually receive. 
11.2.3
Pharmacokinetics 
The PK data set will include all available plasma concentrations and PK parameters for SGI-110 
and decitabine from subjects at selected centers who have received SGI-110 or decitabine IV and 
for whom PK samples were collected and successfully analyzed. PK data will be analyzed using 
the PK data set.  


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11.2.4
Pharmacodynamics Analyses 
Pharmacodynamics analyses are not applicable to this study. 
11.3
Schedule of Analyses 
Data listings and summary tables will be reviewed by the DMC approximately every 6 months to 
ensure the safety of study subjects and to enhance the quality of trial conduct (refer to Section 
4.4). An interim analysis of OS will also be conducted by the DMC when approximately half of 
the required death events have occurred. All available study data will be analyzed after 670 death 
events have occurred to achieve a mature analysis of OS. 
11.4
Disposition 
The number and percentage (n, %) of subjects enrolled, treated, lost to follow-up, and withdrawn 
(with reason) will be summarized. Sample size for efficacy and safety analysis data sets will be 
clearly identified for each treatment group. All screened subjects will be included in the 
disposition analysis. 
11.5
Analysis of Demographic and Baseline Data 
Subject demographic and baseline characteristics will be summarized by mean, standard 
deviation, median, minimum, and maximum for continuous variables; and by counts and 
percentages for categorical variables. The Efficacy and Safety datasets will be used for the 
summaries. The summaries will be done for each treatment group and both treatment groups 
combined. 
11.6
Efficacy Analyses 
Efficacy analyses will be based on the Efficacy dataset. Unless otherwise specified, this section 
describes the analyses conducted at the primary analysis time point when 670 death events have 
occurred, assuming that the study continued after the planned interim analysis. The alpha levels 
referenced in this section are nominal alpha levels for judging statistical significance, taking into 
consideration the planned interim analysis and the hierarchical testing order of the (final) 
primary analysis. The overall experimental alpha error is controlled at the 2-sided 0.05 level. 
The co-primary efficacy endpoints are  
•
CR rate by modified IWG 2003 AML Response Criteria (Cheson et al 2003) as described in 
Section 11.6.1. Assessments will be blinded as described in Section 11.6.1. 
•
OS, defined as the number of days from randomization to death.  
If either of the co-primary efficacy endpoints reaches statistical significance in favor of SGI-110 
at either the interim analysis (OS only) or final analysis (CR and OS), then the study will be 
considered positive in efficacy. 


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Secondary efficacy endpoints are the following and will be defined in more detail in the 
statistical analysis plan: 
•
CRc (CR+CRi+CRp) rate. 
•
NDAOH. 
•
PFS, defined as the number of days from randomization to disease progression or death, 
whichever occurs first. 
•
Number of RBC or platelet transfusions (units) over the duration of the study treatment. 
•
Health-related QOL by EQ-5D-5L (consisting of the EQ-5D-5L descriptive system and the 
EQ Visual Analogue Scale [EQ VAS]). 
•
Duration of CR, defined as the time from first CR to time of relapse. 
11.6.1
Criteria for Response Assessment 
Modified IWG 2003 Response Criteria (Table 18) will be used by an independent blinded reader 
to identify AML subjects with CR, CRp, CRi, or partial response. BM biopsy/aspirate and 
corresponding concomitant PB counts will be assessed by a blinded central pathologist, and all 
assessments of response will be reviewed and confirmed by an independent blinded central 
reviewer (either the same person who assessed pathology or a different blinded independent 
reviewer).  
Table 18: 
Modified 2003 IWG AML Response Criteria  
Responsea 
Peripheral Blood (PB) 
Bone Marrow (BM) 
CR 
ANC 1000/ȝL, Platelets 100,000/ȝL, independence from 
RBC and platelet transfusions over the past week, no 
leukemic blastsb 
<5% leukemic blasts 
CRp 
ANC 1000/ȝL, Platelets <100,000/ȝL, independence from 
RBC transfusions over the past week, no leukemic blastsb 
<5% leukemic blasts 
CRi 
ANC <1000/ȝL, no leukemic blastsb 
<5% leukemic blasts 
Partial 
response 
ANC 1000/ȝL, Platelets 100,000/ȝL, no leukemic blastsb 
Decrease of 50% in leukemic 
blasts to level of 5% to 25% 
a 
Responses are based on both PB and BM conditions. 
b 
For the purpose of response assessment and according to published IWG criteria, blasts may be seen in PB as 
rare PB blasts may be identified during regeneration, but the subject is in CR if BM blasts are <5% with no 
Auer rods (Cheson et al 2003). 
ANC=absolute neutrophil count; CR=complete response; CRp=complete response with incomplete platelet 
recovery; CRi=CR with incomplete blood count recovery. 
Source: Cheson et al 2003 
Subjects with these different response categories, as well as nonresponders and nonevaluable 
subjects described below, will be listed and summarized. In particular, best response will be used 
when a subject experienced different response levels at different visits. Response rate will be 
calculated for best response categories described below to assess overall efficacy observed. 


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•
CR, CRp, CRi, partial response.  
•
Composite CR (CRc=CR+CRp+CRi). 
Subjects who did not have a post-treatment efficacy assessment (ie, no BM or PB assessment) 
will be classified as nonevaluable for response presentations. These subjects will be included in 
the denominator of the ITT analysis for calculation of different response rates. Subjects who 
cannot be classified into a response category (CR, CRp, CRi, partial response) or the 
nonevaluable category will be classified as nonresponders. 
11.6.2
Complete Response (CR) 
The primary endpoint of CR rate will be calculated as the number of subjects with a best 
response of CR divided by the total number of subjects included in the efficacy analysis. The CR 
rate will be compared between the 2 treatment groups using a Cochran Mantel-Haenszel test at 
an alpha level of 0.04 stratified by age (<75 or 75 years), ECOG performance status (0-1 or 
2-3), study center region (North America, Europe, ROW), and secondary AML (secondary to 
MDS or other antecedent hematologic disorder) or poor-risk cytogenetics (either, neither). 
A 2-sided p value of 0.04 will be judged as statistically significant. In addition, the Mantel-
Haenszel weighted difference in CR rate between the 2 treatment groups and its 2-sided 96% CI 
will be provided.  
11.6.3
Overall Survival (OS) 
OS is defined as the number of days from the day the subject was randomly assigned to study 
treatment to the date of death (regardless of cause). Survival time will be censored on the last 
date the subject is known alive or lost to follow-up before reaching the event of death. As a 
separate sensitivity analysis, survival time will also be censored on the date the subject receives 
other anti-leukemia therapy such as chemotherapy or HCT. 
OS will be estimated by a stratified Kaplan-Meier method and compared between the 2 treatment 
groups using a stratified log-rank test. If the CR rate analysis is significant, OS will be tested at 
an alpha level of 0.05; without a significant CR rate test result, OS will be tested at an alpha level 
of 0.01, as described in Section 11.6.7. The stratification variables will include age (<75 or 75 
years), ECOG performance status (0-1 or 2-3), study center region (North America, Europe, 
ROW), and secondary AML or poor-risk cytogenetics (either, neither). The medians and 
quartiles of OS will be summarized. 
In addition, the hazard ratio (HR) and the 95% (or 99%, as appropriate) CI will be estimated 
using a Cox proportional-hazard model with treatment group as the independent variable and 
stratified by the same randomization stratification factors as used for the log-rank test. 
For the planned interim analysis, OS will be compared between the 2 treatment groups using a 
stratified log-rank test at an alpha level provided by the Lan-DeMets implementation of the 
O’Brien-Fleming monitoring guideline, as described in Section 11.9. 


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11.6.4
Composite CR (CRc) 
The CRc rate is calculated as the number of subjects with a best response of CR, CRp, or CRi 
divided by the total number of subjects included in the efficacy analysis. The CRc rate will be 
compared between the 2 treatment groups using a Cochran Mantel-Haenszel test with the 
stratification variables the same as for CR and OS. If CR rate analysis and OS analysis are both 
significant, the CRc rate will be tested at an alpha level of 0.05; with a nonsignificant CR rate 
result (p>0.04) and a significant OS result at the 0.01 level, the CRc rate will be tested at an 
alpha level of 0.01. In addition, the 2-sided 95% (or 99%, as appropriate) CI for the Mantel-
Haenszel weighted difference in CRc rate between the 2 treatment groups will be provided. 
11.6.5
Number of Days Alive and Out of the Hospital (NDAOH) 
The date of each hospital admission and discharge will be collected for each subject. The average 
NDAOH will be summarized by treatment group and compared between the 2 treatment groups 
using a 2-sample t-test at an alpha level of 0.05 or 0.01 as appropriate, if the CRc test result is 
significant at that required level. 
11.6.6
Progression-free Survival (PFS) 
Progression is defined as the earliest occurrence of one of the following: 
•
For subjects with CR, CRi, or CRp, the confirmed (at least 2 PB samples at least 1 week 
apart) appearance of leukemic blasts in PB by investigator or central assessment, OR 5% 
leukemic blasts in the BM by blinded central pathologist assessment. 
•
For all other subjects, when PB or BM shows evidence of continued increase in blasts % that 
necessitates alternative therapy. 
•
Death. 
PFS is defined as the number of days from randomization to the earliest date of investigator's 
assessment of disease progression or relapse by PB assessment or blinded BM assessment, 
whichever occurs first, or death (regardless of cause). PFS time will be censored on the last date 
the subject is known to be alive without a relapse/disease progression. Subjects receiving other 
anti-leukemia therapy before occurrence of a relapse/ disease progression will also be censored 
at the date of the start of other anti-leukemia therapy. 
PFS will be compared between the 2 treatment groups using a stratified log-rank test at an alpha 
level of 0.05, or 0.01, as appropriate, if CRc and NDAOH test results are significant at that 
required level. The medians and quartiles of PFS will be summarized. 


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11.6.7
Test Sequence and Procedures of Statistical Tests for Efficacy Endpoints 
To control the alpha errors associated with testing the multiple endpoints of CR rate, OS, CRc 
rate, NDAOH, and PFS, the following test sequence and procedures will be followed, assuming 
that the study continues after the planned interim analysis. 
The primary efficacy variable CR rate will be tested first in the sequence at an alpha level of 
0.04. If this test is positive (ie, p0.04), then analysis will proceed to the test for the co-primary 
efficacy variable of OS at the 0.05 alpha level. A positive CR analysis (p0.04) serves as a 
gatekeeper (Westfall and Krishen 2001) for proceeding to the analysis of OS at the 0.05 level. If 
the test for CR is not significant at the 0.04 level, the co-primary efficacy variable of OS will be 
tested at an alpha level of 0.01.  
If the test for OS is positive at the 0.05 level, analysis will proceed to the test for the secondary 
efficacy variables of CRc rate, NDAOH, and PFS (in that order) at an alpha value of 0.05. For 
testing the secondary efficacy variables, CRc rate will be tested first. If the test for CRc rate is 
positive, then analysis will proceed to the test for NDAOH at the 0.05 alpha level; if the test for 
NDAOH is positive, then analysis will proceed to the test for PFS at a 0.05 alpha level. Similar 
to the primary endpoint analyses, a positive (ie, p<0.05) test result of a secondary endpoint tested 
earlier in the sequence serves as a gatekeeper for proceeding to the subsequent secondary 
analyses. If the test for CR is not significant at the 0.04 level, but the test for OS is significant at 
the 0.01 level, the secondary efficacy variables of CRc, NDAOH, and PFS will be tested 
hierarchically at an alpha level of 0.01. The hierarchical test order and alpha value to be used for 
each test at the primary analysis time point are further described in Figure 4. 


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Figure 4: 
The Hierarchical Test Order and Related Alpha Values 
 
 
The overall alpha error rate is controlled at the 0.05 level by following the above testing 
sequence and procedures. 
Other secondary efficacy endpoints (number of transfusions, health-related QOL, and duration of 
CR) will be used as supportive evidence of the beneficial treatment effect. The 95% CIs for these 
endpoints, if applicable, will be constructed. 


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11.6.8
Number of Red Blood Cell (RBC) or Platelet Transfusions 
One transfusion is defined as 1 unit of RBC or 1 unit of platelets. Dates and the number of RBC 
or platelet transfusions will be collected for each subject. The average number of RBC or 
separately platelet transfusions per month will be summarized by treatment group. In addition, 
the number of RBC or platelet transfusions will also be summarized as a per-patient-year rate for 
each treatment group. The RR of these 2 per-patient-year rates (SGI-110 versus TC) and the 
associated 95% CI will be provided. 
11.6.9
EQ-5D-5L 
The calculation for EQ-5D-5L (EQ-5D-5L descriptive system and EQ VAS; Appendix 4) scores 
(health profile, self-rated health status, and index value) will be performed according to EuroQol 
group (http://www.euroqol.org/about-eq-5d.html; 2009). Change from baseline in EQ-5D-5L 
scores will be summarized by visit. A repeated measures analysis of variance model will be used 
to compare the groups for change from baseline in EQ-5D-5L scores.  
11.6.10
Duration of CR 
Duration of CR (in number of days) will be calculated from the first time a CR is observed to 
time of relapse (defined as the earliest time point whereby BM assessment or PB assessment [see 
Section 11.6.6] indicate relapse/disease progression due to reappearance of leukemic blasts in PB 
or 5% leukemic blasts in BM). The duration of CR will be censored at the last available time 
point at which a relapse/disease progression was not observed. Duration of CR will be estimated 
using the Kaplan-Meier method for subjects who achieved a CR during the study. To take the 
proportion of responders into consideration when analyzing duration of CR, a separate analysis 
including all subjects will be conducted with a 0-day event duration assigned to subjects who did 
not achieve a CR, with the 2 groups compared using a log-rank test. 
11.6.11
Subgroup Analyses 
Subgroup analyses will be performed to explore the influence of baseline variables, and the 
individual TC therapy administered, on the efficacy outcome of CR rate and OS, and to evaluate 
the treatment effect at different levels of each baseline variable. The analyses described in 
previous sections for these 2 outcome variables will be repeated for each level of the baseline 
variables and each TC therapy listed below: 
•
Age (<75, 75). 
•
AML category (primary, secondary). 
•
Baseline cytogenetic risk (poor-risk, others). 
•
Baseline ECOG PS (0-1 and 2-3). 
•
Baseline BM blasts (30%, >30%). 
•
Baseline total WBC counts (<20,000/ȝL, 20,000/ȝL). 


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•
Study center region (North America, Europe, Asia-Pacific, Other). 
•
Race (White, Black, Asian, Other). 
•
Presence of baseline genetic abnormalities such as FLT3-ITD, NPM1, CEBPA (for each 
gene: yes, no). 
•
Individual TC (cytarabine, decitabine, azacitidine) compared with SGI-110 treatment. 
•
Additional subgroups may also be further described in the Statistical Analysis Plan. 
11.7
Safety Analyses 
Safety will be assessed by subject-reported and investigator-observed AEs and 30- and 60-day 
all-cause mortality, along with physical examination, clinical laboratory tests (hematology, 
chemistries), and ECGs. Safety variables will be tabulated and presented for all subjects who 
receive any amount of study treatment (SGI-110 or TC). Exposure to study treatment, reasons for 
discontinuation, deaths and causes of deaths will be tabulated. Treatment-emergent AEs 
(TEAEs) are defined as events that first occurred or worsened after the first dose of study drug 
given on Cycle 1 Day 1. TEAEs will be mapped to the appropriate System Organ Class (SOC) 
and Preferred Term (PT) according to the Medical Dictionary for Regulatory Activities 
(MedDRA). Severity of AEs will be graded using CTCAE version 4.03.  
Summaries will be provided for all AEs, AEs considered related to study treatment, SAEs, and 
related SAEs as follows: 
•
By maximum severity.  
•
Incidence by SOC (by severity grade and overall). 
•
Incidence by PT (by severity grade and overall) within each SOC. 
The percentage of 30- and 60-day all-cause mortality will be calculated based on each subject's 
date of death relative to Course 1 Day 1 (C1D1; ie, date of death minus date of C1D1) and 
compared between the 2 treatment groups using a Chi-square test. 
Laboratory values reported by different local labs will be listed. Laboratory values will also be 
graded, if possible, by CTCAE in conjunction with the Harrison (18th edition) lab book normals  
(Longo 2011). Shift tables will display (1) shift from baseline grade to the worst grade, and 
(2) shift from baseline grade to the last grade.  
Concomitant medication will be coded by the WHO Drug Dictionary and summarized by 
Therapeutic subgroup (ATC level 2) and PT, sorted alphabetically, using counts and percentages. 
Concomitant medications are the medications taken with a start date on or after the start of the 
administration of study treatment (C1D1), or those with a start date before the start of the 
administration of study treatment (C1D1) and a stop date on or after the start of the 
administration of study treatment (C1D1). 


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Vital signs will be summarized by visit using proportion of subjects with each vital sign being 
too high or too low according to conventionally accepted vital sign normal ranges. ECG data will 
be listed. 
11.8
Pharmacokinetic Analyses 
PK parameters will be derived using noncompartmental analyses for each subject for whom 
sparse PK samples were collected and successfully analyzed. Descriptive statistics will include 
mean, standard deviation, minimum, median, and maximum for SGI-110 and decitabine PK 
parameters.
The relationship between 
 will be assessed based on the PK data and 
efficacy/safety data collected in this study. The methods will include a population PK modeling 
approach using the sparse data collected. The details of population PK modeling and full results 
of the 
 analyses will be reported in a separate document, and the summary of 
key findings will be included in the clinical study report. 
11.9
Interim Analysis 
One formal interim analysis of OS is planned. This interim analysis will be conducted by the 
independent DMC after approximately half (ie, approximately 335) of the required death events 
have occurred. The nominal alpha value for the interim and final OS analyses is based on 
Lan-DeMets implementation of the O’Brien-Fleming boundary (Lan and DeMets 1983; O’Brien 
and Fleming 1979). With one interim analysis at 50% information time point plus one final 
analysis, the 2-sided alpha-boundaries are 0.00014 and 0.00995, respectively. If the trial 
continues after the interim analysis, and if the primary analysis of CR rate is significant at the 
0.04 level, the alpha level for the primary analysis of OS will be 0.04+0.00995=0.04995§0.05. If 
the trial continues after the interim analysis, and if the primary analysis of CR rate is not 
significant at the 0.04 level, the alpha value for the primary analysis of OS will be 0.00995§0.01. 
The overall alpha error is controlled at the 0.05 level. 
Refer to Section 11.3 for further details on the schedule of analyses. 
11.10 Procedures for Handling Missing, Unused, and Spurious Data 
No missing data imputations are planned for the study, except as specified. Subjects lost to 
follow-up will be included in statistical analyses to the point of their last evaluation.  
12.0
STUDY DURATION 
The expected study duration is approximately 36 months, including 21 months for completing 
enrollment and approximately 12-15 months follow-up before final analyses. The study is 
expected to start in Q1 2015 and end in Q1 2018. 


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13.0
STUDY COMPLIANCE AND ETHICAL CONSIDERATIONS 
13.1
Compliance Statement 
The study will be conducted in accordance with the ICH GCP guidelines; US Title 21 CFR Parts 
11, 50, 54, 56, and 312; the EU Clinical Trials Directive and its successor; principles enunciated 
in the Declaration of Helsinki; and all human clinical research regulations in countries where the 
study is conducted. 
13.2
Informed Consent 
The ICFs used for the study must comply with the Declaration of Helsinki, federal regulations 
US 21 CFR Part 50, and ICH GCP guidelines and any other local regulations. The investigator, 
or a person delegated by the investigator, must explain the medical aspects of the study, 
including the nature of the study and the treatment, orally and in writing, in such a manner that 
the subject is aware of potential benefits and risks. Subjects must be informed that participation 
is voluntary and that they may withdraw from the study at any time, without prejudice. Subjects, 
or a legal guardian if the subject is unable to, must give informed consent in writing. 
The informed consent process must be conducted, documented in the source document 
(including the date), and the form must be signed, before the subject undergoes any study-
specific procedures. 
13.3
Institutional Review Board or Independent Ethics Committee (IRB/IEC) 
The investigator must submit the protocol, protocol amendments, and the ICF for the proposed 
study, along with any other documents required by the center's IRB/IEC to the center's duly 
constituted IRB/IEC for review and approval. The investigator must also ensure that the IRB/IEC 
reviews the progress of the study on a regular basis and, if necessary, renews its approval of the 
study on an annual basis. A copy of each IRB/IEC approval letter must be forwarded to the 
sponsor before the study is implemented. Documentation of subsequent reviews of the study 
must also be forwarded to the sponsor. 
14.0
ADMINISTRATIVE PROCEDURES 
14.1
Sponsor Responsibilities 
Astex Pharmaceuticals reserves the right to terminate the study and remove all study materials 
from a study center at any time. Astex Pharmaceuticals and the investigators will assure that 
adequate consideration is given to the protection of the subjects' interests. Specific circumstances 
that may precipitate such termination are: 
•
Request by Health Authority to terminate the study. 
•
Unsatisfactory subject enrollment with regard to quality or quantity. 


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•
Significant or numerous deviations from study protocol requirements, such as failures to 
perform required evaluations on subjects; maintain adequate study records; or inaccurate, 
incomplete, or late data recording on a recurrent basis. 
•
The incidence or severity of AEs in this or other studies indicating a potential health hazard 
caused by the study treatment. 
14.1.1
Study Supplies 
Refer to the SGI-110 -04 Study Procedures Manual for sponsor-provided supplies for this study.  
14.1.2
Investigator Training 
All study centers will have a center-specific study initiation meeting to ensure the center staff 
understand the protocol, study requirements, and data capture processes. This training will take 
place before the first subject is enrolled. Each study center will be provided with information 
regarding GCP and regulations specific to the conduct of clinical studies. Each center is 
responsible for ensuring that new team members are adequately trained and the training is 
documented. 
14.1.3
Ongoing Communication of Safety Information during the Study 
The sponsor will provide the investigator with documentation of SAEs, from this study and other 
studies, that are related to Astex IMP and unexpected (see Section 10.3.1), as appropriate. The 
investigator must forward this documentation to the IRB/IEC, as described in Section 10.3.1. 
The sponsor will also notify the investigator about any other significant safety findings that could 
alter the safety profile of the IMP from what is described in the protocol and significantly affect 
the safety of subjects, affect the conduct of the study, or alter the IRB/IEC's opinion about 
continuation of the study. This does not include safety issues that could be mitigated by simple 
changes in the protocol decided by the DMC (Section 4.4) such as limiting some of the eligibility 
criteria or reducing the IMP dose or dosing schedule. 
14.1.4
Study Monitoring 
Representatives of Astex Pharmaceuticals will monitor the study. Routine monitoring visits will 
be conducted to: 
•
Assure compliance with the study protocol and appropriate regulations. 
•
Verify that (1) the informed consent process was conducted before initiation of any study-
specific procedures (ie, performed solely for the purpose of determining eligibility for the 
study) and before provision of study treatment, and (2) this process is adequately 
documented. 
•
Verify that the protocol, protocol amendments, and safety information are submitted to the 
IRB/IECs and approved by the IRB/IECs in a timely manner. 


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•
Review the CRF/eCRFs and source documents to ensure that reported study data are 
accurate, complete, and verifiable from source documents. 
•
Verify that study treatments are stored properly and under the proper conditions, that they are 
in sufficient supply, and that receipt, use, and return of SGI-110 at the study centers are 
controlled and documented adequately. 
•
Verify that the investigator and study center personnel remain adequately qualified 
throughout the study. 
•
Verify that the research facilities, including laboratories and equipment, are maintained 
adequately to safely and properly conduct the study. 
14.1.5
Study Auditing and Inspecting 
The sponsor may audit the study conduct, compliance with the protocol and accuracy of the data 
in one or more centers.  
The investigator(s)/institution(s) will permit study-related monitoring, audits, and inspections by 
the sponsor, IRB/IEC, government regulatory bodies and Astex Pharmaceuticals Quality 
Assurance personnel or its designees by providing direct access to source data/documents after 
appropriate notification from sponsor. 
14.2
Investigator Responsibilities 
14.2.1
Subject Screening Log 
The investigator must keep a record that lists all subjects who signed an informed consent and 
the reason for non-inclusion if they were not ultimately randomized or treated. 
14.2.2
Study Treatment Accountability 
An initial supply of SGI-110 will be shipped to each study center's pharmacy when all the 
initiation documents, including IRB/IEC approvals, IRB/IEC approved ICF, and business 
agreements, have been received and reviewed by Astex Pharmaceuticals and upon activation of 
the study center by Astex Pharmaceuticals.  
Keep study treatment in a locked, limited-access room. The study treatment must not be used 
outside the context of the protocol. Under no circumstances should the investigator or other 
study center personnel supply study treatment to other investigators, subjects, or clinics or allow 
supplies to be used other than as directed by this protocol without prior authorization from Astex 
Pharmaceuticals.  
The monitor will regularly review and verify all study treatment supplies and associated 
documentation. 


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Maintain an accurate accounting of the study treatments. These records must show dates, lot 
numbers, quantities received, dispensed, and returned and must be available for monitoring by 
the sponsor. The investigator will ensure that any used and unused study treatment and other 
study material is destroyed or returned to the sponsor on completion of the study. If the study 
treatment is destroyed at the study center, there should be documentation of destruction at the 
study center. The sponsor and/or their representatives will verify final drug accountability. Study 
treatment accountability records must be maintained and readily available for inspection by 
representatives of Astex Pharmaceuticals and are open to inspections by regulatory authorities at 
any time. 
14.2.3
Reporting and Recording of Study Data 
Data will be captured and compiled using procedures developed by the sponsor or their 
representatives. Clearly record all requested study data on the CRF/eCRF and other study forms 
as required. Whenever possible, record the reason for missing data in the source document. Only 
individuals who are identified on the study personnel responsibility/signature log may enter or 
correct data in the CRF/eCRF. Incomplete or inconsistent data on the CRF/eCRFs will result in 
data queries that require resolution by the investigator or designee. 
The investigator must assure subject anonymity and protection of identities from unauthorized 
parties. On CRF/eCRFs or other documents or subject records provided to Astex 
Pharmaceuticals, identify subjects by code (subject number, initials, date of birth) and not by 
names. The principal investigator should maintain documents not for submission to Astex 
Pharmaceuticals (eg, subjects' signed informed consent) in strict confidence. 
14.2.4
Source Documentation 
The investigator must maintain adequate and accurate source documents upon which 
CRF/eCRFs for each subject are based. They are to be separate and distinct from CRF/eCRFs, 
except for cases in which the sponsor has predetermined that direct data entry into specified 
pages of the subject's CRF/eCRF is appropriate. These records should include detailed notes on: 
•
The oral and written communication with the subject regarding the study treatment 
(including the risks and benefits of the study). Record the date of informed consent in the 
source documentation. 
•
The subject's medical history before participation in the study. 
•
The subject's basic identifying information, such as demographics, that links the subject's 
source documents with the CRF/eCRFs. 
•
The results of all diagnostic tests performed, diagnoses made, therapy provided, and any 
other data on the condition of the subject. 
•
The subject's exposure to study treatment. 
•
All AEs. 


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•
The subject's exposure to any concomitant therapy (including start and stop dates, route of 
administration, and dosage). 
•
All relevant observations and data on the condition of the subject throughout the study. 
14.2.5
Tissue and Blood Sample Collection/Storage 
Tissue and blood components samples which are collected as part of routine medical care or as 
part of protocol procedures may be stored and analyzed for PK or pharmacodynamic analyses.  
After the study, samples may be used for additional investigation to help identify factors that 
may influence response to therapy. Such samples will be used in compliance with guidelines 
defined by FDA Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using 
Leftover Human Specimens that are Not Individually Identifiable (issued 25 April 2006) and 
European Agency for the Evaluation of Medicinal Products (EMEA)'s Reflection Paper on 
Pharmacogenomic Samples, Testing and Data Handling (EMEA 2007).  
14.2.6
Records Retention 
The investigator must ensure that clinical study records are retained according to national 
regulations, as documented in the clinical trial agreement entered into with the sponsor in 
connection with this study. The investigator will maintain all records and documents pertaining 
to the study including, but not limited to, those outlined above (see Section 14.2.4) for a period 
of: at least 2 years after FDA approval of the drug or at least 2 years after withdrawal of the IND 
under which this study was conducted, whichever is longer. In countries outside the US, records 
must be kept for the period of time required by the US FDA as a minimum, and record retention 
should also comply with the local country regulatory requirements, if longer retention times are 
required than in the US. Mandatory documentation includes copies of study protocols and 
amendments, financial disclosures, each FDA Form 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE forms transmitted to Astex Pharmaceuticals, subject files 
(source documentation) that substantiate entries in CRF/eCRFs, all relevant correspondence, and 
other documents pertaining to the conduct of the study. These records must remain in each 
subject's study file and be available for verification by study monitors at any time. 
The investigator must inform the sponsor immediately if any documents are to be destroyed, 
transferred to a different facility, or transferred to a different owner. The sponsor should be given 
the option of collecting the documents before destruction. 
14.3
Clinical Trial Insurance 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating 
study centers upon request. 


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14.4
Study Administrative Letters and Protocol Amendments 
Astex Pharmaceuticals may issue Study Administrative Letters (1) to clarify certain statements or 
correct obvious errors/typos/inconsistencies in the study protocol, (2) to change the logistical or 
administrative aspects of the study, such as study personnel or contact information, or (3) to instruct 
investigators of DMC safety decisions for immediate implementation for safety reasons (Section 4.4).  
For all other changes, Astex Pharmaceuticals will initiate any change to the protocol in a 
protocol amendment document. Astex Pharmaceuticals will submit the amendment together with 
a revised model ICF (if applicable), to regulatory authorities for approval before implementation, 
as required. The study center will submit the amendment to the IRB/IEC together with, if 
applicable, a revised model ICF. If the change in any way increases the risk to the subject, 
information on the increased risk must be provided to subjects already actively participating in 
the study, and they must read, understand and sign any revised ICF confirming willingness to 
remain in the study. 
The investigator must obtain IRB/IEC approval before any protocol amendment can be 
implemented, except for administrative changes or changes necessary to eliminate an immediate 
risk to study subjects, as outlined above. 
15.0
POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
The sponsor encourages the scientific publication of data from clinical research studies. 
However, investigators may not present or publish partial or complete study results individually 
without review by the sponsor. The principal investigators and the sponsor may propose 
appropriate scientific manuscripts or abstracts from the study data. The sponsor must review and 
comment on all proposed publications before submission for publication. The detailed 
procedures for the review of publications are set out in the clinical trial agreement entered into with 
the sponsor in connection with this study. These procedures are in place to ensure coordination of 
study data publication and adequate review of data for publication against the validated study 
database for accuracy. Names of all investigators and sponsor representatives responsible for 
designing the study and analyzing the results will be included in the publication(s). 
Qualification of authorship will follow the requirements of the International Committee of 
Medical Journal Editors (www.icmje.org). In most cases, the principal investigators at the 
centers with the highest participation and accruals of eligible subjects and data in the study shall 
be listed as lead authors on manuscripts and reports of study results. The sponsor's medical 
monitor, study director and/or lead statistician may also be included in the list of authors. This 
custom can be adjusted upon mutual agreement of the authors and Astex Pharmaceuticals. In 
addition, other than clinical pharmacology studies in healthy volunteers or Phase 1 studies, all 
clinical studies must be registered with ClinicalTrials.gov. 


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16.0
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Cheng HW, Li CW, Chan KY, Au HY, et al. 2015. End-of-life characteristics and palliative care 
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de Greef GE, van Putten WL, Boogaerts M, et al. 2005. Criteria for defining a complete 
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Dombret H, Seymour JF, Butrym A, Wierzbowska A, et al. 2014. Results of a phase 3, 
multicenter, randomized, open-label study of azacitidine (AZA) vs conventional care regimens 
(CCR) in older patients with newly diagnosed acute myeloid leukemia (AML). European 
Hematology Association, Milan, June 12-15. Abstract LB-6212. Please see SN0060. 


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Efficace F, Kemmler G, Vignetti M, Mandelli F, et al. 2008. Health-related quality of life 
assessment and reported outcomes in leukaemia randomised controlled trials - a systematic 
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EMEA. 2007. European Agency for the Evaluation of Medicinal Products (EMEA)'s reflection 
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Oncol. 25:1908–1915. Please see SN0044. 
Fang F, Munck J, Tang J, Taverna P, et al. 2014. The novel, small-molecule DNA methylation 
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Griffiths EA, Choy G, Redkar S, Taverna P, Azab M, Karpf AR. 2013. SGI-110, DNA 
Methyltransferase Inhibitor, Oncolytic. Drugs of the Future. 38(8):535–543. Please see SN0042. 
Grimwade D, Walker H, Harrison G, et al. 2001. The predictive value of hierarchical cytogenetic 
classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients 
entered into the United Kingdom Medical Research Council AML11 trial. Blood. 98(5):1312–
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Administration approval of oncology drugs. J Clin Oncol. 21:1404-1411. Please see SN0060. 
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candidates for the treatment outcome prediction of SGI-110, a novel DNA hypomethylating 
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Kantarjian HM, Jabbour E, Yee K, et al. 2013. First clinical results of a randomized phase 2 
study of SGI-110, a novel subcutaneous (SQ) hypomethylating agent (HMA), in adult patients 
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leukemia. J Clin Oncol. 30(21):2670–2677. Please see SN0042. 


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Kantarjian HM, Roboz GJ, Rizzieri DA, et al. 2012. Results from the dose escalation phase of a 
randomized phase 1-2 First in Human (FIH) study of SGI-110, a novel low volume subcutaneous 
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older patients (age 70 years or older) with acute myeloid leukemia. Blood. 116(22):4422–4429. 
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age 65 years or older with acute myeloid leukemia or high risk myelodysplastic syndrome: 
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clofarabine in patients with refractory or relapsed acute leukemia. Blood. 102:2379–2386. Please 
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deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. Clin 
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17.0
APPENDICES 
 


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APPENDIX 1: 
ECOG PERFORMANCE STATUS 
Score 
ECOG Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: ECOG Performance Status — http://www.ecog.org/general/perf_stat.html (accessed 25 March 2014) 
 


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APPENDIX 2: 
POOR-RISK CYTOGENETICS SPECIFICATION 
Poor-risk cytogenetics are defined based on the NCCN Guidelines® (2014) as follows: 
Risk Status Based on Cytogenetics1 
Risk Status 
Cytogenetics 
Better-risk 
inv(16)2,3 or t(16;16)2
t(8;21)2 
t(15;17) 
Intermediate-risk 
Normal cytogenetics 
+8 alone 
t(9;11) 
Other non-defined 
Poor-risk 
Complex (3 clonal chromosomal abnormalities) 
Monosomal karyotype 
-5, 5q-, -7, 7q- 
11q23 - non t(9;11) 
inv(3), t(3;3) 
t(6;9) 
t(9;22)4 
1 
The molecular abnormalities included in this table reflect those for which 
validated assays are available in standardized commercial laboratories. 
Given the rapidly evolving field, risk stratification should be modified 
based on continuous evaluation of research data. Other novel genetic 
mutations have been identified that may have prognostic significance. 
2  
Other cytogenetic abnormalities in addition to these findings do not alter 
better risk status. 
3 
Paschka P, Du J, Schlenk RF, et al. Secondary genetic lesions in acute 
myeloid leukemia with inv(16) or t(16;16): a study of the German-
Austrian AML study group (AMLSG). Blood 2013;121:170-177. 
4 
For Philadelphia+ AML t(9;22), manage as myeloid blast crisis in chronic 
myeloid leukemia, with addition of tyrosine kinase inhibitors. 
Source: NCCN Guidelines: Acute Myeloid Leukemia. Version.2. 2014. NCCN.org. 
 


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APPENDIX 3: 
NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS 
Adverse events and/or adverse drug reactions will be graded according to the CTCAE version 
4.03. 
View the NCI CTCAE criteria electronically at the following web link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 (accessed 07 
August 2014) 
Click on "Common Terminology Criteria for Adverse Events (CTCAE) v4.0." 
 


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APPENDIX 4: 
EQ-5D-5L SAMPLE  
The attached sample (in English) was downloaded from the EuroQol website: 
http://www.euroqol.org/home.html  
(accessed on 24 November 2014) 


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APPENDIX 5: 
SUMMARY OF CHANGES, AMENDMENT 1 
Protocol: 
SGI-110-04 
Amendment Date: 
6 March 2015 
Amendment 1 incorporates changes required by the Voluntary Harmonization Procedure (VHP) 
assessment of the protocol after clinical trial application in Europe.  
Rationale for Amendment 1: VHP-required changes and sponsor administrative changes. 
Summary of Changes:  
1.
Requirements were incorporated to specify use of 2 highly effective contraceptive 
measures during the study and for at least 3 months after completing treatment. Highly 
effective contraceptive measures are defined. Monthly pregnancy testing for women of 
child-bearing potential and pregnancy as a reason for discontinuation from study 
treatment were also incorporated (Synopsis and Sections 5.2, 5.4.1, 9.5.1, 9.5.3.1, and 
9.5.4.1). 
2.
Description is added that the use of decitabine, the active metabolite of SGI-110, alters 
fertility and is mutagenic. Recommendation is added to seek advice about preserving 
oocytes and sperm before the start of study treatment for men and women of child-
bearing potential (Section 8.0). 
3.
The timing of the screening pregnancy test was changed so that it must be done within 
7 days of the start of study treatment (Sections 9.5.1 and 9.5.2). 
4.
Prohibition of vaccination with live vaccines was added (Section 7.5.2). 
5.
A statement was added that the sponsor will submit a protocol amendment and a revised 
model ICF to regulatory authorities for approval before implementation (Section 14.4). 
6.
More information about life expectancy, harm, and quality of life for the TCs was added. 
Information on supportive care was also added (Sections 1.2 and 16.0).  
7.
Two additional collection time-points for PK analysis were added (for a total of 4 sparse 
samples from 2 collection days) from SGI-110-treated subjects to enable more robust 
exposure-response analyses using a Population PK modeling approach (Section 9.3). 
8.
A description was added to address alternative therapy upon progression or toxicity in the 
TC group (Section 7.2). 
9.
A description of results from the 10-day regimen in previously untreated subjects with 
AML was added, based on preliminary data from Study SGI-110-01 Phase 2 Dose 
Expansion (Section 2.2.3.2). 
10.
Rationale was added for the recommendation that SGI-110 study treatment should 
continue for at least 6 cycles (Section 7.1.2). 


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11.
Exclusion criterion #3 (“Known core binding factor (CBF) leukemia: t(8,21) or inv(16)”) 
was deleted (Synopsis and Section 5.2). 
12.
Exclusion criterion #7 was changed to include hypersensitivity to the TCs or any of their 
excipients (Synopsis and Section 5.2). 
13.
Allowance of leukapheresis before randomization to reduce tumor burden, and 
prohibition of leukapheresis after randomization, was added (Sections 7.4 and 7.5.1.3). 
14.
Summary of Product Characteristics (SPC) reference safety information was added, and 
existing reference to US prescribing information as examples was clarified (Sections 7.2, 
7.3.2, 8.0, and 16.0). 
15.
Clarification was added that Grade 3 and 4 cytopenias without an associated 
life-threatening clinical AE will not be considered SAEs in this study (Section 10.1.2). 
16.
Clarification was added that “the last dose of study treatment” is synonymous with 
“discontinuation of treatment in the study” (Sections 5.4.1 and 10.2). 
17.
Clarification that the study population eligibility describes adults with previously 
untreated AML who are “unfit to receive” or not considered candidates for intensive 
remission induction chemotherapy (Synopsis and Sections 4.1 and 5.2). 
18.
TC decitabine and azacitidine dosing schedules were clarified to be daily (Synopsis and 
Sections 1.4, 4.1, and 7.2). 
19.
Dose modification “based on Day 28 or later PB counts” was changed to “…Day 29…” 
to correspond with the schedule of events more closely (Section 7.3.1). 
20.
The window for Day 1 assessments for Cycles 3 was widened from +6 days to +7 days 
(Sections 9.5.1 and 9.5.4.1). 
21.
Clarification was added that the window for BM aspirate/biopsy is ±7 days around Day 1 
of Cycles 3, 5, and 7 (Section 9.5.1). 
22.
The sponsor drug safety contact number designation was corrected from phone to fax 
(Title page and Section 10.3.1). 
23.
The address for the sponsor, Astex Pharmaceuticals, Inc., was updated (Title page and 
Sponsor and Investigator Signature Page). 
24.
The model ICF was revised to correspond to these protocol modifications, as applicable. 
  

SAP_001.pdf: 
CONFIDENTIAL 
This document is a confidential communication of Astex Pharmaceuticals, Inc. Acceptance of the document 
constitutes agreement by the recipient that the contents will not be disclosed to any unauthorized personnel without 
the prior written authorization of Astex Pharmaceuticals, Inc. 
SGI-110-04 
Statistical Analysis Plan 
A Phase 3, Multicenter, Open-Label, Randomized Study of SGI-110 Versus 
Treatment Choice (TC) in Adults With Previously Untreated Acute 
Myeloid Leukemia (AML) Who Are Not Considered Candidates for 
Intensive Remission Induction Chemotherapy 
Date: 28 April 2016 
Based on: Protocol Version 2.0 
NCT02348489




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TABLE OF CONTENTS 
1.0 
INTRODUCTION..............................................................................................................6 
1.1 
Acute Myeloid Leukemia in Patients Who Are Not Considered Candidates for 
Intensive Remission Induction Therapy and the Elderly .........................................6 
1.2 
Treatment Options for Patients with AML Who Are Not Considered 
Candidates for Intensive Remission Induction Therapy ..........................................6 
1.3 
Guadecitabine ..........................................................................................................6 
2.0 
STUDY OBJECTIVES ......................................................................................................7 
2.1 
Primary Objective ....................................................................................................7 
2.2 
Secondary Objectives...............................................................................................7 
2.3 
Exploratory Objectives ............................................................................................8 
3.0 
STUDY DESIGN ................................................................................................................8 
3.1 
Overall Study Design ...............................................................................................8 
3.2 
Study Endpoints .....................................................................................................10 
3.2.1 
Co-primary Endpoint ............................................................................10 
3.2.2 
Secondary Endpoints .............................................................................10 
4.0 
SAMPLE SIZE .................................................................................................................10 
5.0 
ANALYSIS SETS.............................................................................................................11 
5.1 
All Subject Analysis Set ........................................................................................11 
5.2 
Efficacy Analysis Set .............................................................................................11 
5.3 
Safety Analysis Set ................................................................................................11 
5.4 
PK Analysis Set .....................................................................................................12 
5.5 
PD Analysis Set .....................................................................................................12 
6.0 
SCHEDULE OF ANALYSES .........................................................................................12 
7.0 
STATISTICAL ANALYSIS ...........................................................................................12 
7.1 
Subject Disposition ................................................................................................12 
7.2 
Demographic and Other Baseline Characteristics .................................................13 
7.3 
Efficacy Variables and Analyses ...........................................................................13 
7.3.1 
Criteria for Response Assessment .........................................................14 
7.3.2 
Complete Response ...............................................................................15 
7.3.3 
Overall Survival ....................................................................................16 
7.3.4 
Composite CR .......................................................................................17 
7.3.5 
Number of Days Alive and Out of the Hospital ....................................17 
7.3.6 
Progression-free Survival ......................................................................18 
7.3.7 
Test Sequence and Procedures of Statistical Tests for Efficacy 
Endpoints ..............................................................................................19 
7.3.8 
Number of RBC or Platelet Transfusions (Units) .................................21 


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7.3.9 
EQ-5D-5L Descriptive System Total Score and the EQ VAS ..............21 
7.3.10 
Duration of Complete Response ...........................................................21 
7.3.11 
Subgroup and Exploratory Analysis .....................................................22 
7.3.12 
Dealing with Technical Issues Caused by Small Cell Count ................23 
7.3.13 
Dealing with Non-Proportional Hazards in OS and PFS Analyses ......23 
7.4 
Safety Variables and Analyses ...............................................................................24 
7.4.1 
Study Treatment Exposure ....................................................................24 
7.4.2 
Adverse Events......................................................................................25 
7.4.3 
30- and 60-Day All-cause Mortality .....................................................26 
7.4.4 
Concomitant Medications .....................................................................26 
7.4.5 
Laboratory Tests....................................................................................26 
7.4.6 
Vital Signs .............................................................................................27 
7.4.7 
Electrocardiogram .................................................................................27 
7.4.8 
ECOG Performance Status ....................................................................27 
7.4.9 
Physical Examination ............................................................................27 
7.5 
Pharmacokinetics Analysis ....................................................................................28 
7.6 
Interim Analyses and Data Monitoring..................................................................28 
7.7 
Handling of Missing Data and Other Data Anomalies ..........................................29 
7.8 
Handling of Protocol Deviations ...........................................................................29 
8.0 
REFERENCES .................................................................................................................30 
 
LIST OF TABLES 
Table 1: 
Modified 2003 IWG AML Response Criteria ...........................................14 
 
LIST OF FIGURES 
Figure 1: 
Study Schema...............................................................................................9 
Figure 2:  
The Hierarchical Test Order and Related Alpha Values ...........................20 
 


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ABBREVIATIONS AND DEFINITIONS
AE 
adverse event 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
BDM 
Biostatistics and Data 
Management 
BID 
twice daily 
BM 
bone marrow 
BSA 
body surface area 
CI 
confidence interval 
Cmax 
maximum concentration 
CR 
complete response 
CRc 
composite CR (CRc = CR + 
CRp + CRi) 
CRi 
CR with incomplete blood count 
recovery 
CRO 
contract research organization 
(CRO) 
CRp 
CR with incomplete platelet 
recovery 
CTCAE 
Common Terminology Criteria 
for Adverse Events 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology 
Group 
EQ VAS 
EQ visual analogue scale 
FAB 
French-American-British 
HCT 
hematopoietic cell transplant 
HR 
hazard ratio 
ITT 
intent-to-treat 
IWG 
International Working Group 
LDAC 
low-dose Ara-C 
MDS 
myelodysplastic syndromes 
MedDRA 
Medical Dictionary for 
Regulatory Activities 
NCCN 
National Comprehensive Cancer 
Network 
NDAOH 
number of days alive and out of 
the hospital 
NE 
nonevaluable 
NR 
nonresponders 
OR 
odds ratio 
OS 
overall survival 
PB 
peripheral blood 
PD 
pharmacodynamic(s) 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PT 
preferred term 
QOL 
quality of life 
QTc 
heart rate corrected QT interval 
ROW 
rest of world 
Remission 
equivalent to "response" 
Response 
equivalent to "remission" 
RR 
relative risk 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SGI-110 
guadecitabine 
SOC 
system organ class 
TC 
treatment choice 
 


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1.0 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on SGI-110-04 protocol version 2, dated 6 March 
2015. Analyses and statistical reporting for SGI-110-04 will be conducted by Astex 
Pharmaceuticals Biostatistics department with the interim analysis results as reported by the 
study's Data Monitoring Committee (DMC).  
1.1 
Acute Myeloid Leukemia in Patients Who Are Not Considered Candidates for 
Intensive Remission Induction Therapy and the Elderly 
Acute myeloid leukemia (AML) is a genetically heterogeneous group of cancers that have in 
common clonal proliferation and arrested differentiation of myeloid precursors. Incidence 
increases with age and is about 12 cases per 100,000 for those at and above the median age at 
diagnosis of 65 years (Schiffer and Anastasi 2014). Overall 5-year survival is 15% and varies 
substantially with age (Shah et al 2013). Patients age 70-79 years and over age 79 years have 
5 year survival rates of 3% and 0%, respectively.  
In addition to age, other adverse prognostic indicators in AML include poor performance status, 
adverse cytogenetic or molecular genetic findings, past exposure to cytotoxic or radiation 
therapy, and history of myelodysplasia or another hematologic disorder (Schiffer 2014). There is 
a correlation between age at diagnosis of AML and complex cytogenetic disease characteristics. 
Complex karyotype also correlates with disease resistance to therapy (Grimwade et al 2001). In 
summary, AML in patients who are not considered candidates for intensive remission induction 
chemotherapy, particularly elderly patients, remains a persistent unmet medical need. 
1.2 
Treatment Options for Patients with AML Who Are Not Considered Candidates for 
Intensive Remission Induction Therapy 
No standard therapy exists for patients with previously untreated AML who are not candidates 
for intensive remission induction chemotherapy. The National Comprehensive Cancer Network 
(NCCN), European Leukemia Net, and European Society for Medical Oncology all recommend 
possible treatments with low-dose Ara-C (LDAC), azacitidine, or decitabine in addition to 
enrolling patients in experimental treatment clinical trials.  
In Study SGI-110-04, treatment choice (TC) will be compared with guadecitabine (SGI-110). 
Available TCs will depend on which TCs are approved locally. TC includes cytarabine, 
decitabine, or azacitidine. 
1.3 
Guadecitabine 
Guadecitabine is a dinucleotide of decitabine and deoxyguanosine, designed to protect the active 
decitabine moiety from inactivation by cytidine deaminase (Griffiths et al 2013). 
Rationale 
for 
Study 
SGI-110-04 
comes 
from 
guadecitabine's 
molecular 
structure, 
pharmacokinetic (PK), pharmacodynamic (PD), and clinical data. Human PK data confirms that 


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gradual in vivo dinucleotide cleavage increases decitabine exposure time and effective half-life 
relative to decitabine IV infusion. Prolonged exposure time is predicted to increase efficacy 
because decitabine activity is dependent on its incorporation into DNA during DNA synthesis, 
ie, S-phase of the cell cycle (Griffiths et al 2013; Karahoca and Momparler 2013). Prolonged 
exposure results in more cancer cells susceptible to decitabine activity as they enter into S-phase. 
Also, a lower decitabine Cmax after guadecitabine relative to decitabine IV infusion might 
improve safety for toxicities associated with peak decitabine concentrations.  
During the first-in-human Phase 1 SGI-110-01 Dose Escalation, potent DNA demethylation, 
complete response (CR) and other clinical responses were observed in heavily pretreated subjects 
with AML and MDS (myelodysplastic syndromes) (Issa et al 2015), including those previously 
treated with other existing hypomethylating agents (decitabine and azacitidine). 
In the Phase 2 SGI-110-01 Dose Expansion, 51 elderly subjects with AML who had other poor 
prognostic features and were not eligible for intensive chemotherapy received guadecitabine. The 
CR rate of 37% and composite CR (CRc) rate of 57% (Kantarjian et al 2015) exceeded those 
observed for available therapies in randomized, multicenter studies (CR rates of 8% to 20% and 
CRc rates of 11% to 28%) (Kantarjian et al 2012; Dombret et al 2014; Burnett et al 2007).  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To assess and compare efficacy (CR rate and overall survival [OS]) between guadecitabine and 
TC in adults with previously untreated AML who are not considered candidates for intensive 
remission induction chemotherapy. 
2.2 
Secondary Objectives 
To assess and compare effects of guadecitabine and TC in adults with previously untreated AML 
who are not considered candidates for intensive remission induction chemotherapy with respect 
to the following variables:  
• CRc (CR + CR with incomplete blood count recovery [Cri] + CR with incomplete platelet 
recovery [CRp]) rate. 
• Number of days alive and out of the hospital (NDAOH). 
• Progression-free survival (PFS). 
• Transfusion needs. 
• Health-related quality of life (QOL). 
• Duration of CR. 
• Safety. 


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2.3 
Exploratory Objectives 
• 
 
  
• 
 
3.0 
STUDY DESIGN 
3.1 
Overall Study Design 
This is a phase 3, multicenter, randomized, open-label study of guadecitabine versus TC. Blinded 
central reading of marrow and disease response will be performed. Subjects will be adults with 
previously untreated AML who are unfit to receive and not candidates for intensive remission 
induction chemotherapy. 
Approximately 800 subjects from approximately 100-160 study centers will be randomly 
assigned (1:1) to 1 of 2 groups: 
• Guadecitabine: 60 mg/m2 guadecitabine given SC daily for 5 days (Days 1-5, Daily×5) in 
28-day cycles. 
• TC: subjects will be assigned (before randomization) by the investigator to 1 of the following 
treatment regimens: 
• 20 mg cytarabine (Ara-C) given SC BID on Days 1-10 every 28 days. 
• 20 mg/m2 decitabine (Dacogen) given IV on Days 1-5 every 28 days. 
• 75 mg/m2 azacitidine (Vidaza) given IV or SC on Days 1-7 every 28 days. 
The randomization will have a ratio of 1:1 between guadecitabine and TC groups, and will be 
stratified by age (<75 or ≥75 years old), ECOG performance status (0-1, 2-3), study center region 
(North America, Europe, rest of world [ROW]), and secondary AML or poor-risk cytogenetics 
(Yes, No/Unknown). Subjects who are older (≥75 years) or have a poor performance status (2 or 
3) tend to have worse response and survival than younger (<75 years) subjects or subjects with a 
good performance status (0 or 1). Similarly, subjects with a secondary AML or poor-risk 
cytogenetics generally do not respond to treatment well and have a shorter survival time. In 
addition, prognosis could have regional differences due to multiple factors including variable 
levels of Standard of Care. Stratification by these known and important prognostic factors 
measured at baseline prevents imbalance between treatment groups within strata, and could 
reduce bias and improve power of the study.  
Selection of 1 of the TCs must be made prior to the randomization of each subject. Subjects 
should receive study treatment as soon as possible after randomization (maximum of 1 week 
between randomization and treatment).  
The sponsor, investigators and study subjects are not blinded in this study. However, to minimize 
the potential bias associated with assessment of treatment outcome, response will be determined 


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by a blinded independent central response reviewer, based on assessment by a blinded 
independent central pathologist. Refer to Section 11.6 of the study protocol. The specific process 
used for handling test samples and reports will be described separately. 
Peripheral blood (PB) will be assessed at baseline and on Day 1 of each cycle for response status 
evaluation. Bone marrow (BM) aspirate/biopsy will be performed at screening and then at the 
end of Cycles 2, 4, and 6 unless PB shows persistence of leukemic blasts that excludes the 
possibility of a marrow response. After Cycle 6 BM assessment, BM aspirate/biopsy will be 
repeated every 3 months for the first year on study and then every 6 months thereafter until PB or 
BM assessment shows disease progression or relapse. Response evaluation will be based on BM 
blinded assessment and the most concomitant PB counts. After blinded BM response is 
confirmed, assessment of normal count recovery will be done based initially on the most 
concomitant PB and in later cycles on PB counts from Day 1 of each cycle to avoid transient 
treatment-induced normal count suppression. 
Figure 1 below summarizes the study design. 
Figure 1: 
Study Schema 
 
a 
Treatment with guadecitabine should continue for at least 6 cycles in the absence of unacceptable toxicity or 
AML progression requiring alternative therapy. Beyond 6 cycles, treatment should continue as long as the 
subject continues to benefit based on investigator judgment. 
b 
TC will be determined before randomization and treatment with the regimens described in the study protocol 
(Section 7.2) should be used. Other treatment parameters should be applied according to institutional standard 
practice and approved local prescribing information. 


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The study is expected to enroll the required number of subjects in 21 months with an additional 
follow-up of 12-15 months before the planned primary analysis. The expected duration of the 
study from the first subject enrollment to the planned primary analysis is approximately 3 years. 
3.2 
Study Endpoints 
3.2.1 
Co-primary Endpoint 
• CR rate based on modified International Working Group (IWG) 2003 AML Response 
Criteria. 
• OS, defined as the number of days from randomization to death. 
3.2.2 
Secondary Endpoints 
• CRc (CR+CRi+CRp) rate. 
• NDAOH. 
• PFS, defined as the number of days from date of randomization to date of disease 
progression, initiation of an alternative anti-leukemia therapy, or death, whichever occurs 
first. 
• Number of red blood cell (RBC) or platelet transfusions (units) over the duration of the study 
treatment. 
• Health-related QOL by EQ-5D (consisting of the EQ-5D-5L descriptive system and the EQ 
Visual Analogue Scale [EQ VAS]). 
• Duration of CR, defined as the time from first CR to time of relapse. 
• Incidence and severity of adverse events (AEs). 
• 30- and 60-day all-cause mortality. 
4.0 
SAMPLE SIZE 
By trial design, the overall (2-sided) alpha level of 0.05 is split between the co-primary endpoints 
of CR (0.04) and OS (0.01). A formal interim analysis will be performed only for OS using a 
group sequential boundary preserving an overall (2-sided) 0.01 alpha level. The sample size 
calculation for the primary analysis of CR is based on testing at the 0.04 nominal alpha level. If 
statistical significance is achieved for CR, hierarchically, the final analysis of OS will be 
conducted to preserve an overall 2-sided 0.05 alpha level, accounting for alpha spent at the 
interim analysis of OS, as described in Section 11.6.7 and Section 11.9 of the study protocol (see 
Section 7.3.7 and 7.6). The sample size calculation for OS will be shown for the setting of a 
2-sided 0.05 alpha level. 
Assuming a CR rate of approximately 0.20 (Kantarjian et al 2012; Fenaux et al 2010; Burnett et 
al 2007) for subjects treated in the TC group (all TC therapies combined) and assuming an 
increase in CR rate to 0.30 or higher can be achieved by treating subjects with guadecitabine, 


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800 subjects (400 per treatment group) will provide approximately 89% power to detect the 
overall difference of 0.10 when using a 2-sided Cochran Mantel-Haenszel test having 2-sided 
alpha level of 0.04. For the purpose of this sample size calculation, the constant CR rates of 0.20 
and 0.30 for the TC and guadecitabine groups, respectively, are assumed for each stratum. 
For survival, an analysis at 670 death events will provide 90% power to detect a HR of 
approximately 0.78 (a difference in median survival of 7 months in the TC group versus 
9 months in the guadecitabine group), when using a 2-sided stratified log-rank test at an 
0.05 alpha level. Accrual is expected to be uniform over a 21 month enrollment period, with an 
additional follow-up of 12 months. Hence, the assessment of survival needs approximately the 
same sample size of 800 subjects. Primary response and survival analyses will be performed 
after 670 death events have occurred. For the purpose of this sample size calculation, a constant 
HR of approximately 0.78 was assumed for all strata defined by the stratification factors. 
5.0 
ANALYSIS SETS 
5.1 
All Subject Analysis Set 
This analysis set will contain information of all screened subjects, including those who did not 
meet the study entry criteria or did not receive a study treatment. 
5.2 
Efficacy Analysis Set 
Efficacy analyses will be based on intent-to-treat (ITT) principle. The Efficacy Analysis Set will 
include data from all subjects randomly assigned to study treatment. All data will be included 
and no subjects excluded because of protocol violations. For the analysis of efficacy data, 
subjects will be included in the treatment group according to their randomly assigned treatment.  
For NDAOH, transfusions, and health-related QOL by EQ-5D-5L, the primary analysis will 
include only the data collected during the first 6 months of the study because, during this study 
period, subjects are assessed whether or not they are still on study treatment. Secondary analysis 
may also include data beyond the first 6 months of the study (eg, over the entire period of study 
treatment). 
5.3 
Safety Analysis Set 
The Safety Analysis Set will include data from all subjects randomly assigned to study treatment 
who receive any amount of study treatment or any component of a multi-dose study treatment 
regimen. All data will be included and no subjects excluded because of protocol violations. For 
safety data analysis, subjects will be included in the treatment group according to the treatment 
they actually receive. If more than one type of study treatment was given for any subject during 
the study, the initial treatment received by the subject will be used to determine which treatment 
group and which specific TC treatment the subject belongs to. 


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5.4 
PK Analysis Set 
The PK Analysis Set will include all available plasma concentrations and PK parameters for 
guadecitabine and decitabine from subjects at selected centers who have received guadecitabine 
or decitabine IV and for whom PK samples were collected and successfully analyzed. PK data 
will be analyzed using the PK Analysis Set.  
5.5 
PD Analysis Set 
Pharmacodynamics analyses are not applicable to this study. 
6.0 
SCHEDULE OF ANALYSES 
Data listings and summary tables will be reviewed by the DMC approximately every 6 months to 
ensure the safety of study subjects and to enhance the quality of trial conduct (refer to protocol 
Section 4.4 and the DMC Charter). These data listings and summary tables will be generated by 
Axio Research LLC, an independent contract research organization (CRO) supporting the DMC 
activities.  
An interim analysis of OS will also be conducted by the DMC when approximately half of the 
required death events have occurred. All available study data will be analyzed after 670 death 
events have occurred to achieve a mature analysis of OS.  
7.0 
STATISTICAL ANALYSIS 
Unless otherwise specified, all statistical tests and confidence intervals (CIs) created will be 
two-sided with alpha = 0.05 (see Section 7.3.7). The SAS® statistical package (SAS Institute 
Inc., Cary, NC, USA, version 9.3 or a later version) will be used for the analyses. 
The following data listings by study center and subject will be provided, as recommended by the 
ICH E3 guideline "Structure and Content of Clinical Study Reports": discontinued subjects, 
important protocol deviations, demographics, compliance and/or drug concentration data 
(including specific batch number), individual efficacy response data, subjects excluded from the 
efficacy analysis, AEs, medications, and the protocol specified laboratory measurements. 
Additional data listings may be generated to support other relevant discussions in CSR.  
Summary tables of disposition, baseline, dosing, efficacy, safety, and PK data will be provided, 
by treatment group (guadecitabine or TC). In addition, similar tables will be generated, as 
appropriate, comparing guadecitabine to each TC option in the patients randomized under that 
preselected TC option. 
7.1 
Subject Disposition 
Subject disposition including numbers screened, randomized, treated, and treatment 
discontinuation by reason, as well as the reasons for withdrawal from study will be summarized 
using frequencies and percentages based on information collected on the relevant study case 


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report form pages. Sample size for efficacy and safety analysis sets will be clearly identified. All 
Subject Analysis Set will be used for the disposition analysis. 
7.2 
Demographic and Other Baseline Characteristics 
The demographic variables consist of age, age category, sex, ethnicity, race and geographical 
region. Baseline characteristics include height, weight, body surface area (BSA), ECOG 
performance status, AML category by French-American-British (FAB) classification as well as 
by WHO classification, time since AML diagnosis, whether the AML is secondary to MDS or 
other antecedent hematologic disorder, cytogenetic risk levels, peripheral blood counts of 
hemoglobin, platelets, total white blood cells (WBCs) with blasts counts, BM blasts and presence 
of baseline genetic mutations in several genes including but not limited to FLT3-ITD, NPM1, 
and CEBPA. Other baseline variables such as relevant medical history or other medically 
relevant criteria could also be included in the baseline tables. 
Baseline values are generally the values collected right before randomization during the 
screening period. For analysis purposes, the value collected closest to but before randomization 
will be used as the baseline value for a particular variable. For variables which are collected on 
Day 1 of Cycle 1 (C1D1) but not during the screening period, the C1D1 values will be used as 
the baseline values. 
Age at baseline, if not already provided through data collection, will be calculated as the integer 
part of (date of consent - date of birth)/365.25.  
Time since diagnosis will be calculated as the (date of randomization - date of diagnosis). If the 
day is missing for date of diagnosis, the 15th of the month is used. If the month is missing, July 
1st is used. If the year is missing, the date is left as missing. Additional date imputation details 
are contained in the Astex Data Programming Conventions. 
Subject demographic and baseline characteristics will be summarized by mean, standard 
deviation, median, minimum, and maximum for continuous variables; and by counts and 
percentages for categorical variables. Both the Efficacy and Safety Analysis Sets will be used for 
the summaries.  
7.3 
Efficacy Variables and Analyses 
Efficacy analyses will be based on the Efficacy Analysis Set, except where it is specified 
otherwise. This section describes the analyses conducted at the primary analysis time point when 
670 death events have occurred, assuming that the study continued after the planned interim 
analysis. The alpha levels referenced in this section are nominal alpha levels for judging 
statistical significance, taking into consideration the planned interim analysis and the hierarchical 
testing order of the (final) primary analysis. The overall experimental alpha error is controlled at 
the 2-sided 0.05 level. 
The co-primary efficacy endpoints are CR rate based on IWG 2003 AML Response Criteria 
(Cheson et al 2003) and OS. If either of the co-primary efficacy endpoints reaches statistical 


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significance in favor of guadecitabine at either the interim analysis (OS only) or final analysis 
(CR and OS), then the study will be considered positive in efficacy. 
Secondary efficacy endpoints include CRc, NDAOH, PFS, number of RBC transfusions, and 
separately, number of platelet transfusions over the duration of the study treatment, the EQ-5D-
5L descriptive system and the EQ VAS, as well as duration of CR.  
7.3.1 
Criteria for Response Assessment 
Modified IWG 2003 Response Criteria (Table 1) will be used by an independent blinded central 
reader to identify AML subjects with CR, CRp, CRi, or partial response (PR) for further 
statistical analyses.  
Table 1: 
Modified 2003 IWG AML Response Criteria 
Responsea 
Peripheral Blood (PB) 
Bone Marrow (BM) 
CR 
ANC ≥1000/μL, Platelets ≥100,000/μL, independence from 
RBC and platelet transfusions over the past week, no 
leukemic blastsb 
<5% leukemic blasts 
CRp 
ANC ≥1000/μL, Platelets <100,000/μL, independence from 
RBC transfusions over the past week, no leukemic blastsb 
<5% leukemic blasts 
CRi 
ANC <1000/μL, no leukemic blastsb 
<5% leukemic blasts 
PR 
ANC ≥1000/μL, Platelets ≥100,000/μL, no leukemic blastsb 
Decrease of ≥50% in leukemic blasts 
to level of 5% to 25% 
a  
Responses are based on both PB and BM conditions. 
b 
For the purpose of response assessment and according to published IWG criteria, blasts may be seen in PB as 
rare PB blasts may be identified during regeneration, but the subject is in CR if BM blasts are <5% with no 
Auer rods (Cheson et al 2003). 
ANC=absolute neutrophil count; CR=complete response; CRp=complete response with incomplete platelet 
recovery; CRi=CR with incomplete blood count recovery; PR=partial response. 
Source: Cheson et al 2003 
Subjects with these different response categories, as well as nonresponders (NR) and 
nonevaluable (NE) subjects will be listed and summarized using frequency counts and proportion 
of subjects with each category of best response. Subjects who did not have a valid post-treatment 
efficacy assessment (ie, no post-treatment BM/PB sample or the quality of BM/PB sample is not 
adequate for the central pathologist to provide an assessment of efficacy) will be classified as NE 
for response classifications. These subjects will be included in the denominator of the ITT 
analysis for calculation of different response rates. Subjects who cannot be classified into a 
response category (CR, CRp, CRi, PR) or the NE category will be classified as NR.  
In particular, the best response in the order of CR, CRp, CRi and PR will be used when a subject 
experienced different response levels at different visits. Subjects who progressed (see 
Section 7.3.6 for definition) without first having a response (CR, CRp, CRi, or PR) will be 
included in the NR category for summary purpose.  


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Response rate based on the central reader's assessments will be calculated for the best response 
categories described below to assess overall efficacy observed. 
• CR, CRp, CRi, PR. 
• Composite CR (CRc=CR+CRp+CRi). 
Investigators will also provide the assessment of response using the same Modified IWG 2003 
Response Criteria (Table 1). However, their assessments will only be provided in a data listing. 
7.3.2 
Complete Response  
The primary endpoint of CR rate will be calculated as the number of subjects with a best 
response of CR divided by the total number of subjects included in the efficacy analysis. The CR 
rate will be compared between the 2 treatment groups using a Cochran Mantel-Haenszel test at 
an alpha level of 0.04 stratified by the stratification factors used at randomization: age (<75 or 
≥75 years), ECOG performance status (0-1, 2-3), study center region (North America, Europe, 
ROW), and secondary AML (secondary to MDS or other antecedent hematologic disorder) or 
poor-risk cytogenetics (Yes, No/Unknown). The null and alternative hypotheses are:  
• Null hypothesis H0: CR rates are the same between the guadecitabine treatment and 
TC treatment 
• Alternative hypothesis H1: CR rates are different between the two treatment arms 
A 2-sided p value of ≤0.04 will be judged as statistically significant. In addition, a normal 
approximated, two-sided 96% CI for the (Mantel-Haenszel weighted) difference in CR rates 
between guadecitabine treatment and TC treatment will be provided (Koch et al 1990).  
The following sensitivity analyses will be conducted for the co-primary endpoint of CR rate for 
evaluating robustness of the treatment effect: 
1) The CR rate will be compared between the guadecitabine and TC using a regular Chi-square 
test without stratification. 
2) A logistic regression analysis will be performed for the primary endpoint of CR with 
treatment group (guadecitabine or TC), age (<75 or ≥75 years old), ECOG performance 
status (0-1, 2-3), the geographic region (North America, Europe, ROW) of the study centers, 
and secondary AML or poor-risk cytogenetics (Yes, No/Unknown) as fixed factors. The 
point estimate and 95% CI, as well as the p value will be provided for the odds ratio (OR) 
comparing the odds of being a responder in guadecitabine treatment with the odds of being a 
responder in TC treatment.   
3) An "as-treated" analysis will be conducted on the CR rate, based on treatment actually 
received as described in Section 5.3, using the same Cochran Mantel-Haenszel test and same 


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stratification variables described above. Subjects who were randomized but not treated will 
not be included in this analysis. 
4) The CR rate will be calculated and analyzed using the same Cochran Mantel-Haenszel test 
and same stratification variables described above with the subjects who were classified as 
nonevaluable for efficacy (NE subjects) excluded from the Efficacy Analysis Set. 
5) The CR rate will be calculated and analyzed using the same Cochran Mantel-Haenszel test 
and stratification variables described above excluding subjects whose AML diagnosis cannot 
be confirmed by WHO classification by the independent central reader. 
7.3.3 
Overall Survival 
For the OS analysis, survival time is defined as the number of days from the day the subject was 
randomly assigned to study treatment to the date of death (regardless of cause).  
Survival time in days = (earliest date of death or censoring - date of randomization) 
Survival time will be censored on the last date the subject is known alive with no event of death. 
OS curves will be estimated using Kaplan-Meier method and formally compared between the 
two treatment groups using a 2-sided stratified log-rank test, stratified by the same stratification 
factors used at randomization. The null and alternative hypotheses are: 
• Null hypothesis H0: Survival curves are the same between the two treatment arms 
• Alternative hypothesis H1: Survival curves are different between the two treatment arms 
If the CR rate analysis is significant, OS will be tested at an alpha level of 0.05; without a 
significant CR rate test result, OS will be tested at an alpha level of 0.01, as described in 
Section 7.3.7. The stratification variables will include age (<75 or ≥75 years), ECOG 
performance status (0-1, 2-3), study center region (North America, Europe, ROW), and 
secondary AML or poor-risk cytogenetics (Yes, No/Unknown). The median (and quartiles) 
duration of OS and the associated 95% CI for each treatment arm will be estimated using the 
Kaplan-Meier method and the log(-log(.)) transformation for the survival function. The 
12-month survival rate estimate will also be provided for each treatment arm.  
In addition, the HR and its 95% CI will be estimated using a Cox proportional-hazard model 
with treatment group as the independent variable and stratified by the same randomization 
stratification factors as used for the log-rank test. In a supportive analysis, the assumption of 
proportional hazards will be evaluated to assist interpretation of the Cox regression analysis 
results. 


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The following sensitivity analyses will be conducted for the co-primary endpoint of OS for 
evaluating robustness of the treatment effect: 
1) The OS will be analyzed using Kaplan-Meier method and compared between the 
guadecitabine and TC using log-rank test without stratification.   
2) An "as-treated" analysis will be conducted for the OS, based on treatment actually received 
as described in Section 5.3, using the same Kaplan-Meier method and 2-sided stratified log-
rank test described above. Subjects who were randomized but not treated will not be included 
in this analysis. 
3) This analysis will be conducted using the same Kaplan-Meier method and 2-sided stratified 
log-rank test described above. However, the survival time will also be censored on the date 
the subject receives other anti-leukemia treatments, including chemotherapy and 
hematopoietic cell transplant (HCT), recognizing the fact that this analysis could diminish a 
true treatment effect since HCT are given to subjects whose disease is well controlled and 
other anti-leukemia therapies are usually given to subjects at the time of their disease 
progression.  
4) This analysis will be conducted using the same Kaplan-Meier method and 2-sided stratified 
log-rank test described above, excluding subjects whose AML diagnosis cannot be confirmed 
by WHO classification by the independent central reader. 
7.3.4 
Composite CR  
The CRc rate is calculated as the number of subjects with a best response of CR, CRp, or CRi 
divided by the total number of subjects included in the efficacy analysis. The CRc rate will be 
compared between the 2 treatment groups using a Cochran Mantel-Haenszel test with the 
stratification variables the same as for CR and OS. If CR rate analysis and OS analysis are both 
significant, the CRc rate will be tested at an alpha level of 0.05; with a nonsignificant CR rate 
result (p>0.04) and a significant OS result at the 0.01 level, the CRc rate will be tested at an 
alpha level of 0.01 (see Section 7.3.7). In addition, the 2-sided 95% (or 99%, as appropriate) CI 
for the Mantel-Haenszel weighted difference in CRc rate between the 2 treatment groups will be 
provided. 
7.3.5 
Number of Days Alive and Out of the Hospital  
The date of each hospital admission and discharge will be collected for each subject for a 
minimum 6 months (and until termination of study treatment if the study treatment lasts for more 
than 6 months), unless the subject dies or withdraws consent prior. The duration of each hospital 
stay in days (regardless of the reason for hospitalization) is calculated as: 
Duration = date of discharge - date of admission 
For a subject who is admitted and discharged on the same day the duration of hospital stay will 
be 0. The total duration of all hospital stays in the first 6 months is the sum of all individual 


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durations of hospital stays occurred between C1D1 and Day 180. For ease of calculation, one 
month is defined as 30 days for analyses conducted in this study. The NDAOH within the first 
6 month period is calculated as: 
NDAOH = 180 - total duration of all hospital stays - number of death days before Day 180 
The number of death days before Day 180 = (date of Day 180 - date of death, if death occurs 
before Day 180). For subjects who die on or after Day 180 the number of death days before Day 
180 will be set to 0. For subjects who are lost to follow-up within 6 months (expected to be a 
very small number), the NDAOH will be calculated conservatively assuming that the subject 
would have died the day after the last contact day. 
The NDAOH will be summarized by treatment group and compared between the 2 treatment 
groups using an analysis of variance model at an alpha level of 0.05 or 0.01 as appropriate, if the 
CRc test result is significant at that required level (see Section 7.3.7). The variables used for 
stratification at randomization will be included in the analysis of variance model as fixed factors. 
In addition, to utilize the information on hospital stays beyond 6 months, the NDAOH will also 
be calculated in a similar way to 6 months or the date of treatment discontinuation (whichever 
occurs later) and summarized as a per patient-year rate for each treatment group.  
7.3.6 
Progression-free Survival 
Progression is defined as the earliest occurrence of one of the following: 
• For subjects with CR, CRi, or CRp, the confirmed (at least 2 PB samples at least 1 week 
apart) appearance of leukemic blasts in PB by investigator or central assessment, OR ≥5% 
leukemic blasts in the BM by blinded central pathologist assessment. 
• For all other subjects, when PB or BM shows evidence of continued increase in blasts % that 
necessitates alternative therapy. 
• Death. 
PFS is defined as the number of days from randomization to the earliest date of investigator's 
assessment of disease progression, subject receives an alternative anti-leukemia therapy, or 
relapse by PB assessment or blinded BM assessment, whichever occurs first, or death (regardless 
of cause). PFS time will be censored on the last date the subject is known to be alive without a 
relapse/disease progression.  
PFS in days = (earliest date of progression, relapse, alternative anti-leukemia therapy,  
death or censoring - date of randomization) 
PFS will be compared between the 2 treatment groups using a stratified log-rank test (by the 
same stratification factors as used at randomization) at an alpha level of 0.05, or 0.01, as 
appropriate, if CRc and NDAOH test results are significant at that required level (see 


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Section 7.3.7). The median (and quartiles) duration of PFS and the associated 95% CI for each 
treatment arm will be estimated using the Kaplan-Meier method. In addition, the HR and its 95% 
CI will be estimated using a Cox proportional-hazard model with treatment group as the 
independent variable and stratified by the same randomization stratification factors as used for 
the log-rank test. In a supportive analysis, the assumption of proportional hazards will be 
evaluated to assist interpretation of the Cox regression analysis results. 
7.3.7 
Test Sequence and Procedures of Statistical Tests for Efficacy Endpoints 
To control the alpha errors associated with testing the multiple endpoints of CR rate, OS, CRc 
rate, NDAOH, and PFS, the following test sequence and procedures will be followed, assuming 
that the study continues after the planned interim analysis.  
The primary efficacy variable CR rate will be tested first in the sequence at an alpha level of 
0.04. A positive CR analysis (p≤0.04) serves as a gatekeeper (Westfall and Krishen 2001) for the 
subsequent analyses. If the test for CR is positive (ie, p≤0.04), then hierarchical analyses will be 
conducted at the 0.05 alpha level for the efficacy variables OS, CRc rate, NDAOH, and PFS (in 
that order). If the test for CR is not significant at the 0.04 level, then hierarchical analyses will be 
conducted at the 0.01 level for the efficacy variables OS, CRc, NDAOH, and PFS. The 
hierarchical test order and alpha value to be used for each test at the primary analysis time point 
are further described in Figure 2. 


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Figure 2:  
The Hierarchical Test Order and Related Alpha Values 
 
 
 
The overall alpha error rate is controlled at the 0.05 level by following the above testing 
sequence and procedures.  
Other secondary efficacy endpoints (number of transfusions, health-related QOL, and duration of 
CR) will be used as supportive evidence of the beneficial treatment effect, without formal 
hypothesis testing. Point estimates and 95% CIs will be obtained for the effect of treatment on 
these endpoints. 


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7.3.8 
Number of RBC or Platelet Transfusions (Units) 
One RBC transfusion is defined as 1 unit of RBC transfusion. Similarly, one platelet transfusion 
is defined as 1 unit of platelet transfusion. Dates and the number of RBC or platelet transfusions 
will be collected for each subject for a minimum 6 months (and until termination of study 
treatment if the study treatment lasts for more than 6 months), unless the subject dies or 
withdraws consent prior.  
The total number of RBC or, separately, the total number of platelet transfusions up to the 
6-month time point for each subject is counted from the date of randomization to Day 180, the 
date of last contact, or date of death, whichever occurs earlier. The number of transfusions up to 
Day 180 will be summarized using mean, standard deviation, median and quartiles. The 95% CI 
of the means will also be provided. 
7.3.9 
EQ-5D-5L Descriptive System Total Score and the EQ VAS 
The EQ-5D-5L descriptive system scores and the EQ VAS will be collected for each subject for 
a minimum 6 months unless the subject dies or withdraws consent prior. The calculation for 
EQ-5D-5L index value will be performed according to EuroQol group's EQ-5D-5L User Guide 
(http://www.euroqol.org/about-eq-5d.html).  
As suggested in the EQ-5D-5L User Guide (http://www.euroqol.org/about-eq-5d.html), the 
EQ-5D-5L  descriptive scores and their dichotomized levels (No problems, Problems) within 
each EQ-5D dimension (mobility, self-care, usual activity, pain/discomfort, anxiety/depression), 
during the first 6 months, will be summarized by time (ie, visit/treatment cycle) descriptively, 
using counts and proportions. The EQ-5D-5L index value and VAS and their respective changes 
from baseline during the first 6 months will be summarized by time (ie, visit/treatment cycle) 
using means, standard deviations, medians and quartiles. 
In addition, the changes from baseline (post baseline value - baseline value) of EQ-5D-5L index 
value, and separately EQ VAS, will be analyzed using a mixed model approach for repeated 
measures. This model will include the following terms as fixed effects: baseline value, treatment, 
time, and treatment-by-time interaction. The unstructured covariance matrix will be used to 
account for the within subject correlation and allow for different variances at different 
measurement times. The difference of the least squares means between the two treatment groups 
at each time (ie, visit/treatment cycle) and its corresponding 95% CI will be provided.  
7.3.10 
Duration of Complete Response  
Duration of CR (in number of days) will be calculated from the first time a CR is observed to 
time of relapse (defined as the earliest time point whereby BM assessment or PB assessment 
indicate relapse/disease progression due to reappearance of leukemic blasts in PB or ≥5% 
leukemic blasts in BM; see Section 7.3.6). The duration of CR will be censored at the last 
available time point at which a relapse/disease progression was not observed. Duration of CR 
will be estimated using a Kaplan-Meier method for subjects who achieved a CR during the study. 


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The median and quartiles of duration of complete response, as well as their respective 95% CIs 
will be provided. 
To take all subjects in the Efficacy Analysis Set into consideration when analyzing duration of 
CR, a separate Kaplan-Meier analysis including all subjects will be conducted with a 0-day event 
duration assigned to subjects who did not achieve a CR. The median and quartiles of duration of 
complete response, as well as their respective 95% CIs will be provided.  
7.3.11 
Subgroup and Exploratory Analysis  
Subgroup analyses will be performed to explore the influence of the baseline variables, and the 
individual TC therapy administered, on the efficacy outcomes of CR rate and OS, and to evaluate 
the treatment effect at different levels of each baseline variable:  
• Age (<75, ≥75). 
• AML category (primary, secondary). 
• Baseline cytogenetic risk (poor-risk, others [No/Unknown]). 
• Baseline ECOG PS (0-1, 2-3). 
• Baseline BM blasts (≤30%, >30%). 
• Baseline total WBC counts (<20,000/μL, ≥20,000/μL). 
• Study center region (North America, Europe, Asia-Pacific, ROW). 
• Race (White, Black, Asian, Other). 
• Presence of baseline genetic abnormalities such as FLT3, NPM1, and CEBPA (for each 
gene: yes, no). 
• Individual TC (cytarabine, decitabine, azacitidine) compared with guadecitabine treatment 
for subjects randomized under that preselected TC option.  
For subgroup analysis of CR, the OR of guadecitabine versus TC and associated 95% CIs will be 
provided for subgroups defined by categories of each variable listed above (except Individual 
TC). The intention is to descriptively display the treatment effect for each of these subgroups on 
Forest plots. 
For subgroup analysis of OS, the HR of guadecitabine versus TC and associated 95% CIs will be 
provided for subgroups defined by categories of each variable listed above (except individual 
TC). Again, the intention is to descriptively display the treatment effect for each of these 
subgroups on Forest plots. 
In addition, the CR and OS will be compared between subjects who were randomized to 
guadecitabine versus those who were randomized to TC within the subjects who were 
preassigned to a particular TC treatment. This comparison will be done for each of the three 
preassigned TC patient groups separately.  


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7.3.12 
Dealing with Technical Issues Caused by Small Cell Count 
If technical issues (such as non-convergence or unstable variance) arise due to small cell counts 
caused by too many levels of stratification variables, the stratification variables will be collapsed 
in the following order, until the technical issues have been resolved:  
1) Collapse North America and EU into one level of geographic region, resulting in a new two-
level geographic region variable (North America/EU vs. ROW). 
2) Collapse geographic regions completely (combine North America, EU and ROW). 
3) Collapse geographic regions completely and collapse Age categories (≥75 and <75 years). 
7.3.13 
Dealing with Non-Proportional Hazards in OS and PFS Analyses 
In supportive analyses, the proportional hazards assumption for treatment over time will be 
assessed by including (effect of) treatment as a time-dependent covariate in the Cox regression 
model. The Cox regression analysis will be conducted with the time-dependent covariate 
(Treatment*Log(time)) in the model, where the variable Treatment has two levels, guadecitabine 
or TC, and Log(time) is natural log of survival time. A below 0.05 p value of this test is an 
indicator that the proportional hazards assumption may not hold. 
If the proportional hazards assumption does not hold, the following additional analyses will be 
conducted to assess the treatment effect over different time intervals or at different time points.  
1) A piece-wise Cox model will be conducted for evaluating a separate HR for each piece or 
interval. The cut-off times for the piece-wise Cox model are >0 to 6 months, >6 to 
12 months, >12 to 18 months, >18 to 24 months and >24 months. For ease of calculation, one 
month is defined as 30 days for analyses conducted in this study.  


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2) The survival rates between the two treatment arms at each of the 6-month, 12-month, 
18-month, and 24-month time points will be evaluated for the treatment effect at these time 
points. The stratified Kaplan-Meier estimates of survival probabilities and the corresponding 
standard errors based on the Greenwood formula (Kalbfleisch and Prentice 1980) will be 
used for constructing this analysis. 
7.4 
Safety Variables and Analyses 
All safety analyses will be performed using the Safety Analysis Set which includes data from all 
subjects who receive any amount of study treatment (guadecitabine or TC; see Section 5.3).  
Safety is assessed by subject-reported and investigator-observed AEs, and 30-day and 60 day all-
cause mortality, along with concomitant medications, physical examination, clinical laboratory 
tests (hematology, serum chemistry, and urinalysis), vital signs, ECOG performance status, and 
ECGs. Safety is also assessed by exposure to guadecitabine or TC, reasons for discontinuation, 
deaths and causes of deaths. 
All safety data collected during the study will be included in the study database. All safety data 
collected during the study will be used for generation of safety summary tables, with the 
exception of AEs and medications. The AE and medication summary tables will only include 
treatment-emergent AEs and concomitant medications as defined in Sections 7.4.2 and 7.4.4. 
7.4.1 
Study Treatment Exposure 
Cycle 1 Day 1 is defined as the first day of study treatment after randomization; cycle days are 
counted sequentially thereafter. Cycle 2 Day 1 is the first day of Cycle 2 regardless of treatment 
delays. The designated cycle duration is 28 days but any cycle could be prolonged to >28 days to 
allow blood count recovery if deemed clinically necessary. This convention for determining the 
start and stop dates for cycles is maintained until treatment is permanently discontinued. For easy 
presentation, Cycle x Day y is often abbreviated as CxDy in this document and statistical 
outputs.  
Frequency counts and percentages of dose cycles received, dose cycles delayed, and dose 
reduced cycles will be summarized by treatment group. Summary statistics of number of cycles 
received, as well as percentages of intended dose received, will also be provided by treatment 
group. Dose delayed cycles are identified by the study site and entered into the electronic data 
capture (EDC) system. A dose reduced cycle is defined as a cycle in which the dose was reduced 
by 20% or more, compared with the planned Cycle 1 dose. Percentage of intended dose is equal 
to actual total dose divided by planned total dose through the last treatment cycle. Both 
completed or partially completed dose cycles are counted in these summaries.  
 


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7.4.2 
Adverse Events  
AE terms reported by study subjects or observed by investigators will be mapped to the 
appropriate System Organ Class (SOC) and Preferred Term (PT) according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Severity of AE will be graded using Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.  
Treatment-emergent AEs are defined as events that first occurred or worsened after the first dose 
of study drug given on C1D1 until 30 days after the last dose of study treatment or the start of an 
alternative anti-leukemia treatment, whichever occurs first, with the following exceptions: events 
that occurred after 30 days beyond the last dose of study treatment or the start of an alternative 
anti-leukemia treatment will also be considered treatment-emergent if the events are both serious 
and related to the study treatment. For the purpose of determining whether an AE is a treatment-
emergent AE, incomplete AE start and stop dates will be imputed conservatively following the 
data programming standards as detailed in the Astex Data Programming Conventions. 
All AE data collected in the study database will be listed, including those that are not treatment 
emergent. However, safety tables will be generated based only on Treatment-emergent AEs. 
An overall safety summary table containing counts and percentages of subjects with any AE, any 
AE Grade ≥3, AE leading to treatment discontinuation, any serious AE (SAE), SAE leading to 
death, and other subjects with an SAE will be produced by treatment group. A similar table with 
related AE counts will also be produced by treatment group. Related events are those that the 
investigator considered to be suspected to be related to study treatment as described in the study 
protocol. 
The number and percentage of subjects experiencing AEs will be summarized by MedDRA 
SOCs (sorted alphabetically) with PTs sorted alphabetically within each SOC, and by CTCAE 
grade. The number and percentage of subjects experiencing AEs will also be summarized by PT 
and sorted by event frequency. Related AEs, serious AEs, and related serious AEs will be 
summarized similarly. In summarizing AEs, if a subject reports the occurrence of a particular AE 
more than once, the event is only counted once with its worst CTCAE grade. 
Treatment-site events (including events at the injection site) are of special interest. These events 
will be tabulated separately. Since it is expected that SC administration will be associated with 
more injection site events, a separate table will be produced to compare guadecitabine SC 
injection events to low dose Ara C (LDAC) SC injection events in subjects randomized under the 
preselected LDAC TC; and a similar table comparing guadecitabine SC to azacitidine (only 
those subjects receiving azacitidine by SC route) under the preselected azacitidine TC option. 
 


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7.4.3 
30- and 60-Day All-cause Mortality 
The percentage of 30- and 60-day all-cause mortality will be calculated based on each subject's 
date of death relative to C1D1 (ie, date of death minus date of C1D1). Subjects who died within 
30 days will also be included in the 60-day mortality calculations. To avoid using a different 
denominator for calculation of the percentage of 30- and 60-day mortality, subjects who were 
lost-to-follow-up within 30- or 60-days from C1D1 (assumed to be a very small number, if any) 
will be considered alive for the corresponding 30- and 60-day mortality calculations. Causes of 
death and relationship to study treatment will also be summarized. 
7.4.4 
Concomitant Medications 
Medications will be coded by the WHO Drug Dictionary.  
Concomitant medications are the medications taken with a start date on or after the start of the 
administration of study treatment (C1D1), or those with a start date before the start of the 
administration of study treatment (C1D1) and a stop date on or after the start of the 
administration of study treatment (C1D1). Medications taken beyond 30 days from the last dose 
of study treatment or after the start of an alternative anti-leukemia treatment are not considered 
concomitant medications, unless they are used for treating a related SAE.  
For the purpose of determining whether a medication is a concomitant medication, incomplete 
medication start and stop dates will be imputed conservatively following the data programming 
standards as detailed in the Astex Data Programming Conventions. 
Concomitant medications will be summarized by WHO Drug Dictionary Therapeutic Subgroup 
(ATC level 2) and Drug Name, sorted alphabetically, using counts and percentages. 
Special interest concomitant medications include anti-emetic drugs, growth factors, broad-
spectrum antibiotics, and antifungals. These concomitant medications will be tabulated 
separately. Transfusions will be described separately as part of the efficacy analyses 
(Section 7.3.8). 
7.4.5 
Laboratory Tests  
Data from different local laboratories will be standardized to consistent SI units, and presented in 
data listings. Laboratory values recorded as an interval such as "≥x", "<x", or "2+" will be 
handled, if necessary for calculation purposes, following the data programming standards as 
detailed in the Astex Data Programming Conventions. 
Laboratory values will be graded, if relevant and possible, by CTCAE version 4.03 in 
conjunction with the Harrison (18th edition) lab book normal values (Longo et al 2011). Shift 
tables will display (1) shift from baseline grade to the worst grade during the study, and (2) shift 
from baseline grade to the last grade at the end of study. 


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7.4.6 
Vital Signs 
Vital signs will be summarized by visit using the proportion of subjects who have vital sign 
values too high or too low, according to the conventionally accepted vital sign normal ranges as 
listed below:  
• Pulse rate ≥110 bpm. 
• Pulse rate ≤50 bpm. 
• Diastolic blood pressure ≥110 mmHg. 
• Diastolic blood pressure ≤55 mmHg. 
• Systolic blood pressure ≥180 mmHg. 
• Systolic blood pressure ≤80 mmHg. 
• Respiration rate ≥20 breaths/min. 
• Body temperature ≥39°C. 
7.4.7 
Electrocardiogram 
At each ECG assessment time point (pre- and post-dose on Day 1 of Cycle 1 and on termination 
visit), the mean of the available electrocardiogram values (repeated three times) will be 
calculated and used in data listings and summary tables as the actual value for that assessment.  
The following data listings will be provided to assist the medical assessment of the ECG 
outcomes: 
• All laboratory electrocardiogram values, including the calculated mean value of each 
triplicate at each time point.  
• All subjects who had a QTc >500 ms or >60 ms increase from baseline including the 
associated baseline values.  
QTc values will also be graded based on CTCAE, and the shift table showing the shift from 
baseline grade to the worse grade, and from baseline grade to the last grade will be provided. 
7.4.8 
ECOG Performance Status 
ECOG performance status will be summarized by visit, at all scheduled visits where performance 
status was assessed, using counts and percentages.  
7.4.9 
Physical Examination 
Physical examination data will be presented in a data listing. 


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7.5 
Pharmacokinetics Analysis  
PK parameters will be derived using noncompartmental analyses for each subject for whom 
sparse PK samples were collected and successfully analyzed (PK Analysis Set; see Section 5.4). 
Descriptive statistics will include mean, standard deviation, minimum, median, and maximum 
for guadecitabine and decitabine PK parameters. 
The relationship between 
 will be assessed based on the PK data and 
efficacy/safety data collected in this study. The methods will include a population PK modeling 
approach using the sparse data collected. The details of population PK modeling and full results 
of the 
 analyses will be reported in a separate document, and the summary of 
key findings will be included in the clinical study report. 
7.6 
Interim Analyses and Data Monitoring 
Data will be reviewed by an independent DMC at regular intervals primarily to evaluate safety 
during study conduct. The committee will operate independently from the Sponsor and the 
clinical investigators. 
One formal interim analysis of OS is planned, providing the DMC a chance to recommend 
stopping the trial earlier in case the study treatment shows an overwhelming effect on survival. 
This interim analysis will be conducted by the independent DMC after approximately half 
(ie, approximately 335) of the required death events have occurred using the same statistical 
methods as described in Section 7.3. All data available at the time of clinical data cut for the 
interim analysis will be included in the interim analysis. Inclusion of additional available data 
beyond the clinical data cut will be at the discretion of DMC. The nominal alpha values for the 
interim and final OS analyses are based on Lan-DeMets implementation of the O'Brien-Fleming 
boundary (Lan and DeMets 1983; O'Brien and Fleming 1979). With one interim analysis at 50% 
information time point plus one final analysis, the 2-sided alpha-boundaries are 0.00014 and 
0.00995, respectively.  
If the trial continues after the interim analysis, and if the primary analysis of CR rate is 
significant at the 0.04 level, the alpha level for the primary analysis of OS will be 
0.04+0.00995=0.04995≈0.05. If the trial continues after the interim analysis, and if the primary 
analysis of CR rate is not significant at the 0.04 level, the alpha value for the primary analysis of 
OS will be 0.00995≈0.01. The overall alpha error is controlled at the 0.05 level. 
In the unlikely scenario of having observed a significant (p≤0.00014) positive OS result at the 
planned interim analysis time point with an acceptable safety profile of guadecitabine, the DMC 
may choose to analyze the co-primary endpoint CR at an appropriate alpha level to be 
determined by DMC before making a recommendation to the Company. The Company does not 
intend to announce the interim analysis results and make any decision to prematurely terminate 
the study, for any reason other than major safety concerns, without discussing the data and 
recommendation from the DMC first with the major regulatory agencies. 


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7.7 
Handling of Missing Data and Other Data Anomalies 
No missing data imputations are planned for the study, except as specified. Subjects lost to 
follow-up will be included in statistical analyses to the point of their last evaluation. 
7.8 
Handling of Protocol Deviations 
Protocol deviations that occur during the study are captured by study monitors and recorded in 
the CRO's clinical trial management system. Study medical monitors conduct regular reviews of 
all recorded protocol deviations to ensure the quality conduct of the study. Study medical 
monitors also identify and categorize important protocol deviations. Important protocol 
deviations will be summarized by deviation category using counts and percentages. A data listing 
of all important protocol deviations will also be provided. 


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8.0 
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